ICERZ INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW Tezepelumab for Severe Asthma Final Report December 16, 2021 Updated February 13, 2023 Prepared for EV"<e MIDWEST 7 == CEPAC BT COMPARATIVE EFFECTIVENESS PUBLIC ADVISORY COUNCIL New evidence regarding treatments and therapies gets published on an ongoing basis. ICER reached out to key stakeholders included in this review 12 months after the publication of this report giving them an opportunity to submit public comments regarding new relevant evidence or information on coverage that they wish to highlight. Their statements can be found here. ICER has launched ICER Analytics to provide stakeholders an opportunity to work directly with ICER models and examine how changes in parameters would affect results. You can learn more about ICER Analytics here. ©Institute for Clinical and Economic Review, 2021 AUTHORS: ICER Staff and Consultants Modeling Team David M. Rind, MD, MSc Chief Medical Officer ICER Jon Campbell, PhD, MS Senior Vice President for Health Economics ICER Belén Herce-Hagiwara, BA Research Assistant, Evidence Synthesis ICER Serina Herron-Smith, BA Senior Research Assistant, Evidence Synthesis ICER Noemi Fluetsch, MPH Research Assistant, Health Economics and Outcomes Research ICER Steven D. Pearson, MD, MSc R. Brett McQueen, PhD Assistant Professor, University of Colorado Anschutz Medical Campus Eric Gutierrez, MPH Statistical Analyst, University of Colorado Anschutz Medical Campus The University of Colorado was responsible for the development of the cost-effectiveness model, interpretation of results, and drafting of the economic sections of this report; the resulting ICER reports do not President necessarily represent the views of the University of ICER Colorado. DATE OF PUBLICATION: December 16, 2021 How to cite this document: Rind DM, McQueen RB, Herron-Smith S, Herce-Hagiwara B, Gutierrez E, Campbell J, Fluetsch N, Pearson SD. Tezepelumab for Severe Asthma; Final Report. Institute for Clinical and Economic Review, December 16, 2021. https://icer.org/wp- content/uploads/2021/05/ICER Severe-Asthma_Final-Evidence-Report 121621.pdf David Rind served as the lead author for the report and wrote the background, comparative clinical effectiveness, other benefits, and contextual considerations sections of the report. Serina Herron- Smith and Belén Herce-Hagiwara led the systematic review and contributed to the associated sections in the comparative clinical effectiveness chapter. Brett McQueen and Eric Gutierrez developed the cost-effectiveness model and authored the corresponding sections of the report. Noemi Fluetsch conducted the potential budget impact analysis. Jon Campbell provided methods guidance and model validation for the cost-effectiveness and budget impact modeling efforts. Steven Pearson provided methodologic guidance on the clinical and economic evaluations. We would also like to thank Cat Koola, Ashton Moradi, and Monica Frederick for their contributions to this report. OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Pagei 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/PBMs and life science companies. Life science companies relevant to this review who participate in this program include: AstraZeneca, Genentech, Sanofi, and Regeneron. 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 Midwest CEPAC The Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) - 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. Midwest CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. The Midwest CEPAC is an independent committee of medical evidence experts from across the Midwest, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All Council 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 Midwest CEPAC is available at https://icer.org/who-we-are/people/independent-appraisal- committees/midwest-comparative-effectiveness-public-advisory-council-m-cepac/. 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. ©lInstitute for Clinical and Economic Review, 2021 Page ii Final Report - Severe Asthma 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. It is possible that expert reviewers may not have had the opportunity to review all portions of this 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 dffiliated researchers. For a complete list of stakeholders from whom we requested input, please visit: https://icer.org/wp- content/uploads/2021/05/ICER_Severe-Asthma_Stakeholder List 050621.pdf Expert Reviewers Kaharu Sumino, MD, MPH Associate Professor of Medicine Washington University School of Medicine No relevant conflicts of interest to disclose, defined as more than 510,000 in health care company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. Michael E Wechsler, MD Professor of Medicine, Director NJH Cohen Family Asthma Institute National Jewish Health Dr. Michael Wechsler has received consulting fees and honoraria from the following health care companies: AstraZeneca, Amgen, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Regeneron, and Sanofi. ©lnstitute for Clinical and Economic Review, 2021 Page iii Final Report - Severe Asthma EXECULIVE SUMMIAIY ... cccccaciaaaiiiiii e e et e ee e e e e et e e e e e e e e e e e e et et e et e e e et e e aeeaessassssssssssssssssnsnnansnnnnnnn ES1 1. BaCKBIOUNM ....eeeeieecieecceenciie s s s e s s es e se et e s s m e e s e e s e me e e e as e s sen e e ne e e e arasamee s neeneneasaneenananenns 1 2. Patient and Caregiver PErspeCtiVes ..........cccoicrierccrriniir e scseeeseeessseresesee e s s e e s s e e s ses e s neasssmnesenenens 3 3. Comparative Clinical EffeCtiVENESS ......cuvvirvreiiirciieiiirisire s rrrseersrscseerreeseseessssssssessssssesssssssssessesnsseesss 4 3.1. Methods OVEIVIEW.......cccoiimiiirei i receereece et s ae e s s s n e st sne e 4 5 07 =T 1] P 6 3.3. SuMmMary and COMMENT ... ..ottt e e e s s e st e s e sar e s ea e e sneees et e s aeneseneasannananenens 11 4. LoNg-Term CoSt-EffeCtiVENESS. ... ccovuiiiieeieecieecteeeee ettt st et e e seessae e et e s saesae s se e e s e s eae e s s aeanaan 15 I Y =T d o To o E =T T S 15 Target POPUIGTION......co ettt rcrr et s e e e s er e st e s e e e s se e s e en e s e e e e smeananenenane 16 INEEIVENTIONS ..ottt s 17 COMPATALOLS .....cccciiiiiiiiiecceeece e e e e aaanemmmmmaaess e rrrrrrrrrassrssssssssrssrssssassssssrssrssssaranaaaaaaaasaaaaaaaaas 17 4.2. Key Model Assumptions and INPULS .......cccccereerriiimrerrririrrinrrserrisessereeresssssesssssseesssssssesssssssresses 17 I TR 0] ] L (3OS RO 22 4.4 Summary and COMMENT ..o iere e e e e e et e e e e e et e eeame e e e ceeeeemeeeeameeeeaneeeameeeeameeeenns 26 5. Contextual Considerations and Potential Other Benefits.........ccccvveriivenniiinninceeeee 27 6. Health Benefit Price BenChmMarks ..ot 31 7. Potential BUAZEt IMPACT .....ccevrieiiiiericirr s ircveteerccetee s rissssresssssss s e e sessseeeseesseesssssssnessssssnsessssnnseeseesnsees 32 7.1. Overview Of KeY ASSUMPLIONS ...c.viivvverrircrerrerciireeerrssneerisesssreessssseeressssssnsesssssssessssssessssssssseeses 32 728 U= P I 33 3 o [Ton VN 2 1=Teto T 0 o T4 =T g o = A o 4T3 35 REFEIENCES ...t s s s s et s s ae s e s s s s n e ae s n e e s ne s 43 A. Background: Supplemental INformation ..........ccccceciniincencenctecees e s s eee s Al AL DefinitioNS....coceeiececcceei s Al A2. Potential Cost-Saving Measures in Severe Asthma............oovcircvnrcccn e A3 B. Patient Perspectives: Supplemental INformation..........cceeceeceeeceensenccccceene e B1 23T = T T L R B1 C. Clinical GUIAEIINES ....coeeiieiiiiiiii ittt sae s st a e s s s s s s a s san s C1 D. Comparative Clinical Effectiveness: Supplemental Information.........ccccccccvrnmmnrnniincceecseenceenceenne D1 D1. Detailed Methods ...t e s e s s s ns e D1 OInstitute for Clinical and Economic Review, 2021 Pageiv Final Report - Severe Asthma D2. Additional CliNICAl EVI@NCE....iiiiiieeeeeeeieeeeieeeeieeeerirrreeereersrrreeeeeeereeeeeeeeeeessssssssssssssssssssssnnsssssnnen D10 D3. Evidence TabIes ..ot e D23 DA. ONGOING STUIES ... eeiciririeiieecieeeeee et e s e ere e s s e e e e sar e s e ses e s e e s e sar e senar e e sene s e eneasaneasananennes D57 D5. Previous Systematic Reviews and Technology AsSESSMENTS ......cccccvcceerrierrmerrrsrererrsreeerreenee D64 E. Long-Term Cost-Effectiveness: Supplemental Information..........cccccvecveveniimnnnncss e El E1l. Detailed Methods.........ccccommmmmmiiiiiiirc s e El E2. Model Inputs and ASSUMPLIONS ....c.ccciiriiiieiiereirireercrercseees e sescr e s e ee e s e s e e seen e s e e e essmeaneenenane E2 At B O Y ittt SEa e e e e eae e A S e e e e e e SRREEeee e e e e anaeaaaeeaaaas E8 IMIBAN e R e e ReE e e SRR R RS e e s n e aa e e e s ES R 01U o= TS E8 E3. RESUIES ..ttt E8 E4. SENSITIVITY ANGIYSES couueeieeiiieerrrircreterrereeerrssrneeersssernnresesssseessssssseesssssneeesssnssnnessnssssneesessnsessasans E10 E5. SCENAIIO ANAIYSES...ciiueeieiiireieerrircierrrrsreerrrsereeer s rsssseeeessssneeerssssereessssasesssasssnneessssssneesessnnessnsns E12 E6. Heterogeneity and SUDBIOUPS ...ttt rer e s E14 E7. MOdel Validation..... oot E14 F. Potential Budget Impact: Supplemental INformation.......ccccccvvvcvcerrrrvrerrcrcrreeeeercreererrreeerersesseeeenas F1 MELROMS ... e F1 RESUIES ...t s F2 LG V] o] To e 4o 0 =T 0 £ G1 H. Conflict of Interest DISCIOSUIES..........coeiieiriietiirr et H1 O©Institute for Clinical and Economic Review,2021 Pagev Final Report - Severe Asthma List of Acronyms and Abbreviations Used in this Report AAER ACQ AE AHRQ AQLQ CDC Cl ED evLY FEV1 ICS LABA MCID ocCs