Mavacamten for Hypertrophic Cardiomyopathy: Effectiveness and Value Final Evidence Report and Meeting Summary November 16, 2021 Prepared for ©Institute for Clinical and Economic Review, 2021 ICER Staff and Consultants University of Illinois at Chicago Modeling Group Jason H. Wasfy, MD, MPhil Surrey M. Walton, PhD, MA Associate Professor, Harvard Medical School Professor, Pharmacy Systems, Outcomes and Policy Medical Director, Massachusetts General Physicians Assistant Director, Center for Pharmacoepidemiology Organization and Pharmacoeconomic Research Director of Outcomes Research, Massachusetts University of Illinois at Chicago College of Pharmacy General Hospital Heart Center Massachusetts General Hospital Jyotirmoy Sarker, MPharm, MBA, MBiotech Graduate Student, Pharmacy Systems, Outcomes, and Molly Beinfeld, MPH Policy Senior Research Lead, Evidence Synthesis University of Illinois at Chicago Institute for Clinical and Economic Review The role of the University of Illinois at Chicago is Emily Nhan limited to the development of the cost-effectiveness Research Assistant model, and the resulting ICER report does not Institute for Clinical and Economic Review necessarily represent the views of the University of Illinois at Chicago. Melanie D. Whittington, PhD Associate Director of Health Economic Institute for Clinical and Economic Review Steven D. Pearson, MD, MSc President Institute for Clinical and Economic Review David M. Rind, MD, MSc Chief Medical Officer Institute for Clinical and Economic Review None of the above authors disclosed any conflicts of interest defined as more than $10,000 in health care company stock or more than $5,000 in honoraria or consultancies relevant to this report during the previous year from health care manufacturers or insurers. DATE OF PUBLICATION: November 16, 2021 How to cite this document: Wasfy JH, Walton SM, Beinfeld M, Nhan E, Sarker J, Whittington MD, Pearson SD, Rind DM. Mavacamten for Hypertrophic Cardiomyopathy: Effectiveness and Value; Final Evidence Report and Meeting Summary. Institute for Clinical and Economic Review, November 16, 2021. https://icer.org/hypertrophic-cardiomyopathy-2021/. Jason H. Wasfy served as the lead author for the report. Molly Beinfeld led the systematic review and authorship of the comparative clinical effectiveness section in collaboration with Emily Nhan. Surrey M. Walton developed the cost-effectiveness model and authored the corresponding sections with assistance from Jyotirmoy Sarker. Melanie Whittington provided oversight of the cost-effectiveness analyses and developed the budget impact model. Steven D. Pearson and David M. Rind provided methodologic guidance on the clinical and economic evaluations. We would also like to thank Laura Cianciolo, Maggie Houle, and Mrinmayee Joshi (University of Illinois at Chicago) for their contributions to this report. ©Institute for Clinical and Economic Review, 2021 Page i Final Evidence Report – Mavacamten for HCM About ICER The Institute for Clinical and Economic Review (ICER) is an independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs. Through all its work, ICER seeks to help create a future in which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and just health care system. More information about ICER is available at https://icer.org/. The funding for this report comes from government grants and non-profit foundations, with the largest single funder being the Arnold Ventures. No funding for this work comes from health insurers, pharmacy benefit managers, or life science companies. ICER receives approximately 29% of its overall revenue from these health industry organizations to run a separate Policy Summit program, with funding approximately equally split between insurers/pharmacy benefit managers and life science companies. There are no life science companies relevant to this review who participate in this program. For a complete list of funders and for more information on ICER's support, please visit https://icer.org/who-we-are/independent-funding/. For drug topics, in addition to receiving recommendations from the public, ICER scans publicly available information and also benefits from a collaboration with IPD Analytics, an independent organization that performs analyses of the emerging drug pipeline for a diverse group of industry stakeholders, including payers, pharmaceutical manufacturers, providers, and wholesalers. IPD provides a tailored report on the drug pipeline on a courtesy basis to ICER but does not prioritize topics for specific ICER assessments. About CTAF The California Technology Assessment Forum (CTAF) – a core program of ICER – provides a public venue in which the evidence on the effectiveness and value of health care services can be discussed with the input of all stakeholders. CTAF seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. CTAF is an independent committee of medical evidence experts from across California, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All members meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness and value of medical interventions. More information about CTAF is available at https://icer.org/who-we-are/people/independent-appraisal-committees/ctaf. The findings contained within this report are current as of the date of publication. Readers should be aware that new evidence may emerge following the publication of this report that could potentially influence the results. ICER may revisit its analyses in a formal update to this report in the future. The economic models used in ICER reports are intended to compare the clinical outcomes, expected costs, and cost effectiveness of different care pathways for broad groups of patients. Model results therefore represent average findings across patients and should not be presumed to represent the clinical or cost outcomes for any specific patient. In addition, data inputs to ICER models often come from clinical trials; patients in these trials may differ in real-world practice settings. ©Institute for Clinical and Economic Review, 2021 Page ii Final Evidence Report – Mavacamten for HCM In the development of this report, ICER's researchers consulted with several clinical experts, patients, manufacturers, and other stakeholders. The following experts provided input that helped guide the ICER team as we shaped our scope and report. None of these individuals is responsible for the final contents of this report, nor should it be assumed that they support any part of it. The report should be viewed as attributable solely to the ICER team and its affiliated researchers. For a complete list of stakeholders from whom we requested input, please visit: https://icer.org/wp- content/uploads/2021/05/ICER_HCM_Stakeholder_List_050721.pdf. Expert Reviewers Milind Desai, MD, MBA Director of Clinical Operations Director, Hypertrophic Cardiomyopathy Center, Department of Cardiovascular Medicine Heart, Vascular & Thoracic Institute Cleveland Clinic Dr. Desai served as the principal investigator for the VALOR study of mavacamten sponsored by Bristol Myers Squibb/MyoKardia. Martin S. Maron, MD Director, Hypertrophic Cardiomyopathy Center Tufts Medical Center Co-Director, Chanin T. Mast Hypertrophic Cardiomyopathy Center Morristown Medical Center Atlantic Health System Dr. Maron served as a site investigator for a Phase I study of mavacamten and currently serves as a steering committee member for a Phase II study of a second-generation myosin inhibitor sponsored by Cytokinetics. Steve R. Ommen, MD Medical Director, Mayo Hypertrophic Cardiomyopathy Clinic Mayo Clinic No relevant conflicts of interest to disclose, defined as more than $10,000 in health care company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. ©Institute for Clinical and Economic Review, 2021 Page iii Final Evidence Report – Mavacamten for HCM Lisa Salberg Founder and CEO Hypertrophic Cardiomyopathy Association The Hypertrophic Cardiomyopathy Association receives 20% of its sponsorship for educational programming from Bristol Myers Squibb/MyoKardia. ©Institute for Clinical and Economic Review, 2021 Page iv Final Evidence Report – Mavacamten for HCM Table of Contents Executive Summary................................................................................................................................... ES1 1. Background ............................................................................................................................................... 1 2. Patient and Caregiver Perspectives .......................................................................................................... 3 3. Comparative Clinical Effectiveness ........................................................................................................... 6 3.1. Methods Overview ............................................................................................................................ 6 Scope of Review.................................................................................................................................... 6 Evidence Base ....................................................................................................................................... 6 3.2. Results ................................................................................................................................................ 9 Clinical Benefits .................................................................................................................................... 9 Harms.................................................................................................................................................. 12 Subgroup Analyses and Heterogeneity .............................................................................................. 14 Uncertainty and Controversies ........................................................................................................... 15 3.3. Summary and Comment .................................................................................................................. 17 CTAF Votes .......................................................................................................................................... 19 4. Long-Term Cost Effectiveness ................................................................................................................. 20 4.1. Methods Overview .......................................................................................................................... 20 4.2. Key Model Assumptions and Inputs ................................................................................................ 22 Sensitivity and Threshold Analyses .................................................................................................... 24 4.3. Results .............................................................................................................................................. 24 Base-Case Results ............................................................................................................................... 24 Sensitivity Analyses............................................................................................................................. 25 Scenario Analyses ............................................................................................................................... 28 Threshold Analyses ............................................................................................................................. 29 Model Validation ................................................................................................................................ 29 Uncertainty and Controversies ........................................................................................................... 30 4.4. Summary and Comment .................................................................................................................. 31 5. Contextual Considerations and Potential Other Benefits ....................................................................... 32 CTAF Votes .......................................................................................................................................... 34 6. Health-Benefit Price Benchmarks ........................................................................................................... 36 CTAF Votes .......................................................................................................................................... 36 ©Institute for Clinical and Economic Review, 2021 Page v Final Evidence Report – Mavacamten for HCM 7. Potential Budget Impact ......................................................................................................................... 37 7.1. Overview of Key Assumptions ......................................................................................................... 37 7.2. Results .............................................................................................................................................. 38 8. Policy Recommendations ........................................................................................................................ 40 All Stakeholders .................................................................................................................................. 40 Manufacturers .................................................................................................................................... 42 Payers ................................................................................................................................................. 44 Clinical Investigators and Grant Funding Organizations..................................................................... 47 Patient Groups .................................................................................................................................... 48 References .................................................................................................................................................. 50 A. Background: Supplemental Information ................................................................................................ 55 A1. Definitions ........................................................................................................................................ 55 A2. Potential Cost-Saving Measures in Symptomatic HOCM ................................................................. 56 B. Patient Perspectives: Supplemental Information ................................................................................... 57 B1. Methods............................................................................................................................................ 57 B2. Results............................................................................................................................................... 57 Experience with HCM ......................................................................................................................... 57 Treatment Effects ............................................................................................................................... 62 C. Clinical Guidelines ................................................................................................................................... 67 American College of Cardiology and American Heart Association6 ................................................... 67 European Society of Cardiology.......................................................................................................... 68 National Institute for Health and Care Excellence ............................................................................. 68 Ludwig Boltzmann Institute for Health Technology Assessment ....................................................... 69 D. Comparative Clinical Effectiveness: Supplemental Information ............................................................ 70 D1. Detailed Methods ............................................................................................................................. 70 PICOTS (Population, Intervention, Comparator, Outcomes, Timing, Setting).................................... 70 Data Sources and Searches................................................................................................................. 73 Study Selection ................................................................................................................................... 77 Data Extraction and Quality Assessment............................................................................................ 77 Assessment of Level of Certainty in Evidence .................................................................................... 78 Assessment of Bias ............................................................................................................................. 78 Data Synthesis and Statistical Analyses .............................................................................................. 78 ©Institute for Clinical and Economic Review, 2021 Page vi Final Evidence Report – Mavacamten for HCM D2. Additional Clinical Evidence ............................................................................................................. 78 Evidence Base ..................................................................................................................................... 78 Effectiveness ....................................................................................................................................... 83 Harms.................................................................................................................................................. 86 Subgroup Analyses and Heterogeneity .............................................................................................. 87 Uncertainties and Controversies ........................................................................................................ 87 D3. Evidence Tables ................................................................................................................................ 88 D4. Ongoing Studies.............................................................................................................................. 118 D5. Previous Systematic Reviews and Technology Assessments ......................................................... 121 E. Long-Term Cost Effectiveness: Supplemental Information .................................................................. 122 E1. Detailed Methods ........................................................................................................................... 122 Target Population ............................................................................................................................. 123 Treatment Strategies ........................................................................................................................ 123 Model Inputs..................................................................................................................................... 124 Clinical Inputs.................................................................................................................................... 124 Health State Utilities ......................................................................................................................... 126 Cost Inputs ........................................................................................................................................ 128 E2. Results ............................................................................................................................................. 129 Description evLY Gained Calculations .............................................................................................. 129 E3. Sensitivity Analyses ......................................................................................................................... 130 E4. Scenario Analyses ........................................................................................................................... 138 E5. Model Validation............................................................................................................................. 138 Prior Economic Models..................................................................................................................... 138 F. Potential Budget Impact: Supplemental Information ........................................................................... 139 Methods ................................................................................................................................................ 139 G. Public Comments .................................................................................................................................. 140 H. Conflict of Interest Disclosures ............................................................................................................. 152 ©Institute for Clinical and Economic Review, 2021 Page vii Final Evidence Report – Mavacamten for HCM List of Acronyms and Abbreviations Used in this Report AHRQ Agency for Healthcare Research and Quality CDC Centers for Disease Control and Prevention CI Confidence interval cm Centimeter cMRI Cardiac magnetic-resonance imaging CPET Cardiopulmonary exercise testing evLY Equal value of life years FDA Food and Drug Administration HCM Hypertrophic cardiomyopathy HCMSQ [SoB] Hypertrophic Cardiomyopathy Symptom Questionnaire [Shortness of Breath] HOCM/OHCM Hypertrophic obstructive cardiomyopathy HRQoL Health-related quality of life hs-cTnl High-sensitivity cardiac troponin I ICD Implantable cardioverter defibrillator ICER Institute for Clinical and Economic Review IQR Interquartile range KCCQ [OS][CS] Kansas City Cardiomyopathy Questionnaire [overall summary][clinical summary] kg Kilogram L Liter LVEF Left ventricular ejection fraction LVOT Left ventricular outflow tract mg Milligram mL Milliliter mm Millimeter mm Hg Millimeter of mercury MRI Magnetic-resonance imaging ms Millisecond N Total number n Number N/A Not applicable ng Nanogram NR Not reported NT-proBNP N-terminal pro B-type natriuretic peptide NYHA New York Heart Association P/I Promising but inconclusive PICOTS Population, Intervention, Comparator, Outcomes, Timing, Setting PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses pV02 Peak oxygen consumption QALY Quality-adjusted life year SD Standard deviation SoC Standard of care US United States USPSTF United States Preventive Services Task Force ©Institute for Clinical and Economic Review, 2021 Page viii Final Evidence Report – Mavacamten for HCM Executive Summary Hypertrophic cardiomyopathy (HCM) is a genetic disorder involving sarcomeres in heart muscle that can cause symptoms such as chest discomfort and shortness of breath, particularly with exertion. Additional symptoms can include palpitations, dizziness, and syncope (passing out). Although many patients with HCM have a normal life expectancy without symptoms, even patients without symptoms are at risk of sudden cardiac death. Apart from managing symptoms, key components of therapy include placement of implanted cardioverter defibrillators (ICDs) for patients at high risk of sudden death, and anticoagulation for patients who have both HCM and atrial fibrillation. For patients with a specific subtype of HCM, hypertrophic obstructive cardiomyopathy (HOCM), obstruction of the left ventricular outflow tract (LVOT) can be an important contributor to exertional symptoms. The LVOT is the conduit through which blood exits the heart to the rest of the body. Among the effects of dynamic narrowing of the LVOT are increased pressure within the left ventricle, increased myocardial oxygen demand, and increased mitral regurgitation. While LVOT obstruction is one important target for therapy to reduce symptoms, there are other causes of symptoms that can also affect non-obstructive HCM patients. Those symptoms include diastolic dysfunction, microvascular angina (obstruction of small heart artery vessels), and irregular heart rhythms. For HOCM patients with shortness of breath related to LVOT obstruction, medications can improve symptoms. Beta blockers and calcium channel blockers reduce the forcefulness of the heart's contraction, reducing the LVOT gradient, thus improving symptoms. However, beta blockers and calcium channel blockers have important side effects, including fatigue that can interfere with work or daily activities, dizziness, and sexual dysfunction. When these first-line therapies are insufficient or not well tolerated, second-line treatment options include adding disopyramide or performing septal reduction procedures. Disopyramide has important side effects as well, and drug shortages limit access to the long-acting version. Septal reduction procedures include surgical myectomy (a type of open-heart surgery) or alcohol septal ablation, a controlled heart attack that reduces the thickness of the heart muscle causing LVOT obstruction. Those procedures can have substantial benefit, but they have a low but meaningful risk of death. Furthermore, clinical outcomes following these procedures may be worse outside centers of excellence. As such, there is substantial unmet need for the management of exertional symptoms in patients with symptomatic HOCM, particularly among patients that do not have good access to specialized centers. A novel agent, mavacamten, has been tested in clinical trials. Mavacamten reduces adenosine triphosphatase activity in cardiac myosin heavy chain, one of the proteins in heart muscle cells, and thus reduces the contraction of the heart that can contribute to obstruction. A United States (US) ©Institute for Clinical and Economic Review, 2021 Page ES1 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Food and Drug Administration (FDA) decision on approval of mavacamten is expected in early 2022. This report examines the comparative effectiveness and cost effectiveness of mavacamten in patients with symptomatic HOCM. The key trial in such patients is EXPLORER, a Phase III randomized trial comparing mavacamten to placebo in 251 patients receiving first-line treatments. Mavacamten was more effective than placebo at meeting a primary composite endpoint of 1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one New York Heart Association (NYHA) class reduction or a 3.0 mL/kg per min or greater pVO2 increase without NYHA class worsening (37% vs. 17%, p=0.0005). Among patients who completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the KCCQ overall summary score was more improved among patients assigned to mavacamten than placebo (+14.9 vs. +5.4, p<0.0001). Serious adverse events were uncommon in EXPLORER and similar between arms of the trial. Some clinical experts noted conceptual concerns about reductions in ejection fraction and myocardial thickness with mavacamten: these changes can be beneficial but could result in long-term harm if they persist or recover then worsen over time. Other clinical experts are much less concerned about this potential harm. In the absence of additional long-term evidence on mavacamten, we need to consider the potential for possible net harms, and we rate mavacamten in addition to usual care compared with usual care alone as promising but inconclusive ("P/I"). When comparing mavacamten with disopyramide, we are limited by the absence of head-to-head randomized trials and the absence of randomized trials of disopyramide. Disopyramide has known side effects and contraindications. Furthermore, data supporting use of disopyramide are relatively weak and potentially exaggerate the true treatment effect due to study design. On balance, we consider the evidence for mavacamten compared with disopyramide to be promising but inconclusive ("P/I") as well. We lack randomized trials of septal reduction therapies either to each other, compared with no procedure, or compared with mavacamten. Observational data appear to show greater improvements in functional outcomes with such procedures than was seen in the EXPLORER trial, however, these procedures have a small risk of short-term serious adverse events including death. Overall, among patients who are eligible for a septal reduction procedure, net benefits are likely greater with a procedure than with mavacamten. However, we also believe the choice between a procedure with a short-term risk of death and mavacamten would be highly dependent on individual patient preferences. Given this, we are not assigning an evidence rating to this comparison: such decisions will need to be made on a case-by-case basis through discussions among patients, families, and clinicians. ©Institute for Clinical and Economic Review, 2021 Page ES2 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table ES1. Evidence Ratings Treatment Comparator Evidence Rating Mavacamten Plus Beta Blockers Beta blockers and calcium channel P/I and Calcium Channel Blockers blockers alone Mavacamten Plus Beta Blockers Disopyramide P/I and Calcium Channel Blockers Mavacamten Plus Beta Blockers Septal reduction therapies See discussion in Section 3.3 and Calcium Channel Blockers P/I: promising but inconclusive For more information on the rationale for these evidence ratings, please see Section 3.3. We created a semi-Markov model to estimate discounted lifetime time horizon costs, quality- adjusted life years (QALYs), life years, years in NYHA class I, and equal value of life years (evLYs) for mavacamten along with standard first-line therapies and several comparators. Table ES2 presents the base-case cost-effectiveness results. Table ES2. Incremental Cost-Effectiveness Ratios for Mavacamten* in the Base Case Cost per Cost per QALY Cost per Life Cost per evLY Treatment Comparator Additional Gained Year Gained Gained NYHA I Year Standard treatment $1,200,000 Undefined $1,200,000 $219,000 Disopyramide $1,500,000 Undefined $1,500,000 $278,000 Mavacamten Myectomy Dominated $5,600,000 N/A† Dominated Septal ablation Dominated $7,000,000 N/A† Dominated evLY: equal value of life years, N/A: not applicable, NYHA: New York Heart Association, QALY: quality-adjusted life year *Price assumed for mavacamten was a placeholder of $75,000 per year. †Incremental cost per evLY gained not applicable due to fewer lifetime QALYs for mavacamten as compared to myectomy and septal ablation. Mavacamten used along with standard first-line treatment was projected to generate higher amounts of QALYs than standard first-line treatment alone. However, at the placeholder cost of $75,000, the incremental cost-effectiveness ratio was well above standard thresholds ($1,200,000 per QALY). When compared with disopyramide, the incremental cost per QALY was even higher, and mavacamten was found to be dominated by both myectomy and septal ablation. From the cost-effectiveness analysis, we estimated the health-benefit price benchmark (HBPB) for mavacamten to be $12,000 to $15,000 annually. The actual cost effectiveness of mavacamten will depend on its price. At the placeholder price of $75,000 per year, approximately 25% of eligible patients could be treated with mavacamten within five years before crossing the ICER potential budget impact threshold of $734 million per year. This could create a short-term potential budget impact that exceeds the potential threshold at this price. However, because this is based on a placeholder ©Institute for Clinical and Economic Review, 2021 Page ES3 Final Evidence Report – Mavacamten for HCM Return to Table of Contents price, ICER is not issuing an access and affordability alert. All eligible patients could be treated within five years without crossing the ICER potential budget impact threshold at the price to reach $150,000 per QALY. Potential other benefits of mavacamten include more access to treatment options because septal reduction procedures are mainly available at specialized centers. When septal reduction procedures are performed at lower-volume centers, outcomes are worse although these differences could reflect both differences in quality and/or unmeasured confounding. There have also been national shortages of the long-acting form of disopyramide. In part based on the shortage as well as other issues including side effects and limited efficacy, few patients are actually taking disopyramide. However, some patients and patient groups emphasized that disopyramide is still an important treatment option. Finally, mavacamten will be a new option available for patients at points in their lives when they are making important life choices regarding education, work, and raising families, which could provide benefits over and above the improvement in QALYs calculated in the model. Appraisal committee votes on questions of comparative effectiveness and value, along with key policy recommendations regarding pricing, access, and future research are included in the main report. Several key themes are highlighted below. • All stakeholders have a responsibility to facilitate meaningful patient access to multidisciplinary centers of excellence for HCM in ways that do not exacerbate disparities. • The manufacturer of mavacamten should commit to sponsoring research that will address the lack of data on the comparative effectiveness of mavacamten versus disopyramide and septal reduction procedures. • The manufacturer of mavacamten should align the price of mavacamten with the explicit and transparent estimates of its treatment benefits for patients and families. Pricing should also be moderated to reflect the uncertainty about longer-term safety until such time as further outcomes data are generated. • Payers should use the FDA label as the guide to coverage policy and engage clinical experts and diverse patient representatives in considering how to address coverage issues for which there is limited or no evidence at the current time. ©Institute for Clinical and Economic Review, 2021 Page ES4 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 1. Background Hypertrophic cardiomyopathy (HCM) is a heart muscle disorder that can cause symptoms such as chest discomfort and shortness of breath, particularly with exertion. Although many patients with HCM have a normal life expectancy without symptoms, even patients without symptoms are at risk of sudden cardiac death. Patients with HCM who develop atrial fibrillation are at elevated risk of stroke.1 The mechanisms that cause patients to have exertional symptoms are diverse and can include diastolic dysfunction (difficulty filling the heart with blood) and microvascular angina (obstruction of small heart artery vessels) as well as other causes. HCM is a condition with different subtypes. For patients with hypertrophic obstructive cardiomyopathy (HOCM), which is one of the subtypes of HCM, narrowing and obstruction of the left ventricular outflow tract (LVOT) can occur with exertion or sometimes at rest. The LVOT is the conduit through which blood begins to exit the heart. Since this type of obstruction can interfere with the heart's pumping function, it is a major cause of exertional symptoms for patients with the HOCM subtype of HCM. However, not all exertional symptoms are caused by LVOT obstruction even among the subset of HCM patients with HOCM. The underlying cause of HCM is dysfunction in proteins called sarcomeres that help cardiac muscle cells (myocytes) squeeze and pump blood.2 The sarcomere dysfunction in HCM can lead to hypertrophy (thickening) of the heart. HCM can occur due to a number of heritable genetic defects affecting sarcomere proteins. Hypertrophy related to sarcomere dysfunction distinguishes HCM from other forms of cardiac conditions, such as hypertrophy caused by chronic high blood pressure, infiltrative disorders such as cardiac amyloidosis, or healthy adaptive hypertrophy from athletic training. As such, doctors often need to perform tests to distinguish HCM from other forms of hypertrophy; in some cases, the diagnosis can be difficult to make. Specific single-gene mutations in 15 genes have been identified as associated with HCM,3 although patients can have the clinical appearance of HCM (phenotypic HCM) without an identified gene mutation. Because of difficulties with detection, the observed prevalence of HCM varies in studies conducted with different methods. Asymptomatic patients may only be diagnosed with HCM when an imaging test is performed for a different reason. An estimate using echocardiographic screening suggested a prevalence of HCM of one in 500,4 but screening with cardiac magnetic-resonance imaging (cMRI), which is more sensitive and specific for cardiac hypertrophy, found a prevalence of about one in 70.5 Not all patients with HCM mutations develop hypertrophy. Guidelines for the treatment of patients with HCM were most recently published in 2020.6 With appropriate selection of higher-risk patients for implantable cardioverter defibrillators (ICDs), which can shock the heart out of dangerous heart rhythms, the risk of sudden cardiac death has declined to 0.5% per year.7 When patients develop atrial fibrillation, anticoagulation is generally recommended to prevent cardioembolic stroke regardless of conventional stroke risk factors. For HOCM patients with ©Institute for Clinical and Economic Review, 2021 Page 1 Final Evidence Report – Mavacamten for HCM Return to Table of Contents exertional symptoms thought to be related to the LVOT gradient, principles of therapy involve reducing the magnitude of the LVOT gradient, which generally improves symptoms. Pharmacological approaches involve therapies that reduce cardiac contractility (negative inotropic agents) including beta blockers and calcium channel blockers.8 For patients who still have symptoms or who are unable to tolerate these agents, adding disopyramide as a second-line agent and invasive strategies such as septal myectomy (open-heart surgery to remove a portion of heart muscle) or alcohol septal ablation (a controlled heart attack to reduce the heart muscle tissue in the obstructed area) are considered.8 No randomized trial has compared surgical myectomy to septal ablation, but guidelines favor surgical myectomy in most patients.6 A novel agent, mavacamten, has been tested in clinical trials. Mavacamten is a direct myosin inhibitor and an oral medication administered once per day that directly reduces adenosine triphosphatase activity in cardiac myosin heavy chain, one of the proteins in heart muscle cells.9 This is a key step in how heart muscle cells make energy for contracting the heart.9 A United States (US) Food and Drug Administration (FDA) decision on approval of mavacamten is expected in early 2022. Multispecialty guidelines were most recently revised in 2020 and, as such, do not yet specify the role of mavacamten in HCM.10 Any use of mavacamten will likely occur in symptomatic HOCM patients who are refractory or intolerant to beta blocker and calcium channel blockers. Given that evidence does not yet exist comparing mavacamten to disopyramide, surgical myectomy, or septal ablation, clinical experts differ about the role of mavacamten as an alternative to those strategies. A randomized trial, VALOR-HCM (NCT04349072), is evaluating the use of mavacamten to reduce utilization of septal reduction procedures in patients who would otherwise be eligible for invasive therapies. As such, this trial is not designed to provide a direct comparison of up-front septal reduction procedures versus mavacamten.11 Given that the mechanism of action addresses the underlying pathophysiology of sarcomeric dysfunction, the cause of HCM, it remains conceptually possible that mavacamten may reduce symptoms for patients with HCM without obstruction. The MAVERICK-HCM trial demonstrated improvement in cardiac biomarkers, which are known surrogates for myocardial wall stress.12 These therapeutic concepts are mechanistically appealing and could lead to further trials with clinical endpoints including symptoms. Other therapeutic concepts for HCM are in development and validation. For example, sacubitril/valsartan attenuates cardiac fibrosis and hypertrophy in a rat model of myocardial infarction.13 Since these processes are key aspects of the pathophysiology of HCM, ongoing trials are evaluating the clinical effectiveness of sacubitril/valsartan in HCM without obstruction.14 Additionally, other myosin inhibitors are being evaluated15 with results of a Phase II trial of aficamten (REDWOOD-HCM, NCT04219826) recently reported at a conference in September 2021. ©Institute for Clinical and Economic Review, 2021 Page 2 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 2. Patient and Caregiver Perspectives ICER met virtually with patients with HCM, representatives from patient organizations, and clinical experts to understand patient and caregiver perspectives and unmet needs, contextual considerations, and outcomes important to patients with all types of HCM, including symptomatic HOCM. Dr. Jason H. Wasfy also participated in the 2020 American College of Cardiology Roundtable on Advances in Hypertrophic Cardiomyopathy to gain additional perspective. Finally, to obtain more detailed information about patient, family, and caregiver perspectives, ICER conducted a national survey in partnership with the Hypertrophic Cardiomyopathy Association, the nation's most prominent organization providing support, advocacy, and education for patients with HCM. This survey encouraged free-text responses from HCM patients, allowing flexibility to express diverse perspectives. Responses were coded using qualitative methods to identify common themes and both common themes and direct patient quotes were reported. Of 641 total responses, 606 were from HCM patients, 29 were from caregivers and/or family members, and six were from patient advocates. Many patients and caregivers emphasized difficulties accessing specialized HCM centers, finding cardiology subspecialists knowledgeable about HCM, and difficulties with insurance. Patients reported substantial financial burdens associated with travel, co-payments, and high deductibles. Patients also reported a variety of symptoms including fatigue, exertional intolerance, and difficulty breathing. About a third of patients reported that their current treatments "work okay" and nearly a tenth report that their current treatments "do not work," suggesting a large unmet need related to symptoms. Many patients on treatments including beta blockers, calcium channel blockers, and disopyramide reported fatigue. Detailed information about the survey methods and both qualitative and quantitative results are presented in Section B. The spectrum of severity of illness in HCM is wide, and many patients do not have severe symptoms (see Report Supplement Section B). For many other patients with HCM, the burden of disease can be severe. In addition to the relatively small risk of sudden cardiac death