OR SoC SLR RCT RR TSLP QALY Annualized Asthma Exacerbation Rate Asthma Control Questionnaire Adverse Event Agency for Healthcare Research and Quality Asthma Quality of Life Questionnaire Centers for Disease Control and Prevention Confidence Interval Emergency Department Equal Value Life Year Forced Expiratory volume in one second Inhaled Corticosteroids Long-Acting Beta Agonist Minimal Clinically Important Differences Oral Corticosteroids Odds Ratio Standard of Care Systematic Literature Review Randomized Controlled Trial Rate Ratio Thymic Stromal Lymphopoietin Quality Adjusted Life Year OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page vi Executive Summary The Centers for Disease Control and Prevention (CDC) estimates that 25 million Americans, including 5 million children, have asthma. Asthma leads to approximately 1.6 million emergency room visits, 180,000 hospitalizations, and 3,500 deaths each year in the US.12 The societal costs are estimated to be $82 billion, including $50 billion in direct medical costs, $29 billion from asthma- related mortality, and $3 billion from missed work and school.? In the US, asthma is more than twice as common among Black children as among White children (13.5% and 6.4%, respectively), and remains somewhat more common among Black adults.? Patients with severe asthma represent fewer than 5-10% of all individuals with asthma.? Asthma has been divided into different phenotypes with some overlap. About half of individuals with mild- to-moderate asthma exhibit the type 2 phenotype, and the proportion is believed to be larger in severe asthma.* Allergic asthma and eosinophilic asthma are generally forms of type 2 asthma.> None of the five biologic therapies that ICER reviewed in 2018 appeared to be effective for patients who had neither allergic asthma nor eosinophilia. Tezepelumab is a new monoclonal antibody that targets thymic stromal lymphopoietin (TSLP).® It is administered by subcutaneous injection every four weeks. In this report, we review the clinical effectiveness of tezepelumab for severe asthma and also compare it with agents indicated for certain subpopulations: 1) omalizumab for patients with allergic asthma; and 2) dupilumab for patients with eosinophilic asthma. We also compare the efficacy of tezepelumab and dupilumab in patients dependent on chronic oral corticosteroids. Patients, patient groups, and clinicians have emphasized the need for treatments that allow patients to return to their usual activities of daily living. Symptom relief, asthma control, and quality of life matter much more to patients than a reduction in asthma exacerbations. In two randomized trials in a broad population of patients with severe asthma, tezepelumab improved symptom scores compared with placebo, but these improvements (0.20 to 0.34) were smaller than the minimal clinically important differences (MCIDs) of 0.5 on these scales.®" However, in both trials, tezepelumab substantially reduced annualized asthma exacerbation rate (AAER) compared with placebo {RR 0.29 to 0.44).57 For patients with eosinophilic asthma, improvements in symptom scores and reductions in AAER were similar to the results seen with dupilumab. For patients with allergic asthma, improvements in symptoms were similar to those seen in older trials of omalizumab while reductions in AAER were somewhat greater than with omalizumab. Patients with non-eosinophilic asthma treated with tezepelumab showed similar improvements in symptom scores to patients with eosinophilic asthma in one of the two randomized trials, and only minimal improvement in the other trial. In one of the ©Institute for Clinical and Economic Review, 2021 Page 1 Final Report - Severe Asthma Return to Table of Contents two randomized trials, patients with non-eosinophilic asthma had larger reductions in AAER than those with eosinophilic asthma, while in the other randomized trial, reductions in AAER were smaller in such patients, but still appeared to be clinically meaningful. In a separate randomized trial of tezepelumab in patients with steroid-dependent asthma, patients treated with tezepelumab were not more likely to reduce their oral corticosteroid (OCS) dose at week 48 than patients treated with placebo (odds ratio [OR] 1.28, 95% Cl 0.69 to 2.35).% In contrast, a randomized trial of dupilumab found a greater reduction in OCS dose compared with placebo (70% vs 42%; p<0.001), and more patients had a reduction of OCS dose of at least 50% (80% vs. 50%; p<0.001). In all trials, adverse events with tezepelumab did not appear to be significantly different from placebo.®' This is also true of dupilumab,'® and long-term studies of dupilumab provide additional evidence of safety.'11? Adverse events with omalizumab are uncommon,'® however omalizumab carries a "black box" warning for anaphylaxis.3 Important uncertainties include the lack of head-to-head trials of these agents, the lack of longer term data on safety of the new mechanism of action of tezepelumab, and the inability to evaluate subpopulation effects among racial groups given the notable paucity of Black patients in the trials of tezepelumab; at least some trials of dupilumab and omalizumab had participation of Black patients closer to their percentages in the US population. Overall, given the strength of evidence in different patient groups, ICER's ratings for comparative clinical effectiveness are as shown below. Table ES1. Evidence Ratings Treatment Comparator Population Evidence Rating Tezepelumab Standard of care All Patients With Severe Asthma C++ Tezepelumab Dupilumab Eosinophilic Asthma | Tezepelumab Omalizumab Allergic Asthma | Tezepelumab Dupilumab Steroid-Dependent Asthma C- We performed an economic analysis of tezepelumab in the broad population of patients with severe asthma. Treatment with tezepelumab results in gains of 1.09 QALYs and 1.12 evLYs. From a health system perspective and using a placeholder net price of approximately $28,000 per year, we estimate a cost of $430,000 per QALY gained and $422,000 per evLY gained, which would exceed usual cost-effectiveness thresholds. Cost-effectiveness is only modestly improved when productivity and other broader effects are included within a modified societal perspective. The Health Benefit Price Benchmark (HBPB) for a drug is defined as the price range that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY or per evlY gained. The HBPB of tezepelumab is $9,000 to $12,100 per year. OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 2 Return to Table of Contents In summary, tezepelumab reduces exacerbations in patients with severe asthma, including in some types of asthma for which other biologic therapies are not effective. Because severe asthma is more prevalent among Black Americans, health gains from a successful treatment that has consistent benefits across racial subgroups would provide proportionally greater benefit to that racial group on a population basis. As discussed above, however, studies have not adequately enrolled Black Americans to demonstrate such a consistent effect. Additionally, as with other biologic therapies, improvements in daily symptoms and quality of life are relatively small. Pricing for tezepelumab is not yet known but at anticipated prices, the treatment will not reach traditional thresholds considered cost-effective in the US market. 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. e All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with severe asthma are introduced in a way that will help reduce health inequities. e Payers will need to consider subpopulations of people with severe asthma when designing coverage policies for tezepelumab and other biologics. e For tezepelumab and other biologics for severe asthma, payers should meet criteria for fair access, including criteria related to cost sharing, clinical eligibility, step therapy, and provider qualifications. e Payers should recognize that step therapy has generally not been used for biologic therapy in asthma. Individual biologic therapies frequently fail and so all options using different mechanisms of action should be available to patients with asthma. ¢ Biologic therapies for asthma are expensive; prices should be reduced. e Researchers looking at real world evidence in treatments of asthma should be aware of potential threats to validity, including selection bias. ©Institute for Clinical and Economic Review, 2021 Page 3 Final Report - Severe Asthma Return to Table of Contents 1. Background This Report incorporates information and language from prior ICER reviews of asthma in 2016 and 2018. The Centers for Disease Control and Prevention (CDC) estimates that 25 million Americans, including 5 million children, have asthma.> Asthma causes the airways of the lungs to narrow or become blocked, making it hard to breathe. Many processes contribute to the narrowing, including tightening of the muscles around the airways, inflamed tissue lining the airways, and mucous plugging of the airways. The disease follows a waxing and waning course with exacerbations initiated by allergens, cold weather, exercise, pollution, and other triggers. This leads to approximately 10 million office visits, 1.6 million emergency room visits, 180,000 hospitalizations, and 3,500 deaths each year in the US.** The societal costs are estimated to be $82 billion including $50 billion in direct medical costs, $29 billion from asthma-related mortality, and $3 billion from missed work and school.? In the US, asthma is more than twice as common among Black children as among white children (13.5% and 6.4%, respectively), and remains somewhat more common among Black adults.? Severe asthma comprises a small but important subset of all individuals with asthma. Those with severe asthma represent fewer than 5-10% of all individuals with asthma but account for a substantial proportion of all asthma costs.*>'* In addition to being treated with inhaled corticosteroids (ICS) and long-acting beta agonist (LABA) therapy, these patients are often treated with oral corticosteroids (OCS).% Asthma has been divided into different phenotypes with some overlap. T helper 2 (Th2) cells secrete interleukin {IL)-4, IL-5, and IL-13, which increase the proliferation, survival and recruitment of eosinophils and increase IgE levels.*!¢ About half of individuals with mild-to-moderate asthma exhibit the type 2 phenotype with increases in Th2 cells, and the proportion with this phenotype is believed to be larger in severe asthma.* Allergic asthma, which is associated with allergic rhinitis, atopy, and elevated IgE levels, is characteristic of approximately half of all patients with asthma and is generally a form of type 2 asthma.> The ICER report in 2018 reviewed five monoclonal antibodies that primarily targeted pathways involved in the allergic or type 2 inflammatory phenotypes of asthma. At that time, none of the biologic therapies appeared to be effective for patients who had neither allergic asthma nor eosinophilia. Tezepelumab is a new monoclonal antibody that targets thymic stromal lymphopoietin (TSLP); TSLP is believed to play important roles in type 2 immunity but, also in other inflammatory pathways (see Figure A1).>® It is administered by subcutaneous injection every four weeks (see Table D2.1).>5 By targeting a new pathway, tezepelumab may provide a new option both for patients for whom prior monoclonal antibodies were indicated but did not work, and also for the large number of patients ©Ilnstitute for Clinical and Economic Review, 2021 Page 1 Final Report - Severe Asthma Return to Table of Contents for whom existing monoclonal antibodies are not indicated. The US Food and Drug Administration granted breakthrough therapy designation to tezepelumab for the treatment of patients with severe asthma without an eosinophilic phenotype,'" and an FDA decision is expected near the end of 2021. Additional background information and definitions are available in the Supplement. ©Ilnstitute for Clinical and Economic Review, 2021 Page 2 Final Report - Severe Asthma Return to Table of Contents 2. Patient and Caregiver Perspectives This Report was developed with input from diverse stakeholders, including patient groups, patients, clinicians, researchers, and manufacturers of the agents of focus in this review. This document incorporates feedback gathered during calls with stakeholders and open input submissions from the public. ICER looks forward to continued engagement with stakeholders throughout its review and encourages comments to refine our understanding of the clinical effectiveness and value of preventive treatments. ICER, both for this report, and for prior reports, has heard from patients, patient groups, and clinicians about the need for treatments that allow patients to return to their usual activities of daily living. Symptom relief, asthma control, and quality of life matter much more to patients than a reduction in asthma exacerbations. The majority of patients with severe asthma report having symptoms more than once a day and being scared and burdened by their symptoms. They report that their asthma prevents them from living the life that they want to live. The patients report that it also impacts their loved ones: they report that their asthma is a burden to their family and that their caregivers are scared about the possible consequences of asthma. They also have learned to fear the side effects of corticosteroids and want to minimize the use of both systemic and inhaled corticosteroids as much as possible. We also heard about the excess burdens that asthma places on patients marginalized by society, both because of racism and because of economic inequality. We heard specific concerns that underrepresentation of marginalized groups in clinical trials is a problem in general and for the ICER Report in particular, and that ICER should highlight this issue and its implications for results and conclusions in the Evidence Report. ©Ilnstitute for Clinical and Economic Review, 2021 Page 3 Final Report - Severe Asthma Return to Table of Contents 3. Comparative Clinical Effectiveness 3.1. Methods Overview Procedures for the systematic literature review (SLR) assessing the evidence of tezepelumab, dupilumab, and omalizumab in severe asthma are described in Supplement D1. Scope of Review We reviewed the clinical effectiveness of tezepelumab plus usual care compared with usual care alone in adults and adolescents with severe asthma. We also reviewed the comparative effectiveness of tezepelumab and omalizumab in the subgroup of these patients for whom omalizumab is indicated (allergic asthma) and tezepelumab and dupilumab in the subgroup of these patients for whom dupilumab is indicated {eosinophilic asthma and asthma requiring chronic systemic corticosteroids). In ICER's 2018 Review, 3¢ we found insufficient evidence to distinguish the net benefit of the four treatments for eosinophilic asthma (mepolizumab, reslizumab, benralizumab, and dupilumab), so for this review, rather than comparing tezepelumab to all four treatments, we chose to compare only to dupilumab, given its broader indication for steroid- dependent asthma. We sought evidence on patient-important outcomes including daily quality of life/daily symptom:s, requirements for oral corticosteroids (OCS), and exacerbations, and also on physiologic measures of pulmonary function. The full scope of the review is detailed in the Supplement. Evidence Base Tezepelumab Our search identified a total of 10 references arising from three randomized controlled trials of tezepelumab. Additional details of the study designs can be found in the Supplement D2. The key randomized trials of tezepelumab are the phase 2 PATHWAY trial,® the phase 3 NAVIGATOR trial," and the phase 3 SOURCE trial ® PATHWAY compared low (70 mg every four weeks), medium (210 mg every four weeks), and high (280 mg every two weeks) dose tezepelumab with placebo in 550 adults with uncontrolled asthma.® The primary endpoint was the annualized asthma exacerbation rate (AAER) at 52 weeks. We will focus on the medium dose of tezepelumab. Additional information on this trial is provided in the Supplement D2. ©Institute for Clinical and Economic Review, 2021 Page 4 Final Report - Severe Asthma Return to Table of Contents NAVIGATOR randomized 1061 adult and adolescent patients with severe, uncontrolled asthma to receive tezepelumab 210 mg every 4 weeks or placebo for 52 weeks." The primary endpoint was AAER. Additional information on this trial is provided in the Supplement D2. SOURCE randomized 150 adult patients with severe, oral corticosteroid (OCS)-dependent asthma to receive tezepelumab 210 mg every 4 weeks or placebo for 48 weeks.? The primary endpoint was the categorized percentage reduction in daily OCS dose at week 48 without loss of asthma control. Additional information on this trial is provided in the Supplement D2. Dupilumab When used to treat eosinophilic asthma, dupilumab is approved at doses of 200 mg every two weeks and 300 mg every two weeks. An unnamed phase 2b trial of dupilumab included both those dosing regimens (as well as two other dosing regimens) with 150 patients assigned to receive 200 mg every two weeks, 157 patients assigned to receive 300 mg every two weeks, and 158 patients assigned to receive placebo.!® Patients had uncontrolled, persistent asthma. LIBERTY ASTHMA QUEST (QUEST) randomized 1902 adults and adolescents with moderate-to- severe uncontrolled asthma to receive one of those two dosing regimens or one of two matched placebo regimens (with different volumes of placebo to match the different dupilumab dosing arms), with twice as many patients receiving dupilumab as placebo.'® Additional information on this trial is provided in the Supplement D2. In an analysis that combined the dosing regimens from QUEST and examined the subgroup of patients with eosinophils 2150 cells/pL, there were 889 such patients treated with dupilumab and 469 treated with placebo.?® LIBERTY ASTHMA VENTURE (VENTURE) randomized 210 adults and adolescents with OCS- dependent asthma to dupilumab 300 mg every two weeks or placebo for 24 weeks.® Steroid dosing was adjusted prior to randomization and then held steady for four weeks before being adjusted downward according to protocol through week 20. The primary endpoint was the percentage reduction in glucocorticoid dose at week 24. Additional information on this trial is provided in the Supplement D2. Omalizumab Omalizumab was first approved by the FDA in 2003,2! and so much of the evidence base was generated when standards of care for the management of asthma were different from those today. ICER's 2018 evidence report included seven placebo-controlled trials of omalizumab in patients with ©Institute for Clinical and Economic Review, 2021 Page 5 Final Report - Severe Asthma Return to Table of Contents allergic asthma;?%28 the results from those trials in that report are presented below. Additional information on these trials is provided in the Supplement D2. 