for most HCM patients, about one in six patients develop exertional symptoms.16 Both patients with HCM generally and with HOCM specifically can have these exertional symptoms, and among patients with HOCM, a larger outflow tract gradient is associated with a higher likelihood of having symptoms.16 Patients with HOCM also face anxiety, depression, and concerns about activities of daily living and social events. There is uncertainty about the extent to which exercise can increase the risk of sudden cardiac death for HOCM patients, and guidelines have shifted over time,10 allowing recommendations for more athletic activity for HOCM patients. These changes have led to uncertainty and confusion among HOCM patients about optimal self-care. Since patients often have electrocardiograms and echocardiograms that mimic other conditions, including acute myocardial infarction and hypertensive heart disease, misdiagnosis is common and patients with HCM often have frustrations with the health care system. This can be minimized with care at large ©Institute for Clinical and Economic Review, 2021 Page 3 Final Evidence Report – Mavacamten for HCM Return to Table of Contents high-volume centers of excellence, but many patients do not have access to these centers because of cost and location. The total cost of care for symptomatic patients with HOCM is greater than six times that of patients of similar age and gender.17 Patients and their representatives particularly highlighted exertional symptoms. Patients were most concerned with how symptoms impair everyday functioning and prevent them from living their lives. The cornerstones of therapy, beta blockers and calcium channel blockers, have important limitations. In the survey, one patient told us: "I think the medications cause fatigue and brain fog that prompted me to take an early retirement from work as I felt I was not capable of performing my work tasks to full capability/commitment." For another patient, the fatigue caused by beta blockers made caring for her children more difficult: "I was a single mom on beta blockers and had a hard time doing anything – my kids needed me to drive, make meals, etc., and sometimes I was just too tired." Patients also expressed concerns about representing functional status with New York Heart Association (NYHA) classification in part because of concerns about the term "heart failure." Furthermore, patients emphasized that there is a "good day, bad day" phenomenon in symptomatic HOCM, since symptoms can vary substantially from day-to-day, and this variation is not well described by NYHA class. Clinical experts expressed additional concerns with NYHA class, including that patients may underreport clinical symptoms. As such, objective patient-reported outcomes were preferred when possible. Patients also emphasized that HCM is not "traditional" heart failure, with very different treatments and prognoses even though some symptoms, including exertional dyspnea, are similar. Some patients described the fear of sudden cardiac death. Although most patients have a normal life expectancy, early studies reported higher mortality rates. This fear has substantial effects on patients' life choices. Particularly when patients are diagnosed early in life, uncertainty and fear can lead to pressured life decisions about educational programs, marriage and relationships, and decisions about whether to have children. Patients reported concern about passing along genes associated with HCM to children. Patients also reported concerns about convincing children (who are sometimes adults at time of the patient's diagnosis) to receive screening. In addition, patients reported that the diagnosis of HOCM can lead to difficulties receiving life insurance, being admitted to educational programs, and receiving loans. In that context, patients reported feeling reluctant to discuss their condition for fear of being misunderstood. One patient told us, "I was living with a flopping, living fish in my chest and there was no one around to talk about it." Public focus on prominent athletes' deaths also takes away attention from other patient concerns, such as obstruction, exertional symptoms, and traditional heart failure in later-stage HCM. ©Institute for Clinical and Economic Review, 2021 Page 4 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Palpitations with arrythmias was a common source of concern for patients. Many patients reported feeling much worse when having irregular heart rhythms, and they reported fear about how to distinguish dangerous from less dangerous heart rhythms. Some patients and their friends and families consider buying automated electronic defibrillators, which are expensive, to reduce the risk of sudden cardiac death. Patients with HOCM also reported substantial difficulties interacting with caregivers, clinics, and hospitals. According to the Hypertrophic Cardiomyopathy Association's Patient-Focused Drug Development Meeting report, "The underlying emotional toll for HCM patients can be intense and can cripple…a sense of wellbeing."18 Given that HCM is a less common condition, many physicians do not understand how to manage it, and physicians sometimes overestimate risk. The electrocardiogram pattern for many patients with HCM can mimic a heart attack and, as such, many patients reported inappropriate escalations in care that would have been avoided with better access to HCM-specific expertise. Patients also reported worse access for non-cardiac ambulatory procedures (such as office-based colonoscopy) because of caregiver fear of cardiac complications. Fainting in public places is often a source of severe distress because patients need to advocate for themselves and give directions to both bystanders and emergency personnel given their unique circumstances. A common concern was the organization and availability of centers of excellence. Access to procedural care for surgical myectomy and septal ablation is limited because these procedures are only performed at highly specialized centers. The excellent outcomes for these procedures represent care delivered at these centers and may not be generalizable to other settings. The Hypertrophic Cardiomyopathy Association has developed an assessment model that has identified 42 centers of excellence for HCM. Patients from rural areas, patients with less money to travel, and people of color may have disproportionally less access to these centers. Black patients in particular have less access to septal reduction therapies and genetic testing.19 Furthermore, women are referred to subspecialty HCM care later than men.20 Many patients noted concern about underdiagnosis, since HCM can often be asymptomatic or misdiagnosed. Patients in different racial and socioeconomic groups have differential access to cardiac imaging used for diagnosis. Patients and patient groups report concern about the financial burden to both patients and caregivers. Patients and patient groups are specifically concerned about the potential cost of mavacamten including cost-sharing arrangements such as co-payments. When caregivers are needed to provide care for HCM patients, they sometimes cannot work, exacerbating financial problems. Patients themselves are often underemployed because they fear moving to new jobs or communities because these moves could disrupt insurance, social supports, and access to caregivers. ©Institute for Clinical and Economic Review, 2021 Page 5 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 3. Comparative Clinical Effectiveness 3.1. Methods Overview Procedures for the systematic literature review assessing the evidence on mavacamten for symptomatic HOCM are detailed in Section D1 of the Report Supplement. Scope of Review We reviewed the clinical effectiveness of mavacamten plus usual care versus usual care alone, disopyramide, and septal reduction therapies. Usual care is defined as beta blockers and/or calcium channel blockers. We sought evidence on patient-important outcomes, including functional status and health-related quality of life (HRQoL). We also sought evidence on changes NYHA class, echocardiographic parameters, peak oxygen consumption (pVO2), left ventricular ejection fraction (LVEF), and serum cardiac biomarkers. The full scope of the review is detailed in Section D1 of the Report Supplement. Evidence Base Mavacamten Evidence informing our review of mavacamten in symptomatic HOCM was derived from one Phase III randomized controlled trial and one Phase II trial. Due to differences in trial design and outcomes assessed, the Phase II trial was not the primary focus of review and is described in detail in Section D2 of the Report Supplement. A randomized trial of mavacamten in symptomatic non- obstructive HCM, which is outside the scope of this review, is described in Section D2 of the Report Supplement. EXPLORER-HCM was a multi-center Phase III trial that randomized 251 patients with HOCM in a 1:1 ratio to 5-15 mg oral mavacamten or placebo (Table 3.1).24,25 Patients were eligible to participate if they were 18 years of age or older, met the criteria for HOCM based on current American College of Cardiology/American Heart Association guidelines,6 and had documented LVEF ≥55% and NYHA class II-III symptoms. Patients were excluded if they were on current treatment with disopyramide or had been treated with septal reduction therapy (myectomy or septal ablation) within six months prior to screening. Randomization was stratified by four baseline clinical characteristics: NYHA class, beta blocker use, ergometer type (treadmill or bicycle), and consent for a cardiovascular MRI sub-study. All patients received mavacamten or placebo over a 30-week treatment period. Cardiopulmonary exercise testing (CPET) and post-exercise echocardiography were performed at screening and week 30, while resting echocardiography, electrocardiograms, and lab tests were performed every two to four weeks across 12 visits. ©Institute for Clinical and Economic Review, 2021 Page 6 Final Evidence Report – Mavacamten for HCM Return to Table of Contents The primary outcome was a composite outcome of an objective physiological parameter as well as a clinician-estimated clinical measure to assess clinical response, defined as ≥1.5 mL/kg per min increase in pV02 and ≥1 NYHA class reduction or ≥3.0 mL/kg per min increase in pV02 and no worsening of NYHA class.23 Secondary outcomes included change from baseline to 30 weeks in post-exercise LVOT gradient, pV02, NYHA improvement, and HRQoL. Exploratory outcomes included N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnl). Safety outcomes included treatment-emergent adverse events and serious adverse events. Participants in the EXPLORER-HCM trial had a mean age of 58.5 years and were predominantly male and white (91%). In the mavacamten group, a minority of patients (9%) had undergone septal reduction therapy and all but 3% were taking background medication (beta blockers or calcium channel blockers). Most patients in both arms (72-74%) were classified as having NYHA class II symptoms at baseline. The study arms were balanced across baseline characteristics, with a few exceptions. The mavacamten arm included a greater percentage of female participants than the placebo arm (46% vs. 35%), fewer participants with a history of atrial fibrillation (10% vs. 18%), and had a higher mean NT-proBNP (777 vs. 616 ng/L) (Table 3.1). Additional information about the trial population is available in Table D4 and Table D14 of the Report Supplement. The EXPLORER trial also included a five-year extension study (MAVA-LTE) to evaluate the long-term safety and efficacy of mavacamten. At the time of the report, only interim results from MAVA-LTE were available.24 ©Institute for Clinical and Economic Review, 2021 Page 7 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 3.1. Selected Baseline Characteristics of the Randomized Controlled Trial of Mavacamten, Retrospective Study of Disopyramide, and Systematic Review of Septal Reduction Therapies25-27 Systematic Review of Randomized Controlled Trial Retrospective Study of Septal Reduction of Mavacamten (EXPLORER) Disopyramide (Sherrid 2005) Therapies (Liebregts 2015) Non- Septal Mavacamten Placebo Disopyramide Myectomy Disopyramide Ablation (n=123) (n=128) (n=118) (n=2,013) (n=373) (n=2,791) Age, Mean (SD) 58.5 (12.2) 58.5 (11.8) 47 (20) 43 (21) 56 (54-58)*† 47 (40-47)† Female Gender, n (%) 57 (46)* 45 (35) NR (49) NR (47) NR (49)* NR (40) Medical History, n (%): Atrial Fibrillation 12 (10)* 23 (18) NR (20) NR (18) NR NR Septal Reduction Therapy 11 (9) 8 (6) NR (28) NR (18) NR NR ICD 27 (22) 29 (23) NR (5) NR (2) NR (3) NR (10) Background Therapy, n (%): Beta Blocker 94 (76) 95 (74) NR (98)* NR (70) NR NR Calcium Channel Blocker 25 (20) 17 (13) NR (32) NR (27) NR NR Neither 4 (3) 16 (13) NR NR NR NR NYHA Class I, n (%) 0 (0) 0 (0) 14 (12) NR 2.9 (2.7- NYHA Class II, n (%) 88 (72) 95 (74) 59 (50) NR 2.8 (2.8-3)† 3.1)† NYHA Class III, n (%) 35 (28) 33 (26) 45 (38) NR ICD: implantable cardioverter defibrillator, n: number, NR: not reported, NYHA: New York Heart Association, SD: standard deviation *Indicates a statistically significant difference between groups. †Reported value is weighted median (interquartile range). Disopyramide Evidence on disopyramide is very limited. To inform our review of disopyramide, we describe one retrospective study of 118 patients with HOCM treated with disopyramide at four US-based specialized HCM centers between 1990 and 1999 and 373 patients not treated with disopyramide during the same time period. Patients were followed for a mean of 4.2 years (±2.9 months).26 At baseline, patients treated with disopyramide had a mean age of 47 years (±20), 28% had undergone septal reduction therapy, 98% were on beta blockers, and 50% had NYHA class II symptoms (Table 3.1). Additional baseline characteristics of this study and information about other studies of disopyramide are discussed in Section D2 of the Report Supplement. Septal Reduction Therapies Evidence to inform our review of septal reduction therapies (myectomy and septal ablation) came from existing systematic literature reviews. A 2015 review with meta-analysis pooled long-term outcomes from 24 studies comprising 16 myectomy cohorts (mean follow-up 7.4 years) and 11 septal ablation cohorts (mean follow-up 6.2 years).27 Patients in the septal ablation cohorts were older than in the myectomy cohorts (56 years compared to 47, p=0.0009) and more likely to be female (49% female compared to 40%, p=0.058) (Table 3.1). Additional baseline characteristics and ©Institute for Clinical and Economic Review, 2021 Page 8 Final Evidence Report – Mavacamten for HCM Return to Table of Contents systematic reviews of septal reduction therapy are discussed in Section D2 of the Report Supplement. One major challenge in assessing comparative effectiveness for symptomatic HOCM is that while randomized data exist to compare mavacamten versus beta blockers and calcium channel blockers, there are not randomized data for comparisons of mavacamten versus either disopyramide or septal reduction therapies. 3.2. Results Clinical Benefits Mavacamten Clinical Response Clinical response was achieved by 45 (37%) patients in the mavacamten arm at 30 weeks compared to 22 (17%) in the placebo arm (p=0.0005).21 NYHA Class, LVOT Gradients, LVEF, and pV02 Thirty-two (27%) patients in the mavacamten group achieved NYHA class I status and all LVOT peak gradients <30 mm Hg at 30 weeks compared to one patient (1%) in the placebo group, a difference of 26.6% (95% confidence interval [CI]: 18.3-34.8) (Table 3.2). Improvement in NYHA by at least one class at 30 weeks was reported in 80 (65%) patients in the mavacamten group and 40 (31%) in the placebo group (p<0.0001) (Table 3.2).21 At baseline, no patients in either treatment arm had NYHA class I. By week 30, 49.6% of patients in the mavacamten group achieved NYHA class I status compared to 21.1% of patients in the placebo group. Furthermore, the proportion of patients with a NYHA class III status declined from 28.5% at baseline to 6.5% at 30 weeks in the mavacamten group and from 25.8% to 19.5% in the placebo group (Table 3.3). In the long-term extension study of mavacamten (MAVA-LTE), continued improvements in NYHA class were observed. At week 48, 29 of 49 (59%) patients on mavacamten reached NYHA class I.24 Changes in post-exercise and resting LVOT gradients from baseline to 30 weeks in the mavacamten and placebo groups are presented in Table 3.2. Improvements in resting LVOT gradient and Valsalva LVOT gradient were sustained out to 60 weeks in the long-term extension study (MAVA- LTE).24 ©Institute for Clinical and Economic Review, 2021 Page 9 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Mean decrease in LVEF was -3.9% in the mavacamten group compared to -0.01% with placebo, a -4% difference (95% CI: -5.5 to -2.5) (Table 3.2).21 These changes in LVEF were sustained in the long- term extension study (MAVA-LTE).24 Mean increase in pVO2 was 1.4 mL/kg per min greater in the mavacamten group than in the placebo group (95% CI: 0.6-2.1; p=0.0006) (Table 3.2).21 Cardiac Biomarkers Mean NT-proBNP declined from 777.4 ng/L at baseline to 163.1 ng/L at 30 weeks in the mavacamten group and increased from 615.7 ng/L at baseline to 645.9 ng/L at 30 weeks in the placebo group (proportion of geometric mean ratio between the two groups 0.202, 95% CI: 0.169- 0.241) (Table 3.2).21 NT-proBNP levels were sustained in the long-term extension study (MAVA- LTE). At week 60, median NT-proBNP was 153 ng/L.24 Mean hs-cTnl started at 12.5 ng/L in both groups and declined to 7.4 ng/L in the mavacamten group at 30 weeks and remained constant at 12.6 ng/L in the placebo group (proportion of geometric mean ratio between the two groups 0.589, 0.500-0.693) (Table 3.2).21 Table 3.2. EXPLORER-HCM Key Trial Results21 Outcome at 30 Weeks Mavacamten (n=123) Placebo (n=128) NYHA Class I and All LVOT Peak Gradients <30 mm Hg, n/N (%) 32/117 (27) 1/126 (1) NYHA Class Improvement ≥1, n (%) 80 (65) 40 (31) LVOT, Post-Exercise Peak Gradient <50 mm Hg, n/N (%) 75/101 (74) 22/106 (21) LVOT, Post-Exercise, Change from Baseline Mean mm Hg (SD) -47 (40) -10 (30) LVOT Gradient, Resting, Change from Baseline Mean mm Hg -37.6 -5.2 LVEF, Resting, Change from Baseline, % -3.9 -0.01 pVO2 Change from Baseline, Mean mL/kg per min (SD) 1.4 (3.1) -0.1 (3.0) NT-proBNP, Geometric Mean, Change from Baseline, ng/mL -614.3 30.2 Hs-CTnI, Geometric Mean, Change from Baseline, ng/L -5.1 0.1 Hs-CTnI: High-Sensitivity Cardiac Troponin I, kg: kilogram, L: liter, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm Hg: millimeter of mercury, NT-proBNP: N-terminal pro B-type natriuretic peptide, n: number, N: total number, ng: nanogram, NYHA: New York Heart Association, pVO2: peak oxygen consumption, SD: standard deviation Table 3.3. Distribution of NYHA Class, Baseline, and 30 Weeks in the EXPLORER Trial21 Mavacamten (n=123) Placebo (n=128) Baseline 30 Weeks Baseline 30 Weeks NYHA Class I (%) 0 49.6 0 21.1 NYHA Class II (%) 71.5 42.3 74.2 57.8 NYHA Class III (%) 28.5 6.5 25.8 19.5 Missing (%) 0 1.6 0 1.6 NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 10 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Patient-Reported Quality of Life In EXPLORER, patient health status (with a focus on symptoms, physical and social function, and quality of life) was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated cardiomyopathy-specific instrument,28 and the HCM Symptom Questionnaire (HCMSQ) at baseline and weeks six, 12, 18, 30 (end of treatment), and 38 weeks (end of study, after an eight- week washout period).29 Greater improvements in KCCQ overall summary, clinical summary, physical limitation, and quality- of-life scores from baseline (positive is better) were observed for patients in the mavacamten group compared to the placebo group (Table 3.4). These changes at 30 weeks from baseline were all greater than the minimal clinically important difference, estimated to be between 4 and 6 points across all domains.30 All improvements in KCCQ at 30 weeks reversed to baseline eight weeks after withdrawal of treatment during the washout period.29 Mean improvements in the HCMSQ-Shortness-of-Breath (HCMSQ-SoB) sub-score from baseline (negative is better) were -2.8±2.7 in the mavacamten group compared to -0.9±2.4 (least square mean difference -1.8, 95% CI: -2.4 to -1.2).21 Table 3.4. EXPLORER-HCM Change in Selected KCCQ Scores from Baseline29 Outcome at 30 Weeks Mavacamten (n=92) Placebo (n=88) LSM Differences (95% CI) Overall Summary Score, Mean (SD) 14.9 (15.8) 5.4 (13.7) 9.1 (5.5-12.8) Clinical Summary Score, Mean (SD) 13.6 (14.4) 4.2 (13.9) 9.1 (5.5-12.7) Physical Limitation Score, Mean (SD) 14.7 (17.0) 3.6 (15.4) 10.6 (6.2-14.8) Quality of Life Score, Mean (SD) 18.8 (21.6) 8.3 (18.8) 9.6 (4.7-14.5) CI: confidence interval, LSM: least square mean, n: number, SD: standard deviation Disopyramide In the retrospective study, of the 118 patients treated with disopyramide, 40 (34%) required major interventions (myectomy, septal ablation, or dual-chamber pacing) a mean of 2.0±2.1 years after initiating drug treatment because of inadequate symptom control, persistent gradients, drug intolerance, or withdrawal. Among patients who did not require an intervention and remained on treatment during the follow-up period, mean peak flow gradient decreased from 75 mm Hg (±30) at baseline to 40 mm Hg (±32) (p<00001), and mean NYHA class declined from 2.3 (±0.7) to 1.7 (±0.6) (p<0.0001). Among patients who required an intervention, disopyramide was not associated with improvements in NYHA class and modest improvements in peak LVOT gradient (Table 3.5). These outcomes were not reported in the non-disopyramide patients.26 Annualized all-cardiac death was 1.4% in the 118 disopyramide-treated patients and 2.6% in the 373 non-disopyramide-treated patients (p=0.07). Annualized sudden death was 1.0% in the disopyramide group and 1.8% in the non-disopyramide group (p=0.08).26 ©Institute for Clinical and Economic Review, 2021 Page 11 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 3.5. Key Results of Retrospective Study of Disopyramide26 Disopyramide without Intervention Disopyramide with Intervention (n=78) (n=40) Outcome Baseline Follow-Up Baseline Follow-Up Peak LVOT Gradient, Mean 75 (33) 40 (32) 73 (35) 63 (31) mm Hg (SD) NYHA Class, Mean (SD) 2.3 (0.7) 1.7 (0.6) 2.3 (0.7) 2.3 (0.6) I: 9 (12) I: 29 (37) NYHA Class Distribution, n II: 40 (51) II: 42 (54) NR NR (%) III/IV: 29 (37) III/IV: 7 (9) LVOT: left ventricular outflow tract, mm Hg: millimeter of mercury, n: number, NR: not reported, NYHA: New York Heart Association, SD: standard deviation Septal Reduction Therapies In the 2015 systematic review with meta-analysis of septal reduction therapies, the pooled median percentage reduction in NYHA class after both septal ablation and myectomy was 45% and the median proportion of patients remaining in NYHA class III/IV was 8% after septal ablation and 5% after myectomy (p=0.43). Median LVOT gradient reduction was 71% after septal ablation and 77% after myectomy (p=0.63). More patients in the septal ablation cohorts required reintervention than in the myectomy cohorts (7.7% compared to 1.6%, p=0.001) (Table 3.6).27 In a 2020 systematic review with meta-analysis of septal reduction therapies, the pooled mean difference in NYHA class before and after treatment was -1.16 (-1.43 to -0.90) after septal ablation, -1.51 (-1.69 to -1.33) for myectomy, and -1.31 (-1.69 to -1.33) across both therapies.31 Table 3.6. Selected Pooled Outcomes in Studies of Septal Reduction Therapies27 Septal Ablation Myectomy NYHA, % Reduction, Weighted Median (IQR) 45 (45-50) 45 (44-48) Remaining in NYHA III/IV, %, Weighted Median (IQR) 8 (8-8) 4.5 (4.5-12) LVOT Gradient, mm Hg, % Reduction, Weighted Median (IQR) 71 (67-90) 77 (69-90) Re-Intervention, Weighted Median (IQR)* 7.7 (4.2-11.1) 1.6 (0.6-2.6) IQR: interquartile range, LVOT: left ventricular outflow tract, mm Hg: millimeter of mercury, NYHA: New York Heart Association *Indicates a statistically significant difference between groups. Harms Mavacamten In the EXPLORER trial, 88% of participants in the mavacamten group reported any treatment- emergent adverse event compared to 79% in the placebo arm. Common adverse events included ventricular tachycardia, atrial fibrillation, palpitations, cardiac failure, and angina. Eleven serious adverse events were reported by 10 (8%) patients in the mavacamten group versus 20 serious events reported by 11 (9%) in the placebo group. Serious adverse events leading to discontinuation ©Institute for Clinical and Economic Review, 2021 Page 12 Final Evidence Report – Mavacamten for HCM Return to Table of Contents were reported by 1.6% of participants in the mavacamten group versus 0.8% in the placebo arm (Table 3.7).21 The study protocol required temporary treatment discontinuation for LVEF less than 50%, excessive QT interval, and mavacamten plasma concentration >1,000 ng/mL. During the study period, three patients on mavacamten and two patients on placebo temporarily discontinued due to LVEF decreases to less than 50% and an additional four patients on mavacamten had LVEF less than 50% at week 30. In three of the four patients, the LVEF returned to normal, and in one patient, severe systolic dysfunction developed after an atrial fibrillation ablation with complications. One of these patients in the mavacamten group had a procedural complication after ablation for atrial fibrillation and severe LVEF decrease, but partially recovered to LVEF 50% during the washout period. Three patients on mavacamten and three patients on placebo temporarily discontinued due to changes in QT interval. No patients discontinued due to mavacamten plasma levels. All patients who discontinued during the study period resumed treatment.21 In the long-term extension study of mavacamten (MAVA-LTE, n=224), no additional safety concerns were reported. Treatment-emergent adverse events were reported by 141 participants (62.9%). Serious adverse events were reported by 19 (8.5%), and two patients (0.9%) discontinued due to adverse events.24 Table 3.7. Overview of Safety Data for EXPLORER at 30 Weeks24,34 Mavacamten (n=123) Placebo (n=128) Treatment-Emergent Adverse Events, n (%) 108 (88) 101 (79) Serious Adverse Events, n (%) 10 (8) 11 (9) Discontinuation, n (%) 4 (3.3) 3 (2.3) Adverse Events Leading to Discontinuation, n (%) 2 (1.6) 1 (0.8) Cardiac Serious Adverse Events, n (%) 4 (3.3) 4 (3.1) n: number Disopyramide As an antiarrhythmic agent, disopyramide has known risks of proarrythmia. However, in a multi- center retrospective study of disopyramide, sudden cardiac death was similar in the disopyramide- treated patients (1.4%) and non-disopyramide-treated patients (2.6%, p=0.07). It is possible that there was selection bias with patients at greater risk of arrhythmia being less likely to receive disopyramide.26 In a single-site retrospective study focusing on the safety of disopyramide, QT interval was prolonged by a mean 19 ms compared to baseline. The proportion of patients with QT prolongation ≥460 mg was 16% at baseline and 33% after disopyramide.33 Additional substantial concerns with disopyramide are drug-related side effects and treatment discontinuation. ©Institute for Clinical and Economic Review, 2021 Page 13 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Detailed harms of disopyramide were not reported in Sherrid 2005, however, eight patients (7%) discontinued due to intolerance, such as dry mouth (n=5) and prostatism (n=3).26 In a single-site retrospective study, of 168 patients with HOCM who were started on disopyramide, 38 (23%) reported side effects. These side effects included anticholinergic effects (n=27), weakness and fatigue (n=50), and nausea (n=1). Eighteen (11%) discontinued the drug due to side effects. More information on harms of disopyramide is available in Table D30 of the Report Supplement. Septal Reduction Therapies The most important safety concern with septal reduction therapies is procedure-related harms. In a 2015 systematic with meta-analysis of septal reduction therapies, pooled peri-procedural mortality (<30 days) was 1.3% in the septal ablation cohorts and 2.5% in the myectomy cohorts (p=0.051). In addition, in-hospital outcomes are worse at lower-volume centers.34 Peri-procedural adverse arrhythmic events, including sustained ventricular tachycardia and ventricular fibrillation, were 2.2% in the septal ablation cohorts and 1.0% in the myectomy cohorts (p=0.091). The need for permanent pacemaker implantation was higher in the septal ablation cohorts compared to the myectomy cohorts (10% vs. 4.4%, p=<0.001) (Table 3.8).27 Table 3.8. Pooled Safety Outcomes in Studies of Septal Reduction Therapies27 Septal Ablation Myectomy Peri-Procedural Mortality (<30 Days), %, Weighted 1.3 (0.7-1.8) 2.5 (1.4-3.6) Mean (95% CI) Peri-Procedural Adverse Arrhythmic Events, % 2.2 1.0 Cardiac Mortality, %, Weighted Mean 1.1 2.5 Permanent Pacemaker Implantation, %, Weighted 10 (7.8-12.1) 4.4 (2.6-6.2) Mean (95% CI)* CI: confidence interval Subgroup Analyses and Heterogeneity In the EXPLORER trial, treatment effects for mavacamten across most subgroups were consistently indistinguishable from the average treatment effect with the exception that patients receiving concomitant beta blockers in addition to mavacamten were less likely than patients not on beta blockers to achieve the primary composite endpoint of complete response (30% vs. 59%). It is unclear whether this treatment interaction was related to a blunting of the effect of mavacamten or to how the primary endpoint was assessed since it included exercise testing.21 There was no statistically significant difference in the primary endpoint for men versus women. Although outcomes are not reportedly separately by race, there were only six Black patients, one Native American or Alaska Native patient, and six Asian patients in the trial. We sought evidence on the effectiveness of mavacamten in subgroups of interest such as in children, specific genetic variants of HOCM, and non-obstructive HCM, however, the evidence was ©Institute for Clinical and Economic Review, 2021 Page 14 Final Evidence Report – Mavacamten for HCM Return to Table of Contents not available or not sufficient to assess effectiveness in these populations. Data from the MAVERICK trial on the effectiveness of mavacamten in non-obstructive HCM are described in Table D10 of the Report Supplement.24 In the retrospective study of disopyramide, modest improvements in peak gradient and no improvement in NYHA class were observed in the subgroup of patients who required invasive interventions compared to the subgroup of patients who stayed on drug treatment.26 In the 2015 systematic review with meta-analysis of septal reduction studies, septal ablation was associated with fewer peri-procedure complications than myectomy, but greater need for reintervention and permanent pacemaker implantation.27 Uncertainty and Controversies While mavacamten improved physiologic parameters and symptoms in the EXPLORER trial, the available data are mostly short term, and symptomatic HOCM, once it appears, can last a lifetime. Clinical experts differed on whether the reductions in ejection fraction with mavacamten reflected beneficial improvements in cardiac function, including healthy remodeling, or worrisome changes that could be associated with clinical harm with longer observation times. Rapid loss of improvements in quality of life when mavacamten was stopped suggest that neither of these may be occurring, although any regression in physiological measurements (such as peak VO2) is unclear. In a Phase II trial of a different myosin inhibitor, aficamten, one patient had transient reduction in LVEF.15 Longer-term data are needed to understand if this has prognostic importance. More than 90% of patients in EXPLORER were white leaving questions about the representativeness of the study population and the external validity of the results. Also, the mean age in the trial was 58.5, but treatment can be needed in younger patients. As such, the external validity of these results in real-world populations is uncertain. Trials have inclusion and exclusion criteria that are different than patients who receive a treatment in actual practice. Results from real-world use after FDA approval will help assess these potential concerns. While patients and patient groups and some clinical experts have identified disopyramide as an important later-line medical therapy for HOCM and an important comparator for mavacamten,35 it has not been studied in high-quality randomized trials, either against placebo or against mavacamten, limiting the ability to make direct or indirect comparisons of the agents. The largest retrospective multicenter analysis reports treatment effects for disopyramide among patients who did not have major interventions such as dual-chamber pacing or septal reduction therapy.26 In addition, patients who received major interventions did not have improvement with disopyramide before receiving interventions. As such, the reported treatment effect among patients who did not receive interventions is larger than the actual treatment effect among all patients. In addition, this analysis reports changes in symptoms as measured by NYHA class when patients initially presented ©Institute for Clinical and Economic Review, 2021 Page 15 Final Evidence Report – Mavacamten for HCM Return to Table of Contents for evaluation at a specialized HCM center (rather than immediately before starting disopyramide). Both of these effects likely exaggerate the reported efficacy of disopyramide in this analysis although the direction of bias is uncertain. Furthermore, patients enrolled in this retrospective, real-world analysis at four referral centers likely differ from patients enrolled in EXPLORER. These issues pose problems for the comparison of mavacamten to disopyramide.35 Furthermore, long- acting disopyramide suffers from a drug shortage and in real-world practice, few patients are actually taking disopyramide.36 There are also no randomized data comparing surgical myectomy to septal ablation or comparing either type of septal reduction therapy to mavacamten. An ongoing randomized trial is examining whether mavacamten can reduce the need for septal reduction procedures,11 but this does not directly assess the relative benefits of mavacamten and such procedures. Even in patients who are otherwise indifferent to the varying benefits and risks of a procedure or a medication, the lack of direct randomized evidence of the procedures versus mavacamten (or the procedures vs. one another) limits the ability to make rigorous comparisons. Furthermore, it is unclear whether the results of septal procedures at centers of excellence, where many patient series are from, can be generalized to other centers. Patients treated with mavacamten who received cMRI during the trial demonstrated substantial regression in the pathological hypertrophic characteristic of this syndrome.37 However, as mentioned above, symptoms of clinical dyspnea as measured by the KCCQ dropped from week 30 at the end of the trial to baseline by week 38, after eight weeks off study medication.29 This discordance between 1) imaging results in the cMRI sub-study showing regression of hypertrophy and 2) patient-reported outcomes worsening after discontinuation of mavacamten raise concerns about the adequacy of imaging findings as surrogate outcomes. Furthermore, if any recurrence of hypertrophy occurs after stopping mavacamten, the clinical implication of that recurrence is unclear. ©Institute for Clinical and Economic Review, 2021 Page 16 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 3.3. Summary and Comment An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided here. Figure 3.1. ICER Evidence Rating Matrix ©Institute for Clinical and Economic Review, 2021 Page 17 Final Evidence Report – Mavacamten for HCM Return to Table of Contents The randomized EXPLORER trial demonstrates that mavacamten improves exertional symptoms and quality of life in patients with symptomatic HOCM and had relatively few adverse effects during the trial period. This trial has reported data including patient-reported outcomes and physician- assessed outcomes, which are concordant with an objective measure of physiologic oxygen consumption. As such, EXPLORER presents a range of concordant, relevant patient outcomes with a strong study design (prospective randomized placebo-controlled trial) creating evidence for the efficacy of mavacamten. Taken alone, this information could have led to a better evidence rating. Importantly, however, with any new therapy there are concerns about adverse effects not detected during pre-approval trials. In our review, experts had starkly contrasting interpretations of the safety signals from EXPLORER. In particular, some experts worry that the reduction in LVEF and myocardial muscle thickness could lead to long-term harms rather than benefits.35 Thus, in the absence of additional long-term evidence on mavacamten, we need to consider the potential for possible net harms, and we rate mavacamten in addition to usual care compared with usual care alone as promising but inconclusive ("P/I"). When comparing mavacamten with disopyramide, we are limited by the absence of head-to-head randomized trials and the absence of randomized trials of disopyramide. The best observational evidence on disopyramide appears to show similar benefits to mavacamten in those who continue taking it, but the study design could inflate the benefits of disopyramide: those who did not improve on it would be more likely to discontinue therapy. Additionally, disopyramide has known common side effects from its anticholinergic effects and the potential for serious harms from being pro-arrhythmic. The long-acting form suffers from a drug shortage and in practice, few patients take disopyramide. On balance, and considering the lack of long-term evidence on mavacamten, we consider the evidence for mavacamten compared with disopyramide to be promising but inconclusive ("P/I") as well. We lack randomized trials of septal reduction therapies either to each other, compared with no procedure, or compared with mavacamten. Observational data appears to show greater improvements in functional outcomes with such procedures than was seen in the EXPLORER trial. However, these procedures carry risks of serious harms including death and the need for pacemakers to manage damage to the cardiac conduction system. Additionally, most data on these procedures comes from centers of excellence and it is uncertain how these results generalize when the procedures are done elsewhere. As discussed later in this report, modeling suggests greater quality-adjusted life year (QALY) gains with septal reduction procedures than with mavacamten. On balance, it seems likely that for patients who qualify for a septal reduction procedure, overall benefits are greater with a procedure than with mavacamten. However, this choice is highly dependent on patient preferences given the potential for short-term harms with procedures. Evidence-based medicine groups have considered that there can be rare situations in which assigning a preferred strategy is unhelpful given expected wide discrepancies in patient choices based on individual patient preferences. That is, the effects of common individual patient ©Institute for Clinical and Economic Review, 2021 Page 18 Final Evidence Report – Mavacamten for HCM Return to Table of Contents preferences are so important that large variation will persist even with ideal comparative effectiveness evidence. We believe the tradeoffs between a more effective procedure for HOCM with a small but important short-term risk of death and a less effective medication are very preference dependent. Given this profound preference dependence, recommending a specific strategy is unhelpful. As such, we are not assigning an evidence rating to this comparison. These decisions will need to be made on a case-by-case basis through discussions among patients, families, and clinicians. Table 3.9. Evidence Ratings Treatment Comparator Evidence Rating Mavacamten plus beta blockers Beta blockers and calcium channel P/I and calcium channel blockers blockers alone Mavacamten plus beta blockers Disopyramide P/I and calcium channel blockers Mavacamten plus beta blockers Septal reduction therapies See discussion in text and calcium channel blockers P/I: promising but inconclusive CTAF Votes Table 3.10. CTAF Votes on Comparative Clinical Effectiveness Question Yes No Is the currently available evidence adequate to demonstrate that the net health benefit of mavacamten added to background therapy is superior to that provided by background therapy 6 9 alone? Is the currently available evidence adequate to demonstrate that the net health benefit of 2 13 mavacamten is superior to that provided by disopyramide? A majority of the panel voted that the evidence is not adequate to demonstrate that mavacamten plus background therapy is superior to background therapy alone. Panelists who voted with the majority cited the lack of long-term data and voiced concerns about potential adverse events, such as reductions in ejection fraction. Members who voted "Yes" noted EXPLORER's strong study design and the apparent improvements demonstrated in the trial in NYHA class, LVEF, pVO2, cardiac biomarkers, and several patient-reported outcomes, such as the KCCQ. A larger majority of the panel voted that the evidence is not adequate to demonstrate that mavacamten is superior to disopyramide due to the lack of head-to-head and randomized trials. ©Institute for Clinical and Economic Review, 2021 Page 19 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 4. Long-Term Cost Effectiveness 4.1. Methods Overview The primary aim of this analysis was to estimate the incremental cost effectiveness of mavacamten used along with first-line standard of care treatments for patients with symptomatic HOCM. We developed a de novo semi-Markov model for this evaluation, informed by key clinical trials and prior relevant economic models. Costs and outcomes were discounted at 3% per year. The model focused on an intention-to-treat analysis, with a hypothetical cohort of patients with symptomatic HOCM starting the model and being treated with mavacamten along with standard first-line therapy, standard first-line therapy alone, myectomy along with standard first-line therapy, septal ablation along with standard first-line therapy, or disopyramide along with standard first-line therapy. Model cycle length was four weeks based on available clinical data. Figure 4.1 shows the treatment pathways and health states that form the Markov model. The model was programmed in Microsoft Excel 2016 (Redmond, WA). Treatment effects were characterized via observed changes in NYHA class post-treatment available from clinical trial data for mavacamten and standard first-line treatment and standard first-line therapy alone. Literature- based estimates of NYHA class changes for myectomy and standard first-line therapy, septal ablation with first-line therapy, and for disopyramide and standard first-line therapy were extrapolated to be comparable to the patient population in EXPLORER (see further detail below). Proportion of alive patients across NYHA class was assumed to be constant after Cycle 8 (week 32) in the mavacamten and standard first-line therapy and standard first-line therapy alone arms and past Cycle 1 (week four) in the myectomy and standard first-line therapy, septal ablation and standard first-line therapy, and disopyramide and standard first-line therapy arms. Based on discussions with clinical experts and a literature review, mortality rates, adjusted for age and gender, reflected US average all-cause mortality from the Centers for Disease Control and Prevention (CDC) and were assumed constant across NYHA class in this model. As such, the only mortality effect across treatments in the base-case model was associated with perioperative mortality from myectomy and septal ablation. A scenario analysis was also conducted that assigned higher mortality to patients in NYHA class III/IV. Patients remained in the model until they died. ©Institute for Clinical and Economic Review, 2021 Page 20 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure 4.1. Model Structure HOCM: hypertrophic obstructive cardiomyopathy, NYHA: New York Heart Association Various changes were made in response to public comments. First, several errors were identified in the model inputs, including an incorrect disutility for age and a switch of the perioperative mortality rates for septal ablation and myectomy. We had also reported undiscounted totals of time in NYHA class I. Additional detail surrounding costs was added to the input tables. We have updated the sensitivity analyses and they are shown separately for cost and QALYs and we have added a scenario analysis mentioned above considering increased mortality associated with NYHA class III/IV. Our base-case analysis continues to take a health care sector perspective (i.e., focuses on direct medical care costs only) and uses a lifetime time horizon. Unfortunately, data to conduct a formal societal perspective analysis were not available. However, we have also added several scenario analyses showing the impact of hypothetical employment effects of mavacamten and standard first-line therapy relative to first-line therapy alone. ©Institute for Clinical and Economic Review, 2021 Page 21 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 4.2. Key Model Assumptions and Inputs Table 4.1. Key Model Assumptions Assumption Rationale Patient utilities were estimated via NYHA class with age decrements Utilities were available by NYHA class from the EXPLORER trial but not by age, so applied in the model using US we adjusted for age using US average differences by age. average utilities across age. We used a placeholder price of The only available estimate for the price of mavacamten was a projected annual $75,000 per year for mavacamten. cost found online. This assumption ensured that there were no relative mortality effects of the treatments, which was consistent with conversations with clinical experts and Mortality was the same across NYHA available literature regarding mortality in general in HOCM as well as relative classes. effects of treatments on mortality. A scenario analysis that assigned higher mortality to patients in NYHA class III/IV tested this assumption. We used transition rates across NYHA classes for mavacamten along The only available data to model NYHA class transitions in HOCM patients across with standard first-line therapy and time for mavacamten with first-line therapy and for first-line therapy alone were for first-line therapy, based on those from EXPLORER. There were slight upward trends in NYHA I proportions between seen in weeks 26-30 to project NYHA week 26 and week 30; however, there was also reason to believe NYHA class class up to Cycle 8 in the model and would begin to deteriorate at some point. As a middle ground assumption, we then held the proportion of alive opted to hold the proportions of alive patients fixed across NYHA classes post patients in each NYHA class Cycle 8. constant. The data on treatment effects for myectomy with standard first-line therapy, The treatment effect of myectomy septal ablation with standard first-line therapy, and disopyramide with standard with standard first-line therapy, first-line therapy were based on longer time periods, years rather than weeks, septal ablation with standard first- making it impossible to know how rapid the treatment effects occurred or to line therapy, and disopyramide along know particular dynamics in the treatment effect that may have occurred over with standard first-line therapy the first several months/years. It is possible that the treatment effects were occurred between weeks 0-4 and larger or smaller in earlier time periods following the treatment in question than then the proportions of alive what was measured. It is also likely that eventually NYHA status would patients across NYHA classes in deteriorate across the lifetime. As a middle ground assumption, we opted to hold those arms were held constant. the proportion of alive patients across NYHA class constant after the first cycle in those two arms. Comparable data were not available for these aspects of the treatment courses other than directly between mavacamten with first-line therapy and first-line therapy alone where the rates of adverse events were very similar. Discontinuation was considered indirectly in the disopyramide treatment effect (see below) in a way consistent with how mavacamten was being modeled in The model did not include terms of projections over a lifetime based on the trial data. Discontinuation over discontinuation or serious adverse the long term in mavacamten was not available nor the extent to which events. discontinuation would result in surgical options. Minor disutility differences in comparing mavacamten and first-line therapy vs. first-line therapy alone are included. Substantial relative differences in adverse events associated with the treatments were not apparent in the literature other than perioperative mortality for myectomy and septal ablation, disutility from major surgery for myectomy and septal ablation, and higher use of pacemakers with septal ablation than myectomy, which were included in the model. HOCM: hypertrophic obstructive cardiomyopathy, NYHA: New York Heart Association, US: United States ©Institute for Clinical and Economic Review, 2021 Page 22 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 4.2 below lists selected base-case model inputs along with the lower and upper values used in the deterministic sensitivity analyses. See the Report Supplement for more detailed descriptions of the model inputs. Table 4.2. Model Inputs Lower Upper Input Name Treatment Base Case Value Value Epidemiological Inputs Age -- 58.00 34.00 82.00 Female -- 0.41 -- -- Clinical Inputs Mavacamten Treatment Effect Mavacamten 0.24 0.18 0.31 (% NYHA I in Cycle 1) First-Line Treatment Effect Standard 0.08 0.06 0.10 Myectomy Treatment Effect Myectomy 0.77 0.58 0.96 Disopyramide Treatment Effect Disopyramide 0.28 0.21 0.36 Septal Ablation Treatment Effect Septal ablation 0.77 0.58 0.96 Quality-of-Life Inputs Utility of NYHA Class I for Mavacamten Mavacamten 0.95 0.65 1.00 Utility of NYHA Class II for Mavacamten Mavacamten 0.87 0.66 0.98 Utility of NYHA Class III and IV for Mavacamten 0.71 0.56 0.84 Mavacamten Utility of NYHA Class I for SoC Standard 0.95 0.65 1.00 Utility of NYHA Class II for SoC Standard 0.85 0.65 0.97 Utility of NYHA Class III and IV for SoC Standard 0.70 0.56 0.83 Myectomy, septal Utility of NYHA Class I for Other ablation, and 0.95 0.65 1.00 Comparators disopyramide Myectomy, septal Utility of NYHA Class II for Other ablation, and 0.86 0.65 0.98 Comparators disopyramide Myectomy, septal Utility of NYHA Class III and IV for ablation, and 0.71 0.56 0.83 Other Comparators disopyramide Cost Inputs* Per Cycle Cost of Mavacamten Mavacamten $5,769 $4,694 $6,954 First Cycle Cost of Metoprolol Metoprolol cycle 1 $38 $31 $46 Per Cycle Cost of Metoprolol Metoprolol $64 $52 $77 First Cycle Cost of Verapamil Verapamil cycle 1 $49 $40 $59 Per Cycle Cost of Verapamil Verapamil $56 $46 $67 First Cycle Cost of Disopyramide Disopyramide $309 $252 $373 Per Cycle Cost of Disopyramide Disopyramide $413 $336 $497 Disopyramide Hospitalization Cost Disopyramide $8,559 $6,964 $10,316 Myectomy Procedure Cost Myectomy $122,759 $99,881 $147,960 Septal Ablation Procedure Cost Septal ablation $55,706 $45,325 $67,142 NYHA: New York Heart Association, SoC: standard of care *All costs used in the model were updated to 2021 dollars based on the methods outlined in the ICER Reference Case. ©Institute for Clinical and Economic Review, 2021 Page 23 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Sensitivity and Threshold Analyses We conducted deterministic one-way sensitivity analyses to identify the impact of parameter uncertainty and key drivers of model outcomes. Probabilistic sensitivity analyses were also performed by jointly varying all model parameters over 1,000 simulations, then calculating 95% credible range estimates for each model outcome based on the results. We also performed threshold analyses for drug costs across a range of incremental cost-effectiveness ratios ($50,000, $100,000, $150,000, and $200,000 per QALY and evLYG) for mavacamten and first-line therapy relative to first-line therapy alone. We included a scenario analysis that incorporates higher mortality for patients in NYHA class III/IV (hazard ratio [HR] 1.96) based on a meta-analysis of HCM patients.38 We had also wanted to include a formal scenario analysis from a societal perspective but were unable to acquire the necessary data. We do consider several scenario analyses to examine the impact of potential differences from a societal perspective. First, we look at mavacamten and standard first-line therapy relative to standard first-line therapy alone where we model patients in NYHA class I as working full time and those in NYHA class II and class III/IV as being unemployed. In a second related scenario, we model mavacamten patients as all being employed and have all patients on first-line therapy alone as unemployed. In each case, we use average US wages ($27.07) across all occupations and 2,000 hours per year to model the annual financial gains for employed patients.39 4.3. Results Base-Case Results Tables 4.3 and 4.4 present the base-case results. Table 4.3. Results for the Base Case for Each of the Treatments Life NYHA I Treatment Total Drug Cost Total Cost QALYs evLY Years Years Mavacamten*† $1,258,000 $1,568,000 14.75 16.58 8.50 14.75‡ Standard $12,600 $434,000 13.78 16.58 3.33 13.78 Treatment Disopyramide* $116,000 $509,000 14.06 16.58 4.69 14.06 Septal $67,800 $297,000 14.97 16.40 12.49 14.97 Ablation* Myectomy* $135,000 $364,000 14.97 16.37 12.47 14.97 evLY: equal-value of life years, N/A: not applicable, NYHA: New York Heart Association, QALY: quality-adjusted life year *Each of these treatments includes use of standard first-line therapy. †Cost estimates for mavacamten were based on a placeholder price of $75,000 per year. ‡evLY for mavacamten is calculated as compared to standard treatment. ©Institute for Clinical and Economic Review, 2021 Page 24 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 4.4. Incremental Cost-Effectiveness Ratios for Mavacamten in the Base Case Cost per Cost per QALY Cost per Life Cost per evLY Treatment Comparator Additional Gained Year Gained Gained NYHA I Year Standard treatment $1,200,000 Undefined $1,200,000 $219,000 Disopyramide $1,500,000 Undefined $1,500,000 $278,000 Mavacamten* Myectomy Dominated $5,600,000 N/A† Dominated Septal ablation Dominated $7,000,000 N/A† Dominated evLY: equal-value of life years, N/A: not applicable, NYHA: New York Heart Association, QALY: quality-adjusted life year *Incremental cost ratios are based on a placeholder price of $75,000 per year for mavacamten. †Incremental cost per evLY gained not applicable due to fewer lifetime QALYs for mavacamten as compared to myectomy and septal ablation. In the model, mavacamten along with standard first-line therapy was projected to produce more QALYs than standard first-line therapy alone but with very high additional costs when assuming a placeholder price of $75,000 per year for mavacamten. This resulted in an incremental cost per QALY well above standard thresholds. The incremental cost per QALY is even higher when comparing mavacamten to disopyramide. When compared to myectomy and septal ablation in terms of QALYs, mavacamten costs more and produced fewer QALYs. In terms of life years, due to procedural mortality, mavacamten produces more life years but at a very high cost per life year gained. Sensitivity Analyses One-way sensitivity analyses were conducted to measure the effect of uncertainty on projected incremental costs and QALYs between mavacamten with first-line therapy relative to first-line therapy alone. Figures 4.2A and 4.2B and Tables 4.5A and 4.5B present the results of these deterministic sensitivity analyses. Table 4.6 presents a summary of the probabilistic sensitivity analyses comparing mavacamten to standard treatment alone. Given the lifetime horizon model, naturally, the incremental costs were sensitive to the discount rate though always sizable. The projected incremental costs were also relatively sensitive to potential variance in the treatment effects and NYHA-class-related costs although, once again, the projected incremental costs were always sizable. The incremental QALYs were relatively sensitive to the NYHA class utilities although, overall, mavacamten ranged from negative to relatively small gains in comparison with the incremental costs. Potential variance in the treatment effects of mavacamten with first-line therapy and first-line therapy alone had lesser effects on the QALYs than the utility scores of the NYHA. ©Institute for Clinical and Economic Review, 2021 Page 25 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure 4.2A. Tornado Diagram of Incremental Cost for Mavacamten versus Standard of Care NYHA: New York Heart Association, SoC: standard of care Table 4.5A. Inputs and Results for Mavacamten versus Standard of Care Incremental Cost Tornado Diagram Low-Input High-Input Input Lower Cost Upper Cost Value Value Discount Rate for Cost $1,459,478 $909,141 0.01 0.05 Mavacamten Treatment Effect $1,172,786 $1,094,769 0.18 0.31 NYHA III Heath State Cost $1,150,089 $1,115,809 $2,299.24 $3,405.99 SoC Treatment Effect $1,117,467 $1,150,088 0.06 0.10 NYHA II Heath State Cost $1,147,666 $1,118,478 $1,663.84 $2,464.74 NYHA I Heath State Cost $1,124,338 $1,144,176 $611.31 $905.57 Percent of Patients in Mavacamten $1,131,167 $1,136,388 0.57 0.95 Group Taking Metoprolol Percent of Patients in SoC Group Taking $1,136,319 $1,131,236 0.56 0.93 Metoprolol Percent of Patients in Mavacamten $1,133,174 $1,134,381 0.15 0.25 Group Taking Verapamil Percent of Patients in SoC Group Taking $1,134,170 $1,133,385 0.10 0.16 Verapamil NYHA: New York Heart Association, SoC: standard of care *Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. ©Institute for Clinical and Economic Review, 2021 Page 26 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure 4.2B. Tornado Diagram of Incremental QALY for Mavacamten versus Standard of Care NYHA: New York Heart Association, SoC: standard of care Table 4.5B. Inputs and Results for Mavacamten versus Standard of Care Incremental QALY Tornado Diagram Low-Input High-Input Input Lower QALY Upper QALY Value Value Utility of NYHA Class II for SoC 2.91 -0.21 0.65 0.97 Utility of NYHA Class I for Mavacamten -1.55 1.40 0.65 1.00 Utility of NYHA Class II for Mavacamten -0.47 1.78 0.66 0.98 Utility of NYHA Class I for SoC 1.98 0.81 0.65 1.00 Utility of NYHA Class III and IV for SoC 1.50 0.52 0.56 0.83 Discount Rate for Outcomes 1.26 0.78 0.01 0.05 Mavacamten Treatment Effect 0.75 1.20 0.18 0.31 Utility of NYHA Class III and IV for 0.80 1.13 0.56 0.84 Mavacamten SoC Treatment Effect 1.09 0.86 0.06 0.10 NYHA: New York Heart Association, QALY: quality-adjusted life year, SoC: standard of care Tables 4.6A and 4.6B below show the results of the probabilistic sensitivity analysis. The tables illustrate that extremely few and/or none of the simulations resulted in mavacamten along with first-line treatment being deemed cost effective relative to first-line therapy alone even at a willingness-to-pay threshold of $200,000 per QALY. The results were the same in looking at costs per evLY gained. Table 4.6A. Probabilistic Sensitivity Analysis Cost per QALY Gained Results: Mavacamten versus Standard of Care Cost Effective at Cost Effective at Cost Effective at Cost Effective at $50,000 per QALY $100,000 per QALY $150,000 per QALY $200,000 per QALY Mavacamten 0.0% 0.0% 0.0% 0.0% QALY: quality-adjusted life year ©Institute for Clinical and Economic Review, 2021 Page 27 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 4.6B. Probabilistic Sensitivity Analysis Cost per evLY Gained Results: Mavacamten versus Standard of Care Cost Effective at Cost Effective at Cost Effective at Cost Effective at $50,000 per evLYG $100,000 per evLYG $150,000 per evLYG $200,000 per evLYG Mavacamten 0.0% 0.0% 0.0% 0.0% evLYG: equal value of life years gained Scenario Analyses Tables 4.7 and 4.8 show the incremental results when higher mortality for NYHA class III/IV is incorporated into the model. Again, we find that mavacamten plus standard of care had high incremental cost utility ratios relative to standard of care and to disopyramide plus standard of care and that it was dominated by the other arms. Table 4.7. Results for the Scenario with Higher Mortality for NYHA Class III/IV Intervention Intervention Costs Total Costs QALYs Life Years NYHA I Years evLY Mavacamten $1,242,000 $1,544,000 14.60 16.37 8.49 14.97 Standard Treatment $12,100 $410,000 13.33 15.94 3.32 13.33 Disopyramide $112,000 $485,000 13.68 16.04 4.69 13.68 Septal Ablation $67,700 $295,000 14.92 16.33 12.49 14.88 Myectomy $135,000 $361,000 14.92 16.30 12.47 14.89 evLY: equal value of life years, NYHA: New York Heart Association, QALY: quality-adjusted life year Table 4.8. Incremental Cost-Effectiveness Ratios for Mavacamten in the Scenario with Higher Mortality for NYHA Class III/IV Cost per Cost per QALY Cost per Life Cost per evLY Treatment Comparator Additional Gained Year Gained Gained NYHA I Year Standard $893,000 $2,600,000 $693,000 $219,000 treatment Mavacamten Disopyramide $1,100,000 $3,100,000 $874,000 $279,000 Myectomy Dominated $15,800,000 N/A* Dominated Septal ablation Dominated $29,900,000 N/A* Dominated evLY: equal value of life years, N/A: not applicable, NYHA: New York Heart Association, QALY: quality-adjusted life year *Incremental cost per evLY gained not applicable due to fewer lifetime QALYs for mavacamten as compared to myectomy and septal ablation. Table 4.9 presents the incremental results of mavacamten and first-line therapy versus first-line therapy alone for the case when NYHA class I was associated with full employment and NYHA class II and III/IV were associated with no employment and also for an even more extreme case where mavacamten was associated with full employment in all NYHA classes and standard first-line therapy was associated with zero employment. In both, the incremental costs for QALYs remain above standard thresholds. ©Institute for Clinical and Economic Review, 2021 Page 28 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 4.9. Societal-Perspective-Related Scenario Analysis Cost per Cost per QALY Cost per Life Cost per Scenario Additional Gained Year Gained evLY Gained NYHA I Year Full Employment for NYHA I and Not for Class II and Not /IV (Both Mavacamten and $876,000 N/A $876,000 $165,000 Standard Treatment Group) Full Employment for All Patients in $242,000 N/A $242,000 $46,000 Mavacamten Group and Not for Standard Treatment Group evLY: equal value of life years, N/A: not applicable, NYHA: New York Heart Association, QALY: quality-adjusted life year Threshold Analyses Tables 4.10A and 4.10B show per-year threshold costs for mavacamten that would be needed to achieve willingness-to-pay thresholds per QALY and per evLYG of $50,000, $100,000, $150,000, and $200,000. Table 4.10A. QALY-Based Threshold Analysis Results Placeholder Price to Achieve Price to Achieve Price to Achieve Price to Achieve $50,000 per $100,000 per $150,000 per $200,000 per Cost QALY QALY QALY QALY Mavacamten $75,000 $9,600 $12,500 $15,400 $18,400 QALY: quality-adjusted life year Table 4.10B. evLYG-Based Threshold Analysis Results Placeholder Price to Achieve Price to Achieve Price to Achieve Price to Achieve $50,000 per $100,000 per $150,000 per $200,000 per Cost evLYG evLYG evLYG evLYG Mavacamten $75,000 $9,600 $12,500 $15,400 $18,400 evLY: equal value of life years gained Model Validation We used several approaches to validate the model. First, we provided the preliminary model structure, methods, and assumptions to the manufacturer, patient organizations, and clinical experts. Based on feedback from these groups, we refined the data inputs used in the model, as needed. Second, we varied model input parameters to evaluate the face validity of changes in results. We also performed model verification for model calculations using internal reviewers. As part of ICER's efforts in acknowledging modeling transparency, we also shared the model with Bristol Myers Squibb for external verification around the time of publishing the draft Evidence Report for this review. The model was also subject to numerous internal checks for logical functioning by changing the inputs and also several reviews of the inputs for accuracy. ©Institute for Clinical and Economic Review, 2021 Page 29 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Uncertainty and Controversies There were only 30 weeks of data available for mavacamten in the EXPLORER trial on which to base projected treatment effects by NYHA class, and the EXPLORER data may not generalize to other patient populations. The utilities in the model across NYHA class also come from the trial and may not generalize to other HOCM patients. However, they were derived from HOCM patients, which we deemed to be an improvement over using utilities from more general heart failure populations. In addition, there were multiple comparators but insufficient data to conduct a network meta- analysis or other quantitative analyses controlling for treatment effects across baseline characteristics of patients in forming estimates for the comparators such as myectomy, septal ablation, and disopyramide relative to mavacamten. Further, the evidence for myectomy, septal ablation, and disopyramide comes from observational studies while the evidence for mavacamten and standard first-line therapy used in the modeling came from the EXPLORER trial. The modeling of the treatment arms did not include discontinuation and subsequent use of other options. Though it is beyond the scope of this analysis, it is possible that greater or smaller proportions of patients on mavacamten may elect to have myectomy or septal ablation in the future as compared to standard first-line treatment alone and/or disopyramide along with standard first-line treatments. In terms of cost effectiveness, the procedures were dominant to mavacamten to begin with, but if mavacamten plus standard first-line therapy was associated with fewer follow- up procedures than standard first-line treatments alone that could impact the cost effectiveness of mavacamten and first-line therapy relative to first-line therapy alone. In addition, some mavacamten patients in the EXPLORER trial had previously undergone septal reduction procedures, which was not included in the model. Further, the procedural options involve tradeoffs between short-term mortality and long-term expected gains in QALYs that are not present in the pharmaceutical-only options. Also, we were unable to include a societal perspective analysis using actual data. However, we did present several scenarios based on hypothetical data. Even under extreme assumptions, mavacamten was above commonly-cited thresholds from this hypothetical extreme societal perspective assuming the placeholder price for mavacamten. Further, we conducted the two additional scenario analyses to examine the impact of having treatment associated with employment. Finally, available non-drug cost estimates by NYHA class are for a private payer and/or based on data from heart failure patients and we only had access to a placeholder cost for mavacamten. ©Institute for Clinical and Economic Review, 2021 Page 30 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 4.4. Summary and Comment Mavacamten used along with standard first-line treatment was projected to generate higher amounts of QALYs than standard first-line treatment alone. However, at the placeholder cost of $75,000, the incremental cost-effectiveness ratios were well above standard thresholds. When compared with disopyramide, the incremental cost per QALY was even higher, and mavacamten was found to be dominated by both myectomy and septal ablation. The sensitivity and scenario analyses suggested, using the placeholder price, that these findings were robust. However, the actual cost effectiveness of mavacamten will depend on its price. ©Institute for Clinical and Economic Review, 2021 Page 31 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 5. Contextual Considerations and Potential Other Benefits Our reviews seek to provide information on potential other benefits offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that was not available in the evidence base nor could be adequately estimated within the cost-effectiveness model. These elements are listed in the tables below, with related information gathered from patients and other stakeholders. Following the public deliberation on this report, the appraisal committee voted on the degree to which each of these factors should affect overall judgments of long-term value for money of the intervention(s) in this review. Table 5.1. Contextual Considerations Contextual Consideration Relevant Information For many patients with symptomatic HOCM, the burden of disease can be very severe. In addition to exertional symptoms and the risk of sudden cardiac death, patients with HOCM also face anxiety, depression, concerns about activities of daily living and social events. There is uncertainty about the extent to which Acuity of need for treatment of individual exercise can increase risk of sudden cardiac death for HOCM patients based on short-term risk of death patients, and guidelines have shifted over time, leading to or progression to permanent disability uncertainty and confusion among HOCM patients about optimal self-care. Since patients often have electrocardiograms and echocardiograms that mimic other conditions, including acute myocardial infarction and hypertensive heart disease, misdiagnosis is common and patients with HCM and HOCM often have frustrations with the health care system. Patients with symptomatic HOCM are often at points in their lives when they are making important life choices regarding education, work, and raising families, which could provide benefits over and Magnitude of the lifetime impact on above the improvement in QALYs calculated in the model. individual patients of the condition being treated The fear of death given the potential of malignant ventricular arrythmias is often present throughout life, causing a large burden to patients. Patients also report lifelong grief related to life decisions made because of fear of HCM-related complications. HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy, QALY: quality-adjusted life year ©Institute for Clinical and Economic Review, 2021 Page 32 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table 5.2. Potential Other Benefits or Disadvantages Potential Other Benefit or Disadvantage Relevant Information Particularly when patients are diagnosed early in life, uncertainty and fear can lead to pressured life decisions about educational programs, marriage and relationships, and decisions about whether to have children. Patients reported concern about passing along genes associated with HCM to children. Some of those concerns about children are related to lack of treatment options for symptoms. Patients' ability to achieve major life goals related to education, work, or family life Patients themselves are often underemployed because they fear moving to new jobs or communities because these moves could disrupt insurance, social supports, and access to caregivers. Symptoms of HCM or arrythmias related to HCM can interfere with work or social activities, affecting both career advancement and relationships. Patients also reported that the diagnosis of HCM can lead to difficulties receiving life insurance, being admitted to educational programs, and receiving loans. This can lead to underemployment Caregivers' quality of life and/or ability to since patients are reluctant to switch jobs, which often creates a achieve major life goals related to shift in insurance policy. education, work, or family life When caregivers are needed to provide care for HCM patients, they sometimes cannot work, exacerbating financial problems. Mavacamten could provide more access to treatment options Society's goal of reducing health inequities because septal reduction procedures are only available at specialized centers in specific cities. HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy ©Institute for Clinical and Economic Review, 2021 Page 33 Final Evidence Report – Mavacamten for HCM Return to Table of Contents CTAF Votes At the public meeting, CTAF deliberated and voted on the relevance of specific potential other benefits and contextual considerations on judgments of value for the interventions under review. The results of the voting are shown below. Further details on the intent of these votes to help provide a comprehensive view on long-term value for money are provided in the ICER Value Assessment Framework. When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for HOCM on the basis of the following contextual considerations? Very Low Low Average High Very High Contextual Consideration Priority Priority Priority Priority Priority Acuity of need for treatment of individual patients based on the short-term risk of death or 2 3 7 3 0 progression to permanent disability Magnitude of the lifetime impact on individual 0 0 4 10 1 patients of the condition being treated A majority of the panel voted that a treatment for HOCM should be given average priority relative to other diseases. Panelists cited expert testimony, noting that the progression of disease is slow over time for most patients, and, on average, patients live a normal life expectancy with a low risk of death. However, panelists acknowledged that the lifetime impact of the disease is large as most patients live with HOCM and its attendant complications and high symptom burden for many years. ©Institute for Clinical and Economic Review, 2021 Page 34 Final Evidence Report – Mavacamten for HCM Return to Table of Contents What are the effects of mavacamten on the following outcomes that inform judgment of the overall long-term value for money of mavacamten? Major Minor Minor Major No Potential Other Benefit or Disadvantage Negative Negative Positive Positive Difference Effect Effect Effect Effect Patients' ability to achieve major life goals related to 0 1 1 11 2 education, work, or family life Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family 0 1 2 11 1 life Society's goal of reducing health inequities 0 1 8 5 1 Opportunity to improve access to treatment 0 0 6 8 1 Availability of a treatment with different timing and types of risks and benefits, relative to existing 0 0 1 9 5 procedural and surgical options A majority of the panel voted that mavacamten could have a potentially minor positive effect on patients' and caregivers' ability to achieve life goals related to education, work, or family life. These two votes were driven primarily by patient testimony, which highlighted the difficulties that patients and caregivers encounter throughout a lifetime. Among many such obstacles, patients stressed that individuals with HOCM have delayed or truncated their education, rethought marriage or children, and endured untenable jobs due to the impact of the disease on their social lives, insurance coverage and cost, and ability to conduct activities of daily living. About half the panel voted that mavacamten would make no difference in reducing health inequities, but a bare majority did acknowledge that the drug may improve access to treatment. As stated in the most recent set of guidelines, centers of excellence play an essential role in HCM care; however, the distribution of these centers across the US is geographically unbalanced and there exist large swaths of the country without convenient access to specialists with expertise in HCM.40 To access the highest level of care, many patients face burdensome and costly travel, and encounter difficulties taking time away from work or family obligations. Panelists noted that an oral treatment option could benefit these patients, especially in the era of telemedicine, which could encourage collaboration between a specialist at a center of excellence and a community cardiologist or primary care physician. Lastly, although outcomes for myectomy are generally good and the risk of death is low, the procedure is invasive and requires significant aftercare. As such, a majority of the panel voted that the availability of an oral option with different risks and benefits compared to surgery may have a potentially minor or major positive effect on the disease. As advocates noted, surgery is not attainable or the best option for all patients, and access to an oral therapy may increase the number of patients who are adequately treated. ©Institute for Clinical and Economic Review, 2021 Page 35 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 6. Health-Benefit Price Benchmarks Health-benefit price benchmarks (HBPBs) for the annual cost of treatment are presented in Table 6.1 below. The HBPB for a drug is defined as the drug price range that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY gained or per evLY gained. For mavacamten, this range is $12,000 to $15,000 annually. Table 6.1. Annual Health Benefit Price Benchmarks for Mavacamten Annual Price at $100,000 Threshold Annual Price at $150,000 Threshold QALYs Gained $12,000 $15,000 evLY Gained $12,000 $15,000 evLY: equal value of life years, QALY: quality-adjusted life year CTAF Votes Value votes were not taken at the public meeting because a net price for mavacamten was not available. ©Institute for Clinical and Economic Review, 2021 Page 36 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 7. Potential Budget Impact 7.1. Overview of Key Assumptions Using results from the cost-effectiveness model, we estimated the potential budgetary impact of mavacamten for patients with symptomatic HOCM. We used the mavacamten price from the base- case analysis (placeholder price of $75,000 per year) and three annual threshold prices (at $50,000, $100,000, and $150,000 per QALY). Potential budget impact is defined as the total differential cost of using each new therapy rather than the relevant existing therapy for the treated population, calculated as differential health care costs (including intervention costs) minus any offsets in these costs from averted health care events. All costs were undiscounted and estimated over a five-year time horizon. The analysis included the estimated number of individuals in the US who would be eligible for mavacamten. To estimate the size of the potential candidate population for treatment, we used inputs from best-available evidence. A study published in 2016 that examined a large claims database to calculate the prevalence of clinically-recognized HCM reported that diagnosed HCM occurred in one in 3,195 (i.e., 3.1 in 10,000) adult patients in the US.41 Other literature has suggested that 70% of HCM patients have obstructive disease.42 Applying these sources results in estimates of 2.2 in 10,000 patients who are diagnosed with symptomatic HOCM, or approximately 72,300 eligible patients in the US. For the purposes of this analysis, we assumed that 20% of these patients would initiate treatment in each of the five years, or approximately 14,460 patients per year. In this potential budget impact analysis, we assumed that patients eligible for mavacamten would otherwise have been treated with standard treatment. The aim of the potential budgetary impact analysis is to document the percentage of patients who could be treated at selected prices within five years without crossing a potential budget impact threshold that is aligned with overall growth in the US economy. For 2021-2022, the five-year annualized potential budget impact threshold that should trigger policy actions to manage access and affordability is calculated to be approximately $734 million per year for new drugs. ©Institute for Clinical and Economic Review, 2021 Page 37 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 7.2. Results Figure 7.1 depicts the cumulative per-patient potential budget impact calculations for mavacamten as compared to standard therapy, based on a placeholder cost for mavacamten of $75,000 per year. The average potential budgetary impact for mavacamten was approximately $70,000 in year one, with cumulative net cost increasing each year to reach approximately $336,000 in year five. Figure 7.1. Cumulative Net Cost per Patient Treatment with Mavacamten at Placeholder Price Assuming the placeholder price of $75,000 per year, only 25% of the eligible patients could be treated within five years (assuming 20% uptake each year), before crossing the ICER potential budget impact threshold of $734 million per year. This could create a short-term potential budget impact that exceeds the potential threshold at this price. However, because this is based on a placeholder price, ICER is not issuing an access and affordability alert. All eligible patients could be treated within five years without crossing the ICER potential budget impact threshold at the price to reach $150,000 per QALY. Figure 7.2 depicts the potential budgetary impact of mavacamten. ©Institute for Clinical and Economic Review, 2021 Page 38 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure 7.2. Potential Budgetary Impact of Mavacamten in Symptomatic HOCM BI: budget impact ©Institute for Clinical and Economic Review, 2021 Page 39 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 8. Policy Recommendations Following its deliberation on the evidence, CTAF engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on the use of mavacamten for symptomatic HOCM. The policy roundtable members included two patient advocates, two clinical experts, and two payers. The manufacturer declined to send a representative to participate in the policy roundtable. The discussion reflected multiple perspectives and opinions, and therefore, none of the statements below should be taken as a consensus view held by all participants. All Stakeholders All stakeholders have a responsibility to facilitate meaningful patient access to multidisciplinary centers of excellence for HCM in ways that do not exacerbate disparities. The most recent clinical guidelines developed by the American Heart Association/American College of Cardiology in 2020 for management of HCM explicitly recommend (class 2a) "consultation with or referral to" experienced multidisciplinary centers to aid in complex management decisions. Furthermore, for patients with HOCM, the guidelines strongly recommend that septal reduction procedures are performed in such centers (class 1). Access to the expertise offered by these experienced multidisciplinary centers is critically important for several reasons. Although HCM is not a rare condition, many general cardiologists do not have deep expertise in diagnosis or management of HCM. HCM can mimic other disease conditions such as infiltrative cardiomyopathies and hypertensive heart disease, and even variants of normal (such as normal athlete's heart). Electrocardiograms for patients with HCM often mimic electrocardiograms for acute myocardial infarction (heart attack). As such, patients report unnecessary care escalations. In part because of these issues, patients report frustration interacting with care teams that do not have expertise in HCM. Furthermore, the diagnosis, monitoring, and management of patients with HCM often require specialized expertise in cardiac imaging and the interpretation of genetic data available only at specific centers. Lack of access to specialized centers can lead to health care disparities with respect to wealth, income, location, and race. However, community-based physicians, including general cardiologists, also have an important role in the management of patients with HCM. Ideal care pathways could include regular care from an accessible local cardiologist with intermittent input from experts at centers of excellence. These ideal care pathways, however, are complicated by lack of access to telemedicine, restrictions on the practice of medicine between states, and payment policies limiting reimbursement for interprofessional (community physician to specialist physician) consultation. ©Institute for Clinical and Economic Review, 2021 Page 40 Final Evidence Report – Mavacamten for HCM Return to Table of Contents To address these concerns: Payers should take the following actions: • Provide adequate reimbursement for telemedicine and interprofessional consultation between centers of excellence and community cardiologists to facilitate both access to care and appropriate subspecialist expertise when needed. Adequate reimbursement for telemedicine is also important both for initial consultation and ongoing monitoring for patients taking mavacamten. • If payers restrict access to mavacamten to providers at specialized centers of excellence, they should work with the patient community as well as clinical experts to select these centers. Designations of centers of excellence should be meaningful. For example, provider self-attestation of expertise is unlikely to be meaningful and accurate. The HCM patient community has spent many years developing an understanding of which centers reflect the full spectrum of expertise and experience needed for excellent care of patients with HCM, and payers should collaborate with the patient community to leverage this work. • Ensure that in the setting of promising short-term efficacy but long-term unresolved questions about safety, mavacamten is prescribed in centers with appropriate expertise and monitoring protocols. In the policy roundtable, both patients and clinical experts expressed safety concerns about the prospect of widespread use of mavacamten shortly after approval prior to the generation of longer-term data. If longer-term