3.2. Results Clinical Benefits The definition of an asthma exacerbation varied somewhat across trials (see Supplement A1), but generally counted worsening of asthma that led to: hospitalization; or an emergency department visit for where systemic glucocorticoids were administered; or treatment with systemic glucocorticoids for three or more days. Tezepelumab Additional results are available in the Supplement D2. In this main report, we focus on treatment with tezepelumab 210 mg every four weeks and present results from PATHWAY (adults with uncontrolled asthma), NAVIGATOR (adults and adolescents with severe, uncontrolled asthma), and SOURCE (adults with severe, OCS-dependent asthma). Results from all three trials inform the key outcomes presented in the main report of daily symptoms and quality of life and exacerbation rate. Subgroup results from PATHWAY and NAVIGATOR examine these outcomes in patients with eosinophilic asthma (to match the approved population for dupilumab) and allergic asthma (to match the approved population for omalizumab). Last, we present results from SOURCE on tezepelumab for OCS-dependent asthma (also an approved indication for dupilumab), as this trial has the best evidence for the outcome of reduction of OCS requirements. Daily Symptoms and Quality of Life The six-item Asthma Control Questionnaire (ACQ-6) averages responses to six questions on a zero- to-six scale with lower numbers indicating better disease control; the minimal clinically important difference (MCID) is considered to be 0.5.2° The Asthma Quality of Life Questionnaire averages responses to 32 questions on a one-to-seven scale with higher numbers indicating better asthma- related quality of life; the MCID is considered to be 0.5.3° In PATHWAY at 52 weeks, the decrease in ACQ-6 from baseline with tezepelumab was greater than with placebo but smaller than the MCID (-1.20 vs. -0.91; diff 0.29, 95% Cl 0.01 to 0.56).% The increase in AQLQ was not statistically significantly different from placebo (1.17 vs. 0.97; diff 0.20, Cl -0.09 to 0.48). In NAVIGATOR at 52 weeks, the decrease in ACQ-6 from baseline with tezepelumab was greater than with placebo but smaller than the MCID (-1.55 vs. -1.22; diff 0.33, C1 0.20 to 0.46)." The ©Institute for Clinical and Economic Review, 2021 Page 6 Final Report - Severe Asthma Return to Table of Contents increase in AQLQ was greater with tezepelumab than with placebo but smaller than the MCID (1.49 vs. 1.15; diff 0.34, Cl 0.20 to 0.47). In SOURCE at 48 weeks, the decrease in ACQ-6 with tezepelumab was not statistically significantly different from placebo (-0.87 vs. -0.51; diff 0.37, Cl -0.02 to 0.71).2 Annualized Asthma Exacerbation Rate (AAER) In PATHWAY, the AAER was lower with tezepelumab compared with placebo (0.20 vs. 0.72; rate ratio [RR] 0.29, 95% C1 0.16 to 0.51).% Reductions in the AAER were also seen in NAVIGATOR (0.93 vs. 2.10; RR 0.44, C1 0.37 to 0.53). 7 In SOURCE, in patients with OCS-dependent asthma, there was no statistically significant reduction in AAER (RR 0.69, Cl 0.44 to 1.09).2 Subgroups To examine effects in eosinophilic asthma, we present in Table 3.1 the above outcomes with tezepelumab in patients with baseline eosinophil counts <150 cells/puL and 2150 cells/uL to match a typical definition used. Of note, the primary outcome of reduction in AAER was numerically greater in patients without than with eosinophilia in PATHWAY while the reverse pattern was seen in NAVIGATOR.3! To examine results in allergic asthma, we present in Table 3.2 the data on tezepelumab in patients with a positive or negative serum IgE result specific to any perennial aeroallergen. A positive IgE result typically defines allergic asthma. Table 3.1. Key Outcomes at Week 52 by Blood Eosinophil Count Blood Eosinophil Trial Reduction in AAER Difference in ACQ-6 Difference in AQLQ Count (cells/pL) vs. Placebo (RR) vs. Placebo vs. Placebo 5150 PATHWAY 0.34 -0.35 0.29 NAVIGATOR 0.39 -0.41 041 <150 PATHWAY 0.17 -0.30 0.44 NAVIGATOR 0.61 -0.09 0.11 Data provided by Amgen.?! AAER: annualized asthma exacerbation rate, ACQ-6: Asthma Control Questionnaire-6, AQLQ: Asthma Quality of Life Questionnaire, RR: rate ratio Table 3.2. Key Outcomes at Week 52 by Serum IgE Specific to any Perennial Aeroallergen Serum IgE Trial Reduction in AAER Difference in ACQ-6 Difference in AQLQ vs. Placebo (RR) vs. Placebo vs. Placebo Positive PATHWAY 0.20 -0.10 0.07 NAVIGATOR 0.42 0.29 0.34 Negative PATHWAY 0.34 -0.59 0.66 NAVIGATOR 0.49 -0.42 0.36 Data provided by Amgen.3! AAER: annualized asthma exacerbation rate, ACQ-6: Asthma Control Questionnaire-6, AQLQ: Asthma Quality of Life Questionnaire, RR: rate ratio OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 7 Return to Table of Contents Reduction in OCS Requirements In SOURCE, patients treated with tezepelumab were not more likely to reduce their OCS dose at week 48 than patients treated with placebo (odds ratio [OR] 1.28, 95% Cl 0.69 to 2.35).8 Dupilumab Additional results are available in the Supplement D2. Dupilumab is indicated for adults and adolescents with moderate-to-severe asthma and either an eosinophilic phenotype or OCS dependence.?? Although an exact definition of eosinophilic asthma does not appear in the label, a cutoff of 2150 cells/pL is typically used. Outcomes of daily symptoms and quality of life and AAER in the subgroup of patients with eosinophilic asthma are available from the QUEST trial but not, at this cut point, for the unnamed phase 2b trial. Baseline eosinophil status cannot be assessed accurately in patients on chronic OCS (as in the VENTURE trial). The VENTURE trial provides the best evidence on dupilumab's effects on reducing OCS requirements. Daily Symptoms and Quality of Life Across the phase 2b trial and QUEST, as described in ICER's 2018 report and looking at patients across all eosinophil levels, the mean improvements in ACQ and AQLQ were greater with dupilumab 200 mg than with placebo (diff 0.39, 95% Cl 0.25 to 0.53 and 0.29, Cl 0.15 to 0.44, respectively), but the difference from placebo was smaller than the MCID.1® Similar results were seen with the 300 mg dose (diff 0.22, Cl 0.08 to 0.36 and 0.26, Cl 0.12 to 0.40, respectively). In the analysis looking at patients with eosinophilic asthma from QUEST, reduction in ACQ-5 from baseline was greater with dupilumab than with placebo (-1.47 vs -1.13, diff 0.34, p<0.001), but smaller than the MCID.%° In patients with OCS-dependent asthma in VENTURE, the decrease in ACQ-5 score from baseline was greater with dupilumab than with placebo (diff 0.47, Cl1 0.18 to 0.76) but smaller than the MCID.? Annualized Asthma Exacerbation Rate (AAER) Across the phase 2b trial and QUEST, dupilumab 200 mg and 300 mg reduced the rate of exacerbations compared with placebo (RR 0.44, 95% Cl 0.34 to 0.58 and 0.40, C1 0.31 to 0.53, respectively).®? In the analysis looking at patients with eosinophilic asthma from QUEST, patients treated with dupilumab had fewer exacerbations than those treated with placebo (0.44 vs 1.05, RR 0.42, p<0.001).%° ©lnstitute for Clinical and Economic Review, 2021 Page 8 Final Report - Severe Asthma Return to Table of Contents VENTURE assessed the rate of severe exacerbation events (those leading to hospitalization, an ED visit, or treatment for three or more days with systemic glucocorticoids at two or more times the current dose of OCS in patients with OCS-dependent asthma.® Patients treated with dupilumab had fewer such exacerbations than those treated with placebo (0.65 vs. 1.60; RR 0.41, Cl 0.26 to 0.63) Reduction in OCS Requirements In VENTURE, the reduction in OCS dose was greater with dupilumab than with placebo (70% vs 42%; p<0.001).° More patients treated with dupilumab also had a reduction from baseline OCS dose of at least 50% (80% vs. 50%,; p<0.001) and had a reduction in OCS dose to less than 5 mg/day (69% vs. 33%). Omalizumab Additional results are available in the Supplement D2. Omalizumab is indicated for patients with allergic asthma, defined as having a positive skin test or in vitro testing demonstrating reactivity to a perennial aeroallergen.'®* We present results from patients meeting this indication. Daily Symptoms and Quality of Life Across trials, the mean increase in AQLQ with omalizumab was greater than with placebo but smaller than the MCID (diff 0.26, 95% Cl 0.05 to 0.57).1° ACQ results were not available. Annualized Asthma Exacerbation Rate (AAER) Across trials, the rate of asthma exacerbations was lower with omalizumab than with placebo (RR 0.52,95% C10.37 to 0.73).1° Harms Additional results are available in the Supplement D2. In PATHWAY, adverse events, serious adverse events, and events leading to discontinuation of the trial agent were similar between tezepelumab and placebo.® In NAVIGATOR, adverse events, serious adverse events, and events leading to discontinuation were more common with placebo than with tezepelumab." As described in ICER's 2018 report, serious adverse events were similar between dupilumab and placebo. Adverse events leading to discontinuation were lower with the 200 mg dose than placebo but higher with the 300 mg dose than placebo. This was felt to possibly be a chance finding. Open- label extension studies in asthma,! as well as in atopic dermatitis,'? provide evidence suggesting the safety of long-term treatment with dupilumab. ©Ilnstitute for Clinical and Economic Review, 2021 Page 9 Final Report - Severe Asthma Return to Table of Contents As described in ICER's 2018 report, serious adverse events were less common with omalizumab than placebo and adverse events leading to drug discontinuation were similar between omalizumab and placebo. Omalizumab carries a "black box" warning for anaphylaxis.? Subgroup Analyses and Heterogeneity Subgroup effects by race are discussed below. NAVIGATOR included 82 adolescents and the point estimate of reduction in AAER appeared to be smaller than that seen in the group as a whole and was not statistically significant (RR 0.70, 95% Cl 0.34 to 1.46)." Uncertainty and Controversies The lack of head-to-head trials reduces our certainty in comparisons between tezepelumab and the other active therapies in the subgroups for which those therapies have been approved. Populations were not identical across the trials and standards of care have changed, raising the possibility that effects seen in a trial might have been different if used with different background therapy. Additionally, definitions of exacerbations have changed over time, and as medical care has changed it is possible that the likelihood of any particular exacerbation response, whether additions of OCS, referral to an ED, or hospitalization has changed as well. We are more concerned with this issue when comparing trials of omalizumab, most of which were performed many years ago, with more recent trials of tezepelumab For both of these concerns, we are uncertain of the magnitude or directionality of any such effects. Patients treated in randomized trials of biologics typically have very high response rates even in the placebo arms of these trials. One paper noted proportions of patients treated with placebo achieving clinically meaningful improvements across biologics based on ACQ or AQLQ of 61% to 78% and 70% to 77%, respectively.3* The authors raised the possibility that the very high placebo response was due to improved adherence to standard-of-care treatments while patients were being closely followed and monitored in randomized trials. This both suggests the possibility for substantially improving asthma outcomes in many patients through better administration of standard therapies alone, and raises the question of the generalizability of the results from randomized trials of biologics to patients being treated in routine practice. Although we have evidence showing benefits of tezepelumab in patients without eosinophilic asthma and without allergic asthma, we do not have data on the subgroup with neither eosinophilic asthma nor allergic asthma. We asked the manufacturer for data for this subgroup but these data were not provided. As such, we have less certainty about the efficacy of tezepelumab in this subgroup. The trials of tezepelumab (SOURCE) and dupilumab (VENTURE) in OCS-dependent asthma had somewhat different protocols.>*> SOURCE was longer than VENTURE (48-weeks vs. 24 weeks) and ©Ilnstitute for Clinical and Economic Review, 2021 Page 10 Final Report - Severe Asthma Return to Table of Contents did not consider an exacerbation during the dose reduction phase as an endpoint. It is unclear how these differences might have affected the trial results both in terms of magnitude and direction. Additionally, individual arm response rates are not available for SOURCE and so it is not possible to know the comparative response rates in the placebo arms of the two trials. Tezepelumab has a new mechanism of action. In clinical trials to date, serious adverse events have been uncommon, but new biologic treatments are commonly found to have new safety concerns even after FDA approval.® As discussed above, asthma is more common in Black Americans than in most other racial groups in the US. However, in PATHWAY 92.5% of patients were white, and in NAVIGATOR most patients were white or Asian with only 5.8% who were Black.5" Data were not presented from either trial showing outcomes by racial subgroup, and given the small number of Black participants such data would likely be hard to interpret. As such, there are some questions about how the results generalize across important racial subgroups. 3.3. Summary and Comment An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided here. ©lnstitute for Clinical and Economic Review, 2021 Page 11 Final Report - Severe Asthma Return to Table of Contents Figure 3.1. ICER Evidence Rating Matrix Comparative Clinical Effectiveness High Certainty _ Moderate Certainty Level of Certainty in the Evidence Low Certainty | * | * MNegative Comparable Small Substantial Net Benefit Net Benefit Net Benefit Net Benefit Comparative Net Health Benefit A = "Superior" - High certainty of a substantial (moderate-large) net health benefit B = "Incremental" - High certainty of a small net health benefit € = "Comparable™- High certainty of a comparable net health benefit D= "Negative"- High certainty of an inferior net health benefit B+= "Incremental or Better" - Moderate certainty of o small or substantial net health benefit, with high certainty of at least o small net health benefit £+ = "Comparable or Incremental" - Maderate certainty of o comparable or small net heaith benefit, with high certainty of at least a comparable net health benefit C- = "Comparable or Inferior" = Moderate certainly that the net health benefit is either comparable or inferiar with high certainty of at best a comparable net health benefit €+ = "Comparable or Better™ - Moderate certainty of @ comparable, small, or substantial net health benefif, with high certainty of al least o comparable net health benefit P/I = "Pramising but Inconclusive" - Moderate certainty of o smail or substantial net heaith benefit, small (but nonzero) likelihood of a negative net health benefit I = "Insufficlent" - Any situation in which the level of certainty in the evidence is low In the overall population of adults and adolescents with severe, uncontrolled asthma, tezepelumab added to standard-of-care therapy without biologics (as estimated by the placebo arm of the clinical trials) substantially reduces AAER. This is the case even in patients without eosinophilic asthma. However, in both eosinophilic and non-eosinophilic asthma patients the average effects of tezepelumab on daily symptoms and quality of life are small and generally smaller than the minimal clinically important difference (MCID) on scales measuring such outcomes. Improvements in AAER without large improvements in daily symptoms have been seen with other biologic therapies as well. Tezepelumab has a new mechanism of action, targeting TSLP.6 We do not find important safety signals in the clinical trials, but as noted above, new biologic therapies are frequently found to have safety concerns even after drug approval.3® This uncertainty is balanced by the severity of disease in the patients for whom tezepelumab is intended such that we think net harm is unlikely. Additionally, in the absence of longer-term trials, it is uncertain whether benefits may increase or decrease over time. ©Institute for Clinical and Economic Review, 2021 Page 12 Final Report - Severe Asthma Return to Table of Contents On balance, we rate the net health benefit of tezepelumab added to standard-of-care therapy without biologics, compared with standard-of-care therapy alone in adults and adolescents with severe, uncontrolled asthma as "Comparable or Better" (C++). We have somewhat greater uncertainties about the effects in younger patients given the small number of adolescents studied. In the subgroup of patients with eosinophilic asthma, reductions in AAER and (small) improvements in daily symptoms and quality of life seem similar to those seen with dupilumab. Dupilumab has substantially more evidence on long-term safety. In the absence of head-to-head trials we rate the evidence for tezepelumab compared with dupilumab in patients with eosinophilic asthma as "Insufficient" (l). In the subgroup of patients with allergic asthma, reductions in AAER appear to be somewhat larger with tezepelumab than omalizumab while {small) improvements in daily symptoms and quality of life appear similar to those seen with omalizumab. However, there are important uncertainties introduced by the different time periods in which these therapies were assessed which affect both background therapies and outcome measurement. Omalizumab has substantially more evidence on long-term safety than tezepelumab, but omalizumab also is known to carry a risk for anaphylaxis. In the absence of more recent data on omalizumab and/or head-to-head trials, we rate the evidence for tezepelumab compared with omalizumab in patients with allergic asthma as "insufficient" (l). In patients with steroid-dependent asthma, treatment with tezepelumab did not reduce the required dose of OCS. In contrast, in such patients, treatment with dupilumab led to substantial reduction in OCS dose. As noted above, dupilumab has substantially more evidence than tezepelumab on long-term safety. In the absence of head-to-head trials comparing the drugs in this population, and given the somewhat limited data available from the tezepelumab trial, for patients with steroid-dependent asthma we rate treatment with tezepelumab as "Comparable or Inferior" (C-) to treatment with dupilumab. ©Ilnstitute for Clinical and Economic Review, 2021 Page 13 Final Report - Severe Asthma Return to Table of Contents Midwest CEPAC Votes Table 3.3. Midwest CEPAC Votes on Comparative Clinical Effectiveness Questions Question Yes | No For adults and adolescents with severe asthma, is the evidence adequate to 10 4 demonstrate that the net health benefit of