concerns about safety are resolved with time, however, any restrictions could be loosened to allow mavacamten to be prescribed in broader settings by a greater range of cardiologists. Clinical specialty societies should take the following actions: • Work with patient organizations to develop and validate standards for centers of excellence for HCM. For example, the Hypertrophic Cardiomyopathy Association has identified centers of excellence available on their website (www.4hcm.org/center-of-excellence). Aligning this type of list with input from professional societies could inform payer policy in a patient- and clinician-informed way. • Work with payers, regulators, and patients to develop educational tools to improve knowledge about the management of HCM among community providers, including situations in which referral to a center of excellence is important. • Continue to educate cardiologists about the critical importance of shared decision-making for all treatment options for HCM, including therapies to reduce LVOT gradient in patients with symptomatic HOCM. The 2020 guidelines recommend shared decision-making in HCM (class 1). ©Institute for Clinical and Economic Review, 2021 Page 41 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Organizations that provide health care should take the following actions: • Develop and use platforms to share primary imaging data between community providers and centers of excellence to improve accuracy of diagnosis and appropriate utilization of treatments for HCM, including symptomatic HOCM. Both diagnosis and ongoing management for patients with HCM require relevant imaging and genetic counseling expertise. • Restrict the performance of surgical myectomy and alcohol septal ablation to high-volume procedural centers with appropriate supportive services including cardiac critical care. • Centers and providers with less expertise should establish referral pathways to and relationships with high-volume centers to ensure equity in access to patients (despite the restriction of the procedures to higher-volume centers). Since patients with HCM often seek emergency care in different settings, for example when traveling, emergency providers should have pathways to communicate with subspecialty experts in HCM when needed even when they are not physically available. Manufacturers The manufacturer of mavacamten should: Commit to sponsoring research that will address the lack of evidence on the comparative effectiveness of mavacamten versus disopyramide and septal reduction procedures. When patients with symptomatic HOCM have inadequate relief or intolerable side effects with beta blockers and calcium channel blockers, clinical guidelines support the use of disopyramide and or septal reduction procedures. After mavacamten is available, it will also become an important treatment option. Disopyramide has been approved for clinical use for many decades. The evidence evaluating the effectiveness of disopyramide is limited, but there are fewer concerns about long-term adverse effects because of more experience. As a practical matter, the short- acting form is difficult to use for patients because of a short half-life and four times per day daily dosing. However, the long-acting form, which can be given twice per day, is difficult to obtain because of drug shortages. If access to the long-acting form of disopyramide improves, it could provide a treatment option that works for many patients. Many of the patients with NYHA class III symptoms in the EXPLORER trial may also have been potential candidates for septal reduction therapies. Although VALOR-HCM will likely provide some important information for these patients, VALOR-HCM does not compare mavacamten to septal reduction procedures directly and as such, will not resolve the question of comparative effectiveness of mavacamten versus these procedures. ©Institute for Clinical and Economic Review, 2021 Page 42 Final Evidence Report – Mavacamten for HCM Return to Table of Contents In that context, data are inadequate to inform important clinical choices such as: 1) Disopyramide versus mavacamten 2) Mavacamten versus alcohol septal ablation 3) Mavacamten versus surgical myectomy 4) Surgical myectomy versus alcohol septal ablation. Although prospective, randomized trials with at least one to two years follow up would be ideal to establish evidence for these comparisons, some comparisons such as surgical myectomy versus alcohol septal ablation are likely never to occur. In that context, observational analyses with proper statistical methods to account for confounding and selection bias may be able to provide some information on the comparative effectiveness of these options. Align the price of mavacamten with the explicit and transparent estimates of its treatment benefits for patients and families. Pricing should also be moderated to reflect the uncertainty about longer-term safety until such time as further outcomes data are generated. • There is no available price for mavacamten. However, an analyst estimate suggests that the price of mavacamten could far exceed a price aligned with its value. Our analysis suggests an HBPB of $12,000-$15,000 per year. However, our estimate does not account for legitimate concerns about longer-term safety. In that context, an appropriate price after initial approval could be even lower. • In 2020, Bristol Myers Squibb purchased MyoKardia. The purchase price for the smaller company should not be a basis of a price that is higher than a value-based price. • A lower price would have several benefits for patients. First, it would likely expand access to mavacamten for patients who wish to try the medication early. Second, by expanding the proportion of patients who have access to the drug, it would allow a more rapid assessment of longer-term safety through post-approval monitoring with real-world evidence. Although there are known limitations to this type of observational data, a larger number of patients creates more statistical power to detect rarer side effects. • If this type of longer-term evidence provides reassurance about longer-term safety, it would be appropriate to raise the price of mavacamten to the HBPB established in our analysis or to an even higher level should the effectiveness of the drug exceed early estimates. Until rigorous evidence is available, avoid speculative suggestions about potential therapeutic benefits of novel treatment options. The clinical evidence is inadequate to suggest that mavacamten may confer a survival benefit, irrespective of improvement in cardiac structure as measured by cMRI as well as improvements in ©Institute for Clinical and Economic Review, 2021 Page 43 Final Evidence Report – Mavacamten for HCM Return to Table of Contents cardiac biomarkers. Particularly given the discordance between cMRI and patient-reported outcomes after mavacamten is stopped, there is substantial uncertainty about longer-term effects of the medication on cardiac structure and longer-term outcomes. Any suggestion that mavacamten reduces mortality at this point is speculative and carries the risk of creating false hope for this patient community. Engage fully with patient groups, clinical experts, and independent entities seeking to produce transparent evaluations of the effectiveness and value of mavacamten. Access to novel therapies for patients who will benefit at a price aligned with the benefits of that therapy is an important societal goal. This type of access can result from open communication between manufacturers, payers, and patients and their advocates. A representative of Bristol Myers Squibb delivered public comments at the public meeting on mavacamten but declined to participate in the policy roundtable. Avoiding this type of transparent public discussion does a disservice to the patient community and ultimately harms patient access to mavacamten. All manufacturers of treatments for patients with HCM should be encouraged to assess patient- reported outcomes in clinical trials. One of the important strengths of the EXPLORER study was that patient-reported outcomes were collected and a new patient-reported outcome specific to HCM was developed. These data complemented physiologic endpoints as well as clinician assessed measures of health status. Future trials should be encouraged to follow this example of including patient-reported outcomes, in particular when therapies are intended to improve subjective health status as opposed to "hard" event outcomes such as mortality. Payers Payers should use the FDA label as the guide to coverage policy and engage clinical experts and diverse patient representatives in considering how to address coverage issues for which there is limited or no evidence at the current time. Given the significant uncertainty that will remain about the relative benefits and longer-term risks of mavacamten for different patients, it will be reasonable for payers to use prior authorization as a component of coverage policy. Prior authorization criteria should be based on the FDA label, clinical evidence and patient eligibility criteria from pivotal trials, specialty society guidelines, and input from clinical experts and patient groups. The process for authorization should be clear and efficient for providers and patients. Options for specific elements of coverage criteria within insurance coverage policy are discussed below. ©Institute for Clinical and Economic Review, 2021 Page 44 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Coverage Criteria Age: Mavacamten is likely to be covered for adult patients (18 years or greater), in line with the inclusion criteria of the EXPLORER trial. There is greater uncertainty about both treatment effects and risks in younger patients, since the mean age in the trial was 58.5 years. However, younger adults were eligible for and included in the key trial. Clinical Eligibility: Current evidence pertains to patients with symptomatic, obstructive HCM with LVOT gradients greater than or equal to 50 mmHg at rest after Valsalva maneuver or exercise. Inclusion Criteria: When mavacamten is prescribed with the intent of improving symptoms in symptomatic HOCM, key clinical issues include establishing the presence of a LVOT gradient and excluding non-cardiac sources of exertional symptoms (such as pulmonary symptoms). Conditions that mimic HCM are common but are very unlikely to result in the subtype of HCM that causes obstruction. We are aware that therapeutic concepts are in development that eventually may lead to the use of mavacamten for HCM without obstruction. In that case, depending on the evidence available at the time, it may become reasonable to establish specific anatomic cutoffs for ventricular wall thickness. Overall, the distinction between HCM generally and conditions that mimic HCM are subtle and require interdisciplinary discussion among experts in cardiac imaging, genetics, and clinical cardiology. That integrative expertise is more helpful than specific anatomic cutoffs. For these reasons, it seems unreasonable for payers to establish specific cutoffs for left ventricular dimensions prior to approving mavacamten for symptomatic HOCM. Although the diagnosis of HCM is subtle and often requires specialist expertise and, in some cases, confirmation through genetic testing, there are multiple important limitations to genetic testing. For example, some genetic variants that cause HCM are unknown. Secondly, of all the pathologic conditions (like hypertension and infiltrative cardiomyopathies) and non-pathologic conditions (athlete's heart) that can mimic HCM, they are unlikely to cause a hemodynamic gradient in the outflow tract. Since mavacamten is likely to be used in patients with symptomatic HOCM, rigorous establishment and confirmation of a hemodynamic outflow tract gradient is important. Conversely, in this situation, genetic testing will not be useful for establishing candidacy for mavacamten. For these reasons, it is unreasonable for payers to require genetic testing to confirm diagnosis prior to approval of mavacamten for symptomatic HOCM. Exclusion Criteria: There are no specific medical comorbidities that would serve as exclusion criteria for mavacamten. Patients with permanent atrial fibrillation who are either not on anticoagulation for more than four weeks or not adequately rate controlled for more than six months, or any patients with paroxysmal atrial fibrillation were not included in the EXPLORER trial (see section on atrial fibrillation below). However, there is no specific contraindication to using mavacamten in patients with atrial fibrillation. Since atrial fibrillation is a common source of symptoms in patients with all types of HCM, distinguishing between symptoms related to outflow tract obstruction and ©Institute for Clinical and Economic Review, 2021 Page 45 Final Evidence Report – Mavacamten for HCM Return to Table of Contents symptoms related to atrial fibrillation is important before attempting to reduce outflow tract obstruction with mavacamten. Duration of Coverage and Renewal Criteria: Experts advised that patients initiated on mavacamten generally should have documented benefits within three months. Accordingly, patients generally should be reevaluated by clinicians within that timeframe (either in person or via telemedicine). Patients who remain on mavacamten should then again be reevaluated within one year. Provider Restrictions: Both clinical experts and patients expressed concern about the safety of early widespread use of mavacamten in community-based settings outside of centers of excellence. As such, it seems reasonable to keep use of mavacamten very narrow within two to five years after FDA approval. As more safety data are available and clinicians gain more experience, it seems reasonable to widen provider access. This reflects a difficult balance between potentially concerning safety signals and patient access. Particularly given this balance, we encourage payers to collaborate with patient organizations to establish lists of preferred providers at centers of excellence. The Hypertrophic Cardiomyopathy Association has identified centers of excellence available on their website (www.4hcm.org/center-of-excellence). Step Therapy It is reasonable for payers to require an attempt to manage symptomatic HOCM with beta blockers and calcium channel blockers before approving mavacamten. Patients in both the placebo and mavacamten arms of the EXPLORER trial could take beta blockers and calcium channel blockers. Very few patients enrolled in the trial were taking neither medication. As such, it is reasonable to require an attempt at managing symptoms with beta blockers and calcium channel blockers alone before approving mavacamten. Many patients report intolerable side effects with these medications. As such, intolerable side effects or contraindications are reasonable justifications for defining treatment failure of beta blockers and/or calcium channel blockers. It is unreasonable for insurers to require either myectomy or septal ablation prior to approval of mavacamten. Given that surgical myectomy and alcohol septal ablation involve very different trade-offs and risks for patients relative to an oral medication, it is unreasonable for insurers to require either myectomy or septal ablation prior to access to mavacamten. The comparative effectiveness of these treatment options is obscured by the absence of relevant trials. Even if more definitive evidence is established, the decision of an oral medication versus a procedure or surgery seems very dependent on the preferences and circumstances of an individual patient. Shared decision- making is appropriate in these situations. ©Institute for Clinical and Economic Review, 2021 Page 46 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Despite this recommendation, if insurers ever do require either surgical myectomy or septal ablation prior to coverage of mavacamten, they should recognize that patients lose considerable time from work while recuperating from these procedures and full consideration should be given to compensating patients for this lost time in some way. Unless patients have better access to disopyramide, it seems unreasonable to consider requiring a trial of disopyramide prior to coverage of mavacamten. Further clinical evidence on the clinical benefits of disopyramide is also required to strengthen any consideration of this step therapy option. Clinical experts disagreed about whether requiring a trial of disopyramide prior to approval of mavacamten would be reasonable. If the initial price of mavacamten is high, there would be more justification of the importance of a trial of disopyramide before mavacamten. Despite that, short- acting disopyramide requires onerous dosing every six hours. Long-acting disopyramide is a more reasonable option but is currently in a drug shortage, limiting access. Clinical Investigators and Grant Funding Organizations Researchers and funding agencies should ensure that future research assesses the potential benefits of treatment related to improved productivity and reductions in caregiver burden. In determining a value-based price for a novel therapy, standard methods account for both increases in life expectancy and improvement in health status for patients. However, it is also reasonable to account for potential other benefits. Novel clinical innovations can provide additional benefits by easing caregiver burden and improving patient workforce productivity, but these benefits are often not measured. Unfortunately, these potential other benefits have not been well- captured in prior research. Patient-centered research that aims to quantify these potential other benefits would allow inclusion in decision-analytic models. Inclusion of this information in decision- analytic models would more fully capture the benefits of a novel therapy but also could potentially increase a value-based price estimate. Further research should be targeted at evaluating the safety and benefits of mavacamten for patients with HOCM and atrial fibrillation. Patients with permanent atrial fibrillation not on anticoagulation who are either not on anticoagulation for more than four weeks or not adequately rate controlled for more than six months, or any patients with paroxysmal atrial fibrillation were not included in the EXPLORER trial. In the setting of these exclusion criteria, only 12 patients (10%) in mavacamten arm of EXPLORER had even a history of atrial fibrillation. Atrial fibrillation is common in patients with HOCM, thromboembolic risk off anticoagulation is high, and because atrial fibrillation can exacerbate the hemodynamic gradient in the LVOT, atrial fibrillation often causes intolerable symptoms. In a ©Institute for Clinical and Economic Review, 2021 Page 47 Final Evidence Report – Mavacamten for HCM Return to Table of Contents patient with symptomatic HOCM and atrial fibrillation, it is often difficult to distinguish between symptoms caused by atrial fibrillation and symptoms caused by the outflow tract gradient. The comparative effectiveness and safety of mavacamten in many patients with atrial fibrillation is therefore unclear. More work is required to establish the efficacy and safety of mavacamten for patients with atrial fibrillation including paroxysmal atrial fibrillation. Post-approval clinical registries should be established to detect rare side effects as well as assess the efficacy of mavacamten in more diverse populations. Since the MAVA-LTE study uses the same population as the EXPLORER population, there is very limited representation among patients of color. Furthermore, this cohort that includes 224 patients will be underpowered to detect rarer side effects among all patients. Especially because there is a substantial concern about longer-term safety, clinical registries will be essential for detecting rarer adverse events and for assessing if the results of EXPLORER are extrapolatable to more diverse populations. Patient Groups Patient groups should continue to demonstrate leadership in defining clinical excellence and appropriate pricing. • The Hypertrophic Cardiomyopathy Association has played a longstanding leadership role in advocacy for this patient community, including work generating educational information for patients and families, supporting research efforts, and identifying centers of excellence for HCM. Their actions serve as a model for other patient communities seeking to advance the best interests of patients today and in the future. Given the critical importance of centers for excellence for HCM generally, the Hypertrophic Cardiomyopathy Association should continue this involvement and seek to work with payers to find the right balance between breadth of access and quality of the care provided at diverse provider organizations. • Hypertrophic Cardiomyopathy Association representatives and others have expressed concerns about the potential that the manufacturer will set a high price of mavacamten. The Hypertrophic Cardiomyopathy Association has established its credibility within its own community and with clinical experts. It has a powerful voice that will be used to advocate for appropriate access for patients to mavacamten and other new treatments. This group, and others, should fully exercise that voice and that power in support of responsible pricing that will advance the best interests of patients while sending a strong signal to innovators that they should develop robust evidence of benefits to patients to support their pricing. We hope that government, manufacturers, private payers, and other advocates will work ©Institute for Clinical and Economic Review, 2021 Page 48 Final Evidence Report – Mavacamten for HCM Return to Table of Contents with the Hypertrophic Cardiomyopathy Association to facilitate their advocacy, which is critically important for patients with HCM. ©Institute for Clinical and Economic Review, 2021 Page 49 Final Evidence Report – Mavacamten for HCM Return to Table of Contents References 1. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of Atrial Fibrillation on the Clinical Course of Hypertrophic Cardiomyopathy. Circulation. 2001;104(21):2517-2524. 2. 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J Am Heart Assoc. 2017;6(6). ©Institute for Clinical and Economic Review, 2021 Page 51 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 34. Kim LK, Swaminathan RV, Looser P, et al. Hospital Volume Outcomes After Septal Myectomy and Alcohol Septal Ablation for Treatment of Obstructive Hypertrophic Cardiomyopathy: US Nationwide Inpatient Database, 2003-2011. JAMA Cardiology. 2016;1(3):324-332. 35. Maron MS, Ommen SR. Exploring New and Old Therapies for Obstructive Hypertrophic Cardiomyopathy: Mavacamten in Perspective. Circulation. 2021;143(12):1181-1183. 36. Neubauer S, Kolm P, Ho CY, et al. Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry. Journal of the American College of Cardiology. 2019;74(19):2333-2345. 37. Saberi S, Cardim N, Yamani M, et al. Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy. Circulation. 2021;143(6):606-608. 38. Liu Q, Li DD, Berger AE, Johns RA, Gao L. Survival and prognostic factors in hypertrophic cardiomyopathy: a meta-analysis. Sci Rep-Uk. 2017;7. 39. Occupational Employment and Wage Statistics. US Department of Labor; 2020. https://www.bls.gov/oes/2020/may/oes_nat.htm#00-0000. Accessed 9/30/21. 40. Hypertrophic Cardiomyopathy Association (HCMA). HCMA Recognized Centers of Excellence. https://4hcm.org/center-of-excellence/. Published 2021. Accessed 10/28/21, 2021. 41. Maron MS, Hellawell JL, Lucove JC, Farzaneh-Far R, Olivotto I. Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in the United States. The American Journal of Cardiology. 2016;117(10):1651-1654. 42. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114(21):2232-2239. 43. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981;64(6):1227-1234. 44. Ross R, Blair SN, Arena R, et al. Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign: A Scientific Statement From the American Heart Association. Circulation. 2016;134(24):e653-e699. 45. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European Heart Journal. 2014;35(39):2733-2779. 46. (NICE) NIfHaCE. Non-surgical reduction of the myocardial septum. 2004. 47. Wild C. Perkutane transluminale septale Myokardablation/PTSMA bei PatientInnen mit hyperthrophobstruktiver Kardiomyopathie. 2013. 48. Moher D, Liberati A, Tetzlaff J, Altman DG, The PG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS Medicine. 2009;6(7):e1000097. 49. Agency for Healthcare Research and Quality. U.S. Preventive Services Task Force Procedure Manual. Published 2008. Accessed. 50. Ollendorf DA, Pearson SD. An integrated evidence rating to frame comparative effectiveness assessments for decision makers. Medical care. 2010;48(6 Suppl):S145-152. 51. Ollendorf D, Pearson, SD. ICER Evidence Rating Matrix: A User's Guide. https://icer- review.org/methodology/icers-methods/icer-evidence-ratingmatrix/. . Published 2020. Updated January 31, 2020. Accessed. 52. Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy a clinical trial. Annals of Internal Medicine. 2019;170(11):741-748. 53. Clinicaltrials.gov. A Phase 2 Open-label Pilot Study Evaluating MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (PIONEER-HCM). Published 2020. Accessed. ©Institute for Clinical and Economic Review, 2021 Page 52 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 54. Clinicaltrials.gov. A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) (MAVERICK-HCM). Published 2020. Accessed. 55. Haruki S, Minami Y, Suzuki A, Hagiwara N. Effects of flecainide on left ventricular pressure gradient and symptoms in obstructive hypertrophic cardiomyopathy: a comparison of flecainide and disopyramide. Heart and Vessels. 2015;30(5):604-610. 56. Sherrid MV, Shetty A, Winson G, et al. Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to First-Line Therapy With &#x3b2;-Blockade or Verapamil. Circ. 2013;6(4):694-702. 57. Osman M, Kheiri B, Osman K, et al. Alcohol septal ablation vs myectomy for symptomatic hypertrophic obstructive cardiomyopathy: Systematic review and meta-analysis. Clinical Cardiology. 2019;42(1):190-197. 58. Sherrid MV, Shetty A, Winson G, et al. Treatment of obstructive hypertrophic cardiomyopathy symptoms and gradient resistant to first-line therapy with β-blockade or verapamil. Circ Heart Fail. 2013;6(4):694-702. 59. MyoKardia. Pioneering Precision Cardiovascular Medicine: MyoKardia PIONEER-HCM Data Summary March 2018. 2018. 60. Heitner SB, Lester S, Wang A, et al. Precision pharmacological treatment for obstructive hypertrophic cardiomyopathy with mavacamten: One-year results from pioneer-ole. Circulation. 2019;140. 61. MyoKardia. March 4, 2019 Investor Call - PIONEER-OLE 12- and 24- Week Results. 2019. 62. Sanders GD, Neumann PJ, Basu A, et al. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. Jama. 2016;316(10):1093-1103. 63. Jiang M, You JHS. Cost-effectiveness analysis of 30-month vs 12-month dual antiplatelet therapy with clopidogrel and aspirin after drug-eluting stents in patients with acute coronary syndrome. Clin Cardiol. 2017;40(10):789-796. 64. M Butzner PS, M Maron, E Rowin, CC Teng, E Stanek, H Tan, L Robertson. PCV35 Costs of Septal Reduction Therapy for Obstructive Hypertrophic Cardiomyopathy: A US Claims Analysis. Value in Health. 2021;24:S73. 65. Pickard AS, Law EH, Jiang R, et al. United States Valuation of EQ-5D-5L Health States Using an International Protocol. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2019;22(8):931-941. 66. Institute for Clinical and Economic Review. 2020-2023 Value Assessment Framework. https://icer-review.org/wp-content/uploads/2019/05/ICER_2020_2023_VAF_013120-4.pdf. Published 2020. Accessed. 67. Pearson SD. The ICER Value Framework: Integrating Cost Effectiveness and Affordability in the Assessment of Health Care Value. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018;21(3):258-265. ©Institute for Clinical and Economic Review, 2021 Page 53 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Report Supplement ©Institute for Clinical and Economic Review, 2021 Page 54 Final Evidence Report – Mavacamten for HCM Return to Table of Contents A. Background: Supplemental Information A1. Definitions The outcomes in the key trials include the following variables: • Kansas City Cardiomyopathy Questionnaire (KCCQ)28: This is a disease-specific patient- reported outcome specific for patients with heart failure. The instrument is based on a self- administered 23-item questionnaire that quantified patient-reported physical limitations, symptoms, self-efficacy, social interference, and quality of life. The original validation of the KCCQ demonstrated correlation between KCCQ scores and measures of physical limitation, clinician-measured estimate of functional status, another patient-reported measure of general health (the SF-36 scale), and clinical events such as death or hospitalization. The KCCQ ranges from 0-100, with higher scores indicating better health. The KCCQ overall summary score (KCCQ-OS) includes all health domains measured by KCCQ and the KCCQ clinical summary (KCCQ-CS) measures only physical limitations and total symptoms. The KCCQ-OS includes questions such as "How well do you understand what things you are able to do to keep your heart failure symptoms from getting worse?" that would be reflected in the KCCQ-OS but not the KCCQ-CS. • New York Heart Association (NYHA) Functional Classification43: The NYHA classification is a clinician-assessed measure of functional status broadly applicable to patients with cardiac disease, including angina from coronary artery disease but also exertional intolerance from heart failure. Class I refers to patients with cardiac disease but without limitations of physical activity. Class II refers to patients with cardiac disease resulting in slight limitation of physical activity. Class III refers to patients with cardiac disease resulting in marked limitation of physical activity. Class IV refers to patients with cardiac disease resulting in inability to exert physically at all and/or the presence of symptoms at rest. • Peak V0244: The maximal oxygen consumption of a patient estimated from peak work rate. This provides an objective, quantitative estimate of the functional capacity of a patient. Functional capacity can be limited by cardiac function but also other physiological processes including pulmonary function, the ability of the circulatory system to deliver oxygenated blood to muscle tissues, and other processes. • Left ventricular outflow tract (LVOT) gradient: The LVOT gradient is the pressure gradient in the LVOT, the conduit through which blood passes from the left ventricle of the heart to the aorta. Patients with obstructive HOCM have gradients that cause pressure drops in the LVOT, impairing the ability of the heart to provide blood to the rest of the body. ©Institute for Clinical and Economic Review, 2021 Page 55 Final Evidence Report – Mavacamten for HCM Return to Table of Contents A2. Potential Cost-Saving Measures in Symptomatic HOCM ICER includes in its reports information on wasteful or lower-value services in the same clinical area that could be reduced or eliminated to create headroom in health care budgets for higher-value innovative services (for more information, see https://icer.org/our-approach/methods- process/value-assessment-framework/). These services are ones that would not be directly affected by mavacamten (e.g., need for septal myectomy of ablation), as these services will be captured in the economic model. Rather, we are seeking services used in the current management of symptomatic HOCM beyond the potential offsets that arise from a new intervention. During stakeholder engagement and public comment periods, ICER encouraged all stakeholders to suggest services (including treatments and mechanisms of care) currently used for patients with symptomatic HOCM that could be reduced, eliminated, or made more efficient. No suggestions were received. ©Institute for Clinical and Economic Review, 2021 Page 56 Final Evidence Report – Mavacamten for HCM Return to Table of Contents B. Patient Perspectives: Supplemental Information B1. Methods ICER collaborated with the Hypertrophic Cardiomyopathy Association to conduct an online patient- input questionnaire to gather more insight on people living with and people who care for those living with HCM. Responders were recruited from social media and through a listserv of Hypertrophic Cardiomyopathy Association members. The survey results informed the scope of our review and helped focus our assessment on outcomes of most interest to patients and caregivers. Because this survey consisted of qualitative, open-ended questions, responses were categorized and frequency of each category were quantified, summed, and then put into graphical or table form. Respondents could have more than one category assigned to their response and the categories are not all mutually exclusive; thus, the number of responses varies by question. Select individual unedited quotes are reported below to more fully capture narrative experiences of those living with HCM that were not fully captured by our quantitative summary. All responses were anonymous. B2. Results ICER received a total of 641 responses on the survey, including 606 patients, six patient advocates, and 29 caregivers/family members. We limited our summary below to 541 responses from patients that included information relevant to our review. Experience with HCM Type of HCM While 14.3% and 12.5% of patients responded that the type of HCM that they live with is either obstructive and/or associated with a known, specific HCM gene variant, a large majority of patients (67.1%) did not know the subtype of HCM that they live with. Additionally, 2.4% of patients reported having HCM without obstruction. Since these categories were not mutually exclusive, patients could have reported they live with a known HCM gene variant and a specific HCM subtype (Table B1). ©Institute for Clinical and Economic Review, 2021 Page 57 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table B1. HCM Type HCM Type (N=538) n (%) I Don't Know 361 (67.1%) Obstructive 77 (14.3%) Genotype 67 (12.5%) Other 20 (3.7%) Non-Obstructive 13 (2.4%) n: number, N: total number HCM Treatment and Management A figure depicting patients' current management of HCM is below (Figure B1). Use of medications alone was reported by most patients (59%), followed by septal reduction therapy (20%), ICD (15%), and diet and exercise alone (4.3%). Figure B1. Management of HCM How do you currently manage your HCM (any treatments such as medications, diet, exercise, other)? (n=376) 250 223 200 150 100 76 57 50 16 3 1 0 Medications Septal ICD Diet and Other None Alone Reduction Exercise Therapy HCM: hypertrophic cardiomyopathy, ICD: implantable cardiac device, n: number • "I try with diet and physical activity. I couldn't stand beta blockers. My doctor advises me to have a myectomy, but I really don't want open heart surgery. I have a lot of shortness of breath on activity, even walking, and forget walking up hill." • "Twice daily Toprol XL (my body metabolizes it quickly for some reason and we found out the hard way that I get tachycardic if I take it only once daily) and an ICD for safety. I've experienced ventricular tachycardia and atrial fibrillation each a couple times (or just one several times, it was hard to tell) but never ventricular fibrillation, thankfully. My heart has behaved itself for almost 18 years. I have a lot of fatigue but no more cardiac events. I do what I can to keep stress to a minimum." ©Institute for Clinical and Economic Review, 2021 Page 58 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "I have two sons that have each had a myectomy in their early and late 30s, and one also has a mechanical mitral valve at 23. Each of us have defibrillator/pacemaker." • "Medications - fairly large doses of Norpace CR and metoprolol, as well as moderate exercises and lifestyle changes like not exercising after meals, eating small meals, avoiding being outside on hot days, and hydrating." Treatment Access Issues Barriers to acquiring treatment are demonstrated in Figure B2 below. Most patients (54%) reported no difficulties in getting treatment. The most cited barriers to treatment included: difficulty finding a specialist (18%), issues with insurance (12%), and travel (8%). Figure B2. Difficulty Getting Treatment Do you have any difficulty getting treatment (such as lack of specialists, insurance coverage, costs, travel)? (n=280) Difficulty finding specialist 49 Insurance 33 Travel 23 Cost 14 Other 9 None 152 0 20 40 60 80 100 120 140 160 n: number • "We live in Illinois and have to travel to Cleveland for treatment. During my surgery, we stayed 21 days in a hotel. The lack of specialists and high-volume hospitals for this is very limited. Even in Chicago, the 'specialist' there told me I would need to get evaluated for transplant. Global knowledge is very challenging for care. Travel requirements for receiving quality care are burdensome... We had to open a credit card just for travel expenses for Cleveland. HMO insurance is free and 100% coverage with my husband's employer, they would not allow coverage of Cleveland with multiple appeals. For us to switch to PPO, my husband pays $330 per paycheck, percent of all services, and a $10,000 out-of-pocket deductible. We are actually in process of selling our home and downsizing due to drowning in medical debt from surgeries, checkups, and travel expenses." ©Institute for Clinical and Economic Review, 2021 Page 59 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "The nearest center of excellence is more than six hours away. Travel is difficult during the months of October-May due to weather. The time off work that a trip requires is a situation as well. The money it costs for said travel is also a financial burden as I still have to pay for insurance, patient portion insurance doesn't cover as well as fuel, food, and a place to stay. It adds up quickly." • "I have two daughter who have HCM as well as myself. The cost of yearly screening and testing is a huge financial burden on our family as well as I'm sure other HCM families even after insurance." • "Yes, many cardiologists have not studied the disease as it is a sub-specialty. It is weird when the patient knows more than they. It worries me as I feel I always need to be alert to head off disaster. What if I appear unconscious in an ER or hospital? I don't generally feel safe away from Mayo Clinic." • "Yes. My insurance does not cover a center of excellence in HCM. As a result, I must stay informed about the latest evidence-based guidelines and advocate for myself. It's exhausting and time consuming." • "There are no cardiologists in my borough who understand HCM, so I was misdiagnosed for 54 years. Also, after my septal myectomy, there was no local cardiac rehab available to me and I could not go into a nursing facility because I wasn't old enough." • "There is a severe shortage of Norpace CR, and I can only order it month-to-month from a pharmacy in New York at a co-pay of $280 per month plus mailing expense. Large pharmaceutical chains like CVS and Walgreens no longer carry it. I am on Medicare, and only one drug plan covers it at all. I have tried a generic that must be taken four times a day, and cut back on my dosage to save money. Neither worked for me. I live with the fear that I will no longer be able to obtain a medication I have been using successfully for more than 15 years." ©Institute for Clinical and Economic Review, 2021 Page 60 Final Evidence Report – Mavacamten for HCM Return to Table of Contents HCM Symptoms Fatigue was the most reported symptom of HCM (30.6%), followed by exercise intolerance (21.9%), difficulty breathing (16.4%), and depression and anxiety (9.6%) (Figure B3). Figure B3. How HCM Affects Day-to-Day Life How does HCM affect your day-to-day life? (n=324) Fatigue 99 Exercise intolerance 71 Difficulty breathing 53 Depression and anxiety 31 Irregular heartbeat 14 Dizziness 4 Chest pain 3 Other 14 None 35 0 20 40 60 80 100 120 HCM: hypertrophic cardiomyopathy, n: number • "Arrhythmias, exhaustion, retaining fluid in legs makes exercise/stairs/walking distances challenging, short of breath impacts everything, difficulty sustaining active sex life, difficultly being the active parent I wish to be for my kids." • "My heart is continuing to get worse and I'm transitioning into congestive heart failure. For the first 10 to 15 years after my myectomy, I didn't feel that limited. The main issues were the defibrillator maintenance and battery replacements. But now I do have trouble breathing with a lot of exertion, so I am somewhat limited in recreational activities that I enjoyed like hiking. Also, I'm not supposed to shovel snow, so I have to hire somebody to do that. And I'm more restrictive in carrying heavy things than I used to be. As I have more restrictions, it's frustrating and humbling." • "It has a huge impact on my life, and it affects my job. I can't walk more than 10 minutes without stopping to catch my breath, I can't work out like I used to, I am gaining weight, I can only walk up one flight of stairs at a time, I am embarrassed to be around people who may see me struggling to breathe – it keeps me secluded in my home. And what is most depressing is seeing how I am getting worse and can't stop it." ©Institute for Clinical and Economic Review, 2021 Page 61 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "Breathlessness getting out of bed, washing my hair, etc. I work but have had to reduce to a sedentary job and decrease my hours. Can't do garden chores. Have to space out home duties (can't change all the sheets in the house in the same day)." • "Have to be careful when working out for heart rate to stay within the given beats per minute. Some symptoms are debilitating, and I have to always be on my toes. It continuously plays on my mind so keeping stress levels down is not easy." • "I become short of breath on exertion, especially going up stairs or uphill. I love to be active, but I lag behind my family and friends on walks and hikes. I use an electric bicycle, or I would not be able to bike ride with others." Treatment Effects Treatment Effectiveness When asked about how well their treatments work, about half of patients reported that their treatments work well (50%), a third thought their treatments work okay (33%), and 9% thought their treatments don't work. Table B2. Treatment Effectiveness Treatment Effectiveness (N=341) n (%) They Work Well 172 (50.4%) They Work Okay 114 (33.4%) They Don't Work 31 (9.1%) Other 24 (7.0%) n: number, N: total number • "Fairly well, but it is still worrisome knowing that something is wrong and feeling the symptoms of the HCM despite medically and lifestyle treatments." • "I felt great after the myectomy in 2002. Prior to that I was on so much medication that I was always struggling from the side effects, even though I did work full-time and had a pretty active life. Once I had the myectomy, I did well for about 15 years, at which point my ejection fraction started to dip. For the most part, I still feel like I live a pretty normal life without too many restrictions, but as more medications are added due to my heart weakening, I'm starting to deal with side effects again." • "I'm sure they are helping maintain my lower blood pressure but not so sure they are really helping my shortness of breath." ©Institute for Clinical and Economic Review, 2021 Page 62 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "The drug treatments have been effective in slowing the increase in gradient. And reducing the LVOT disruption. However, the side effects of the treatments are about the side as the physical effects of the disease." • "They keep my blood pressure under control, help prevent heart pain and keep my heart rate from being too fast. They work well, but are not a cure for the condition, they just help me manage with the condition." • "I am so much better than at my sickest, but very far from healthy. I don't know when I will have a bad day and no longer do a lot of the charitable work that I used to do out of fear that I will have heart issues and but someone at risk." • "They have definitely decreased my angina and my arrhythmias. But they also contribute to my tiredness and possibly to my fluid retention." Side Effects of Treatment The most reported side effect of treatment was fatigue (22.1%), followed by weight gain (6.8%), and depression and anxiety (3.3%). The majority of patients reported that they had no side effects (Figure B4). Figure B4. Treatment Side Effects Are you bothered by any side effects of your treatment(s)? (n=307) 140 133 120 100 80 68 69 60 40 21 20 10 6 0 Fatigue Weight gain Depression Constipation None Other and anxiety n: number • "When I tried metoprolol, it made me really tired, lethargic, depressed, and gain weight, even on a very small dose. So, I gave up on beta blockers." • "I'm 61 years old. I have little interest in the joys of life. I believe my meds are decreasing my interest in sex." ©Institute for Clinical and Economic Review, 2021 Page 63 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "Yes, I think beta blockers and calcium channel blockers being taken to slow down the blood pressure may be having some side effects as I notice some swelling in ankles and feet sometimes." • "Yes, prior to my myectomy, I felt like I was walking underwater. I was fatigued all the time, had digestive issues, memory problems. This had a lot to do with the high dosages I was on, 480 mg of Inderal, 800 mg of Norpace. After the myectomy, I wasn't on that much medication, and didn't really feel side effects. Now, being on IV medications, I am noticing them coming back, some issues with depression and anxiety, and some lowered sexual functioning." Downsides to Treatment Fatigue was the most reported downside to treatment for HCM (18.3%), followed by inability to perform unusual activities and inability to work (11.3% and 5.3%, respectively) (Figure B5). Most patients, however, reported "no" or "other downsides not listed" (12.7% and 48.2%, respectively). Figure B5. Treatment Downsides Are there any downsides to these treatment(s) that are important to you (such as your ability to work or go to school, more difficulty following your care plan, or inability to perform daily tasks)? (n=284) 150 137 100 52 50 32 36 15 12 0 Fatigue Unable to do Unable to Weight gain Other None usual activities work n: number • "Daily tasks that involve bending over (laundry, cleaning floors) are still difficult. Limits on types of exercise are frustrating, but there are work arounds. Difficulty traveling by air and long car rides limit business opportunities and visits to family." • "I have been on a do-not-work order for almost four years now due to my intolerance to medication and to help my heart not over working itself as my blood pressure drops when my heart rate rises, and I become very breathless and at times my hands and feet turn purple from lack of blood flow and swelling sucks." ©Institute for Clinical and Economic Review, 2021 Page 64 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "The downside is really that I feel so dependent on these medications for survival and to get through my daily activities. The side effects don't disrupt my routine, but managing the medications and the HCM is very stressful and takes its toll on me and my family." • "Being 100% dependent on a device is challenging. I always have to think about keeping magnets or other electronics away from the ICD." • "I think the medications cause fatigue and brain fog that prompted me to take an early retirement from work as I felt I was not capable of performing my work tasks to full capability/commitment." • "Yes, can't always perform daily tasks. Worry about driving. Always check to see if there is a shoulder I can pull off into. What if there is no shoulder? What if I have atrial fibrillation? I have become a lethal weapon. I try to make all appointments in the morning. I have cataract surgery coming up, but I worry. What if I go into atrial fibrillation? At home, I would drop to the floor. I may be flipping a hamburger one minute and on the floor the next." • "I was a single mom on beta blockers and had a hard time doing anything – my kids needed me to drive, make meals, etc. and sometimes I was just too tired." Impact of Treatment On Caregivers About a third (33%) of patients reported that treatments had no impact on caregivers, while 22% reported that treatments had a large impact and 10% reported that treatments had a small impact (Table B3). Table B3. Treatment Caregiver Impact Treatment Caregiver Impact (N=257) n (%) Large Impact 56 (21.8%) Small Impact 25 (9.7%) No Impact 84 (32.7%) Not Applicable 76 (29.6%) Other 16 (6.2%) n: number, N: total number • "As a patient, because medications lower your heart rate and thereby everything, on specific days you might become more quiet and not as functioning and this could add physical and mental burden to your caregiver. As a patient and depending on the dosage of your medications, you are not as active or capable to satisfy your partner physically or sexually or engage in activities that might bring joy to both of you and as a family." ©Institute for Clinical and Economic Review, 2021 Page 65 Final Evidence Report – Mavacamten for HCM Return to Table of Contents • "My condition itself has been enormously stressful to my family. My septal myectomy has improved their lives as I can function better now. I don't tell them how bad I am feeling." • "Financial impact on the family has been intense – we max out co-pays and deductibles EVERY year. We don't take vacations and we must go without things others take for granted. My husband and family members worry about my health causing stress and lots of trips to doctors, hospitals and 'rescue' calls when I am not feeling well, which disrupts normal life." • "No impact at this time to caregivers since the device was implanted in Minneapolis in 2012. I am independent and ambulatory. No caregiver needed." ©Institute for Clinical and Economic Review, 2021 Page 66 Final Evidence Report – Mavacamten for HCM Return to Table of Contents C. Clinical Guidelines Guidelines relevant to treatment of patients, including those with symptomatic HOCM have been published by a joint committee in the US as well as other non-US based organizations. Key elements focusing on the management of symptoms in HCM including HOCM from these guidelines are summarized below. The guidelines address many other topics relevant to HCM, including HOCM, including risk stratification for sudden cardiac death, genetic testing, and diagnostic imaging. American College of Cardiology and American Heart Association6 In 2020, the joint committee on clinical practice guidelines of the American College of Cardiology and the American Heart Association issued a report on diagnosis and treatment for all patients with HCM, including those with symptomatic HOCM. These guidelines emphasize the importance of shared decision making for testing and treatment options. They explicitly recommend (level 2a) consultation with or referral to comprehensive HCM centers for complex management decisions. When indicated, the guidelines recommend (class 1) that septal reduction procedures including surgical myectomy and septal ablation are performed at these specialized centers. With respect to pharmacological therapies for patients with HOCM and exertional limitations, such as shortness of breath, the guidelines recommend beta blockers as first-line therapy (class 1). For patients for whom beta blockers are ineffective or poorly tolerated, centrally-acting calcium channel blockers are recommended (class 1). For patients with persistent severe symptoms attributable to left ventricular outflow obstruction, either adding disopyramide or performing a septal reduction procedure is recommended (class 1). For patients with clinical fluid retention, cautious use of diuretics, avoiding dehydration can be considered (class 2b). Vasodilating blood pressure agents including angiotensin-converting enzyme inhibitors, dihydropyridine calcium channel blockers (such as amlodipine), and digoxin are reasonable to consider stopping, given that they can worsen left ventricular outflow tract obstruction (class 2b). Finally, in patients with severe shortness of breath at rest, very high left ventricular outflow tract gradients (>80-100 mm Hg), or low blood pressure, calcium channel blockers are contraindicated because of potential harm (class 3). For patients who remain severely symptomatic because of LVOT gradients despite medical therapy, guidelines support septal reduction therapy (class 1). Patients who are at acceptable surgical risk and/or who have other surgical heart disease (such as intrinsic structural mitral valvular dysfunction) should receive surgical myectomy (class 1). Conversely, patients who are at elevated surgical risk should receive alcohol septal ablation (class 1). It is also reasonable to consider surgical myectomy for patients with severe progressive pulmonary hypertension or mitral regurgitation, left atrial enlargement with atrial fibrillation, poor functional capacity due to LVOT obstruction, or ©Institute for Clinical and Economic Review, 2021 Page 67 Final Evidence Report – Mavacamten for HCM Return to Table of Contents young adults with very high resting LVOT gradients (>100 mm Hg) (class 2b). Any type of septal reduction, including alcohol septal ablation and surgical myectomy, is contraindicated for patients with HCM who are asymptomatic and have normal exercise capacity (class 3). European Society of Cardiology The European Society of Cardiology convened a task force for diagnosis and management of hypertrophic cardiomyopathy and most recently issued guidelines in 2014.45 For patients with symptomatic HOCM, guidelines recommend beta blockers first and then calcium channel blockers for those patients who are intolerant to beta blockers (class 1). Unlike American guidelines, which offer disopyramide or septal reduction therapies next as a choice, the European Society of Cardiology guidelines explicitly recommend disopyramide for patients with persistent symptoms (class 1). Verapamil is explicitly favored in European guidelines over diltiazem (class 2a). Unlike American guidelines, which recommend that disopyramide is used only with beta blockers or calcium channel blockers (due to the risk of enhanced atrioventricular nodal conduction if atrial fibrillation develops), the European guidelines allow the consideration of disopyramide as monotherapy (class 2b). For patients with clinical congestion judicious use of diuretics can be considered (class 2b). For patients with resting or provoked gradients of 50 mm Hg or greater and who have NYHA class III-IV symptoms despite maximum tolerated medical therapy, European guidelines recommend septal reduction therapies by highly experienced operators within expert multidisciplinary teams (class 1). While surgical myectomy is favored (class 1) when there is concurrent cardiac surgical disease, European guidelines emphasize uncertainty about the comparative effectiveness of septal ablation versus myectomy. For patients with HOCM, the guidelines recommend generally against the use of arterial and venous dilators (class 2a) and more strongly against digoxin (class 3) since these agents can worsen LVOT obstruction. The guidelines also emphasize that restoration of sinus rhythm or better rate control is recommended before considering invasive septal reduction therapies (class 2a). National Institute for Health and Care Excellence In 2004, the United Kingdom's National Institute for Health and Care Excellence cites "adequate" evidence to support the use of septal ablation for patients with symptomatic HOCM as an alternative to surgical myectomy.46 ©Institute for Clinical and Economic Review, 2021 Page 68 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Ludwig Boltzmann Institute for Health Technology Assessment In 2013, the Ludwig Boltzmann Institute for Health Technology Assessment in Austria issued a report recommending that septal ablation only be performed in highly-specialized centers and all patients with the procedure be enrolled in procedural registries.47 ©Institute for Clinical and Economic Review, 2021 Page 69 Final Evidence Report – Mavacamten for HCM Return to Table of Contents D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods PICOTS (Population, Intervention, Comparator, Outcomes, Timing, Setting) Population The population of focus for the review is adults with symptomatic HOCM. As data allowed, we planned to review any available data in children with symptomatic HOCM. We also separately reviewed available evidence for the intervention in patients with symptomatic HCM without obstruction. Interventions The intervention of interest is mavacamten in addition to usual care. Comparators Mavacamten was compared with usual care. This included comparisons with adding mavacamten to existing therapy as estimated by the placebo arms of clinical trials, but also comparisons with alternative therapies including medications typically used later than first line (e.g., disopyramide) and septal reduction procedures (surgical myectomy and septal ablation). Outcomes The outcomes of interest are described in the list below. • Patient-Important Outcomes o Symptoms of HOCM such as exertional intolerance, fatigue, shortness of breath, dizziness, arrhythmia, chest discomfort, mental acuity (with particular attentiveness to patient-reported outcomes) o Requirement for exercise restriction o Anxiety and depression o Overall mortality o Sudden cardiac death o Need for implantation of ICD o Heart failure o Rate of septal reduction therapy (septal ablation or myectomy) ©Institute for Clinical and Economic Review, 2021 Page 70 Final Evidence Report – Mavacamten for HCM Return to Table of Contents o Atrial fibrillation and stroke o Adverse events including:  Treatment-emergent adverse events and serious adverse events • Other Outcomes o Peak oxygen consumption (pVO2 exercise capacity) o Post-exercise LVOT gradient and resting LVOT gradient o Left ventricular ejection fraction o NYHA functional class o Cardiac biomarkers such as NT-proBNP and hs-cTnl Timing Evidence on intervention effectiveness and harms were derived from studies of any duration. Settings All relevant settings were considered, with a focus on outpatient settings in the US. ©Institute for Clinical and Economic Review, 2021 Page 71 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D1. PRISMA 2009 Checklist Checklist Items TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. ABSTRACT Provide a structured summary including, as applicable: background; objectives; data Structured sources; study eligibility criteria, participants, and interventions; study appraisal and 2 Summary synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. Provide an explicit statement of questions being addressed with reference to Objectives 4 participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Indicate if a review protocol exists, if and where it can be accessed (e.g., Web Protocol and 5 address), and, if available, provide registration information including registration Registration number. Specify study characteristics (e.g., PICOS, length of follow-up) and report Eligibility Criteria 6 characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Describe all information sources (e.g., databases with dates of coverage, contact Information 7 with study authors to identify additional studies) in the search and date last Sources searched. Present full electronic search strategy for at least one database, including any limits Search 8 used, such that it could be repeated. State the process for selecting studies (i.e., screening, eligibility, included in Study Selection 9 systematic review, and, if applicable, included in the meta-analysis). Describe method of data extraction from reports (e.g., piloted forms, independently, Data Collection 10 in duplicate) and any processes for obtaining and confirming data from Process investigators. List and define all variables for which data were sought (e.g., PICOS, funding sources) Data Items 11 and any assumptions and simplifications made. Describe methods used for assessing risk of bias of individual studies (including Risk of Bias in 12 specification of whether this was done at the study or outcome level), and how this Individual Studies information is to be used in any data synthesis. Summary 13 State the principal summary measures (e.g., risk ratio, difference in means). Measures Synthesis of Describe the methods of handling data and combining results of studies, if done, 14 Results including measures of consistency (e.g., I2) for each meta-analysis. Risk of Bias Across Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., 15 Studies publication bias, selective reporting within studies). Additional Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, 16 Analyses meta-regression), if done, indicating which were pre-specified. RESULTS Give numbers of studies screened, assessed for eligibility, and included in the Study Selection 17 review, with reasons for exclusions at each stage, ideally with a flow diagram. Study For each study, present characteristics for which data were extracted (e.g., study 18 Characteristics size, PICOS, follow-up period) and provide the citations. Risk of Bias Present data on risk of bias of each study and, if available, any outcome level 19 Within Studies assessment (see item 12). ©Institute for Clinical and Economic Review, 2021 Page 72 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Checklist Items For all outcomes considered (benefits or harms), present, for each study: (a) simple Results of 20 summary data for each intervention group (b) effect estimates and confidence Individual Studies intervals, ideally with a forest plot. Synthesis of Present results of each meta-analysis done, including confidence intervals and 21 Results measures of consistency. Risk of Bias Across 22 Present results of any assessment of risk of bias across studies (see Item 15). Studies Additional Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, 23 Analysis meta-regression [see Item 16]). DISCUSSION Summarize the main findings including the strength of evidence for each main Summary of 24 outcome; consider their relevance to key groups (e.g., health care providers, users, Evidence and policy makers). Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level Limitations 25 (e.g., incomplete retrieval of identified research, reporting bias). Provide a general interpretation of the results in the context of other evidence, and Conclusions 26 implications for future research. FUNDING Describe sources of funding for the systematic review and other support (e.g., Funding 27 supply of data); role of funders for the systematic review. From: Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097. Data Sources and Searches Procedures for the systematic literature review assessing the evidence on new therapies for symptomatic HOCM followed established best research methods. We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.48 The PRISMA guidelines include a checklist of 27 items, which are described further in Table D1. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for relevant studies. Each search was limited to English-language studies of human subjects and excluded articles indexed as guidelines, letters, editorials, narrative reviews, case reports, or news items. We included abstracts from conference proceedings identified from the systematic literature search. All search strategies were generated utilizing the Population, Intervention, Comparator, and Study Design elements described above. The proposed search strategies included a combination of indexing terms (MeSH terms in MEDLINE and EMTREE terms in EMBASE) as well as free-text terms. To supplement the database searches, we performed manual checks of the reference lists of included trials and systematic reviews and invited key stakeholders to share references germane to the scope of this project. We also supplemented our review of published studies with data from conference proceedings, regulatory documents, information submitted by manufacturers, and ©Institute for Clinical and Economic Review, 2021 Page 73 Final Evidence Report – Mavacamten for HCM Return to Table of Contents other grey literature when the evidence met ICER standards (for more information, see https://icer.org/policy-on-inclusion-of-grey-literature-in-evidence-reviews/). Where feasible and deemed necessary, we also accepted data submitted by manufacturers "in-confidence," in accordance with ICER's published guidelines on acceptance and use of such data (https://icer.org/guidelines-on-icers-acceptance-and-use-of-in-confidence-data-from- manufacturers-of-pharmaceuticals-devices-and-other-health-interventions/). Table D2. Search Strategy of Medline 1996 to Present with Daily Update and Cochrane Central Register of Controlled Trials 1 Exp Cardiomyopathy, Hypertrophic/ (((hypertroph* or obstruct*) adj3 (cardiomyopath* or subaortic stenosis or Asymmetric*)) or hcm or 2 hocm or ihss or Symptomatic obstructive hypertrophic cardiomyopathy).ti,ab. 3 1 OR 2 4 (Mavacamten).ti,ab 5 ('myk 461' OR myk461).ti,ab 6 ('sar 439152' OR sar439152).ti,ab 7 4 OR 5 OR 6 8 3 AND 7 (addresses or autobiography or bibliography or biography or comment or congresses or consensus development conference or duplicate publication or editorial or guideline or in vitro or interview or 9 lecture or legal cases or legislation or letter or news or newspaper article or patient education handout or periodical index or personal narratives or portraits or practice guideline or review or video audio media).pt 10 8 NOT 9 11 animals.mp. not (humans and animals).sh. 12 10 NOT 11 13 limit 12 to English language *Search last updated on August 30, 2021. ©Institute for Clinical and Economic Review, 2021 Page 74 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D3. Search Strategy of EMBASE SEARCH #1 'hypertrophic obstructive cardiomyopathy'/exp OR 'hypertrophic obstructive cardiomyopathy' cardiomyopathy OR 'hypertrophic obstructive' OR 'cardiomyopathy, obstructive' OR 'hypertrophic cardiomyopathy, obstructive' OR 'myocardiopathy, obstructive' OR 'obstructive cardiomyopathy' OR #2 'obstructive hypertrophic myocardiopathy' OR 'obstructive myocardiopathy' OR 'hypertrophic cardiomyopathy' OR (((hypertroph* OR obstruct*) NEAR/3 (cardiomyopath* OR 'subaortic stenosis' OR Asymmetric*)) OR hcm OR hocm OR ihss):ti,ab #3 #1 OR #2 #4 Mavacamten/exp OR mavacamten #5 ('myk 461' OR myk461 OR 'sar 439152' OR sar439152):ti,ab #6 #4 OR #5 #7 #3 AND #6 ('case report'/de OR 'human tissue'/de OR 'nonhuman'/de OR 'practice guideline'/de OR #8 'questionnaire'/de OR 'chapter'/it OR 'conference review'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'review'/it OR 'short survey'/it) #9 #7 NOT #8 #10 ('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp) NOT 'human'/exp #11 #9 NOT #10 #12 #11 AND [english]/lim *Search last updated on August 30, 2021. ©Institute for Clinical and Economic Review, 2021 Page 75 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure D1. PRISMA Flowchart Showing Results of Literature Search for Mavacamten 36 references identified 12 references identified through literature search through other sources 40 references after duplicate removal 40 references screened 18 citations excluded 12 citations excluded 21 references assessed for 9 duplicate or outdated eligibility in full text information 3 outcomes not of interest 10 total references 2 RCTs, 1 nonrandomized (2 for HOCM, 1 for non- obstructive HCM) ©Institute for Clinical and Economic Review, 2021 Page 76 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Study Selection We performed screening at both the abstract and full-text level. A single investigator screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. One investigator reviewed full papers and provided justification for exclusion of each excluded study. Data Extraction and Quality Assessment We used criteria published by the US Preventive Services Task Force (USPSTF) to assess the quality of randomized controlled trials and comparative cohort studies, using the categories "good," "fair," or "poor" (see Table F2).49 Guidance for quality ratings using these criteria is presented below, as is a description of any modifications we made to these ratings specific to the purposes of this review. Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study; reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention is paid to confounders in analysis. In addition, intention-to-treat analysis is used for randomized controlled trials. Fair: Studies were graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are addressed. Intention-to-treat analysis is done for randomized controlled trials. Poor: Studies were graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For randomized controlled trials, intention-to-treat analysis is lacking. Note that case series are not considered under this rating system – because of the lack of comparator, these are generally considered to be of poor quality. ©Institute for Clinical and Economic Review, 2021 Page 77 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Assessment of Level of Certainty in Evidence We used the ICER Evidence Rating Matrix to evaluate the level of certainty in the available evidence of a net health benefit among each of the interventions of focus.49,50 Assessment of Bias As part of our quality assessment, we evaluated the evidence base for the presence of potential publication bias. We performed an assessment of publication bias for mavacamten using the clinicaltrials.gov database of trials. We selected studies which would have met our inclusion criteria and for which no findings have been published and did not find any evidence of publication bias. Data Synthesis and Statistical Analyses Data on relevant outcomes were summarized in evidence tables and synthesized qualitatively in the body of the review. Due to insufficient evidence and lack of comparative data on disopyramide and septal reduction therapy, we did not perform any network meta-analyses comparing mavacamten with these comparators. Additionally, we did not perform any pairwise meta-analyses due to differences in study design, population characteristics, and outcomes between the mavacamten trials. We instead descriptively made these comparisons in the main report of the review and supplement. D2. Additional Clinical Evidence Evidence Base Mavacamten The main report focused primarily on outcomes of mavacamten in patients with symptomatic, obstructive HCM. In this section, we also describe outcomes in patients with symptomatic non- obstructive HCM. Symptomatic Obstructive HCM In addition to the pivotal Phase III EXPLORER trial and related long-term extension study (MAVA- LTE, which is described in the sections above), we also identified a Phase II trial of mavacamten for patients with HOCM, PIONEER-HCM52 and a Phase II trial of mavacamten for patients with non- obstructive HCM (MAVERICK-HCM).12 Selected baseline characteristics of EXPLORER are below in Table D4. ©Institute for Clinical and Economic Review, 2021 Page 78 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D4. Selected Baseline Characteristics of EXPLORER-HCM21 Mavacamten (n=123) Placebo (n=128) Age, Mean (SD) 58.5 (12.2) 58.5 (11.8) Female Gender, n (%)* 57 (46) 45 (35) Race, n (%): White 115 (93) 114 (89) Black or African American 1 (1) 5 (4) Native American or Alaskan Native 0 1 (1) Asian 4 (3) 2 (2) Unknown 3 (2) 6 (5) Medical History, n (%): HOCM Gene Variant, n/N 28/90 (31) 22/100 (22) Family History of HOCM 33 (27) 36 (28) Atrial Fibrillation* 12 (10) 23 (18) Septal Reduction Therapy 11 (9) 8 (6) ICD 27 (22) 29 (23) Background HOCM Therapy, n (%): Beta Blocker 94 (76) 95 (74) Calcium Channel Blocker 25 (20) 17 (13) Neither 4 (3) 16 (13) NYHA Class II, n (%) 88 (72) 95 (74) NYHA Class III, n (%) 35 (28) 33 (26) pVO2, Mean mL/kg Per Min (SD) 18.9 (4.9) 19.9 (4.9) NT-proBNP, Geometric Mean, ng/L (CV%)* 777 (136) 616 (108) Hs-CTnI, Geometric Mean, ng/L (CV %) 12.5 (208) 12.5 (373) Echocardiographic Parameters: LVEF Mean, % (SD) 74 (6) 74 (6) Maximum LV Wall Thickness, Mean mm (SD) 20 (4) 20 (3) LVOT Gradient, Rest, Mean mm Hg (SD) 52 (29) 51 (32) LVOT Gradient, Valsalva, mm Hg (SD) 72 (32) 74 (32) LVOT Gradient, Post-Exercise, mm Hg (SD) 86 (34) 84 (36) CV: coefficient of variation, HOCM: hypertrophic obstructive cardiomyopathy, Hs-CTnI: high-sensitivity cardiac troponin I, ICD: implantable cardiac device, kg: kilogram, L: liter, LF: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mm: millimeter, mm Hg: millimeter of mercury, n: number, N: total number, ng: nanogram, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pVO2: peak oxygen consumption, SD: standard deviation *Indicates a statistically significant difference between groups. PIONEER was a prospective, open-label multi-center study conducted at five sites in the US with two sequential cohorts totaling 21 patients (Table D12).52 Patients were eligible to participate if they were 18-70 years old, had HCM, with LV wall thickness ≥15 mm at time of initial diagnosis or ≥13 mm with a positive family history of HCM, LVEF ≥55%, resting LVOT gradient ≥30 mm Hg and post-exercise peak LVOT gradient ≥50 mm Hg, and NYHA class II or higher.53 In cohort A, patients were taken off concomitant beta-blockers, calcium-channel blockers, and disopyramide two weeks prior to treatment with a high dose of mavacamten (10 or 15 mg per day depending on body weight). In cohort B, patients were allowed to continue use of beta blockers ©Institute for Clinical and Economic Review, 2021 Page 79 Final Evidence Report – Mavacamten for HCM Return to Table of Contents and were started on a lower dose of mavacamten (2 mg per day, increasing to 5 mg per day at four weeks depending on resting LVOT gradient). Patients were followed for 12 weeks on treatment followed by a four-week washout period. The primary outcome was change in post-exercise LVOT gradient at 12 weeks compared to baseline. Secondary outcomes included post-exercise LVOT gradient less than 30 mm Hg, change in numerical rating dyspnea score, change in pVO2, change in Valsalva LVOT gradients, and resting LVEF. Exploratory outcomes included NYHA class, KCCQ-OS, and NT-proBNP. Participants in PIONEER-HCM had a mean age of 56 in cohort A and 58 in cohort B, were predominantly male (64% in cohort A and 50% in cohort B), and the majority were on beta-blockers prior to treatment with mavacamten (82% in cohort A and 90% in cohort B) (Table D5). Table D5. Selected Baseline Characteristics of PIONEER-HCM52 Cohort A (n=11) Cohort B (n=10) Age, Mean (range) 56 (22-70) 58 (26-67) Female Gender, n (%)* 4 (36) 5 (50) Background HOCM Therapy, n (%): Beta Blocker 9 (82) 9 (90) Calcium Channel Blocker 1 (9) 0 (0) Disopyramide 5 (45) 0 (0) NYHA Class II, % 64 50 NYHA Class III, % 36 50 Echocardiographic Parameters: Interventricular Septum Thickness (SD), Mean, cm 1.7 (0.2) 1.5 (0.2) Systolic Anterior Motion of Mitral Valve, n (%) 11 (100) 9 (90) Left Atrial Volume Index (SD), Mean, mL/m2 30 (10) 41 (20) Mitral Regurgitation Present, n (%) 11 (100) 10 (100) cm: centimeter, HOCM: hypertrophic obstructive cardiomyopathy, m: meter, mL: milliliter, n: number, NYHA: New York Heart Association, SD: standard deviation Symptomatic Non-Obstructive HCM MAVERICK-HCM was a Phase II multi-center, double-blind, randomized controlled trial of two doses of mavacamten compared to placebo in patients with symptomatic, non-obstructive HCM.12 Fifty- nine patients were randomized to three groups: 200 ng/mL mavacamten (n=19), 500 ng/mL mavacamten (n=21) or placebo (n=19). Patients were eligible to participate if they were adults with a diagnosis of symptomatic non-obstructive HCM, defined as being NYHA function class II/III, an elevated NT-proBNP, LVEF ≥55%, and left ventricular wall thickness ≥15 mm or ≥13 mm with family history of HCM. Participants were excluded if they had resting or Valsalva and/or exercise LVOT gradient >30mm Hg. Participants were allowed to continue use of beta blockers or calcium channel blockers during the study period. Primary outcomes were safety and tolerability. Exploratory outcomes included clinical response, defined as a composite measure of 1.5 mL/kg per min or greater increase in pVO2 and at least one NYHA class reduction or a 3.0 mL/kg per min or greater increase in pVO2 and no worsening in NYHA class, pVO2 change from baseline, and NYHA class.54 ©Institute for Clinical and Economic Review, 2021 Page 80 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Participants in MAVERICK-HCM had a mean age of 58 and 50 in the mavacamten 200 ng/mL arm and 500 ng/mL arms, respectively, and 54 in the placebo arm (Table D6). The majority (62-63%) were taking beta blockers at baseline and were in NYHA class II (68-86%). Mean resting LVEF at baseline was 66-69%. Table D6. Selected Baseline Characteristics of MAVERICK-HCM12 Group 1 Group 2 Placebo 200 ng/mL 500 ng/mL (n=19) Mavacamten (n=19) Mavacamten (n=21) Age, Mean (SD) 58 (14) 50 (15) 54 (18) Female Gender, n (%) 9 (47) 12 (57) 13 (68) Background HOCM Therapy, n (%): Beta Blocker 12 (63) 13 (62) 12 (63) Calcium Channel Blocker 5 (26) 5 (24) 3 (16) Neither 3 (16) 3 (14) 4 (21) NYHA Class II, % 79 86 68 NYHA Class III, % 21 14 32 Pathogenic or Likely Pathogenic HCM Gene Variant, n/N (%) 7/14 (50) 7/14 (50) 8/12 (67) Echocardiographic Parameters: LVEF, % (SD) 68 (5) 69 (6) 66 (8) Maximal LV Wall Thickness, mm 21 (3) 20 (5) 19 (4) Peak LVOT Gradient, mm Hg (SD) 8 (3) 9 (4) 8 (3) pVO2, Mean, mL/kg/min (SD) 20 (5) 21 (7) 18 (5) NT-proBNP, Geometric Mean, pg/mL 914 (770-1558) 889 (747-1575) 763 (606-1261) (Range) 0.02 (0.013- 0.024 (0-0.503) 0.023 (0.016-0.080) CTnl, Geometric Mean, ng/L (Range) 0.119) CTnI: cardiac troponin I, HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy, kg: kilogram, L: liter, LV: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm: millimeter, mm Hg: millimeter of mercury, n: number, ng: nanogram, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pg: picogram, pVO2: peak oxygen consumption, SD: standard deviation Disopyramide The main report discusses the primary source of data to inform our comparison of mavacamten to disopyramide, a multicenter retrospective study of observational data.26 Three additional studies were identified, all single center retrospective studies.54,55 One of these focused primarily on safety outcomes.33 Baseline characteristics of a multi-center retrospective study of disopyramide are provided in Table D7. ©Institute for Clinical and Economic Review, 2021 Page 81 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D7. Selected Baseline Characteristics in Retrospective Study of Disopyramide26 Disopyramide (n=118) Non-Disopyramide (n=373) Age at Initial Evaluation, Mean (SD) 47 (20) 43 (21) Female Gender (%) 49 47 Medical History, (%): Atrial Fibrillation at Initial Evaluation 20 18 Syncope or Pre-Syncope* 47 26 Dyspnea* 82 60 Septal Reduction Therapy 28 18 ICD 5 2 Background HOCM Therapy (%): Beta Blocker* 98 70 Calcium Channel Blocker 32 27 NYHA Class at Initial Evaluation, Mean (SD)* 2.3 (0.7) 1.9 (0.8) LV Outflow Gradient, Mean mm Hg (SD)* 74 (35) 62 (32) HOCM: hypertrophic obstructive cardiomyopathy, ICD: implantable cardiac device, LV: left ventricular, mm Hg: millimeter of mercury, n: number, NYHA: New York Heart Association, SD: standard deviation *Indicates a statistically significant difference between groups. Septal Reduction Therapies The main report discusses the primary source of data to inform our comparison of mavacamten to septal reduction therapies, a 2015 systematic literature review with meta-analysis of long-term outcomes of septal ablation and myectomy.27 Baseline characteristics of this systematic review are provided in Table D8. A more recent systematic review with meta-analysis reported on pooled short and long-term outcomes of septal reduction therapies, primarily all-cause mortality, cardiovascular mortality, reintervention, and complications,57 while another reported improvements other outcomes such as symptoms of HOCM (NYHA class) and LVOT gradient.31 Table D8. Pooled Baseline Characteristics of Septal Reduction Therapy Studies27 Septal Ablation Myectomy (n=2,791) (n=2,013) Age, Weighted Median (IQR)* 56 (54-58) 47 (40-47) Female Gender (%) 49.4 (45-49.4) 40.1 (37-49) Medical History, (%): Syncope or Pre-Syncope (%) 16 (15-26) 21 (21-29) ICD (%) 3 (3-5) 10 (10-10) NYHA Class, Weighted Median (IQR) 2.8 (2.8-3) 2.9 (2.7-3.1) LVOT Gradient, mm Hg, Weighted Median (IQR) 78 (78-104.4) 93 (67.3-103) ICD: implantable cardioverter defibrillator, IQR: interquartile range, LVOT: left ventricular outflow tract, LVWT: left ventricular wall thickness, mm: millimeter, mm Hg: millimeter of mercury, n: number, NYHA: New York Heart Association *Indicates a statistically significant difference between groups. ©Institute for Clinical and Economic Review, 2021 Page 82 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Effectiveness Mavacamten Symptomatic Obstructive HCM LVOT Gradients, LVEF, PV02, and NT-proBNP The main report summarizes primary and secondary outcomes in the pivotal Phase III randomized controlled trial of mavacamten (EXPLORER). In the Phase II trial (PIONEER), post-exercise, resting, and Valsalva LVOT gradients improved from baseline to week 12 in both cohort A and cohort B (Table D9). Resting LVEF declined 15% (-23 to -6) from baseline to week 12 in cohort A and 6% (-10 to -1) in cohort B. Mean pVO2 increased 4 mL/kg/min (1 to 6) from baseline to week 12 in cohort A and a mean of 2 mgL/kg/min (0.03 to 3) in cohort B. Median NT-proBNP levels decreased 425 pg/mL in cohort A and 81 pg/mL in cohort B (Table D9). Table D9. Selected Primary, Secondary and Exploratory Outcomes of PIONEER-HCM52 Cohort A (n=11) Cohort B (n=10) Post Exercise LVOT Gradient, Mean -90 (-138 to -41) (n=8) -25 (-47 to -3) (n=9) Change from Baseline, mm Hg (SD) Resting LVOT Gradient, Mean Change -48 (-72 to -23) (n=10) -49 (-83 to -14) from Baseline, mm Hg (SD) Valsalva LVOT Gradient, Mean change -85 (-114 to -56) (n=10) -47 (-82 to -12) from Baseline, mm Hg (SD) Resting LVEF, Mean Change from -15 (-23 to -6) (n=10) -6 (-10 to -1) Baseline, % (SD) pVO2, Mean Change from Baseline, 4 (1 to 6) (n=10) 2 (0.3 to 3) mL/kg/min (95% CI) NT-proBNP Level, Median Change from -425 (-748 to -68) (n=10) -81 (-637 to -16) (n=9) Baseline, pg/mL (IQR) kg: kilogram, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm Hg: millimeter of mercury, n: number, NT-proBNP: N-terminal pro B-type natriuretic peptide, pg: picogram, pVO2: peak oxygen consumption, SD: standard deviation NYHA Class The main report presents details on NYHA class outcomes in the pivotal Phase III randomized controlled trial of mavacamten (EXPLORER). In the Phase II trial (PIONEER), mean NYHA class declined -0.9 (-1.4 to -0.04) from baseline to week 12 in cohort A and -1.0 (-1.3 to -0.7) in cohort B.52 More detailed outcomes from both the EXPLORER and PIONEER trail are provided in Tables D19- D20. ©Institute for Clinical and Economic Review, 2021 Page 83 Final Evidence Report – Mavacamten for HCM Return to Table of Contents HRQoL The main report provides details on HRQoL outcomes in the pivotal Phase III randomized controlled trial of mavacamten (EXPLORER). In the Phase II trial (PIONEER), mean KCCQ overall summary score, a measure of overall health, improved 14 points (7 to 22) from baseline to 12 weeks in cohort A and 16 points (0.3 to 32) in cohort B.52 Details on HRQoL outcomes from EXPLORER and PIONEER are provided in Tables D24-D25. Symptomatic Non-Obstructive HCM LVEF, PV02, and Cardiac Biomarkers In the Phase II trial (MAVERICK), mean LVEF decreased 2% (-5 to 0.4) from baseline to week 16 in the lower-dose mavacamten group (200 ng/mL, Group 1, n=19) and 6% (-10 to -1) in the higher- dose mavacamten group (500 ng/mL, Group 2, n=21) and 2% (-5 to 0.2) in the placebo group (n=19) (Table D10). Mean pVO2 increased 0.4 mL/kg/min (-1.4 to 2) from baseline to week 16 in Group 1 and 0.1 mL/kg/min (-1.8 to 2) in Group 2 and 0.6 (-0.6 to 1.8) in the placebo group. Mean NT- proBNP decreased 47% from baseline to week 24 in Group 1, 58% in Group 2 and 0.7% in the placebo group (p=0.01 and 0.001, respectively). Mean cTnI decreased 23% from baseline to week 16 in Group 1, 41% in Group 2 and increased 4% in the placebo group (p=0.09 and 0.003, respectively) (Table D10).12 ©Institute for Clinical and Economic Review, 2021 Page 84 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D10. Change from Baseline in Selected Outcomes in the MAVERICK Trial12 Group 1 Group 2 Placebo 200ng/mL 500ng/mL (n=19) Mavacamten (n=19) Mavacamten (n=21) LVEF, Mean Change from Baseline (%) (95% -2 (-5 to 0.4) -6 (-10 to -1) -2 (-5 to 0.2) CI) pVO2, Mean Change from Baseline, 0.4 (-1 to 2) 0.1 (-2 to 2) 0.6 (-0.6 to 2) mL/kg/min (95% CI) NT-proBNP, Geometric Mean, Change from -47 -58 -0.7 Baseline pg/mL (%) cTnl, Geometric Mean, Change from -23 -41 4 Baseline ng/L (%) ≥1 NYHA Class Mean Change from Baseline 53 (29 to 76) 33 (15 to 57) 37 (16 to 62) (%) (95% CI) Mean NYHA Class Change from Baseline -0.6 (-1 to -0.2) -0.3 (-0.5 to -0.3) -0.4 (-0.8 to -0.1) (95% CI) KCCQ-OSS Mean Change from Baseline 0.4 (-5 to 5) 6 (1 to 11) 6 (-3 to 15) (95% CI) KCCQ-CSS Mean Change from Baseline 0.1 (-4 to 5) 6 (1 to 10) 4 (-4 to 13) (95% CI) CI: confidence interval, CTnI: cardiac troponin I, KCCQ-CS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, KCCQ-OS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, kg: kilogram, LVEF: left ventricular ejection fraction, mL: milliliter, n: number, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pVO2: peak oxygen consumption NYHA Class In the MAVERICK trial, the proportion of patients who improved at least one NYHA class from baseline to week 12 was 53% in Group 1 and 33% in Group 2 and 