tezepelumab added to standard-of-care therapy without biologics, is superior to that provided by standard-of-care therapy alone? For adults and adolescents with severe eosinophilic asthma, is the evidence 0 14 adequate to distinguish the net health benefit provided by tezepelumab from that provided by dupilumab? For adults and adolescents with severe allergic asthma, is the evidence adequateto | 1 13 distinguish the net health benefit provided by tezepelumab from that provided by omalizumab? For adults with steroid-dependent asthma, is the evidence adequate to distinguish 4 10 the net health benefit provided by tezepelumab from that provided by dupilumab? For adults and adolescents with severe asthma, a majority of panelists found that the evidence is adequate to demonstrate a net health benefit of tezepelumab added to standard of care when compared to standard of care alone, noting the reduction in exacerbations achieved by tezepelumab. The "no" votes we received on this question may be explained by panelists who cited that no clinically meaningful difference in quality-of-life metrics was achieved, and that exacerbations were deemed to be of secondary importance based on patient expert testimony. For adults and adolescents with severe eosinophilic asthma, the panelists unanimously found that the evidence is not adequate to demonstrate a net health benefit of tezepelumab when compared to dupilumab due to lack of head-to-head trails between these two drugs. For adults and adolescents with severe allergic asthma, a majority of panelists found that the evidence is not adequate to demonstrate a net health benefit of tezepelumab when compared to omalizumab. Similar to the previous question, panelists raised the concern of lack of head-to-head trials for this comparison, as well as the trial for omalizumab being conducted many years prior to that of tezepelumab, precluding an indirect comparison. For adults and adolescents with steroid-dependent asthma, a majority of panelists found that the evidence is not adequate to distinguish the net health benefit of tezepelumab from that of dupilumab, again due to a lack of head-to-head trials. Clinical expert testimony also cited that tezepelumab did not achieve steroid reduction when compared to placebo in the SOURCE trial. OInstitute for Clinical and Economic Review, 2021 Page 14 Final Report - Severe Asthma Return to Table of Contents 4. Long-Term Cost-Effectiveness 4.1. Methods Overview The decision analytic model structure was informed by the primary aim, previous modeling evidence, the evidence review, and stakeholder input. The model structure was based on a previously developed model from prior ICER reports assessing the cost effectiveness of interventions in severe asthma.3*37.3 The base case comparison was tezepelumab plus standard of care versus standard of care alone in patients with severe asthma. Scenarios evaluated subpopulations of those eligible for biologic therapy in patients with eosinophilic asthma and separately, allergic asthma by comparing tezepelumab and other representative biologics plus standard of care versus standard of care alone. The Markov model includes three primary health states: 1) an asthma non-exacerbation state (i.e., day-to-day asthma symptoms), 2) an asthma exacerbation state (including three mutually exclusive subcategories: asthma-related event that requires an oral corticosteroid burst, asthma-related emergency department [ED] visit, or asthma-related hospitalization), and 3) death (including asthma-related mortality and other cause mortality) {(Figure 4.1). The model structure is similar to other published asthma cost-effectiveness analysis {CEA) models, including ICER's 2018 report on biologic agents for the treatment of moderate-to-severe uncontrolled asthma with evidence of type 2 inflammation.3337:3% Given evolving evidence used for model inputs, we do not recommend comparison of the cost-effectiveness findings across ICER reports on asthma. A lifetime time horizon was assumed in the base case, consistent with the ICER Value Framework and other asthma cost-effectiveness models.3?4° The discount rate for all future costs and outcomes was 3% per year. We used a cycle length of two weeks to reflect the average length of time for an asthma exacerbation and to be consistent with prior published cost-effectiveness analyses and asthma guidelines that suggest exacerbation events should only be considered new after at least a 7-day period.4142 Key clinical inputs for the model, informed by the evidence review, include exacerbation rates (including oral steroid bursts, ED visits, and hospitalizations), chronic oral steroid use and potential reductions, asthma-related mortality, health-related quality of life utility, biologic treatment response, and adverse events. Model outcomes for each intervention include total drug and non-drug health care costs, life years (LY) gained, quality-adjusted life years (QALYs) gained, equal value of life years (evlLY) gained, and treatment response. ©Ilnstitute for Clinical and Economic Review, 2021 Page 15 Final Report - Severe Asthma Return to Table of Contents Figure 4.1. Model Structure Intervention N Severe Asthma Non-Exacerbation State (day-to-day symptoms) Comparator Asthma Exacerbation® Asthma - Other Cause Mortality related Mortality *Exacerbation could be defined into different subcategories: 1. Mild exacerbation: Asthma related event that requires an oral steroid burst (but not emergency department or hospitalization) and decrement to quality of life 2. Moderate exacerbation: Asthma related event that requires admittance to the emergency department (but not a hospitalization) and decrement to quality of life 3. Severe exacerbation: Asthma related event that requires a hospitalization, decrement to quality of life, and increased risk of mortality Target Population The population of focus for the economic evaluation includes adults and adolescents with severe asthma. Table 4.1. Baseline Population Characteristics Average Across Tezepelumab Trial Arms Mean (SD) Age 52(12) Percent Female 66% Mean (SD) Weight 78 (18) Proportion of Patients with Chronic Oral 9.6% Corticosteroid Use {SoC) Source NAVIGATOR and PATHWAYS? SD: Standard deviation, SoC: Standard of care OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Return to Table of Contents Interventions The intervention of interest is tezepelumab (Amgen and AstraZeneca) added to SoC (e.g., inhaled corticosteroid therapy and at least one additional controller medication). Comparators The comparator of interest is SoC alone, typically defined as daily inhaled corticosteroids plus at least one additional controller therapy. The SoC comparator mirrors the control arm of the randomized controlled trials that evaluated the clinical efficacy of tezepelumab. Other active comparators added to SoC are also be compared to SoC alone in scenario analyses including: e Dupilumab (Dupixent®, Sanofi and Regeneron) in patients with eosinophilic asthma e Omalizumab (Xolair®, Genentech) in patients with allergic asthma Consistent with ICER's long-term value voting, pairwise comparisons between the interventions of interest were performed only if the clinical evidence review finds sufficient evidence on relevant outcomes suggesting clinical separation. Based on public feedback and data submissions received after the draft report, we made the following updates to this version of the report: e We used sensitivity analyses to evaluate the impact of changing the asthma mortality rate after severe asthma exacerbations. In particular, the manufacturer suggested an alternative estimate for asthma mortality that we did not use in the base case. We assessed this alternative estimate as the upper range of plausible estimates within the one-way sensitivity analysis and included this variation in probabilistic sensitivity analyses as well. e We added a recommendation to not compare the results within this report with those of prior ICER reviews of asthma biologics given changes to evidence used as economic model inputs. e We updated effectiveness evidence for omalizumab (exacerbation relative risk) and for dupilumab (asthma quality of life) to best align with the modeled populations. 4.2. Key Model Assumptions and Inputs Our model includes several assumptions described in Table 4.2, ©Institute for Clinical and Economic Review, 2021 Page 17 Final Report - Severe Asthma Return to Table of Contents Table 4.2. Key Model Assumptions Assumption Rationale Base-case utility for the non-exacerbation health state is allowed to be different for biologic plus SoC versus SoC alone due to potential improvements in day-to- day symptoms. Without direct elicitation of utilities in trials comparing biologic plus SoC versus SoC alone, we rely on evidence of patient reported outcome instruments with known utility mappings. The relationship between EQ-5D utility and the Asthma Quality of Life Questionnaire was used for this analysis.* Additional risks of death given oral steroid burst will not impact mortality over and above the severe asthma-related mortality rate for all living health states in the model. Increased mortality rates are included for severe exacerbations consistent with United Kingdom evidence and calibrated to the United States population with severe asthma. No added mortality is included for oral steroid burst exacerbations given the risk of death found from the United Kingdom evidence was similar to the annual US risk of severe asthma- related mortality conditioned on age.