37% in the placebo group. Mean NYHA class decreased 0.6 points (-1 to -0.2) from baseline to week 16 in Group 1, 0.3 points (-0.5 to -0.3) in Group 2, and 0.4 points (-0.8 to -0.1) in the placebo group (p=0.4 and 0.5, respectively) (Table D10).12 HRQoL In the MAVERICK trial, KCCQ-OS, and clinical summary score (KCCQ-CS) mean change from baseline to week 12 are shown in Table D10. Mean KCCQ-OS increased 0.4 points in Group 1, 6 points in Group 2 and 6 points in the placebo group (p=0.5 and 0.5, respectively). Mean KCCQ-CS increased 0.1 points in Group 1, 6 points in Group 2, and 4 points in the placebo group (p=1 and 0.4, respectively).12 Disopyramide The main report discusses data from the primary source of outcomes data for disopyramide, a multi-site retrospective study.26 We also identified two additional single-site retrospective studies of disopyramide. In a single-site registry-based study of second-line treatments for HOCM, among ©Institute for Clinical and Economic Review, 2021 Page 85 Final Evidence Report – Mavacamten for HCM Return to Table of Contents 221 patients on disopyramide, mean resting gradient decreased from 63mm Hg (±45) at baseline to 25mm Hg (±32) at follow-up (p<0.0001). Of the 221 patients started on disopyramide, 80 (36%) underwent septal reduction over the 4.5-year study period. Among 141 patients on disopyramide who did not undergo septal reduction and remained on disopyramide, mean NYHA class decreased from 2.7 (±0.6) at initial evaluation to 1.9 (±0.5) at last evaluation (p<0.0001).58 In a more recent single-site retrospective study focused primarily on safety, 74 patients (44%) discontinued disopyramide due to side effects (11%) or lack of symptom improvement (33%) over a five-year period. Fifty-five patients underwent septal reduction therapy (eight septal ablation and 47 myectomy).33 Septal Reduction Therapies The main report discusses data from the primary source of outcomes data for septal reduction therapies, a 2015 systematic review with meta-analysis.27 Additional selected outcomes data from 2020 systematic review with meta-analysis was also discussed in the main report.31 Harms Mavacamten The main report provides details on harms in the pivotal Phase III randomized controlled trial of mavacamten (EXPLORER). In the Phase II trial (PIONEER), mavacamten was well tolerated; most adverse events were mild (80%) or moderate (19%). The most common adverse events related to mavacamten were a decrease in LVEF (n=3) and atrial fibrillation (n=5). One patient in cohort A experienced a serious adverse event (atrial fibrillation leading to hospitalization) and discontinued treatment.52 Details on adverse events from EXPLORER and PIONEER are provided in Tables D27-D28. Disopyramide The main report discusses adverse events from the primary sources of data for harms of disopyramide, a multi-center retrospective study as well as a single-site retrospective study focused on safety.29,35 Septal Reduction Therapies The main report discusses adverse events from the primary source of data for septal reduction therapies.27 ©Institute for Clinical and Economic Review, 2021 Page 86 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Subgroup Analyses and Heterogeneity The main report discusses available subgroup analyses in the setting of obstructive HCM. The data on mavacamten in the setting of symptomatic non-obstructive HCM is substantially weaker compared to in the setting of symptomatic obstructive HCM. Improvements in cardiac biomarkers such as NT-proBNP and cTnI with mavacamten in the MAVERICK trial in patients with non-obstructive HCM point to potential benefits of the drug, but improvements in patient- important outcomes such as NYHA class or HRQoL were not observed although the study was not adequately powered for these clinical endpoints.12 Uncertainties and Controversies The MAVERICK-HCM trial (discussed in Section D2) is a Phase II trial that enrolled 59 patients and assessed the effectiveness of mavacamten in non-obstructive HCM patients. Although the trial did not demonstrate a difference in an exploratory composite functional endpoint that includes symptoms, identical to the primary endpoint in EXPLORER-HCM, there were improvements in biomarkers including NT-proBNP and troponin. Non-obstructive symptomatic HCM patients have fewer alternatives for reducing symptoms, since there is not a conceptual basis to support therapies directed at reducing the LVOT gradient. As such, clinicians and patients may use mavacamten to reduce symptoms in non-obstructive HCM patients simply on the conceptual basis of reducing wall stress, even if this indication is not within the FDA label for mavacamten. Phase III trials that are statistically powered for clinical outcomes could assess the effectiveness of mavacamten for symptomatic HCM patients without obstruction. ©Institute for Clinical and Economic Review, 2021 Page 87 Final Evidence Report – Mavacamten for HCM Return to Table of Contents D3. Evidence Tables Table D11. Study Quality Table15,24 Clear Clear Non- Patient/ Selective Intention- Comparable Definition Definition Measurements Approach to USPSTF Trial Differential Investigator Outcome to-Treat Groups of of Valid Missing Data Rating Follow-Up Blinding Reporting Analysis Intervention Outcomes Population: Symptomatic Obstructive HCM NRI for primary composite Yes, with endpoint; exception week 26 EXPLORER- to gender, Yes Yes Yes Yes No Yes Yes timepoint used Good HCM AF rates, for NYHA if and mean week 30 NT-proBNP endpoint was missing Population: Symptomatic Non-Obstructive HCM MAVERICK- Yes Yes Yes Yes Yes No Yes Yes NR Good HCM AF: atrial fibrillation, HCM: hypertrophic cardiomyopathy, NR: not reported, NRI: non-responder imputation, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, USPSTF: United States Preventive Services Task Force ©Institute for Clinical and Economic Review, 2021 Page 88 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D12. Study Design: Mavacamten1,15,24,27,34,51,52,58-60 Study Design Trial (NCT) N Treatment Inclusion & Exclusion Criteria Key Outcomes & Location Symptomatic Obstructive HCM EXPLORER- Phase III N=251 Individualized Inclusion Criteria Percentage of HCM DB, PC, RCT, Patients doses of 2.5, • Age 18 and greater, body weight ≥45 kg Participants Achieving A MC ages 18+ 5, 10, or 15 • Has adequate acoustic windows to enable accurate TTEs Clinical Response: NCT03470545 with mg (n=123) • Diagnosed with HOCM consistent with current ACCF/AHA Primary: Location: symptomatic or placebo and European Society of Cardiology guidelines and has • 1.5 mL/kg per min or global HOCM (n=128) documented LVEF ≥55% and NYHA class II or III greater increase in administered • Has documented O2 saturation at rest ≥90% at screening pVO₂ and at least orally • Able to perform an upright CPET and has a respiratory one NYHA class exchange ratio (RER) ≥1.0 at screening per central reading reduction or a 3.0 30-week Exclusion Criteria mL/kg per min or treatment • Cardiac hypertrophy that mimics HOCM greater pVO₂ • History of syncope or sustained V-tach with exercise, increase without resuscitated sudden cardiac arrest or ICD discharge for NYHA class life-threatening ventricular arrhythmia within 6 months worsening • Has paroxysmal, intermittent AF or persistent or Secondary: permanent AF not on anticoagulation for at least 4 weeks • Change in post- and/or not controlled within 1 year exercise LVOT • Treatment with disopyramide or ranolazine gradient • Any dose adjustment of β-blockers, verapamil, or • Change in pVO₂ diltiazem treatment • Change in NYHA class • Has LVOT gradient with Valsalva maneuver <30 mm Hg • Change in KCCQ-CSS • Has been successfully treated with invasive septal • Change in HCMSQ- reduction (surgical myectomy or septal ablation) within 6 SoB months • ICD placement within 6 months • Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation • Prior treatment with cardiotoxic agents such as doxorubicin or similar ©Institute for Clinical and Economic Review, 2021 Page 89 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Study Design Trial (NCT) N Treatment Inclusion & Exclusion Criteria Key Outcomes & Location MAVA-LTE Phase III Patients Mavacamten Inclusion Criteria Primary: Long-term ages 18+ 5 mg/d, with • Patients who successfully complete either MyoKardia's Frequency and severity of NCT03723655 extension who dose MAVERICK-HCM or EXPLORER-HCM clinical trials TEAS and SAEs (252 trial completed adjustments • Has a body weight greater than 45 kg weeks) either (2.5, 5, 10, or • Has adequate acoustic windows to enable accurate TTEs Location: MAVERICK- 15 mg) at • Has documented LVEF ≥ 50% by echocardiography core global HCM or weeks 4, 8, laboratory read of screening TTE at rest EXPLORER- and 12 if • Has safety laboratory parameters (chemistry, hematology, HCM trials needed coagulation, and urinalysis) within normal limits Exclusion Criteria • Has any ECG abnormality that poses a risk to participant safety • Has a history of syncope or a history of sustained ventricular tachycardia with exercise between Parent Study EOS Visit and screening visit • Has a history of resuscitated sudden cardiac arrest or known history of appropriate ICD discharge for life- threatening ventricular arrhythmia between Parent Study EOS Visit and screening visit • Currently or planned treatment with disopyramide or ranolazine • Has any acute or serious comorbid condition (e.g., major infection or hematologic, renal, metabolic, GI, or endocrine dysfunction) that could interfere with study • History of clinically significant malignant disease that developed since enrollment in the Parent Study. • Has participated in a clinical trial with any investigational drug, except for MAVERICK-HCM or EXPLORER-HCM ©Institute for Clinical and Economic Review, 2021 Page 90 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Study Design Trial (NCT) N Treatment Inclusion & Exclusion Criteria Key Outcomes & Location PIONEER- Phase II N=21 Cohort A: Inclusion Criteria Primary: HCM open-label, Patients Mavacamten • Diagnosed with HCM, with LV wall thickness ≥15 mm at • Change in post- MC, pilot ages 18-70 10 to 20 time of initial diagnosis or ≥13 mm with a positive family exercise peak LVOT NCT02842242 study with mg/d, history of HCM gradient from symptomatic without • Age 18-70 baseline to Week 12 Heitner 2021 Location: U.S. HCM and background • BMI 18-37 kg/m2 Secondary: LVOT medications • Documented LVEF ≥55% at the screening visit as • Change in dyspnea obstruction determined by the investigator and the investigational symptom score from Cohort B: site's echocardiography laboratory baseline to week 12 Mavacamten • Resting LVOT gradient ≥30 mm Hg and post-exercise peak • Change in LVEF 2D 2 to 5 mg/d, LVOT gradient ≥50 mm Hg and 3D, global with β- NYHA functional class II or higher longitudinal strain, blockers Exclusion Criteria and LV fractional allowed • History of sustained V-tach or syncope with exercise shortening from • Active infection baseline to week 12 12-week • Persistent AF or AF at screening or history of paroxysmal • Change in post- treatment AF with resting rate document > 100 bpm within 1 year of exercise peak LVOT screening gradient from week • Has QTc Fridericia (QTcF) > 500 ms, or any other ECG 12 to week 16 abnormality considered by the investigator to pose a risk • Change in pVO₂ and to subject safety VE/VCO2 from • Aortic stenosis or fixed subaortic obstruction baseline to week 12 • History of LV systolic dysfunction (LVEF < 45%) at any time • Plasma PK profile of during their clinical course mavacamten (16 • History of obstructive coronary artery disease weeks) • Part A: Ongoing therapy with beta blockers, calcium • Proportion of channel blockers, or disopyramide subjects achieving an • Part B: Ongoing therapy with calcium channel blockers or LVOT gradient disopyramide response of post- exercise peak • Prior treatment with cardiotoxic agents such as gradient <30 mm Hg doxorubicin or similar, or current treatment with (12 weeks) antiarrhythmic drugs that have negative inotropic activity, e.g., flecainide or propafenone. ©Institute for Clinical and Economic Review, 2021 Page 91 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Study Design Trial (NCT) N Treatment Inclusion & Exclusion Criteria Key Outcomes & Location PIONEER-OLE Phase II, N=13 starting dose: Inclusion Criteria Frequency and severity of ongoing 3- Patients 5 mg/d; • Completed Study MYK-461-004 adverse events: NCT03496168 year ages 18+ titration at -Body weight > 45 kg • LVOT Gradient prospective, with Week 6 to an • Has safety laboratory parameters (chemistry and • E/e at Week 24 open-label, symptomatic individualized hematology) within normal limits • LA Volume Index multicenter HOCM dose (5, 10, Exclusion Criteria (LAVi) at Week 24 study previously or 15 mg) • Has QTcF >480 ms or any other ECG abnormality • NT-proBNP at Week enrolled in 24 • Since enrollment into Study MYK-461-004, has developed Location: US PIONEER- • Interventricular obstructive coronary artery disease or known moderate HCM Septal Thickness (IST) or severe aortic valve stenosis • Since enrollment into Study MYK-461-004, has developed at Week 24 any acute or serious comorbid condition (e.g., major • LVEF at Week 24 infection or hematologic, renal, metabolic, GI, or • NYHA Class endocrine dysfunction) Improvement • Has a positive serologic test at Screening for human immunodeficiency virus, hepatitis C virus, or hepatitis B virus • Since enrollment into Study MYK-461-004 has developed clinically significant malignant disease Symptomatic Non-Obstructive HCM MAVERICK- Phase 2 N=59 Group 1: Inclusion Criteria Primary: HCM DB, MC, PC, Patients Starting dose • Diagnosed with HCM (hypertrophied and non-dilated left • Safety and RCT ages 18+ mavacamten ventricle in absence of systemic or other known cause), tolerability at Week NCT03442764 with body 5 mg/d, with LV wall thickness ≥15 mm at Screening or ≥13 mm 16 (AEs, TEAEs, etc.) Location: US weight ≥45 adjusted at with a positive family history of HCM. kg with week 6 (2.5, • Age 18 and greater, body weight ≥45 kg Exploratory Endpoints at symptomatic 5, 10, or 15 • Documented LVEF ≥55% at Screening Week 16: non-OHCM mg) • LVOT gradient <30 mm Hg • Composite functional and according to • NYHA functional class II or III endpoint (1.5 mL/kg preserved 200 ng/mL • Elevated NT-proBNP at rest per min or greater LVEF target PK Exclusion Criteria increase in peak • History of syncope, sustained ventricular tachycardia with oxygen consumption Group 2: exercise, resuscitated sudden cardiac arrest or ICD (pVO₂) and at least Starting dose discharge one NYHA class ©Institute for Clinical and Economic Review, 2021 Page 92 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Study Design Trial (NCT) N Treatment Inclusion & Exclusion Criteria Key Outcomes & Location mavacamten • Has AF at Screening reduction or a 3.0 5 mg/d, • Treatment with disopyramide, a combination of beta mL/kg per min or adjusted at blockers and verapamil or combination of beta blockers greater pVO₂ week 6 (2.5, and diltiazem increase without 5, 10, of 15 • Has been treated with invasive septal reduction (surgical NYHA class mg) myectomy or septal ablation) within 6 months worsening) according to • Resting or post-exercise LVOT >30mm Hg unless treated • pVO₂ change from 500 ng/mL by septal reduction baseline target PK • Has QTc Fridericia (QTcF) >480 ms or any other ECG abnormality considered to pose a risk to participant safety Placebo • History of obstructive coronary artery disease or myocardial infarction within past 6 months • Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation 3D: three-dimensional, AF: atrial fibrillation, AE: adverse event, ACCF: American College of Cardiology Foundation, AHA: American Heart Association, CPET: cardiopulmonary exercise testing, d: day, DB: double-blind, ECG: electrocardiogram, EOS: end of study, HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy, ICD: implantable cardioverter-defibrillator, KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, kg: kilogram, LV: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, m: meter, MC: multi-center, mg: milligram, mL: milliliter, mm: millimeter, mm Hg: millimeter of mercury, ms: millisecond, n: number, NCT: National Clinical Trial number, NT-proBNP: N-terminal pro B- type natriuretic peptide, NYHA: New York Heart Association, O₂: oxygen, PC: placebo-controlled, PK: pharmacokinetic, pVO₂: peak oxygen consumption, RCT: randomized controlled trial, RER: respiratory exchange ratio, TTE: transthoracic echocardiogram, VE: ventilation, VCO₂: volume of exhaled carbon dioxide ©Institute for Clinical and Economic Review, 2021 Page 93 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D13. Study Design: Comparators29,30 Trial & Study Design & N Treatment Inclusion & Exclusion Criteria Key Outcomes Author Location Disopyramide Disopyramide with initial Inclusion Criteria Retrospective, • Need for non- dose of 200 or 250 • Patients with HCM consecutively multicenter, pharmacologic intervention N=491 mg/day and dose treated at one of the four HCM centers observational (e.g., septal reduction Sherrid et al. adjustments every 2 from 1990-1999 study therapy and pacing) 2005 Patients weeks if needed (n=118) • Outflow obstruction at rest (gradient • LVOT gradient at rest with HOCM ≥30 mm Hg) Location: US, • Mean NYHA functional class No disopyramide Exclusion Criteria Poland, UK • Mortality rates treatment (n=373) NR Septal Reduction Therapy (Septal Myectomy and Septal Ablation) Inclusion Criteria for Studies • Having at least 5 HOCM patients Short-term outcomes: Systematic N=4,804 undergoing septal ablation and/or literature • Mortality rates (24 studies) septal myectomy review of • Necessity of pacemaker • Mean follow-up at least 5 years studies looking Septal ablation implantation Patients Exclusion Criteria for Studies at septal (n=2,013; 11 cohorts) • AEs Liebregts et with HOCM • Other ablative media than ethanol ablation or Long-term outcomes al. 2015 undergoing • Enrollment of primarily patients who septal Septal myectomy • Mortality rates septal underwent rescue ablation or rescue myectomy in (n=2,791; 16 cohorts) • AEs ablation or myectomy after failed previous septal HCM patients • LVOT gradient reduction septal reduction therapy myectomy • NYHA class reduction Location: Varies • Enrollment of primarily patients who • Need for reintervention underwent combined procedures, have a high risk of sudden death, or children AE: adverse events, d: day, HOCM: hypertrophic obstructive cardiomyopathy, HCM: hypertrophic cardiomyopathy, LVOT: left ventricular outflow gradient, mg: milligram, mm Hg: millimeter of mercury, n: number, N: total number, NR: not reported, NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 94 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D14. Baseline Characteristics: Phase III Trials24,27 Trial EXPLORER-HCM MAVA-LTE (EXPLORER-HCM Cohort) Arms Mavacamten Placebo Mavacamten N 123 128 224 Age, Mean (SD) 58.5 (12.2) 58.5 (11.8) 60.3 (11.8) Men 66 (54) 83 (65) 135 (60.3) Sex, n (%) Women 57 (46) 45 (35) 89 (39.7) White 115 (93) 114 (89) NR Black or African American 1 (1) 5 (4) NR Race, n (%) Native American or Alaskan Native 0 1 (1) NR Asian 4 (3) 2 (2) NR Unknown 3 (2) 6 (5) NR USA 53 (43) 55 (43) NR Spain 17 (14) 16 (13) NR Region, n (%) Poland 16 (13) 16 (13) NR Other 37 (30) 41 (32) NR BMI, Mean kg/m² (SD) 29.7 (4.9) 29.2 (5.6) NR Heart Rate, Mean bpm (SD) 63 (10.1) 62 (10.6) NR Blood Pressure, Mean Systolic Blood Pressure 128 (16.2) 128 (14.6) NR mm Hg (SD) Diastolic Blood Pressure 75 (10.8) 76 (9.9) NR Class I NA NA 13 (5.8) NYHA Functional Class, n Class II 88 (72) 95 (74) 146 (65.2) (%) Class III 35 (28) 33 (26) 65 (29) 2 mg/d NA NA NR Mavacamten Dose 5 mg/d 123 (100) NA NR Assignment, n (%) 10 mg/d (≤60 kg), 15 mg/d if (60 kg) NA NA NR pVO₂, Mean mL/kg per Min (SD) 18.9 (4.9) 19.9 (4.9) NR HCM Genetic Testing Performed, n (%) 90 (73) 100 (78) NR Pathogenic or Likely Pathogenic HCM Gene Variant, n/N (%) 28/90 (31) 22/100 (22) NR Family History of HCM 33 (27) 36 (28) NR Atrial Fibrillation 12 (10) 23 (18) NR Septal Reduction Therapy 11 (9) 8 (6) NR Medical History, n (%) Hypertension 57 (46) 53 (41) NR Hyperlipidemia 27 (22) 39 (30) NR Coronary Artery Disease 12 (10) 6 (5) NR ©Institute for Clinical and Economic Review, 2021 Page 95 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial EXPLORER-HCM MAVA-LTE (EXPLORER-HCM Cohort) Arms Mavacamten Placebo Mavacamten N 123 128 224 Obesity 15 (12) 14 (11) NR Type 2 Diabetes 6 (5) 7 (6) NR Asthma 17 (14) 11 (9) NR Chronic Obstructive Pulmonary Disease 2 (2) 3 (2) NR B-blocker 94 (76) 95 (74) 169 (75.4) Background HCM Calcium Channel Blocker 25 (20) 17 (13) 37 (16.5) Therapy, n (%) Neither B-blocker nor Calcium Channel Blocker 4 (3) 16 (13) NR Disopyramide NA NA NR Median: 785* NT-proBNP, Geometric Mean, ng/L (CV%) 777 (136) 616 (108) IQR: 323 to 1586 High-Sensitivity Cardiac Troponin I, Geometric Mean, ng/L (CV%) 12.5 (208) 12.5 (373) NR KCCQ OSS, Mean (SD) NR NR NR NRS Dyspnea, Mean (SD) NR NR NR VE/VCO₂, Mean (SD) NR NR NR LVEF Mean, % (SD) 74 (6) 74 (6) 74 (5.9) Resting LVEF Mean, % (SD) NR NR NR Exercise LVEF Mean, % (SD) NR NR NR Maximum LV Wall Thickness, Mean mm (SD) 20 (4) 20 (3) NR LVOT Gradient, Rest, Mean mm Hg (SD) 52 (29) 51 (32) 48.1 (31.6) Echocardiographic LVOT Gradient, Valsalva, Mean mm Hg (SD) 72 (32) 74 (32) 69.5 (33.2)† Parameters LVOT Gradient, Post-Exercise, Mean mm Hg (SD) 86 (34) 84 (36) NR Interventricular Septum Thickness, Mean cm (SD) NR NR NR Systolic Anterior Motion of Mitral Valve, n (%) NR NR NR LAVI, Mean mL/m² (SD) 40 (12) 41 (14) 37.9 (12.5)‡ Mitral Regurgitation Present, n (%) NR NR NR Left Atrial Diameter, Mean mm (SD) 42 (5) 42 (6) NR bpm: beats per minute, cm: centimeter, d: day, HCM: hypertrophic cardiomyopathy, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, kg: kilogram, L: liter, LAVI: left atrial volume index, LV: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, m: meter, mg: milligram, mL: milliliter, mm: millimeter, mm Hg: millimeter of mercury, n: number, N: total number, NA: not applicable, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *N=223, †N=221, ‡N=216 ©Institute for Clinical and Economic Review, 2021 Page 96 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D15. Baseline Characteristics: Phase II Trials51,52,58-60 Trial PIONEER-HCM PIONEER-OLE Arms Cohort A Cohort B Cohort A Cohort B Mavacamten (Overall) N 11 10 5 8 13 Age, Mean (SD) 56, range: 22-70 58, range: 26-67 NR NR 57.8 Men 7 (64) 5 (50) NR NR 9 (69.2) Sex, n (%) Women 4 (36) 5 (50) NR NR 4 (31.8) White 11 (100) 9 (90) NR NR NR Black or African American 0 1 (10) NR NR NR Race, n (%) Native American or Alaskan Native 0 0 NR NR NR Asian 0 0 NR NR NR Unknown 0 0 NR NR NR USA 11 (100) 12 (100) NR NR NR Spain 0 0 NR NR NR Region, n (%) Poland 0 0 NR NR NR Other 0 0 NR NR NR BMI, Mean kg/m² (SD) 29.7 (4.1) 32.3 (5.4) NR NR NR Heart Rate, Mean bpm (SD) 76 (10) 62 (8) NR NR NR Blood Pressure, Mean Systolic Blood Pressure 136 (13) 132 (14) NR NR NR mm Hg (SD) Diastolic Blood Pressure 75 (8) 77 (15) NR NR NR Class I NA NA NR NR NR NYHA Functional Class, Class II 7 (64) 5 (50) NR NR NR n (%) Class III 4 (36) 5 (50) NR NR NR 2 mg/d NA 10 (100) NR NR NR Mavacamten Dose 5 mg/d NA NA NR NR NR Assignment, n (%) 10 mg/d (≤60 kg), 15 mg/d if (60 kg) 11 (100) NA NR NR NR pVO₂, Mean mL/kg per min (SD) 20.7 (7.4) 19.4 (4.6) NR NR NR HCM Genetic Testing Performed, N (%) NR NR NR NR NR Pathogenic or Likely Pathogenic HCM Gene Variant, n/N (%) 5/21 (23.8) NR NR NR Family History of HCM NR NR NR NR NR Atrial Fibrillation NR NR NR NR NR Septal Reduction Therapy NR NR NR NR NR Hypertension NR NR NR NR NR Hyperlipidemia NR NR NR NR NR Medical History, n (%) Coronary Artery Disease NR NR NR NR NR Obesity NR NR NR NR NR Type 2 Diabetes NR NR NR NR NR Asthma NR NR NR NR NR Chronic Obstructive Pulmonary Disease NR NR NR NR NR ©Institute for Clinical and Economic Review, 2021 Page 97 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial PIONEER-HCM PIONEER-OLE Arms Cohort A Cohort B Cohort A Cohort B Mavacamten (Overall) N 11 10 5 8 13 B-Blocker 9 (82) 9 (90) NR NR 12 (92.3) Calcium Channel Blocker 1 (9) 0 (0) NR NR NR Background HCM Neither B-blocker nor Calcium Channel Therapy, n (%) NR NR NR NR NR Blocker Disopyramide 5 (45) 0 (0) NR NR NR NT-proBNP, Geometric Mean, pg/mL (SD) 930 (647) 1834 (3209)* NR NR 1836 (2886) High-Sensitivity Cardiac Troponin I, Geometric Mean, ng/L (CV%) NR NR NR NR NR KCCQ OSS, Mean (SD) 65 (16) 61 (26) NR NR 74.1 (18.4) NRS Dyspnea, Mean (SD) 4.9 (1.6) 4.0 (2.6) NR NR NR VE/VCO₂, Mean (SD) 32.2 (5.4) 32.3 (4.4) NR NR NR LVEF Mean, % (SD) NR NR 69.4 (5.6†) 73.6 (3.8†) 72 (4.9) Resting LVEF Mean, % (SD) 70 (7) 75 (5) NR NR NR Exercise LVEF Mean, % (SD) 76 (8) 76 (8) NR NR NR Maximum LV Wall Thickness, Mean mm NR NR NR NR 11.7 (2.2)‡ (SD) LVOT Gradient, Rest, Mean mm Hg (SD) 60 (28) 86 (63) NR NR 67.3 (42.8) LVOT Gradient, Valsalva, Mean mm Hg 97 (32) 100 (65) 75.7 (30.7†)¶ 97 (29.7†) 89.9 (30.7) (SD) Echocardiographic LVOT Gradient, Post-Exercise, Mean mm Parameters 103 (50)* 86 (43)* NR NR 127.5 (33.4)# Hg (SD) Interventricular Septum Thickness, 1.7 (0.2) 1.5 (0.2) NR NR 16.7 (2.8) Mean cm (SD) Systolic Anterior Motion of Mitral Valve, 11 (100) 9 (90) NR NR NR n (%) LAVI, Mean mL/m² (SD) 30 (10) 41 (20) NR NR 40.9 (16.4) Mitral Regurgitation Present, n (%) 11 (100) 10 (100) NR NR NR Left Atrial Diameter, Mean mm (SD) NR NR NR NR NR bpm: beats per minute, cm: centimeter, d: day, HCM: hypertrophic cardiomyopathy, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, kg: kilogram, L: liter, LAVI: left atrial volume index, LV: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, m: meter, mg: milligram, mL: milliliter, mm: millimeter, mm Hg: millimeter of mercury, n: number, N: total number, NA: not applicable, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pg: picogram, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *N=9, †Digitized estimate, ‡LV posterior wall thickness, ¶N=4, #N=12 ©Institute for Clinical and Economic Review, 2021 Page 98 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D16. Baseline Characteristics: MAVERICK-HCM12 Trial MAVERICK-HCM Group 1 Mava Group 2 Mava Pooled Arms Placebo (~200 ng/mL) (~500 ng/mL) Mavacamten N 19 21 40 19 Age, Mean (SD) 58.3 (13.7) 50.0 (14.7) 54.0 (14.6) 53.8 (18.2) Men 10 (52.6) 9 (42.9) 19 (47.5) 6 (31.6) Sex, n (%) Women 9 (47.4) 12 (57.1) 21 (52.5) 13 (68.4) White 17 (89.5) 18 (85.7) 35 (87.5) 17 (89.5) Black or African American 1 (5.3) 1 (4.8) 2 (5.0) 0 Race, n (%) Native American or Alaskan Native NR NR NR NR Asian 1 (5.3) 0 1 (2.5) 0 Unknown 0 2 (9.5) 2 (5.0) 2 (10.5) USA 19 (100) 21 (100) 40 (100) 19 (100) Spain NR NR NR NR Region, n (%) Poland NR NR NR NR Other NR NR NR NR BMI, Mean kg/m² (SD) 28.8 (4.1) 29.8 (6.1) 29.3 (5.2) 31.0 (4.9) Heart Rate, Mean bpm (SD) NR NR NR NR Blood Pressure, Mean Systolic Blood Pressure NR NR NR NR mm Hg (SD) Diastolic Blood Pressure NR NR NR NR Class I NA NA NA NA NYHA Functional Class II 15 (78.9) 18 (85.7) 33 (82.5) 13 (68.4) Class, n (%) Class III 4 (21.1) 3 (14.3) 7 (17.5) 6 (31.6) 2 mg/d NA NA NA NA Mavacamten Dose 5 mg/d 19 (100) 21 (100) 40 (100) NA Assignment, n (%) 10 mg/d (≤60 kg), 15 mg/d if (60 kg) NA NA NA NA pVO₂, Mean mL/kg per Min (SD) 19.5 (5.2) 21 (6.6) 20.4 (6) 17.9 (5.1) HCM Genetic Testing Performed, n (%) 14 (73.7) 14 (66.7) 28 (70.0) 12 (63.2) Pathogenic or Likely Pathogenic HCM Gene Variant, n/N (%)* 7/14 (50.0) 7/14 (50.0) 14/28 (50.0) 8/12 (66.7) Family History of HCM NR NR NR NR Atrial Fibrillation NR NR NR NR Septal Reduction Therapy NR NR NR NR Medical History, n (%) Hypertension NR NR NR NR Hyperlipidemia NR NR NR NR Coronary Artery Disease NR NR NR NR Obesity NR NR NR NR ©Institute for Clinical and Economic Review, 2021 Page 99 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial MAVERICK-HCM Group 1 Mava Group 2 Mava Pooled Arms Placebo (~200 ng/mL) (~500 ng/mL) Mavacamten N 19 21 40 19 Type 2 Diabetes NR NR NR NR Asthma NR NR NR NR Chronic Obstructive Pulmonary Disease NR NR NR NR B-Blocker 12 (63.2) 13 (61.9) 25 (62.5) 12 (63.2) Background HCM Calcium Channel Blocker 5 (26.3) 5 (23.8) 10 (25) 3 (15.8) Therapy, n (%) Neither B-Blocker nor Calcium Channel Blocker 3 (15.8) 3 (14.3) 6 (15) 4 (21.1) Disopyramide NR NR NR NR NT-proBNP, Geometric Mean, pg/mL (95% CI) 889 (747 to 1,575) 763 (606 to 1,261) 821 (790 to 1,293) 914 (770 to 1,558) High-Sensitivity Cardiac Troponin I, Geometric Mean, ng/mL (95% CI) 0.023 (0.016 to 0.02 (0.013 to 0.024 (0 to 0.503) 0.023 (0 to 0.253) 0.08) 0.119) KCCQ OSS, Mean (SD) NR NR NR NR NRS Dyspnea, Mean (SD) NR NR NR NR VE/VCO₂, Mean (SD) NR NR NR NR LVEF Mean, % (SD) 68 (5.2) 69.4 (5.8) 68.7 (5.5) 66.4 (7.7) Resting LVEF Mean, % (SD) NR NR NR NR Exercise LVEF Mean, % (SD) NR NR NR NR Maximum LV Wall Thickness, Mean mm (SD) 20.9 (3) 20.4 (4.8) 20.6 (4) 18.8 (3.5) LVOT Gradient, Rest, Mean mm Hg (SD) 8.1 (3.3) 9.4 (3.6) 8.8 (3.5) 7.8 (2.5) LVOT Gradient, Valsalva, Mean mm Hg (SD) NR NR NR NR Echocardiographic LVOT Gradient, Post-Exercise, Mean mm Hg NR NR NR NR Parameters (SD) Interventricular Septum Thickness, Mean cm NR NR NR NR (SD) Systolic Anterior Motion of Mitral Valve, n (%) NR NR NR NR LAVI, Mean mL/m² (SD) 40.3 (16.1) 34.5 (8.9) 37.3 (13) 40.8 (15.2) Mitral Regurgitation Present, n (%) NR NR NR NR Left Atrial Diameter, Mean mm (SD) NR NR NR NR bpm: beats per minute, cm: centimeter, d: day, CI: confidence interval, HCM: hypertrophic cardiomyopathy, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, kg: kilogram, LAVI: left atrial volume index, LV: left ventricular, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, m: meter, mg: milligram, mL: milliliter, mm: millimeter, mm Hg: millimeter of mercury, n: number, N: total number, NA: not applicable, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *Gene mutation of 40 with genetic testing. ©Institute for Clinical and Economic Review, 2021 Page 100 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D17. Baseline Characteristics: Disopyramide26 Trial Sherrid et al. 2005 Disopyramide without Disopyramide with Arms Disopyramide Non-Disopyramide Intervention Intervention N 118 78 40 373 Age at Initial Evaluation, Mean Years (SD) 47 (20) 48 (20) 44 (20) 43 (21) Duration of Follow-Up, Mean Years (SD) 4.2 (2.9) NR NR 6.5 (5.2) Male 60 (51) NR NR 198 (53) Gender, n (%) Female 58 (49) 34 (44) 22 (55) 175 (47) NYHA Functional Class, Mean (SD) 2.3 (0.7) 2.3 (0.7) 2.3 (0.7) 1.9 (0.8) Class I 14 (12) 9 (11.5) NR NR NYHA Functional Class Class II 59 (50) 40 (51.3) NR NR Distribution, n (%) Class III or Class IV 45 (38) 29 (37.2) NR NR Disopyramide Dose, Mean mg/day (SD) 432 (181) 425 (169) 445 (201) NA Syncope or Pre-Syncope 55 (47) NR NR 97 (26) Dyspnea 97 (82) NR NR 224 (60) NSVT 21 (18) NR NR 63 (17) Family History of SCD 18 (15) NR NR 56 (15) AF at Initial Evaluation 24 (20) NR NR 67 (18) Medical History, n (%) Septal Myectomy 22 (19) NR NR 34 (9) Septal Ablation 11 (9) NR NR 34 (9) DDD Pacemaker 13 (11) NR NR 52 (14) MV Surgery NR NR NR NR All Interventions Combined 40 (34) NR NR 104 (28) ICD 6 (5) NR NR 7 (2) LVOT Gradient, Mean mm Hg (SD) 74 (35) 75 (33) 73 (35) 62 (32) MAX LV Wall Thickness, Mean mm (SD) 21.9 (5.5) 21.1 (5) 23.1 (6) 23.7 (6.4) Coronary Stenosis >70%, n (%) 8 (7) NR NR 7 (2) Beta Blocker 116 (98) NR NR 261 (70) Background Therapy, n Calcium Channel Blocker 38 (32) NR NR 101 (27) (%) Amiodarone 12 (10) NR NR 112 (30) AF: atrial fibrillation, DDD: dual chamber, ICD: implantable cardioverter-defibrillator, mg: milligram, mm Hg: millimeter of mercury, MV: mitral valve, n: number, N: total number, NA: not applicable, NR: not reported, NSVT: non-sustained ventricular tachycardia, NYHA: New York Heart Association, SCD: sudden cardiac death, SD: standard deviation ©Institute for Clinical and Economic Review, 2021 Page 101 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D18. Baseline Characteristics: Septal Reduction Therapy27 Trial Liebregts et al. 2015 Arms Septal Ablation Surgical Myectomy N 2,013 2,791 Age at Initial Evaluation, Weighted Median Years (IQR) 56 (54 to 58) 47 (40 to 47) Duration of Follow-Up, Mean Years (SD) 6.2 7.4 Male NR NR Gender, Weighted Median % (IQR) Female 49.4 (45 to 49.4) 40.1 (37 to 49) NYHA Functional Class, Weighted Median (IQR) 2.8 (2.8 to 3) 2.9 (2.7 to 3.1) Class I NR NR NYHA Functional Class Distribution, n (%) Class II NR NR Class III or Class IV NR NR Disopyramide Dose, Mean mg/day (SD) NA NA Syncope or Pre-Syncope 16 (15 to 26) 21 (21 to 29) Dyspnea NR NR NSVT NR NR Family History of SCD NR NR AF at Initial Evaluation NR NR Medical History, Weighted Median % (IQR) Septal Myectomy NR NR Septal Ablation 2.5 (2 to 2.6)* NA DDD Pacemaker NR NR MV Surgery NA 7.1 (0.0 to 26) All Interventions Combined NR NR ICD 3 (3 to 5) 10 (10 to 10) LVOT Gradient, Weighted Median mm Hg (IQR) 78 (78 to 104.4) 93 (67.3 to 103) MAX LV Wall Thickness, Weighted Median mm (IQR) 21 (20.3 to 21) 22.1 (21.9 to 23.5) Coronary Stenosis >70%, n (%) NR NR Beta Blocker NR NR Background Therapy, n (%) Calcium Channel Blocker NR NR Amiodarone NR NR AF: atrial fibrillation, DDD: dual chamber, ICD: implantable cardioverter-defibrillator, mg: milligram, mm Hg: millimeter of mercury, MV: mitral valve, n: number, N: total number, NA: not applicable, NR: not reported, NSVT: non-sustained ventricular tachycardia, NYHA: New York Heart Association, SCD: sudden cardiac death, SD: standard deviation *Alcohol, ml. ©Institute for Clinical and Economic Review, 2021 Page 102 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D19. Efficacy Outcomes: Phase III Trials24,27 Trial EXPLORER-HCM MAVA-LTE Arms Mavacamten Placebo Mavacamten Placebo EXPLORER-HCM Cohort N 123 128 123 128 224 12 24 36 48 60 Timepoint 14 Weeks 30 Weeks Weeks Weeks Weeks Weeks Weeks Either ≥1.5 mL/kg per Min Increase in pVO₂ and NYHA Class Improvement NR NR 45 (37) 22 (17) NR NR NR NR NR ≥1 OR ≥3 mL/kg per Min Increase in pVO₂ and No Worsening in NYHA Class ≥1.5 mL/kg per Min Composite Increase in pVO₂ and Measure NR NR 41 (33) 18 (14) NR NR NR NR NR NYHA Class Improvement Response ≥1 n (%) ≥3 mL/kg per Min Increase in pVO₂ and No Worsening NR NR 29 (24) 14 (11) NR NR NR NR NR in NYHA Class Both ≥3 mL/kg per Min Increase in pVO₂ and NR NR 25 (20) 10 (8) NR NR NR NR NR NYHA Class Improvement ≥1 NYHA Class I & All LVOT Peak Gradients <30 mm 1/126 NR NR 32/117 (27) NR NR NR NR NR Hg, n/N (%) (1) Post-Exercise LVOT Peak Gradient <50 mm Hg, 22/106 NR NR 75/101 (74) NR NR NR NR NR n/N (%) (21) Post-Exercise LVOT Peak Gradient <30 mm Hg, 8/114 NR NR 64/113 (57) NR NR NR NR NR n/N (%) (7) Post-Exercise LVOT Gradient Change from -10 NR NR -47 (40)* NR NR NR NR NR Baseline, Mean (SD) (30)† Resting LVOT Gradient Change from Baseline, - -24.1 NR NR -37.6 -5.2 -30.5# -33.5ˠ -37.7## Mean mm Hg (SD) 37.9†† (30.6)ˠˠ Valsalva LVOT Gradient Change from Baseline, - -42.6 NR NR -47.6 -11.2 -36.4# -42.7ˠ -47.7## Mean mm Hg (SD) 51.6†† (38.1)ˠˠ ©Institute for Clinical and Economic Review, 2021 Page 103 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial EXPLORER-HCM MAVA-LTE Arms Mavacamten Placebo Mavacamten Placebo EXPLORER-HCM Cohort N 123 128 123 128 224 12 24 36 48 60 Timepoint 14 Weeks 30 Weeks Weeks Weeks Weeks Weeks Weeks -7.6 Resting LVEF Change from Baseline, % (95% CI) NR NR -3.9 -0.01 -3.9§ -6.2** -7.1‡‡ -7.9§§ (6.9)*** pVO₂ Change from Baseline, Mean mL/kg per -0.1 NR NR 1.4 (3.1)‡ NR NR NR NR NR Min (SD) (3.0)¶ 35 NYHA Class Improvement ≥1, n (%) NR NR 80 (65) 40 (31) NR NR NR NR (71)## NYHA Class Mean Change from Baseline (95% NR NR NR NR NR NR NR NR NR CI) 21 27 72 29 Class I 39 (31.7) 61 (49.6) NR NR NR (16.4) (21.1) (45.3)§ (59.2)## NYHA Functional 82 74 74 16 Class Distribution, Class II 68 (55.3) 52 (42.3) NR NR NR (64.1) (57.8) (46.5)§ (32.7)## n (%) 19 25 13 4 Class III 4 (3.3) 8 (6.5) NR NR NR (14.8) (19.5) (8.2)§ (8.2)## -2.6 (-3.6 to VE/VCO₂ Mean Change from Baseline (95% CI) NR NR NR NR NR NR NR NR -1.5) NRS Dyspnea Score Mean Change from Baseline NR NR NR NR NR NR NR NR NR (95% CI) -356 (- NT-proBNP Level Change from Baseline, Median - NR NR -614.3 30.2 -600# -605** -655## 1073 to (IQR), pg/mL (95% CI) 632¶¶ -148)ˠˠ Hs-CTnI Change from Baseline, Geometric NR NR -5.1 0.1 NR NR NR NR NR Mean, ng/L CI: confidence interval, IQR: interquartile range, kg: kilogram, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm Hg: millimeter of mercury, n: number, N: total number, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pg: picogram, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *N=117, †N=122, ‡N=120, ¶N=125, #N=162, §N=159, ˠN=110, **N=108, ††N=97, ‡‡N=93, ¶¶N=94, ##N=49, §§N=47, ˠˠN=23, ***N=22 ©Institute for Clinical and Economic Review, 2021 Page 104 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D20. Efficacy Outcomes: Phase II Trials51,59,60 Trial PIONEER-HCM PIONEER-OLE Cohort Cohort Cohort Arms Cohort A Cohort A Cohort B Mavacamten (Overall) B A B N 11* 10 11* 10 5 8 13 12 24 12 24 12 24 36 48 Timepoint 12 Weeks 16 Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Either ≥1.5 mL/kg per Min Increase in pVO₂ and NYHA Class Improvement ≥1 NR NR NR NR NR NR NR NR NR NR NR NR OR ≥3 mL/kg per Min Increase in pVO₂ and No Worsening in NYHA Class ≥1.5 mL/kg per Composite Min Increase in measure pVO₂ and NYHA NR NR NR NR NR NR NR NR NR NR NR NR response Class n (%) Improvement ≥1 ≥3 mL/kg per Min Increase in pVO₂ and No NR NR NR NR NR NR NR NR NR NR NR NR Worsening in NYHA Class Both ≥3 mL/kg per Min Increase in pVO₂ and NR NR NR NR NR NR NR NR NR NR NR NR NYHA Class Improvement ≥1 NYHA Class I & All LVOT Peak NR NR NR NR NR NR NR NR NR NR NR NR Gradients <30 mm Hg, n/N (%) Post-Exercise LVOT Peak NR NR NR NR NR NR NR NR NR NR NR NR Gradient <50 mm Hg, n/N (%) ©Institute for Clinical and Economic Review, 2021 Page 105 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial PIONEER-HCM PIONEER-OLE Cohort Cohort Cohort Arms Cohort A Cohort A Cohort B Mavacamten (Overall) B A B N 11* 10 11* 10 5 8 13 12 24 12 24 12 24 36 48 Timepoint 12 Weeks 16 Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Post-Exercise LVOT Peak 8/11 (72.7) 0 NR NR NR NR NR NR NR NR NR NR Gradient <30 mm Hg, n/N (%) -25 -45.1 -3.5 Post-Exercise LVOT Gradient -89.5 (-47.1 (-91.2 (-27.5 Change from Baseline, Mean (-138.3 to NR NR NR NR NR NR NR NR to to to (95% CI) -40.7)† -3.0)‡ 1.0)† 20.5)‡ -48.5 -9.1 Resting LVOT Gradient Change -47.8 29.5 -55.7 -54.4 -73.6 (-82.8 (-30.0 from Baseline, Mean mm Hg (-72.2 to (-63.1 NR NR NR NR NR (SD: (SD: (SD: to to (95% CI) -23.4) to 4.2) 42.3) 59.2) 45.5) -14.1) 11.7) -47.1 -60.6 -9.5 Valsalva LVOT Gradient Change -84.7 -68.3§ -52.1 -73.6 (-82.1 (-91.8 (-38.5 from Baseline, Mean mm Hg (-113.8 to -47.8 -53¶ -77.8 -76.9# -67.4 (SD: (SD: (SD: to to to (95% CI) -55.7) 28.9) 41) 45.1) -12.1) -29.4) 19.6) -5.5 -6.2 -14.6 -2.8 -2.5 -3.6 -2.6 Resting LVEF Change from (-9.8 (-12.2 (-23.1 to (-7.5 -4.4 -4.8¶ -4.5 -3.1# -4.5 (SD: (SD: (SD: Baseline, % (95% CI) to to -6.2) to 2.0) 3.7) 3.7) 7.2) -1.2) -0.2) 1.7 pVO₂ Change from Baseline, 3.5 (1.2 to (0.03 NR NR NR NR NR NR NR NR NR NR Mean mL/kg per Min (95% CI) 5.9) to 3.3) NYHA Class Improvement ≥1, n 10 NR NR NR NR NR NR NR NR NR NR NR (%) (76.9) -1.0 -0.4 -0.9 -0.4 NYHA Class Mean Change from (-1.3 (-0.8 (-1.4 to (-1.0 NR NR NR NR NR NR NR NR Baseline (95% CI) to to -0.4) to 0.2) -0.7) -0.03) 3 NYHA Class I 7 (70) 6 (60) 4 (44)‡ 1 (10) NR NR NR NR NR 7 (70)ˠ NR (50)# Functional 3 Class Class II 2 (20) 3 (30) 3 (33)‡ 7 (70) NR NR NR NR NR 3 (30)ˠ NR (50)# ©Institute for Clinical and Economic Review, 2021 Page 106 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Trial PIONEER-HCM PIONEER-OLE Cohort Cohort Cohort Arms Cohort A Cohort A Cohort B Mavacamten (Overall) B A B N 11* 10 11* 10 5 8 13 12 24 12 24 12 24 36 48 Timepoint 12 Weeks 16 Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Weeks Distribution Class III 1 (10) 1 (10) 2 (22)‡ 2 (20) NR NR NR NR NR 0 (0)ˠ NR 0 (0)# n (%) -2.5 -2.2 VE/VCO₂ Mean Change from (-4.3 (-6.1 to NR NR NR NR NR NR NR NR NR NR Baseline (95% CI) to 1.7) -0.7) -3.0 -3.1 -2.2 -0.8 NRS Dyspnea Score Mean (-5.0 (-4.1 to (-4.6 (-2.3 NR NR NR NR NR NR NR NR Change from Baseline (95% CI) to -2.1) to 0.2) to 0.7) -1.0) -81 NT-proBNP Level Change from -629.5 -1658 -1689 -2243 -3638 -425 (-748 (-637 240 (4 Baseline, Median (IQR), pg/mL (-804 NR NR NR NR (SD: (SD: (SD: (SD: to -68) to to 311) (95% CI) to 158) -2695) 2816) 3282) 3947) -16)‡ Hs-cTnI Change from Baseline, NR NR NR NR NR NR NR NR NR NR NR NR Geometric Mean, ng/L CI: confidence interval, IQR: interquartile range, kg: kilogram, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm Hg: millimeter of mercury, n: number, N: total number, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pg: picogram, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *N=10 for all reported outcomes unless otherwise stated, †N=8, ‡N=9, ¶N=4, #N=6, §N=12, ˠN=10 ©Institute for Clinical and Economic Review, 2021 Page 107 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D21. Efficacy Outcomes: MAVERICK-HCM12 Trial MAVERICK-HCM Group 1 Mava Group 2 Mava Pooled Arms Placebo (~200 ng/mL) (~500 ng/mL) Mavacamten N 19 21 40 19 Timepoint 16 Weeks Either ≥1.5 mL/kg per Min Increase in pVO₂ 3 (15.8) 6 (28.6) 9 (22.5) 4 (21.1) and NYHA Class Improvement ≥1 OR ≥3 mL/kg (95% CI: 3.4 to (95% CI: 11.3 to (95% CI: 10.8 to (95% CI: 6.1 to per Min Increase in pVO₂ and No Worsening in 39.6) 42.2) 38.5) 45.6) NYHA Class Composite Measure Response ≥1.5 mL/kg per Min Increase in pVO₂ and NR NR NR NR n (%) NYHA Class Improvement ≥1 ≥3 mL/kg per Min Increase in pVO₂ and No NR NR NR NR Worsening in NYHA Class Both ≥3 mL/kg per Min Increase in pVO₂ and NR NR NR NR NYHA Class Improvement ≥1 NYHA Class I & All LVOT Peak Gradients <30 mm Hg, n/N (%) NR NR NR NR Post-Exercise LVOT Peak Gradient <50 mm Hg, n/N (%) NR NR NR NR Post-Exercise LVOT Peak Gradient <30 mm Hg, n/N (%) NR NR NR NR Post-Exercise LVOT Gradient Change from Baseline, Mean (SD) NR NR NR NR Resting LVOT Gradient Change from Baseline, Mean mm Hg (SD) NR NR NR NR Valsalva LVOT Gradient Change from Baseline, Mean mm Hg (SD) NR NR NR NR Resting LVEF Change from Baseline, % (SD) -2.3 (5.3) -5.61 (9.65) -4.09 (8.02) -2.31 (4.94) pVO₂ Change from Baseline, Mean mL/kg per min (SD) 0.36 (3.12) 0.12 (3.76) 0.22 (3.44) 0.58 (2.39) 10 (52.6); 17 (42.5); 7 (36.8); 7 (33.3); NYHA Class Improvement ≥1, n (%) (95% CI: 28.9 to (95% CI: 27 to (95% CI: 16.3 to (95% CI: 14.6 to 57) 75.6) 59.1) 61.6) NYHA Class Mean Change from Baseline (SD) -0.6 (0.7) -0.3 (0.6) -0.4 (0.7) -0.4 (0.6) Class I NR NR NR NR NYHA Functional Class Distribution, n Class II NR NR NR NR (%) Class III NR NR NR NR VE/VCO₂ Mean Change from Baseline (95% CI) NR NR NR NR NRS Dyspnea Score Mean Change from Baseline (95% CI) NR NR NR NR NT-proBNP Level Change from Baseline, Median (IQR), pg/mL (95% CI)* -47.1 -57.1 -53.2 -0.7 Hs-CTnI Change from Baseline, Geometric Mean, ng/L* -23.4 -41 -34 3.8 CI: confidence interval, IQR: interquartile range, kg: kilogram, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, mL: milliliter, mm Hg: millimeter of mercury, n: number, N: total number, NR: not reported, NRS: numerical rating scale, NT-proBNP: N-terminal pro B-type natriuretic peptide, NYHA: New York Heart Association, pg: picogram, pVO₂: peak oxygen consumption, VE: ventilation, VCO₂: volume of exhaled carbon dioxide, SD: standard deviation *Percent change. ©Institute for Clinical and Economic Review, 2021 Page 108 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D22. Efficacy Outcomes: Disopyramide26 Trial Sherrid et al. 2005 Arms Disopyramide without Intervention Disopyramide with Intervention N 78 40 Timepoint 3.1 ± 2.6 years NR Septal Myectomy NA 22 (55) Intervention Type, n (%) Septal Ablation NA 10 (25) Dual-Chamber Pacemakers NA 8 (20) LVOT Peak Gradient Change from Baseline, Mean mm Hg -35* -10* Re-Intervention, Weighted Median (IQR) NR NR NYHA Class Change from Baseline, Mean (SD) -0.6* 0 Class I 29 (37.2)* NR NYHA Class Distribution, n Class II 42 (53.8)* NR (%) Class III/IV 7 (9.0)* NR IQR: interquartile range, LVOT: left ventricular outflow tract, n: number, N: total number: NA: not applicable, NR: not reported, NYHA: New York Heart Association, SD: standard deviation *Statistically significant. Table D23. Efficacy Outcomes: Septal Reduction Therapy27 Trial Liebregts et al. 2015 Arms Septal Ablation Surgical Myectomy N 2,013 2,791 Timepoint Follow-up* Septal Myectomy NR NR Intervention Type, n (%) Septal Ablation NR NR Dual-Chamber Pacemakers NR NR LVOT Peak Gradient Change from Baseline, Weighted Median % (IQR) -71 (-67 to -90) -77 (-69 to -90) Re-Intervention, Weighted Median % (95% CI) 7.7 (4.2 to 11.1) 1.6 (0.6 to 2.6) NYHA Class Change from Baseline, Weighted Median % (IQR) -45 (-45 to -50) -45 (-44 to -48) Class I NR NR NYHA Class Distribution, Class II NR NR Weighted Median % (95% CI) Class III/IV 8 (8 to 8) 4.5 (4.5 to 12) CI: confidence interval, IQR: interquartile range, LVOT: left ventricular outflow tract, n: number, N: total number: NR: not reported, NYHA: New York Heart Association, SD: standard deviation *Timepoints varied between studies in this systematic literature review. ©Institute for Clinical and Economic Review, 2021 Page 109 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D24. Patient-Reported Outcomes: Phase III Trials1,24,27 Trial EXPLORER-HCM MAVA-LTE EXPLORER-HCM Arms Mavacamten Placebo Cohort N 123* 128‡ 224 Timepoint 30 weeks NR KCCQ-CSS Mean Change from Baseline (SD) 13.6 (14.4) 4.2 (13.7) NR KCCQ-OSS Mean Change from Baseline (SD) 14.9 (15.8) 5.4 (13.7) NR KCCQ-PLS Mean Change from Baseline (SD) 14.7 (17) 3.6 (15.4) NR Clinically Worse 9 (10) 22 (25) NR Magnitude of Clinical Change in No significant Change 19 (21) 27 (31) NR KCCS-CSS, Small but Clinically Important Improvement 16 (17) 12 (14) NR n (%) Moderate to Large Clinical Improvement 15 (16) 16 (18) NR Large to Very Large Improvement 33 (36) 11 (13) NR Clinically Worse 8 (9) 20 (23) NR Magnitude of clinical change in No Significant Change 18 (20) 28 (32) NR KCCS-OSS, Small but Clinically Important Improvement 17 (18) 9 (10) NR n (%) Moderate to Large Clinical Improvement 16 (17) 18 (20) NR Large to Very Large Improvement 33 (36) 13 (15) NR HCMSQ-SoB Mean Change from Baseline (SD) -2.8 (2.7)† -0.9 (2.4) NR HCMSQ-SoB: Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub-score, KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, KCCQ-PLS: Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, n: number, N: total number, NR: not reported, SD: standard deviation *N=92 for all reported KCCQ outcomes unless otherwise stated, †N=85, ‡N=88 for all reported KCCQ outcomes unless otherwise stated, ¶N=86 ©Institute for Clinical and Economic Review, 2021 Page 110 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D25. Patient-Reported Outcomes: Phase II Trials51,59 Trial PIONEER-HCM PIONEER-OLE Arms Cohort A Cohort B Cohort A Cohort B Mavacamten (Overall) N 11 10 11 10 13 Timepoint 12 Weeks 16 Weeks 24 Weeks 36 Weeks 48 Weeks KCCQ-CSS Mean Change from Baseline (SD) NR NR NR NR NR NR NR 14.4* 16.0 -0.4* -0.4 KCCQ-OSS Mean Change from Baseline (SD) (95% CI: (95% CI: (95% CI: -1.0 (95% CI: -0.8 15.3 (18.5) NR 16.3 (24.2) 7.3 to 21.5) 0.3 to 31.6) to 0.2) to -0.03) KCCQ-PLS Mean Change from Baseline (SD) NR NR NR NR NR NR NR Clinically Worse NR NR NR NR NR NR NR No Significant Change NR NR NR NR NR NR NR Magnitude Small but Clinically Important of Clinical NR NR NR NR NR NR NR Improvement Change in Moderate to Large Clinical KCCS-CSS, NR NR NR NR NR NR NR Improvement n (%) Large to Very Large NR NR NR NR NR NR NR Improvement Clinically Worse NR NR NR NR NR NR NR No Significant Change NR NR NR NR NR NR NR Magnitude Small but Clinically Important of Clinical NR NR NR NR NR NR NR Improvement Change in Moderate to Large Clinical KCCS-OSS, NR NR NR NR NR NR NR Improvement n (%) Large to Very Large NR NR NR NR NR NR NR Improvement HCMSQ-SoB Mean Change from Baseline (SD) NR NR NR NR NR NR NR CI: confidence interval, HCMSQ-SoB: Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub-score, KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, KCCQ-PLS: Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, n: number, N: total number, NR: not reported, SD: standard deviation *N=10. ©Institute for Clinical and Economic Review, 2021 Page 111 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D26. Patient-Reported Outcomes: MAVERICK-HCM12 Trial MAVERICK-HCM Group 1 Mava Group 2 Mava Pooled Arms Placebo (~200 ng/mL) (~500 ng/mL) Mavacamten N 19 21 40 19 Timepoint 16 weeks KCCQ-CSS Mean Change from Baseline (SD) 0.11 (7.67) 5.66 (10.01) 3.37 (9.41) 4.34 (16.05) KCCQ-OSS Mean Change from Baseline (SD) 0.35 (8.71) 6.24 (10.73) 3.82 (10.24) 6.02 (17.63) KCCQ-PLS Mean Change from Baseline (SD) NR NR NR NR Clinically Worse NR NR NR NR No Significant Change NR NR NR NR Magnitude of Clinical Change Small but Clinically Important in KCCS-CSS, NR NR NR NR Improvement n (%) Moderate to Large Clinical Improvement NR NR NR NR Large to Very Large Improvement NR NR NR NR Clinically Worse NR NR NR NR No Significant Change NR NR NR NR Magnitude of Clinical Change Small but Clinically Important in KCCS-OSS, NR NR NR NR Improvement n (%) Moderate to Large Clinical Improvement NR NR NR NR Large to Very Large Improvement NR NR NR NR HCMSQ-SoB Mean Change from Baseline (SD) NR NR NR NR HCMSQ-SoB: Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub-score, KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, KCCQ-OSS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score, KCCQ-PLS: Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, n: number, N: total number, NR: not reported, SD: standard deviation ©Institute for Clinical and Economic Review, 2021 Page 112 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D27. Adverse Events: Phase III Trials24,27,34 Trial EXPLORER-HCM MAVA-LTE (EXPLORER-HCM Cohort) Arms Mavacamten Placebo Mavacamten N 123 128 224 Timepoint 30 weeks 60 weeks ≥ 1 AE, n (%) NR NR NR ≥ 1 TEAE, n (%) 108 (88) 101 (79) 141 (62.9) ≥1 SAE, n (%) 10 (8) 11 (9) 19 (8.5) Mild NR NR 82 (36.6)¶ AE Severity, n (%) Moderate NR NR 45 (20.1)¶ Serious/Severe NR NR 13 (5.8)¶ Study Drug-Related AEs, n (%) NR NR 20 (8.9)¶ Discontinuation, n (%) 4 (3.3) 3 (2.3) NR AEs Leading to Treatment Discontinuation, n (%) 2 (1.6) 1 (0.8) 2 (0.9) 2.5 mg NR NR NR Mavacamten Dose 5 mg NR NR NR Adjustment, n (%) 10 mg NR NR NR 15 mg NR NR NR Cardiac SAEs, n (%) 4 (3.3) 4 (3.1) 9 (4)# Atrial Fibrillation, n (%) 8 (6.5) 9 (7) 11 (4.9) Atrial Flutter, n (%) NR NR NR Heart Failure, n (%) NR NR 2 (0.9) Systolic Dysfunction, n (%) NR NR NR Dyspnea, n (%) NR NR 10 (4.5) Syncope, n (%) 2 (2) 1 (1) NR Stress Cardiomyopathy, n (%) 2 (2) 0 NR Palpitations, n (%) 7 (5.7) 9 (7.0) NR Coronary Artery Disease, n (%) NR NR NR Cardiac Failure, n (%) 2 (1.6) 3 (2.3) NR Cardiac Failure Congestive, n (%) 0 1 (1) NR Ventricular Tachycardia, n (%) 36 (32)*† 38 (33)‡ NR Angina Pectoris, n (%) 1 (0.8) 5 (3.9) NR AE: adverse event, mg: milligram, n: number, N: total number, NR: not reported, SAE: serious adverse event, TEAE: treatment-emergent adverse event *Based on week 26 outcomes, †N=113, ‡N=117, ¶Based on teaes, #cardiovascular drug-related events ©Institute for Clinical and Economic Review, 2021 Page 113 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D28. Adverse Events: Phase II Trials51,52,59 Trial PIONEER-HCM PIONEER-OLE Arms Cohort A Cohort B Mavacamten (Overall) N 11 10 13 Timepoint 16 weeks 55 weeks ≥ 1 AE, n (%) NR NR 11 (84.5) ≥ 1 TEAE, n (%) NR NR NR ≥1 SAE, n (%) 1 (9) NR NR Mild 76% 85% 74.5% AE Severity, (%)* Moderate 23% 15% 14.9% Serious/Severe 2% 0% 6.4% Study Drug-Related AEs, n (%) 21% NR Discontinuation, n (%) 2 (18) 0 NR AEs Leading to Treatment Discontinuation, n (%) 2% 0% NR 2.5 mg NR NR NR Mavacamten Dose Adjustment, 5 mg NR NR NR n (%) 10 mg NR NR NR 15 mg NR NR NR Cardiac SAEs, n (%) NR NR NR Atrial Fibrillation, n (%) 3 (27) 1 (10) NR Atrial Flutter, n (%) NR NR NR Heart Failure, n (%) NR NR NR Systolic Dysfunction, n (%) NR NR NR Dyspnea, n (%) 2 (18) 0 NR Syncope, n (%) NR NR NR Stress Cardiomyopathy, n (%) NR NR NR Palpitations, n (%) 1 (9.1) 0 NR Coronary Artery Disease, n (%) NR NR NR Cardiac Failure, n (%) 1 (9.1) 0 NR Cardiac Failure Congestive, n (%) NR NR NR Ventricular Tachycardia, n (%) 1 (9.1) 4 (40) NR Angina Pectoris, n (%) 0 2 (20) NR AE: adverse event, mg: milligram, n: number, N: total number, NR: not reported, SAE: serious adverse event, TEAE: treatment-emergent adverse event *Percentages based on numerical instances of each severity of AEs and not number of patients who experienced them. ©Institute for Clinical and Economic Review, 2021 Page 114 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D29. Adverse Events: MAVERICK-HCM12 Trial MAVERICK-HCM Group 1 Mava (~200 Group 2 Mava (~500 Arms Pooled Mavacamten Placebo ng/mL) ng/mL) N 18 21 39 19 Timepoint 24 weeks ≥1 AE, n (%) NR NR NR NR ≥1 TEAE, n (%) 16 (88.9) 19 (90.5) 35 (89.7) 13 (68.4) ≥1 SAE, n (%) 2 (11.1) 2 (9.5) 4 (10.3) 4 (21.1) Mild 76% AE Severity, n (%) Moderate 21% Serious/Severe NR NR NR NR Study Drug-Related AEs, n (%) NR NR NR NR Discontinuation, n (%) 3 (15.8)* 3 (14.3) 6 (15)¶ 0 AEs Leading to Treatment Discontinuation, n (%) NR NR NR NR 2.5 mg 1 (5.6) NA NR NA Mavacamten Dose 5 mg 15 (83.3) 4 (19.0) NR NA Adjustment, n (%) 10 mg 2 (11.1) 9 (42.9) NR NA 15 mg NA 8 (38.0) NR NA Cardiac SAEs, n (%) NR NR NR NR Atrial Fibrillation, n (%)‡ 0 3 (14.3) 3 (7.7) 1 (5.3) Atrial Flutter, n (%)† 0 0 0 1 (5.3) Heart Failure, n (%) NR NR NR NR Systolic Dysfunction, n (%)† 0 1 (4.8) 1 (2.6) 0 Dyspnea, n (%) ‡ 1 (5.6) 3 (14.3) 4 (10.3) 3 (15.8) Syncope, n (%) NR NR NR NR Stress Cardiomyopathy, n (%) NR NR NR NR Palpitations, n (%)‡ 1 (5.6) 5 (23.8) 6 (15.4) 3 (15.8) Coronary Artery Disease, n (%)† 0 0 0 1 (5.3) Cardiac Failure, n (%) NR NR NR NR Cardiac Failure Congestive, n (%) NR NR NR NR Ventricular Tachycardia, n (%) NR NR NR NR Angina Pectoris, n (%)† 0 0 0 1 (5.3) AE: adverse event, mg: milligram, n: number, N: total number, NR: not reported, SAE: serious adverse event, TEAE: treatment-emergent adverse event *N=19, †Based on SAEs, ‡Based on TEAEs, ¶N=40 ©Institute for Clinical and Economic Review, 2021 Page 115 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D30. Adverse Events: Disopyramide26 Trial Sherrid et al. 2005 Arms Disopyramide Non-Disopyramide N 118 373 Timepoint 3.1 ± 2.6 years NR Discontinuation, n (%) 8 (7) NR Pacemaker Implantation, % (95% CI) NR NR Tamponade, % (95% CI) NR NR Sustained Ventricular Tachycardia, % (95% CI) NR NR Ventricular Fibrillation, % (95% CI) NR NR Total Adverse Arrhythmic Events, % (95% CI) NR NR Periprocedural Death, n (%) NR NR Sudden Cardiac Death, n (%) 4 (3.4) NR Aborted Sudden Cardiac Death, n (%) NR NR Surgery-Related Death, n (%) NR 2 (0.5) Cardiac Mortality, % (95% CI) NR NR Non-Cardiac Mortality, n (%) NR NR All-Cause Mortality, % (95% CI) NR NR Non-Cardiac 1.4 1.2 Non-Sudden Cardiac 0.4 0.9 Annualized Death Rate, % Sudden Cardiac 1 1.8 All-Cause Cardiac 1.4 2.6 All Deaths 2.8 3.8 Atrial Fibrillation, n (%) 17 (14) 63 (17) Stroke, n (%) 4 (3) 7 (2) ICD Shock, n (%) NR NR CI: confidence interval, ICD: implantable cardioverter-defibrillator, n: number, N: total number, NR: not reported ©Institute for Clinical and Economic Review, 2021 Page 116 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table D31. Adverse Events: Septal Reduction Therapy27 Trial Liebregts et al. 2015* Arms Septal Ablation Surgical Myectomy Septal Ablation Surgical Myectomy N 2,013 2,791 2,013 2,791 Timepoint Short-term (<30 days)* Long-term (after 30 days) Discontinuation, n (%) NR NR NR NR Pacemaker Implantation, % (95% CI) 10 (7.8 to 12.1) 4.4 (2.6 to 6.2) NR NR Tamponade, % (95% CI) 0.6 (0.1 to 1.1) 1.0 (0 to 2.0) NR NR Sustained Ventricular Tachycardia, % (95% CI) 0.8 (0.2 to 1.4) 0.4 (0.0 to 1.4) NR NR Ventricular Fibrillation, % (95% CI) 0.8 (0.2 to 1.4) 0.3 (0 to 0.8) NR NR Total Adverse Arrhythmic Events, % (95% CI) 2.2 (1.1 to 3.3) 1.0 (0.1 to 1.8) NR NR Periprocedural Death, n (%) 20 (1) 61 (2.2) NR NR Sudden Cardiac Death, n (%) NR NR 36 (1.8) 78 (2.8) Aborted Sudden Cardiac Death, n (%) NR NR 4 (0.2) 15 (0.5) Surgery-Related Death, n (%) NR NR NR NR 1.1% 2.5% Cardiac Mortality, n (%) 76 (3.8) 175 (6.3) (95% CI: 0.6 to 1.6) (95% CI: 1.3 to 3.6) Non-Cardiac Mortality, n (%) NR NR 65 (3.2) 85 (3) 1.3% 2.5% All-Cause Mortality, n (%) 191 (9.5) 302 (10.8) (95% CI: 0.7 to 1.8) (95% CI: 1.4 to 3.6) Non-Cardiac NR NR NR NR Non-Sudden Cardiac NR NR NR NR Annualized Death Sudden Cardiac NR NR 0.41† 0.49† Rate, % All-Cause Cardiac NR NR 0.5 0.74 1.52 1.44 All Deaths NR NR (95% CI: 1.12 to 1.91) (95% CI: 1.13 to 1.76) Atrial Fibrillation, n (%) NR NR NR NR Stroke, % (95% CI) 0.3 (0 to 0.8) 0.9 (0.3 to 1.6) NR NR ICD Shock, n (%) NR NR 14 (0.7) 11 (0.4) CI: confidence interval, ICD: implantable cardioverter-defibrillator, n: number, N: total number, NR: not reported *All short-term timepoint data (with exception to periprocedural death) presented as % (CI). †Aborted sudden cardiac death rate. ©Institute for Clinical and Economic Review, 2021 Page 117 Final Evidence Report – Mavacamten for HCM Return to Table of Contents D4. Ongoing Studies Table D32. Ongoing Studies Estimated Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcomes Completion Date A Study to Evaluate Phase III, double- Arm 1 Inclusion Criteria Primary Outcome December Mavacamten in Adults blind, multicenter, Mavacamten • 18 years old and older and body • Number of subjects 2024 With Symptomatic placebo- weight >45 kg who decide to Obstructive HCM Who controlled, RCT Arm 2 • Diagnosed with HOCM proceed with SRT and Are Eligible for Septal Placebo • Referred or under active number of subjects Reduction Therapy Estimated consideration for and willing to who remain eligible (VALOR-HCM) enrollment: 100 have SRT procedure for SRT at week 16 • Has documented LVEF ≥60% and Secondary Outcomes MyoKardia, Inc. oxygen saturation at rest ≥90% • Number of subjects Key Exclusion Criteria who decide to NCT04349072 • Persistent or permanent atrial proceed with SRT and fibrillation and subject not on number of subjects anticoagulation for ≥4 weeks who remain eligible prior to screening and/or not for SRT at week 32 adequately rate controlled ≤6 • Change from baseline months prior to screening to week 16 in the • Previously treated with invasive mavacamten group vs. septal reduction (surgical placebo group in myectomy or septal ablation) NYHA class • For individuals on beta blockers, • Change from baseline calcium channel blockers, or to week 16 in the disopyramide, any dose mavacamten group vs. adjustment of these medications placebo group in <14 days prior to screening or an KCCQ-23 anticipated change in regimen • Change from baseline during the first 16 weeks of the to week 16 in the study mavacamten group compared with the placebo group in NT- ©Institute for Clinical and Economic Review, 2021 Page 118 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Estimated Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcomes Completion Date • Any medical condition that proBNP and cardiac precludes upright exercise stress troponin testing • Change from baseline • Paroxysmal, intermittent atrial to week 16 in the fibrillation with atrial fibrillation mavacamten group vs. present at screening placebo group in LVOT • Prior treatment with cardiotoxic gradient agents, such as doxorubicin or similar A Long-Term Safety Phase II/III, long- Mavacamten 5 mg/day, Key Inclusion Criteria • Frequency and Extension Study of term safety with dose adjustments • Has completed MAVERICK-HCM severity of TEAEs and Mavacamten in Adults extension study at weeks 4, 8, and 12 if or EXPLORER-HCM SAEs [Timeframe: 252 Who Have Completed needed • Has a body weight >45 kg weeks] MAVERICK-HCM or • Has adequate acoustic windows EXPLORER-HCM to enable accurate TTEs • Has documented LVEF ≥50% MyoKardia, Inc. Key Exclusion Criteria • Has any ECG abnormality that NCT03723655 could pose a risk to participant safety • Has a history of syncope or a history of sustained ventricular tachyarrhythmia with exercise, resuscitated sudden cardiac arrest or known history of appropriate ICD discharge for life- threatening ventricular arrhythmia • Currently treated with disopyramide or ranolazine or treatment with disopyramide or ranolazine is planned during the study ©Institute for Clinical and Economic Review, 2021 Page 119 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Estimated Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcomes Completion Date • Has any acute or serious comorbid condition (e.g., major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that could interfere with the study Extension Study of Phase II, Mavacamten 5 mg/day, Key Inclusion Criteria • Frequency and November Mavacamten (MYK-461) multicenter, open- with individualized • Completed Study MYK-461-004. severity of AEs and 9, 2023 in Adults With label extension dose adjustments (5, Prior participation in a non- SAEs [Timeframe: up Symptomatic study 10, or 15 mg) at week 6 interventional observational to 260 weeks] Obstructive if needed study is allowed Hypertrophic • Body weight >45 kg at screening Cardiomyopathy Key Exclusion Criteria Previously Enrolled in • Has QTcF >500 ms or any other PIONEER (PIONEER- ECG abnormality that could pose OLE) a risk to subject safety • Has developed obstructive MyoKardia, Inc. coronary artery disease (>70% stenosis in one or more arteries), NCT03496168 known moderate or severe aortic valve stenosis, any acute or serious comorbid condition (e.g., major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that interfere with the study AE: adverse event, ECG: electrocardiogram, HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy, ICD: implantable cardioverter-defibrillator, KCCQ: Kansas City Cardiomyopathy Questionnaire, kg: kilogram, LVEF: left ventricular ejection fraction, mg: milligram, ms: millisecond, NT-proBNP: N-terminal pro B-type natriuretic peptide, RCT: randomized controlled trial, SAE: serious adverse event, SRT: septal reduction therapy, TEAE: treatment-emergent adverse event, TTE: transthoracic echocardiogram Source: www.ClinicalTrials.gov (NOTE: studies listed on site include both clinical trials and observational studies). ©Institute for Clinical and Economic Review, 2021 Page 120 Final Evidence Report – Mavacamten for HCM Return to Table of Contents D5. Previous Systematic Reviews and Technology Assessments We did not identify any previous systematic literature reviews on mavacamten in HOCM. ©Institute for Clinical and Economic Review, 2021 Page 121 Final Evidence Report – Mavacamten for HCM Return to Table of Contents E. Long-Term Cost Effectiveness: Supplemental Information E1. Detailed Methods Table E1. Impact Inventory Included in This Analysis Notes on Sources (if Type of Impact from […] Perspective? Quantified), Likely Sector (Add Additional Domains, As Relevant) Health Care Magnitude & Impact Societal Sector (if Not) Formal Health Care Sector Longevity effects X Health Health-related quality of life effects X Outcomes Adverse events X Paid by third-party payers X Paid by patients out-of-pocket   Medical Costs Future related medical costs   Future unrelated medical costs   Informal Health Care Sector Patient time costs N/A  Health- Unpaid caregiver-time costs N/A  Related Costs Transportation costs N/A  Non-Health Care Sector Labor market earnings lost N/A X Cost of unpaid lost productivity due to N/A X Productivity illness Cost of uncompensated household N/A  production Consumption Future consumption unrelated to health N/A  Cost of social services as part of N/A  Social services intervention Legal/Criminal Number of crimes related to intervention N/A  Justice Cost of crimes related to intervention N/A  Impact of intervention on educational N/A  Education achievement of population Cost of home improvements, N/A  Housing remediation Production of toxic waste pollution by N/A  Environment intervention Other Other impacts (if relevant) N/A  N/A: not applicable Adapted from Sanders et al.62 ©Institute for Clinical and Economic Review, 2021 Page 122 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Target Population The population of focus for the economic evaluation included symptomatic HOCM patients in the US, incorporating demographics at onset of treatment similar to those seen in the EXPLORER trial. The mean age and percent female shown below were used to calculate per cycle mortality rates based on CDC statistics for the US. Table E2. Baseline Population Characteristics Mavacamten and Comparators Mean Age 58 % Female 41% Source EXPLORER Treatment Strategies The list of interventions was developed with input from patient organizations, clinicians, manufacturers, and payers on which treatments to include. The full list of interventions is as follows: • Mavacamten used along with standard first-line treatment. The comparator(s) for mavacamten along with first-line therapy will be: • Standard first-line treatment of HOCM (beta blockers and calcium channel blockers) • Disopyramide used along with standard first-line treatment • Myectomy used along with standard first-line treatment • Septal ablation used along with standard first-line treatment. Table E3. Treatment Regimen Recommended Dosage Generic Name Mavacamten Disopyramide Metoprolol Verapamil Brand Name -- Generic Generic Generic Manufacturer Bristol Myers Squibb -- -- -- Route of Oral Oral Oral Oral Administration Dosing (Initial and *5-X mg per day 400-800 mg per day 50-250 mg per day 180-240 mg per day Final Average) mg: milligram *The dose does not impact costs in the mavacamten arm as a per-year placeholder price is used. ©Institute for Clinical and Economic Review, 2021 Page 123 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E4. First-Line Drug Use by Arm Intervention Mavacamten First Line Disopyramide Myectomy Septal Ablation Metoprolol 76% 74% 98% 75% 75% Verapamil 20% 13% 32% 8.25%* 8.25%* EXPLORER, EXPLORER and Source EXPLORER EXPLORER Sherrid et al. literature, and assumption assumption *16.5% in the initial cycle only, then 8.25% beyond where the 50% reduction after treatment is an assumption consistent with evidence in available small studies on myectomy and assumed to be the same for septal ablation.9,10 Model Inputs Clinical Inputs Key clinical inputs included transitions between NYHA class and mortality. The best-available evidence was reviewed for inclusion in the model. The base-case treatment effects influenced NYHA class transitions and, for mavacamten and standard first-line care and standard first-line care alone, came from a Phase III clinical trial of mavacamten. Treatment effects of disopyramide along with first-line treatment, myectomy with first-line treatment and septal ablation with standard first line treatment, came from key literature sources.1,2 Transition Probabilities and Treatment Effects Transitions between NYHA class for mavacamten with first-line therapy and for first-line therapy alone were derived from those seen in EXPLORER clinical trial data up to Cycle 8. For mavacamten and standard first-line therapy and first-line therapy alone, clinical trial data were used directly in Cycles 0 and 1 (weeks 0 and four). For weeks four through 12 in the model, the transition rates were fitted cycle by cycle to match clinical trial data available at week 14 using an assumption of a constant weekly exponential rate. For weeks 12 through 24 in the model, the transitions were based on information available from weeks 14 through 26 in the clinical trial data. For weeks 28 and 32, the transition rates were based on transitions observed between weeks 26 and 30 in EXPLORER trial data. Following Cycle 8, the proportions of live patients across NYHA class were held constant. For disopyramide along with standard first-line therapy, baseline, and week four distributions across NYHA class were based on data in Sherrid et al. where the distribution across NYHA class in week four in the model is as seen in disopyramide patients who remained on treatment for several years in 66% of the patients and assumed to be 0 in 34% of the patients as 34% of the patients in the Sherrid study had eventually opted for surgical options. Following Cycle 1 (week four) in the disopyramide along with standard first-line therapy arm, we held the proportions of alive patients across NYHA classes constant. The disopyramide and standard first-line therapy patients also had ©Institute for Clinical and Economic Review, 2021 Page 124 Final Evidence Report – Mavacamten for HCM Return to Table of Contents their mortality modeled based on US CDC mortality rates corresponding to the average age and percent female characteristics seen in the EXPLORER trial patients. Myectomy patients and septal ablation were modeled having the same baseline distribution of NYHA class as the mavacamten patients in EXPLORER. For the treatment effect of myectomy along with first-line therapy and septal ablation with standard first-line therapy in the model, the percent of patients in week four in NYHA class I is such that it makes the percent reduction in the average NYHA class between Cycles 0 and 1 (weeks 0 and four) equal to the percent reduction seen in the Liebregts meta-analysis (55% reduction), keeping the relative percent of those remaining in NYHA class II and NYHA class III/IV in the same proportion as that seen in the mavacamten population in week four. Simultaneously, between weeks 0 and four, 1.3% of the myectomy patients and 1.1% of the septal ablation patients were be modeled as dying from the procedure based on rates from studies in years later than 2000 as shown in Liebregts. Following week four, the relative portion of alive patients across NYHA class was held constant, and mortality is based on average demographic characteristics seen in EXPLORER. Specific treatment effects are shown via NYHA class below in Table E6 for disopyramide and standard first-line therapy and myectomy and standard first-line therapy. Septal ablation and standard first-line therapy had the same treatment effect in Cycle 1 consistent with results in Liebregts. Table E5. Specific Treatment Effects Clinical Inputs Base Case Input Name (Percent in NYHA I Lower Value Upper Value in Cycle 1) Mavacamten Treatment Effect* 0.24 0.18 0.31 Standard First-Line Therapy Treatment Effect 0.08 0.06 0.10 Myectomy Treatment Effect* 0.77 0.58 0.96 Disopyramide Treatment Effect* 0.28 0.21 0.36 Septal Ablation Treatment Effect* 0.77 0.58 0.96 NYHA: New York Heart Association *With standard first-line therapy. Discontinuation Discontinuation was not included in the model as there was no long-term evidence suggesting an appropriate estimate for mavacamten, and as first-line therapy tends to be used for life in this patient population. We did make an adjustment in the treatment effect for disopyramide described above that is related to discontinuation in those patients, however, in the model, technically, no one discontinues. ©Institute for Clinical and Economic Review, 2021 Page 125 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Mortality Mortality estimates were sourced from the CDC and reflected US average mortality rates adjusted for age and gender as reflected by the overall averages of baseline characteristics of patients seen in the clinical trial. Based on conversations with clinical experts and available evidence, mortality was assumed to be constant across NYHA class as there is not enough evidence from the trial to warrant projecting mortality effects for mavacamten along with first-line therapy relative to other treatments, although this assumption was tested in a scenario analysis. Note that for myectomy and septal ablation, as stated above, there is an initial increase in mortality based on mortality rates associated with the procedure.2 Adverse Events In EXPLORER, 8% of patients experienced a serious adverse event in the mavacamten arm and 9% in the standard-of-care/placebo arm.3 As the rate of serious adverse events across the arms was very similar and because we have limited data to compare serious adverse events with the other comparators, we did not include additional costs or disutilities of serious adverse events in the model. However, utility impacts of the serious adverse events would have been captured in the utility scores used across NYHA class for mavacamten and standard of care (see Health State Utilities section below). For the disopyramide, myectomy, and septal ablation arms, we do not include impacts of adverse events in the model (although there is a surgical disutility for myectomy and septal ablation and there are total cost estimates used from the literature that would include costs of adverse events for those procedures) and we use an average of the utility scores for each NYHA class seen in EXPLORER to project the treatment effect of changes in NYHA class to changes in QALYs. Heterogeneity and Subgroups There is insufficient evidence to warrant or allow modeling of subgroups within the treatments or comparators. Health State Utilities Health state utilities were based on manufacturer-submitted data for NYHA class I, II, and III/IV. We used consistent health state utility values across treatments evaluated in the model. The utilities were taken directly from the patients in the trial and, as such, they include disutilities from the small difference in adverse events seen in the trial. Consequently, we did not add additional disutilities for serious adverse events in the model. No head-to-head data are available to compare adverse event rates in mavacamten and first-line therapy versus disopyramide and first-line therapy and/or myectomy or septal ablation with first-line therapy. It was reported that 7% of patients on disopyramide experienced adverse side effects leading to discontinuation, which is similar to the ©Institute for Clinical and Economic Review, 2021 Page 126 Final Evidence Report – Mavacamten for HCM Return to Table of Contents adverse event rates of 8% and 9% seen in EXPLORER. Given available data, we elected to use an average of the utilities for placebo and mavacamten for the utilities by NYHA class for the other comparators. The utility scores are based on the EQ-5D administered to the patients in EXPLORER.4 In addition, we applied an average disutility by age of 0.0007 per year, which reflects average age decrements seen in the EQ-5D in the US.5 For myectomy, a disutility of 0.086 is applied for the first six cycles matching available numbers for coronary artery bypass surgery patients versus US average utilities for similarly aged patients using the EQ-5D.6 For septal ablation, a one cycle disutility of 0.04 is applied.63 Further, for myectomy and septal ablation there is a 0.05 lifetime disutility applied to 4% and 10% of patients respectively reflecting different rates of pacemaker placement related to those procedures as seen in the literature.27 Table E6. Health State Utilities Base Lower Upper Input Came Treatment Case Value Value Utility of NYHA Class I for Mavacamten Mavacamten 0.95 0.65 1.00 Utility of NYHA Class II for Mavacamten Mavacamten 0.87 0.66 0.98 Utility of NYHA Class III and IV for Mavacamten 0.71 0.56 0.84 Mavacamten Utility of NYHA Class I for SoC Standard 0.95 0.65 1.00 Utility of NYHA Class II for SoC Standard 0.85 0.65 0.97 Utility of NYHA Class III and IV for SoC Standard 0.70 0.56 0.83 Myectomy, septal ablation, Utility of NYHA Class I for Comparators 0.95 0.65 1.00 disopyramide Myectomy, septal ablation, Utility of NYHA Class II for Comparators 0.86 0.65 0.98 disopyramide Utility of NYHA Class III and IV for Myectomy, septal ablation, 0.71 0.56 0.83 Comparators disopyramide Disutility of Pacemaker Myectomy and septal ablation 0.05 0.04 0.05 Disutility of Septal Ablation Procedure Septal ablation (1 cycle) 0.04 0.03 0.05 Disutility of Myectomy Procedure Myectomy (6 cycles) 0.09 0.07 0.10 NYHA: New York Heart Association, SoC: standard of care Drug Utilization Patients in all the arms were modeled as using beta blockers represented by metoprolol and calcium channel blockers represented by verapamil according to usual doses for extended-release versions of those drugs associated with adult hypertension.7,8 For myectomy and septal ablation patients, post-myectomy use of verapamil will be reduced by 50% based on available pre-post studies of myectomy.9,10 See Table E7 for the doses used and Table E8 for the proportions using first-line treatment in the model. ©Institute for Clinical and Economic Review, 2021 Page 127 Final Evidence Report – Mavacamten for HCM Return to Table of Contents The following inputs were used to model drug utilization and associated costs: • Duration of treatment • Schedule of doses for each drug in each regimen • Protocol/label dosage for the indication. Cost Inputs Drug Costs For mavacamten, we used a placeholder price based on market analyst estimates.11 For disopyramide, metoprolol, and verapamil, we calculated the average wholesale acquisition cost (WAC) based on generic formulations in Red Book (see Table E9). Other than an initial hospitalization associated with disopyramide (see Table E10), no administration costs were included because all drugs included in the model are orally administered. Table E7. Drug Costs Input Name Treatment Base Case Lower Value Upper Value Per Cycle Cost of Mavacamten Mavacamten $5,769 $4,694 $6,954 First Cycle Cost of Metoprolol Metoprolol cycle 1 $38 $31 $46 Per Cycle Cost of Metoprolol Metoprolol $64 $52 $77 First Cycle Cost of Verapamil Verapamil cycle 1 $49 $40 $59 Per Cycle Cost of Verapamil Verapamil $56 $46 $67 First Cycle Cost of Disopyramide Disopyramide cycle 1 $309 $252 $373 Per Cycle Cost of Disopyramide Disopyramide $413 $336 $497 *All costs used in the model were updated to 2021 dollars based on the methods outlined in the ICER Reference Case. Non-Drug Costs Non-drug costs were modeled based on NYHA class derived from data provided by Bristol Myers Squibb for NYHA class I and II, which reflect non-symptomatic HOCM and symptomatic HOCM patients, respectively, and were projected from the NYHA class II to NYHA class III proportionally based on proportional differences across those classes seen in general heart failure patients in a recent model.12 In addition, there were echocardiograph costs at week 0, week eight, and week 16 applied to the mavacamten and first-line treatment arm, in addition to having those done initially and every two years for all of the comparators (see Table E10). There are also two days of hospital costs applied to disopyramide upon treatment initiation, and the cost used for myectomy and septal ablation reflects total costs associated inclusive of the surgery costs as well as inpatient, surgical, outpatient and emergency room use in six months following those surgeries in a recent claims data analysis.64 ©Institute for Clinical and Economic Review, 2021 Page 128 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E8. Non-Drug Costs Cost Inputs* Lower Upper Input Name Treatment Base Case Value Value Disopyramide Hospitalization Disopyramide hospitalization $8,559 $6,964 $10,316 Myectomy Procedure Cost Myectomy $122,759 $99,881 $147,960 Septal Ablation Procedure Cost Septal ablation $55,706 $45,325 $67,142 Echocardiogram Cost Transthoracic TTE (93308) $101 $82 $121 NYHA I Heath State Cost NYHA I heath state cost NYHA II Heath State Cost NYHA II heath state cost NYHA III Heath State Cost NYHA III heath state cost $2,826 $2,299 $3,406 NYHA: New York Heart Association, TTE: transthoracic echocardiogram *All costs used in the model were updated to 2021 dollars based on the methods outlined in the ICER Reference Case. E2. Results Description evLY Gained Calculations The cost per evLY gained considers any extension of life at the same "weight" no matter what treatment is being evaluated. Below are the stepwise calculations used to derive the evLY gained in cases where the life expectancy was different across treatment arms. 1. First, we attribute a utility of 0.851, the age- and gender-adjusted utility of the general population in the US that are considered healthy. 65 2. For each cycle (Cycle I) in the model where using the intervention results in additional years of life gained, we multiply this general population utility with the additional life years gained (ΔLYG). 3. We sum the product of the life years and average utility (cumulative LYs/cumulative QALYs) for Cycle I in the comparator arm with the value derived in Step 2 to derive the equal value of life years (evLY) for that cycle. 