*** Reduction in daily chronic oral glucocorticoid dose to a level of less than 5 mg is not harmful in terms of adverse events or disutility. 5 mg is a typical literature cutoff with chronic doses at or above 5 mg being considered harmful.* Disutilities for hospitalizations, ED visits, and oral steroid bursts are assumed to be for two weeks. Disutility is comparable to the NICE omalizumab, mepolizumab, and benralizumab assessment groups' reference-case 4% Base-case model characteristics follow tezepelumab for severe asthma trial population characteristics; however, where possible real-world evidence inputs were included The model characteristics such as baseline annualized exacerbation rates were reflective of pooled placebo arms of the NAVIGATOR and PATHWAY trials assessing the efficacy of tezepelumab; the percentage of exacerbation severity were derived from recent real- world evidence from the CHRONICLE study*' ED: emergency department, SoC: standard of care Model inputs were estimated from the clinical review, published literature, and information from stakeholders. Key model inputs are shown in Table 4.3. These model inputs include ratios for reductions in exacerbations from tezepelumab add-on therapy, annualized exacerbation rates and proportions of exacerbations resulting in different severity levels, non-exacerbation mean health state utilities, annual price of therapies, and unit costs related to management of exacerbations. OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 18 Return to Table of Contents Key Inputs Table 4.3. Key Model Inputs Parameter Inputs Source Annualized Exacerbation Rate, end of study (95% Cl}) 1.82 (95% Cl: 1.58, 2.08) Averaged across placebo arm of NAVIGATOR and PATHWAY trials®' Proportion of Exacerbations Resulting in Death Steroid Burst (without ED visit or 76.8% Soong et al. 2020 Figure 14 hospitalization) Proportion of Exacerbations Resulting in o ) 47 ED visit (without hospitalization) 9-1% Soong et al. 2020 Figure 1 ::;'s':i'tr:l'i';:t'_::xace'bat"'"s Resulting in 14.1% Soong et al. 2020 Figure 1% Severe Asthma Exacerbation Risk of 0.0068 Centers for Disease Control and Prevention *® Tezepelumab plus Alone (95% ClI for tezepelumab mean difference vs. placebo)* Parameter SoC Alone Source SoC Tezepelumab Rate Ratio for Exacerbations Resulting in Steroid Burst 0.41 (0.33, 0.53) Ref::;lejnce P;':S%:figivr::l;fld (without ED visit or hospitalization) group Tezepelumab Rate Ratio for Exacerbations Resulting in ED Visit 0.20 (0.10, 0.41) Reff::"':e P;':\';fgifig\'lfi;fld {without hospitalization) group E::i::i'::s?:ufi?:oi:nor 0.20 (0.10, 0.41) Reference Pooled PATHWAY and e . & ' R group NAVIGATOR trials®' Hospitalization Non-Exacerbation Mean Health State Utility for Tezepelumab plus SoC vs. SoC 0.788 (0.774, 0.81) 0.745 Pooled PATHWAY and NAVIGATOR trials®? Annual Price for Therapy (Tezepelumab plus SoC vs. SoC Alone) $27,859 + annual SoC costs $6,494 ($5,297, $7,827) Placeholder based on Dupilumab net price; Whittington et al. 2018 *Placebo-corrected difference in AQLQ used to derive health state utility values by treatment arm Cl: confidence interval, ED: emergency department, SoC: standard of care Clinical Inputs Rate ratios for exacerbations resulting in steroid bursts, ED visits, and hospitalizations were pooled across the PATHWAY and NAVIGATOR trials and applied to contemporary evidence on the proportion of baseline exacerbation event subtypes from the CHRONICLE study.*" The cycle-specific probability of asthma exacerbations is then calculated using the baseline annualized exacerbation rate and the respective exacerbation rate ratio estimates shown in Table 4.3. The evidence suggests no differences in serious adverse events exceeding 5% of the population that influence costs or disutilities with tezepelumab plus SoC versus SoC alone. The impact of chronic oral steroid use and associated long-run costs and disutility are included. We defined chronic oral steroid use as OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 19 Return to Table of Contents regular use of oral steroids resulting in a dose equivalent to at least 5 mg per day of prednisone, a dose which is considered harmful and associated with increased adverse event costs and disutility.*® We relied on tezepelumab evidence from NAVIGATOR estimating approximately 10% of patients on chronic oral steroid use. We then applied emerging evidence from SOURCE suggesting the odds of reducing oral steroid use was 1.28. We converted this odds ratio to a proportion reduction from SoC, suggesting patients on tezepelumab would reduce that proportion to approximately 8%. Asthma-related mortality and other cause mortality were modeled for all living health states (non- exacerbation and exacerbation)**>%5! There is a known increased risk of death linked with asthma- related hospitalizations as described by Watson and colleagues, who analyzed a United Kingdom database including 250,043 asthma-related hospital admissions to determine the mortality rate following hospitalizations.>® In a recent update described in the NICE benralizumab report, the average probability of death from a severe exacerbation was updated to 0.0078 per hospital admission for people aged 45 to 64 years of age. Specifically, clinical experts noted that some deaths originally recorded as asthma-related in the National Review of Asthma Deaths (NRAD) were later found to be unrelated to asthma, adjusting the probability downward. We relied on this input as a starting point, however, calibrated the model to reflect the expected humber of deaths per year in the United States. In a recent report from the CDC, the reported number of deaths from asthma was approximately 3,500 in 2019.*8 From Section 7, Potential Budget Impact, we estimated approximately 2.2 million patients in the United States with severe asthma. Consistent with NICE analyses, we assumed that all asthma-related deaths occur from severe exacerbations. We further assumed that all asthma-related deaths occurred only within patients with severe asthma; this is a favorable assumption for a drug used to treat severe asthma. If each patient with severe asthma had one severe exacerbation in one year, then the probability of death per severe exacerbation would be approximately 0.0016. Setting the likelihood of a severe asthma exacerbation to the SoC arm input, we adjusted the probability of death given a severe exacerbation to ensure we are not undercounting deaths. These calibration exercises resulted in a severe asthma risk of death per event of 0.0068 as shown in Table 4.3, and estimated 3,526 excess asthma deaths of the 2.2 million patients with severe asthma in the first year of the model. Rate ratios from the use of tezepelumab (among the other biologic therapies) reduced transition to a severe exacerbation and thus reduced mortality indirectly. Without commonly used utilities reported in the tezepelumab trials, we relied on evidence of patient reported outcome instruments with known utility mappings. The non-exacerbation health state utility value is specific to the evidence for tezepelumab plus SoC versus SoC alone. Evidence from tezepelumab trials (NAVIGATOR, PATHWAY, and Amgen data on file) include the responses from the Asthma Quality of Life Questionnaire (AQLQ) to derive utility values using the conversion from the AQLQ to the EQ-5D." The least squares mean change and 95% confidence intervals from the AQLQ for tezepelumab plus SoC versus SoC alone provide the inputs for the aggregate mapping algorithm (EQ-5D = 0.14 + 0.12*AQLQ score). Disutilities for the exacerbation health states and for ©Ilnstitute for Clinical and Economic Review, 2021 Page 20 Final Report - Severe Asthma Return to Table of Contents chronic OCS use were assumed to be the same across treatment strategies (i.e., the same for biologic plus SoC vs. SoC alone).>? Supplemental Tables E2.1 and E2.2 reports the utility mapping instrument results and disutility estimates. Treatment response was defined by a change from baseline in ACQ-6 score of 2 0.5 at week 50 from the PATHWAY trial.3* The analysis by Corren et al. assessed the impact of tezepelumab on patient- reported outcomes using both the ACQ-6 and the AQLQ(S)+12. We used the difference in the proportion of responders between tezepelumab plus SoC versus SoC alone as an outcome variable and the denominator in a cost per response calculation. Economic Inputs All costs used in the model were updated to first quarter of 2021 US dollars using methods following the ICER reference case. The treatment regimen and unit cost for each treatment is reported in Supplemental Tables E2.3 and E2.4. Given that tezepelumab has not received market approval, we assumed a placeholder price for the base-case results similar to dupilumab's current net price estimated in SSR Health. Treatment-related costs {SoC and asthma biologics) were assigned by treatment scenario for all living health states (exacerbation and non-exacerbation states). Unit costs for health care utilization were the same across different treatments and populations. Unit costs are available in Supplemental Table E2.5. The annual cost of SoC in an incremental analysis compared to SoC alone will approximate an incremental difference of $0. We assumed the same annualized cost of SoC from the prior 2018 ICER review and consistent with Whittington et al. 2018, but inflated to current US dollars. Scenario Analyses We conducted the following scenario analyses: 1. Allergic asthma scenario analysis comparing tezepelumab plus SoC versus SoC alone and omalizumab plus SoC versus SoC alone in an allergic asthma population. 