4. If no life years were gained using the intervention versus the comparator, evLYs are equivalent to QALYs 5. The total evLY is then calculated as the cumulative sum of QALYs gained using the above calculations for each arm. 6. We use the same calculations in the comparator arm to derive its evLY. Finally, the evLY gained is the incremental difference in evLY between the intervention and the comparator arms. ©Institute for Clinical and Economic Review, 2021 Page 129 Final Evidence Report – Mavacamten for HCM Return to Table of Contents E3. Sensitivity Analyses To demonstrate effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors) or reasonable ranges to evaluate changes in cost per addition QALY. Figures E1A and E1B and Tables 9A and 9B show the tornado diagrams for mavacamten versus myectomy in terms of costs and then in terms of QALYs. As this is a lifetime model, the incremental costs are sensitive to the discount rate. Varying the treatment effects (increasing the proportion in NYHA I) also has a moderate impact. The treatment effects and NYHA utility scores have a relatively large effect on projected incremental QALYs. Overall, however, the sensitivity analyses demonstrated robust findings that at a price of $75,000 per year, the incremental ratios would be above standard thresholds. These analyses were repeated for the other comparators with similar findings displayed below. Figure E1A. Tornado Diagram of Incremental Cost for Mavacamten versus Myectomy NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 130 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E9A. Inputs and Results for Mavacamten versus Myectomy Incremental Cost Tornado Diagram Upper Low Input High Input Input Lower Cost Cost Value Value Discount Rate for Cost $1,584,965 $940,538 0.01 0.05 Myectomy Treatment Effect $1,147,719 $1,259,440 0.58 0.96 Mavacamten Treatment Effect $1,242,588 $1,164,572 0.18 0.31 Myectomy Procedure Cost $1,226,457 $1,178,379 $99,881.32 $147,959.69 NYHA II Heath State Cost $1,186,641 $1,222,239 $1,663.84 $2,464.74 NYHA I Heath State Cost $1,210,829 $1,195,594 $611.31 $905.57 NYHA III Heath State Cost $1,198,253 $1,209,448 $2,299.24 $3,405.99 Percent of Patients in Mavacamten Group Taking $1,200,969 $1,206,190 0.57 0.95 Metoprolol Percent of Patients in Myectomy Group Taking $1,206,122 $1,201,037 0.56 0.94 Metoprolol Mortality Rate Due to Procedure in Myectomy $1,202,793 $1,204,366 0.01 0.02 Group NYHA: New York Heart Association, SoC: standard of Care *Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. Figure E1B. Tornado Diagram of Incremental QALY for Mavacamten versus Myectomy NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 131 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E9B. Inputs and Results for Mavacamten versus Myectomy Incremental QALY Tornado Diagram Low Input High Input Input Lower QALY Upper QALY Value Value Utility of NYHA Class I for Comparator 3.50 -0.83 0.65 1.00 Utility of NYHA Class I for Mavacamten -2.75 0.20 0.65 1.00 Utility of NYHA Class II for Mavacamten -1.66 0.58 0.66 0.98 Utility of NYHA Class II for Comparator 0.48 -0.63 0.65 0.98 Myectomy Treatment Effect 0.12 -0.56 0.58 0.96 Mavacamten Treatment Effect -0.45 0.01 0.18 0.31 Utility of NYHA Class III and IV for -0.40 -0.07 0.56 0.84 Mavacamten Discount Rate for Outcomes -0.29 -0.17 0.01 0.05 Utility of NYHA Class III and IV for Comparator -0.16 -0.27 0.56 0.83 Mortality Rate Due to Procedure in -0.27 -0.17 0.01 0.02 Myectomy Group NYHA: New York Heart Association, QALY: quality-adjusted life year Figure E2 shows the tornado diagram for mavacamten versus septal ablation. Similar findings as described above. Figure E2A. Tornado Diagram of Incremental Cost for Mavacamten versus Septal Ablation ASA: alcohol septal ablation, NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 132 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E10A. Inputs and Results for Mavacamten versus Septal Ablation Incremental Cost Tornado Diagram Input Lowe Cost Upper Cost Low Input Value High Input Value Discount Rate for Cost $1,651,393 $1,007,202 0.01 0.05 ASA Treatment Effect $1,214,174 $1,326,121 0.58 0.96 Mavacamten Treatment Effect $1,309,156 $1,231,140 0.18 0.31 NYHA II Heath State Cost $1,253,243 $1,288,770 $1,663.84 $2,464.74 ASA Procedure Cost $1,280,529 $1,258,712 $45,324.87 $67,142.21 NYHA I Heath State Cost $1,277,443 $1,262,112 $611.31 $905.57 NYHA III Heath State Cost $1,264,826 $1,276,010 $2,299.24 $3,405.99 Percent of Patients in Mavacamten $1,267,538 $1,272,758 0.57 0.95 Group Taking Metoprolol Percent of Patients in ASA Group $1,272,696 $1,267,600 0.56 0.94 Taking Metoprolol Mortality Rate Due to Procedure in $1,269,482 $1,270,814 0.01 0.01 ASA Group ASA: alcohol septal ablation, NYHA: New York Heart Association, SoC: standard of Care *Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. Figure E2B. Tornado Diagram of Incremental QALY for Mavacamten versus Septal Ablation ASA: alcohol septal ablation, NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 133 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E10B. Inputs and Results for Mavacamten versus Septal Ablation Incremental QALY Tornado Diagram Low Input High Input Input Lowe QALY Upper QALY Value Value Utility of NYHA Class I for Comparator 3.50 -0.83 0.65 1.00 Utility of NYHA Class I for Mavacamten -2.75 0.21 0.65 1.00 Utility of NYHA Class II for Mavacamten -1.66 0.59 0.66 0.98 Utility of NYHA Class II for Comparator 0.49 -0.63 0.65 0.98 ASA Treatment Effect 0.12 -0.56 0.58 0.96 Mavacamten Treatment Effect -0.45 0.01 0.18 0.31 Utility of NYHA class III and IV for -0.39 -0.06 0.56 0.84 Mavacamten Utility of NYHA class III and IV for -0.16 -0.27 0.56 0.83 Comparator Discount Rate for Outcomes -0.28 -0.17 0.01 0.05 Mortality Rate Due to Procedure in ASA -0.26 -0.18 0.01 0.01 Group ASA: alcohol septal ablation, NYHA: New York Heart Association, SoC: standard of Care *Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. Figures E3A and E3B and Table E11 describe the one-way sensitivity analyses for mavacamten versus disopyramide. Figure E3A. Tornado Diagram of Incremental Cost for Mavacamten versus Disopyramide NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 134 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E11A. Inputs and Results for Mavacamten versus Disopyramide Incremental Cost Tornado Diagram Low Input High Input Input Lower Cost Upper Cost Value Value Discount Rate for Cost $1,365,337 $847,335 0.01 0.05 Mavacamten Treatment Effect $1,097,781 $1,019,765 0.18 0.31 Disopyramide Treatment Effect $1,035,926 $1,081,621 0.21 0.36 Per Cycle Cost of Disopyramide $1,075,272 $1,040,599 $335.65 $497.22 NYHA III Heath State Cost $1,071,779 $1,044,447 $2,299.24 $3,405.99 NYHA II Heath State Cost $1,068,255 $1,048,329 $1,663.84 $2,464.74 NYHA I Heath State Cost $1,051,832 $1,066,420 $611.31 $905.57 Percent of Patients in Mavacamten Group Taking $1,056,163 $1,061,384 0.57 0.95 Metoprolol Percent of Patients in Disopyramide Group $1,062,139 $1,058,499 0.74 1.00 Taking Metoprolol Disopyramide Hospitalization $1,060,368 $1,057,016 $6,963.60 $10,315.56 NYHA: New York Heart Association, SoC: standard of care *Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. Figure E3A. Tornado Diagram of Incremental QALY for Mavacamten versus Disopyramide NYHA: New York Heart Association ©Institute for Clinical and Economic Review, 2021 Page 135 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table E11B. Inputs and Results for Mavacamten versus Disopyramide Incremental QALY Tornado Diagram Lower Upper Low Input High Input Input QALY QALY Value Value Utility of NYHA Class I for Mavacamten -1.84 1.12 0.65 1.00 Utility of NYHA Class II for Comparator 2.49 -0.36 0.65 0.98 Utility of NYHA Class II for Mavacamten -0.75 1.50 0.66 0.98 Utility of NYHA Class I for Comparator 2.10 0.46 0.65 1.00 Utility of NYHA Class III and IV for 1.15 0.30 0.56 0.83 Comparator Mavacamten Treatment Effect 0.46 0.92 0.18 0.31 Discount Rate for Outcomes 0.89 0.55 0.01 0.05 Utility of NYHA Class III and IV for 0.52 0.84 0.56 0.84 Mavacamten Disopyramide Treatment Effect 0.85 0.54 0.21 0.36 NYHA: New York Heart Association, QALY: quality-adjusted life year Figures E4-E7 show results of the probabilistic sensitivity analyses for mavacamten plus standard first-line therapy versus all the comparators. At willingness-to-pay threshold levels under $200,000 per QALY essentially none of the simulations project mavacamten to be cost effective. Even at extremely high willingness-to-pay thresholds the proportion of simulations was not much above half for mavacamten plus first-line therapy being cost effective. All of these incorporated the placeholder price of mavacamten as its average cost. Figure E4. Probabilistic Sensitivity Analysis Results: Cost-Effectiveness Acceptability Curves for Mavacamten and Standard of Care Cost-effectiveness Acceptability Curve Comparing Mavacamten and Standard of Care 1.0000 % Cost-Effective 0.8000 0.6000 0.4000 0.2000 0.0000 $1,000,000 $1,200,000 $1,400,000 $1,600,000 $1,800,000 $2,000,000 $2,200,000 $2,400,000 $2,600,000 $2,800,000 $3,000,000 $3,200,000 $3,400,000 $3,600,000 $3,800,000 $4,000,000 $4,200,000 $4,400,000 $4,600,000 $4,800,000 $5,000,000 $200,000 $400,000 $600,000 $800,000 $0 Willingness-to-Pay Threshold Mavacamten SoC SoC: standard of care ©Institute for Clinical and Economic Review, 2021 Page 136 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure E5. Probabilistic Sensitivity Analysis Results: Cost-Effectiveness Acceptability Curves for Mavacamten and Disopyramide Cost-effectiveness Acceptability Curve Comparing Mavacamten and Disopyramide 1.0000 % Cost-Effective 0.8000 0.6000 0.4000 0.2000 0.0000 $1,000,000 $1,200,000 $1,400,000 $1,600,000 $1,800,000 $2,000,000 $2,200,000 $2,400,000 $2,600,000 $2,800,000 $3,000,000 $3,200,000 $3,400,000 $3,600,000 $3,800,000 $4,000,000 $4,200,000 $4,400,000 $4,600,000 $4,800,000 $5,000,000 $200,000 $400,000 $600,000 $800,000 $0 Willingness-to-Pay Threshold Mavacamten Disopyramide Figure E6. Probabilistic Sensitivity Analysis Results: Cost-Effectiveness Acceptability Curves for Mavacamten and Myectomy Cost-effectiveness Acceptability Curve Comparing Mavacamten and Myectomy 1.0000 % Cost-Effective 0.8000 0.6000 0.4000 0.2000 0.0000 $1,000,000 $1,200,000 $1,400,000 $1,600,000 $1,800,000 $2,000,000 $2,200,000 $2,400,000 $2,600,000 $2,800,000 $3,000,000 $3,200,000 $3,400,000 $3,600,000 $3,800,000 $4,000,000 $4,200,000 $4,400,000 $4,600,000 $4,800,000 $5,000,000 $200,000 $400,000 $600,000 $800,000 $0 Willingness-to-Pay Threshold Mavacamten Myectomy ©Institute for Clinical and Economic Review, 2021 Page 137 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Figure E7. Probabilistic Sensitivity Analysis Results: Cost-Effectiveness Acceptability Curves for Mavacamten and Septal Ablation Cost-effectiveness Acceptability Curve Comparing Mavacamten and ASA 1.0000 % Cost-Effective 0.8000 0.6000 0.4000 0.2000 0.0000 $1,000,000 $1,200,000 $1,400,000 $1,600,000 $1,800,000 $2,000,000 $2,200,000 $2,400,000 $2,600,000 $2,800,000 $3,000,000 $3,200,000 $3,400,000 $3,600,000 $3,800,000 $4,000,000 $4,200,000 $4,400,000 $4,600,000 $4,800,000 $5,000,000 $200,000 $400,000 $600,000 $800,000 $0 Willingness-to-Pay Threshold Mavacamten ASA ASA: alcohol septal ablation E4. Scenario Analyses We included a scenario using a higher mortality rate for patients in NYHA class III/IV. We also included a scenario where NYHA class I was associated with full employment and the other classes with no employment in comparing mavacamten and first-line therapy with first-line therapy alone. In addition, we included a scenario where mavacamten and first-line therapy was associated with full employment and first-line therapy alone was associated with having no employment. In all of them, the incremental cost-effectiveness ratio was higher than standard threshold values. E5. Model Validation Prior Economic Models There were no prior published cost-effectiveness models for HOCM patients. Some of the model inputs were informed by heart failure models available in the literature. In particular, Zueger et al. 2018 used a heart failure model based on NYHA class to project the cost effectiveness of various treatments for heart failure. Our model incorporated the percent difference in non-treatment costs between patients in NYHA II and NYHA III/IV seen in that model in projecting non-treatment related costs for HOCM patients. Our model was also informed by discussions and data provided academic in confidence by modelers employed by Bristol Myers Squibb. However, that model has yet to be published. ©Institute for Clinical and Economic Review, 2021 Page 138 Final Evidence Report – Mavacamten for HCM Return to Table of Contents F. Potential Budget Impact: Supplemental Information Methods We used results from the same model employed for the cost-effectiveness analyses to estimate total potential budget impact. Potential budget impact was defined as the total differential cost of using mavacamten rather than standard therapy for the treated population, calculated as differential health care costs (including drug costs) minus any offsets in these costs from averted health care events. All costs were undiscounted and estimated over one- and five-year time horizons. The five-year timeframe was of primary interest, given the potential for cost offsets to accrue over time and to allow a more realistic impact on the number of patients treated with the new therapy. ICER's methods for estimating potential budget impact are described in detail elsewhere and have recently been updated.65,66 The intent of our revised approach to budgetary impact is to document the percentage of patients that could be treated at selected prices without crossing a budget impact threshold that is aligned with overall growth in the US economy. Using this approach to estimate potential budget impact, we then compared our estimates to an updated budget impact threshold that represents a potential trigger for policy mechanisms to improve affordability, such as changes to pricing, payment, or patient eligibility. As described in ICER's methods presentation (https://icer.org/our-approach/methods-process/value-assessment- framework/), this threshold is based on an underlying assumption that health care costs should not grow much faster than growth in the overall national economy. From this foundational assumption, our potential budget impact threshold is derived using an estimate of growth in US gross domestic product +1%, the average number of new drug approvals by the FDA over the most recent two-year period, and the contribution of spending on retail and facility-based drugs to total health care spending. For 2021-2022, the five-year annualized potential budget impact threshold that should trigger policy actions to manage access and affordability is calculated to total approximately $734 million per year for new drugs. ©Institute for Clinical and Economic Review, 2021 Page 139 Final Evidence Report – Mavacamten for HCM Return to Table of Contents G. Public Comments This section includes summaries of the public comments prepared for the CTAF public meeting on Friday, October 22, 2021. These summaries were prepared by those who delivered the public comments at the meeting and are presented in order of delivery. One speaker did not submit summaries of their public comments. A video recording of all comments can be found here. Conflict of interest (COI) disclosures are included at the bottom of each statement for each speaker who is not employed by a pharmaceutical manufacturer. John Whang, MD, FACC, Bristol Myers Squibb Vice President, US Medical for Cardiovascular and Established Brands Obstructive HCM is a debilitating and life-changing disease, sometimes with symptoms limiting even routine daily activities, substantially impairing health-related quality of life. Currently, there are no available medications that target the underlying pathophysiology of HCM. Surgical intervention can be the final option for patients with symptoms refractory to first-line medications. Therefore, there is a substantial unmet need for novel disease-specific therapies that improve quality of life and potentially slow or reverse disease progression, mitigating the need for surgical intervention. Mavacamten is currently under FDA review for the treatment of symptomatic obstructive hypertrophic cardiomyopathy, also known as HCM. Mavacamten represents the first pharmacological breakthrough for HCM in nearly 35 years, and if approved, would be the first-in- class myosin inhibitor, specifically targeting the underlying pathophysiology of HCM. In EXPLORER- HCM, all primary and secondary endpoints were met with statistical significance, including clinically meaningful improvements in symptoms, peak oxygen consumption, and quality of life, with emerging data suggesting regression of some of the HCM-induced abnormalities in heart muscle structure and function, which is consistent with mechanistic, preclinical data. Mavacamten's safety profile, as reported in the peer-review literature, was generally comparable to that of placebo in EXPLORER-HCM. From the outset, BMS is concerned that ICER's review is premature given the fast-evolving evidence for mavacamten. Should mavacamten receive FDA approval, additional data will become available through peer-reviewed publications. ©Institute for Clinical and Economic Review, 2021 Page 140 Final Evidence Report – Mavacamten for HCM Return to Table of Contents However, even within the specified criteria of this review, ICER's methods remain fundamentally flawed due to two major design decisions: 1) Choice of treatment comparators 2) Assumptions about mortality and disease progression. 1) ICER's comparison of septal reduction therapy (SRT) and disopyramide with mavacamten is incorrect and misleading. The SRT patient population in the ICER model was based on the mavacamten arm of EXPLORER- HCM, in which 72% of patients had NYHA class II symptoms at baseline. The ICER assumption that all of these patients with NYHA class II symptoms would receive SRT is inconsistent with the current AHA/ACC 2020 and ESC 2014 guidelines. As for the disopyramide arm, the baseline NYHA class distribution was based on the Sherrid et al. paper, which means the patient population in the disopyramide arm differed from the other treatment arms in terms of baseline disease severity, quality of life, and health care cost. Furthermore, as acknowledged by ICER, there is insufficient data for a scientifically valid and rigorous comparison of the different treatments. Despite recognizing this limitation, ICER proceeded with an inappropriate comparison between the randomized clinical trial evidence on mavacamten9 and real-world observational evidence on SRT and disopyramide because the true treatment effectiveness of SRT and disopyramide relative to mavacamten are unknown. 2) ICER ignores well-documented evidence on mortality and disease progression in obstructive HCM. As seen in the literature, mortality risk increases with higher NYHA class in HCM. The base-case model assumed there is no difference in mortality risk by NYHA class. While ICER's scenario analysis attempted to account for this difference in mortality risk, the analysis was based on a sample in which most patients had non-obstructive disease, yet mortality risks in obstructive and non- obstructive disease are known to be different. Contradictory to patient experience and cumulative literature, there is no disease progression in any patient after week 32 in ICER's model. While HCM is a heterogenous disease with varied clinical presentation, ICER's model focuses on symptomatic obstructive HCM, and mainly in patients with baseline refractory symptoms despite standard first-line treatment. These patients will likely experience disease progression over their remaining lifetime. Any model that doesn't accurately reflect disease progression cannot accurately predict treatment efficacy. ©Institute for Clinical and Economic Review, 2021 Page 141 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Conclusion BMS is concerned with this premature and flawed evaluation given the fast-evolving evidence for mavacamten and the inappropriate choice of disopyramide and SRT as comparators. ICER's model was further based on invalid clinical assumptions-most notably on mortality and disease progression-that underestimate the disease burden and unmet need that patients face and undermine ICER's ability to accurately estimate treatment health benefits. These and other issues were detailed to ICER by patients, providers, and professional organizations, and were largely ignored. BMS is reiterating and expanding on these concerns today. Dr. Whang is a full-time employee of Bristol Myers Squibb. ©Institute for Clinical and Economic Review, 2021 Page 142 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Billur Ternar Dowse, MSc Retired, Patient Advocate I am a patient with HOCM, who had to retire early after I was diagnosed four years ago. I presented my perspectives from a patient's point of view as well as an informed expert with over 25 plus years of experience in pricing, access, drug evaluations, and outcomes both in the academic medical center and in the pharma industry. I am also a Board Director at HCMA, and our work is purely voluntary. Please correct your slide about my "conflicts of interest." Every meeting we attend and advice/ideas we share are completely provided "free of charge." On Oct 22, I had stated that I have endocarditis, well since then I had major complications. I am providing my comments after coming home from the hospital. I thank ICER for giving me an extension until Nov 15. As a patient: My HOCM manifested itself after a sudden uncontrollable asthma attack. Five months after my diagnosis due to my severe symptoms, and the fast progression of my HOCM, I had to retire early from my job. I was given strict medical orders regarding my limitations. Started on medication therapy which became a cocktail of medications, and into dose escalations to control my symptoms. As a person who never had to take beta blockers and calcium channel blockers before in her life, not only it was very difficult for me to initially handle the impact of these medications and the impact of the daily HOCM symptoms, but it was also quite difficult to describe what it does to the quality of life of a person. It took a good three years to understand what triggered some of the symptoms, and how to cope with them. The way HOCM manifested itself, I had to make major lifestyle changes. This had a major economic impact on my family and my life plans. Social and Indirect Costs: Comprehensive models need to determine what is a meaningful improvement when a new medication is added; and if the magnitude of improvement is meaningful enough to improve the quality of life of the patients. ICER highlights these in Section 5, "Contextual Considerations," and lists all the attributes as a must to be considered when evaluating the "value and effectiveness of mavacamten." I highlighted my major concerns regarding the models in previous feedback sessions. On Oct 22, I emphasized again without including "social and indirect costs" in any of the models and assumptions, and even having reworded your questions, there is insufficient (or no) data available to answer them. I do not feel adequate data appears in the ICER report to achieve a meaningful patient-centric opinion on the value of mavacamten. With so many clinical unknowns, and with so many inaccurate non-real-world pricing assumptions and utilization rates, especially your budget impact model is opening the doors for barriers to access. When deciding the value of mavacamten, please consider the following: It is an "Add-on therapy." Please stop talking about the potential of this being a stand-alone therapy without any real-world or Phase IV data being available. ©Institute for Clinical and Economic Review, 2021 Page 143 Final Evidence Report – Mavacamten for HCM Return to Table of Contents This is a novel first-in-class drug. The clinical trial data is based on a limited time, and under 300 patients are being treated worldwide, however, results are promising for some of the HOCM patients. Please stop expanding the patient base to all HCM or other heart failure patients when there is no data available. Access and affordability are essential to learning about the benefits of this drug. More studies and actual patient experiences are needed to fully understand the long-term benefits of the medicine. Adherence to treatment protocols should not be hindered due to cost. By assigning arbitrarily chosen high price points (it is an orphan drug), you are telling payers to engage in cost-sharing schemes, knowingly as a society, we are pushing patients either to bankruptcy or "go fund me" options. Is this what we call "American medical innovation and advancement of care?" HCM is not all the same. Only specialized cardiologists should determine who the appropriate patient population is to administer this drug and when. HOCM patients want to live the best quality of life possible with a chronic, life-threatening heart condition. When determining the "value of mavacamten," you must find a balance in cost, benefit, affordability, and access to ensure all who need it can benefit from it. We are talking about patients' lives. Thank you! Billur T. Dowse has collaborated with the Hypertrophic Cardiomyopathy Association, which receives 20% of its sponsorship for educational programming from Bristol Myers Squibb/MyoKardia. ©Institute for Clinical and Economic Review, 2021 Page 144 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Pastor Kent Sperry, MDiv Patient Advocate My name is Kent Sperry. I live in Beulah, North Dakota, where I pastor Prince of Peace Lutheran Church. And I was diagnosed with HCM about 11 years ago. Even though my father was diagnosed with it a couple of years before me, and even though the doctors knew what to look for, I was repeatedly told that I was fine even after experiencing the symptoms of this disease. It took a doctor who was new to my area, who had been working at Mayo Clinic and was opening his own practice, to identify it. Not long after my diagnosis, I moved to North Dakota. I immediately established myself as the patient of a cardiologist an hour away from home for ongoing monitoring and treatment. There was no one closer I could see. But, about a year later, when my symptoms suddenly became worse for no apparent reason, he refused to even make me an appointment. It was then that I sought treatment at Mayo Clinic and became familiar with the work of the HCMA. I learned very quickly how important it is to have a specialist who works with this disease on a regular basis. The care that I now receive is wonderful, even though it's not convenient in the least. Receiving this care means that I have to drive about nine hours one way. It necessitates that I take the time off of work to do so. And it usually involves a stay of several days in a motel. This trip is made on a regular basis not only for me. Shortly after my first contact with Mayo Clinic, I was gene tested. The gene responsible for my condition was identified. And this enabled us to test my six children to see which of them inherited this gene. It meant a fight with my insurance company to have this approved. But we learned that three of my six children have this gene. This means that not only am I seen at Mayo Clinic to monitor and treat my condition. My children are also monitored there on a regular basis so that we can know if they develop HCM and treat it from the beginning. Some years we've been able to make this trip and to see our doctors at the same time. Other times, however, it's meant more than one trip. As uncertainty is the name of the game with HCM, I recently experienced a worsening of my condition. For several years, my condition was stable and successfully treated with medication. We changed the dose a few times to keep me feeling well. But my doctor didn't believe I would ever need more aggressive treatment. However, about a year ago, my symptoms drastically worsened. My medication was increased one last time. I was told that I was maxed out on that drug, and it still wasn't doing the job. After being ©Institute for Clinical and Economic Review, 2021 Page 145 Final Evidence Report – Mavacamten for HCM Return to Table of Contents seen once again at Mayo, it was discovered that my septum had grown 8-9 mm and that I was now severely obstructed. So, something had to be done. My options were to join the trial of the very medication being discussed today. However, because of the distance and the requirements of the trial, it was determined that it would be very difficult for me to take part in it. I could try a different medication in combination with the one I was already on, but my doctor believed the chances of this helping me to be slim. The last option presented to me, and the one he recommended, was surgery. About five weeks ago, I traveled to Mayo to have a septal myectomy. Again, this involved the long drive, a longer stay in the motel (especially for my wife), and surgery itself. Had it been easier, I believe that I would have joined the trial. Had the drug been available, I more than likely would've tried it before submitting to surgery. After all, the emotional toll of putting yourself in a position to have your chest cut open, your heart stopped, and a chunk of your heart removed is great. Even knowing it was the right thing to do, the worry that it caused as I awaited the procedure was intense. And this was true even knowing that I had a fantastic surgeon at a great hospital, and that the risks in a high-volume center are very low. From my experience, getting proper medical care for HCM can be both difficult and expensive. Even with the help that insurance provides, this remains the case. While I've made the necessary sacrifices to obtain the proper care for myself and my children, I believe it important to have needed medical treatments that are accessible for everyone who is struggling with this condition. And my hope is that, should they develop HCM, my children will be able to affordably access the needed care. No financial conflicts of interest to disclose. ©Institute for Clinical and Economic Review, 2021 Page 146 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Nikora Groomes, JD Patient Advocate My name is Nikora Groomes, and I am an African American mother, lawyer, and caregiver to twins. My twin son Asaun Groomes has HOCM, and his twin sister could ultimately assess positive for HCM. We hold our breath every three years when she gets tested for HCM. In my profession in health care law, I have written the evidence of coverage for health benefits, rx riders, and cost shares for health plans for Maryland, District of Columbia, and Virginia. When my son was diagnosed with this disease at 15 years old, I immediately was inundated with numerous appointments for MRI, EKGs, and my son was also placed in a special study at NIH to explore his heart genetic mutation. All of this was an enormous amount of time, paperwork, and coordination of care through referrals and appeals. If I were not educated this would have been an even bigger nightmare. My son had a scholarship to play basketball at a private school since eighth grade and traveled the country in the Amateur Athletic league (AAU) to play basketball. One horrific asthma attack on the basketball court found his HCM and saved his life. We were lucky enough to have his HCM diagnosed because the facts are "that young African Americans athletes die of Hypertrophic Cardiomyopathy more than any other subgroup. Therefore, lifesaving medication must be reachable and affordable to diverse and marginalized communities and the care must be able to be attainable to underrepresented individuals. My son initially was cared for at Children's Hospital because that is what the health plan directed. Children's care plan was to do experimental test on my son after fibrosis in his heart was detected. Before agreeing to this experimental surgical treatment on my son, I researched and found the organization HCMA. This organization informed me about Centers of Excellence for individuals with HCM. My husband and I decided our son were not going to be a guinea pig experimented on. His diagnosis already puts his life at risk and an experimental surgery could have killed him sooner. We switched Asaun's care to a "COE," which now required an hour drive to receive care. As a caregiver, I have had to endure the possibility of losing my child to this disease, so I was going to fight for him to get the best medical care. One such fight was that the doctors provided my son with medication and indicated he also needed a portable defibrillator. His disease had not progressed enough for an implantable device. The evidence of coverage indicated my health plan covered the defibrillator however I got pushback from the health plan that it was not covered. I continued to push for this lifesaving device. I was so worried because the average price point of the defibrillator is thousands of dollars out of pocket. After appeals and numerous calls, I won the fight and a defibrillator shipped to my home, but I paid the ultimate price and lost my job. I then had to frantically find insurance and utilized the health care exchanges to ensure my family and myself would have insurance at a specified price point. ©Institute for Clinical and Economic Review, 2021 Page 147 Final Evidence Report – Mavacamten for HCM Return to Table of Contents My son is now a freshman in college. With college, we had to work with accessibility services on campus and utilize the Americans with Disabilities Act to make college safer for my son. He required a single room and several defibrillators added to campus. We also had to create an emergency plan in case he has a SCA. This is the kind of advocacy a mother has to do for her sick child. Co-pays, coinsurance four medication or doctor visits are always evaluated and needed as more care at any given time could be needed. FMLA/Family Medical Leave Act is always necessary as a parent of a child with a genetic heart disease. My son's life matters and if you can provide a medication that is attainable and reachable for him it would be lifesaving. Further, by age 26 my son will have to muster enough strength to get his own medical plan with a preexisting condition and be able to get health care to sustain his life. Do no harm here and create this medication at a price point that is reachable for all and able to make a lifesaving difference for my son and others with this disease. Thank you for taking the time to hear our story. We simply need adequate access to your medication. No financial conflicts of interest to disclose. ©Institute for Clinical and Economic Review, 2021 Page 148 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Lisa Salberg, Hypertrophic Cardiomyopathy Association Founder and CEO I submit these comments after the seven months of work on the review of mavacamten, a novel therapy under review by the FDA for the treatment of hypertrophic obstructive cardiomyopathy. I am the Founder and CEO of the HCMA, a patient advocacy organization in operation since 1996 – 4hcm.org. From 1989 to 2005, I was employed as the health plan administrator for a private plan. I come from a 100+ year history of HCM in my family. I am an HCM survivor of a stroke, endocarditis, five implantable defibrillators, multiple medical therapies, clinical trials, and a heart transplant. Twenty-six years ago, my sister Lori's sudden death at the age of 36 began my work to create the Hypertrophic Cardiomyopathy Association. Lori was a casualty of HCM mismanagement. I currently have eight family members with HCM; the HCMA – my larger family, serves over 15,000 families in 52 nations. The HCMA has helped develop and support 43 HCMA recognized Center of Excellence programs, with 16 on the path to review. HCM used to only be in the headlines when a young athlete died, creating the narrative that this was a fatal problem only for young athletes. The reality is that this is a common genetic disorder impacting as many as one in 250 people worldwide, which is an estimated one million Americans, with highly variable presentations from mild to severely debilitating; sadly, only about 15% of those with HCM are in treatment for it today. HCM has had over 75 names since 1959, with each specific anatomical variation of the expression of hypertrophy leading to nomenclature confusion. What HCM patients want and need is to live the best quality of life possible with a chronic, life- threatening heart condition. They want proven treatments options that are meaningful to them and provide some stability in symptoms, leading to a more predictable quality of life. Mavacamten's trial results show that this is achievable for some of them. Today, we have no labeled indication drugs designed explicitly for HCM targeting the underlying mechanism for HCM. That is why this review has been convened because mavacamten is a very different drug as it targets this previously untreated mechanism – myosin heads within the sarcomere. Data related to the use of off-label use of disopyramide in HCM must be approached with the complete understanding that the name brand – NORPACE CR has not had a stable supply history over the last ten years and is currently "OUT OF STOCK" worldwide. The generic requires dosing every six to eight hours, which creates a challenge for young adults. Patients have been left to manage with drugs developed for other forms of heart disease, which has proved challenging. Other treatment options such as surgical myectomy and catheter-based treatments such as alcohol septal ablation are proven therapeutic options when performed at high- volume centers. Patients may want to use medical therapy over invasive options for many reasons – childcare, work, major life events, caring for elderly parents, career implications, to name a few. From an economic point, these treatments are highly effective for their cost – yet they have risks. ©Institute for Clinical and Economic Review, 2021 Page 149 Final Evidence Report – Mavacamten for HCM Return to Table of Contents HCM is not all the same. HCM spectrum disorders include mimickers, including Danon's, Fabry, amyloidosis, Noonan syndrome, and others, some of which have their own labeled medications. We feel it is critically important for future therapeutics to be administered with the guidance of COE's to ensure the proper patient selection and monitoring into the Phase IV aspect of the study. We need the suitable patients to get the right treatments at the right time. We are very early in our understanding of the role of these agents in the HCM population, and the data is limited at this time, with under 300 patients worldwide being treated. We find ourselves here to discuss the economic impact of an agent into our community and do so from a position we feel is absent of the total effect to the patient community. We do not know yet how this novel medication will truly serve many patients. We know the ICER report has not addressed many of the "contextual considerations," which four patients issued public comments on at the meeting. I assure you patients want access to mavacamten once it is available. They want the chance to try a drug designed for them, which the early data suggests may be life-changing for many. The "right to try" applies beyond unapproved therapies, we believe that when it comes to myosin inhibitors, this concept must apply once it hits the market. We want to ensure HCM patients an opportunity to have access to myosin inhibitors like mavacamten with favorable review and formulary placement once to market. When I first became engaged with ICER, the methods explained sounded very strong. We appreciated being involved early and frankly welcomed the opportunity to help improve the process. We had over 600 patients reply to ICERS "survey." The survey was formatted to ask what it was like to have HCM; it was not well designed to answer the question of economic burden, treatment wishes, or the value of therapeutic options. The ICER draft report stated that there was not ample data to evaluate to determine the impact on patients. If there were an attempt to look to the economic impact of HCM on patients and families, the survey conducted would have been specifically worded to gain understanding, in short, the survey was not well aligned with the community's needs, and five patients were given a total of 30 minutes to fill these gaps in knowledge at a public meeting. This seems inadequate. Patients want and need to live the best quality of life possible with a chronic, life-threatening heart condition-HCM-the ability to have treatment options that are meaningful to them and provide some stability in symptoms, leading to a more predictable quality of life. I caution reviewers and payers fully understand how variable New York Heart Association class can be in HCM patients. NYHA class is a moment in time and varies significantly in the lives of HCM patients with reasons that have not been well defined in the literature. Our social media closed community has over 7,500 participants: This post from 10/19/21 explains what patients experience daily "Last week I could hardly walk without feeling like I was going to pass out, and all I did was ©Institute for Clinical and Economic Review, 2021 Page 150 Final Evidence Report – Mavacamten for HCM Return to Table of Contents huff and puff Spend most of my days in bed. The palpitations were nonstop. So two days ago, I felt great went to target today and walked the whole store." We hear this type of comment daily. Drugs like mavacamten may provide stability in symptom burden, which would be a welcomed change for the HCM community. We welcome myosin inhibitors to the community and hope to be priced, placed favorably on formularies, and market access to ALL patients who may benefit from it, not simply the top 1%. We all want affordable drugs for many diseases, and it is essential to understand that HCM has long been ignored and patients left without meaningful drug options. The cost associated with bringing this to market has been steep, and we, the patient community, cannot ignore the risks taken by the developer nor the risk taken by the new owner of the drug to bring this to the patients. We are all in this together. We must find a balance in cost, benefit, affordability, and access to ensure all who can benefit have the chance to try, without payers pushing the prices to the backs of patients and families struggling to survive physically and economically. I look forward to sharing my experience with the ICER team in the near future to help identify more effective ways to ensure future reviews are improved to include a more realistic view of the economic impact to patients, families, and all Americans. Thank you for your time and consideration. The Hypertrophic Cardiomyopathy Association receives 20% of its sponsorship for educational programming from Bristol Myers Squibb/MyoKardia. ©Institute for Clinical and Economic Review, 2021 Page 151 Final Evidence Report – Mavacamten for HCM Return to Table of Contents H. Conflict of Interest Disclosures Tables H1 through H3 contain COI disclosures for all participants at the Friday, October 22, 2021 public meeting of CTAF. Table H1. ICER Staff and Consultants and COI Disclosures ICER Staff and Consultants Molly Beinfeld, MPH, Senior Research Lead, Evidence David Rind, MD, MSc, Chief Medical Officer, ICER* Synthesis, ICER* Jyotirmoy Sarker, MPharm, MBA, MBiotech, Graduate Laura Cianciolo, Program Manager, ICER* Student, Pharmacy Systems, Outcomes, and Policy, University of Illinois at Chicago* Surrey M. Walton, PhD, MA, Professor, Pharmacy Systems, Outcomes, and Policy; Assistant Director, Center for Maggie Houle, Program and Event Coordinator, ICER* Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago* Jason H. Wasfy, MD, MPhil, Associate Professor, Harvard Medical School; Medical Director, Massachusetts General Emily Nhan, Research Assistant, ICER* Hospital Physicians Organization; Director of Outcomes Research, Massachusetts General Hospital Heart Center* Rasheed Mohammed, PharmD, MPH, Health Technology Melanie Whittington, PhD, Associate Director of Health Assessment Fellow, ICER* Economics, ICER* Steven D. Pearson, MD, MSc, President, ICER *None of the above authors disclosed any conflicts of interest defined as more than $10,000 in health care company stock or more than $5,000 in honoraria or consultancies relevant to this report during the previous year from health care manufacturers or insurers. Table H2. Policy Roundtable Participants and COI Disclosures Policy Roundtable Participant Conflict of Interest Dr. Desai served as an investigator for the VALOR study of Milind Desai, MD, MBA, Director of Clinical Operations, mavacamten sponsored by Bristol Myers Hypertrophic Cardiomyopathy Center, Cleveland Clinic Squibb/MyoKardia. Dr. Maron served as a site investigator for a Phase I study Martin Maron, MD, Director, Hypertrophic Cardiomyopathy of mavacamten and currently serves as a steering Center and Research Institute, Tufts Medical Center committee member for a Phase II study of a second- generation myosin inhibitor sponsored by Cytokinetics. Gwendolyn Mayes serves as a consultant to the Hypertrophic Cardiomyopathy Association, which receives Gwendolyn Mayes, JD, MMSc, Founder and Chief Concept 20% of its sponsorship for educational programming from Officer, GwenCo Health Bristol Myers Squibb/MyoKardia. She also consults for Edwards Lifesciences, Paragonix, and Natural Cycles. Carla McSpadden, RPh, BCGP, MBA, Director, Clinical Carla McSpadden is a full-time employee of Humana. Formulary Strategies, Humana The Hypertrophic Cardiomyopathy Association receives Lisa Salberg, Founder and CEO, Hypertrophic 20% of its sponsorship for educational programming from Cardiomyopathy Association Bristol Myers Squibb/MyoKardia. John Watkins, PharmD, MPH, BCPS, Residency Program John Watkins is a full-time employee of Premera Blue Director, Premera Blue Cross Cross. ©Institute for Clinical and Economic Review, 2021 Page 152 Final Evidence Report – Mavacamten for HCM Return to Table of Contents Table H3. CTAF Member Participants and COI Disclosures Participating Members of CTAF Elizabeth J. Murphy, MD, DPhil, Professor of Clinical Ralph G. Brindis, MD, MPH, MACC, FSCAI, FAHA, Clinical Medicine, UCSF; Chief, Division of Endocrinology and Professor of Medicine, UCSF* Metabolism, Zuckerberg San Francisco General Hospital* Kathryn A. Phillips, PhD, Professor of Health Economics and Felicia Cohn, PhD, Bioethics Director, Kaiser Permanente, Health Services Research; Director and Founder, UCSF Center Orange County; Clinical Professor of Bioethics, Department for Translational and Policy Research on Personalized of Medicine, University of California, Irvine School of Medicine; Department of Clinical Pharmacy/School of Medicine* Pharmacy, UCSF Institute for Health Policy Studies, and UCSF Comprehensive Cancer Center* Rita F. Redberg, MD, MSc, FACC, Cardiologist and Professor Robert Collyar, Patient Advocate in Research* of Medicine and Women's Cardiovascular Services at UCSF* Kimberly Gregory, MD, MPH, Vice Chair, Women's Richard Seiden, JD, Patient Advocate, Retired Partner, Foley Healthcare Quality & Performance Improvement, Cedars- & Lardner LLP* Sinai Medical Center* Paul Heidenreich, MD, MS, Professor of Medicine, Alexander Smith, MD, MPH, Professor of Medicine, UCSF Stanford University School of Medicine* Jeffrey Hoch, PhD, Associate Director, Center for Joanna Smith, LCSW, MPH, CHA, Chief Executive Officer, Healthcare Policy and Research, UC Davis* Healthcare Liaison, Inc.* Anthony Sowry, Patient Advocate and Lead Volunteer, Sei Lee, MD, Associate Professor of Medicine, Division of California, National Patient Advocate Foundation; Senior Vice Geriatrics, UCSF* President, Maritime Container Shipping (Retired)* Joy Melnikow, MD, Director of the Center for Healthcare Policy and Research and Professor of Family and Community Medicine at UCD* *No conflicts of interest to disclose, defined as individual health care stock ownership (including anyone in the member's household) in any company with a product under study, including comparators, at the meeting in excess of $10,000 during the previous year, or any health care consultancy income from the manufacturer of the product or comparators being evaluated. ©Institute for Clinical and Economic Review, 2021 Page 153 Final Evidence Report – Mavacamten for HCM Return to Table of Contents