2. Eosinophilic asthma scenario analysis comparing tezepelumab plus SoC versus SoC alone and dupilumab plus SoC versus SoC alone in an eosinophilic population. 3. Modified societal perspective that includes components of productivity loss. Inputs and results are presented in the Supplement E5. ©lnstitute for Clinical and Economic Review, 2021 Page 21 Final Report - Severe Asthma Return to Table of Contents 4.3. Results Base-Case Results The base case comparison was tezepelumab plus standard of care versus standard of care alone in patients with severe asthma. The total discounted costs, life years (LYs), quality-adjusted life years (QALYs), equal value of life years (evLYs) gained, and the proportion who achieved response over the lifetime time horizon are detailed in Table 4.4. Using a placeholder price, Tezepelumab plus SoC had a total discounted cost of $697,000 with discounted QALYs, LYs, and evLYs of 15.00, 19.11, and 15.02, respectively. SoC alone had a total discounted cost of $228,000 with discounted QALYs, LYs, and evlLYs of 13.91, 18.80, and 13.91, respectively. Table 4.4. Results for the Base Case for Tezepelumab plus SoC Compared to SoC Alone Intervention Other Non- % Treatment intervention | Total Cost QALYs LYs evLYs Cost Respondert Costs Tezepelumab | <oy 000 $40,000 | $697,000 | 15.00 19.11 15.02 82% plus SoC SoC Alone $122,000 $106,000 $228,000 | 13.91 18.80 13.91 70% evlYs: equal value of life years, LY: life years, SoC: standard of care, QALY: quality-adjusted life year *Price is a placeholder based on net pricing of dupilumab T response defined as change from baseline in Asthma Control Questionnaire-6 score of 2 0.5 Table 4.5 presents the discounted lifetime incremental results from the base-case analysis, which include incremental cost-effectiveness ratios for incremental cost per QALY gained, cost per LY gained, cost per evLY gained and cost per additional responder. Total discounted costs for tezepelumab plus SoC were approximately $450,000 greater than SoC alone; gains in QALYs, LYs, and evLYs were 1.09, 0.32, and 1.11 in relation to SoC alone. This resulted in incremental cost- effectiveness ratios of approximately $430,000 per QALY gained, $1,480,000 per LY gained, and $422,000 per evLY gained. Table 4.5. Incremental Cost-Effectiveness Ratios for the Base Case Cost per QALY Cost per Life | Cost per evLY Cost per T reatment Comparator Gained Year Gained Gained Respondert Tezepelumab - plus SoC* SoC alone $430,000 $1,480,000 $422,000 | $4.7 million evLYs: equal value of life years, SoC: standard of care, QALY: quality-adjusted life year *Price is a placeholder based on net pricing of dupilumab T response defined as change from baseline in Asthma Control Questionnaire-6 score of > 0.5 ©Ilnstitute for Clinical and Economic Review, 2021 Page 22 Final Report - Severe Asthma Return to Table of Contents 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 plausible parameter ranges). Figure 4.2 presents the tornado diagram resulting from the one-way sensitivity analysis for tezepelumab plus SoC versus Soc alone. Key drivers of cost-effectiveness estimates include the utility for non-exacerbation state for tezepelumab plus Soc and SoC alone, severe asthma exacerbation risk of death, annualized exacerbation rate for SoC alone, and exacerbation rate ratio for tezepelumab plus SoC. Probabilistic sensitivity analyses were also be performed by jointly varying multiple model parameters over at least 1,000 simulations, then calculating 95% credible range estimates for each model outcome based on the results. Tables 4.6 and 4.7 present the probability of reaching certain cost-effectiveness thresholds for tezepelumab plus SoC versus SoC alone. A total of 0% and 0% of iterations for tezepelumab plus SoC versus SoC alone were beneath a threshold of $150,000 per QALY and $150,000 per evlLY, respectively. Additional information on sensitivity analyses are available in E4. Figure 4.2, Tornado Diagram Utility for non-exacerbation state - tezepelumab plus SoC Severe asthma exacerbation risk of death Exacerbation rate ratio - Tezepelumab plus SoC I Annualized exacerbation rate - SoC I Cost for hospitalization - Cost for steroid burst . Cost of non-exacerbation state per cycle - 50C alone ur Utility for steroid burst m Cost for EDvisit I $300,000 $350,000 $400,000 450,000 $500,000 $550,000 $600,000 ncremental $/QALY "Tezepelumab price is a placeholder based on net pricing of dupilumab; grey shade indicates lower input's impact on the cost-per-QALY estimate whereas black shade indicates higher input's impact. ED: emergency department, QALY: quality-adjusted life year, SoC: standard of care Table 4.6. Probabilistic Sensitivity Analysis Cost per QALY Gained Results: Tezepelumab plus SoC vs. SoC alone 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 Gained Gained Gained Gained Tezepelumab plus 2P PIUS | 09 0% 0% 0% SoC SoC: standard of care, QALY: quality-adjusted life year *Price is a placeholder based on net pricing of dupilumab ©Ilnstitute for Clinical and Economic Review, 2021 Page 23 Final Report - Severe Asthma Return to Table of Contents Table 4.7. Probabilistic Sensitivity Analysis Cost Per evLY Gained Results: Tezepelumab plus SoC vs. SoC alone Cost Effective at Cost Effective at Cost Effective at Cost Effective at $50,000 per evLY | $100,000 per evLY | $150,000 per evLY | $200,000 per evLY Gained Gained Gained Gained ;'s:;pelumab plus 0% 0% 0% 0% evlY: equal value of life year, SoC: standard of care *Price is a placeholder based on net pricing of dupilumab Scenario Analyses Full results of all scenario analyses are presented in Supplement Section E5. Threshold Analyses Tables 4.8 and 4.9 present the annual price needed for each therapy to reach commonly cited cost- effectiveness thresholds Table 4.8. QALY-Based Threshold Analysis Results Annual Price | Annual Price | Annual Price | Annual Price WAC per Net Price to Achieve to Achieve to Achieve to Achieve Year per Year $50,000 per $100,000 $150,000 $200,000 QALY per QALY per QALY per QALY Tezepelumab $27,859.88* $6,200 $9,000 $12,000 $15,000 QALY: quality-adjusted life year, WAC: wholesale acquisition cost; *Price is a placeholder based on net pricing of dupilumab Table 4.9. evLY-Based Threshold Analysis Results Annual Price | Annual Price | Annual Price | Annual Price WAC per Net Price to Achieve to Achieve to Achieve to Achieve Year per Year $50,000 per $100,000 $150,000 $200,000 evLY per evLY per evLY per evLY Tezepelumab $27,859.88* $6,300 $9,200 $12,100 $15,000 evlLY: equal value of life year, WAC: wholesale acquisition cost *Price is a placeholder based on net pricing of dupilumab Model Validation We used several approaches to validate the model. First, we provided preliminary model structure, methods and assumptions to manufacturers, patient groups, and clinical experts. Based on feedback from these groups, we refined data inputs used in the model, as needed. Second, we varied model input parameters to evaluate face validity of changes in results. We performed model verification for model calculations using internal reviewers. As part of ICER's efforts in OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 24 Return to Table of Contents acknowledging modeling transparency, we also shared the model with the relevant manufacturers for external verification around the time of publishing the draft report. Finally, we compared results to other cost-effectiveness models in this therapy area. Uncertainty and Controversies The model analysis was limited by several factors. The price of tezepelumab is currently a placeholder price based on the net price of dupilumab per year. Long-run clinical evidence on biologic treatment responders as well as discontinuation was not available and, with respect to that limitation, we assumed constant treatment benefits and long-run (lifetime) treatment duration. Given severe asthma is not thought to be progressive or a worsening disease for most individuals eligible for biologic therapy, changes to model assumptions on treatment discontinuation or the addition of evaluating treatment response and stopping rules would likely have limited impact on the lifetime incremental findings. Mortality was assigned an indirect impact in the model through reduced asthma-related hospitalizations. Differences in mortality were not observed in the clinical evidence review. While there may be mortality reductions from the reduction in severe exacerbations, this has not been proven and there is controversy around appropriate estimates for modeling analyses. NICE's recent assessment of dupilumab included an indirect impact on mortality for OCS bursts; however that evidence was previously generated from an inpatient data sample in the UK with no reference to asthma care outside of the hospital setting. Further, in NICE's assessment of benralizumab, the upper estimate of mortality for those aged greater than 45 was revised downward to 0.0078, suggesting fewer asthma-related deaths than previously estimated. Additionally, both NICE reports acknowledged the considerable uncertainty around mortality estimates and conducted scenario analyses setting added exacerbation-related mortality to 0. Given there is no direct evidence linking asthma biologics, including tezepelumab, to reductions in asthma mortality we calibrated our asthma mortality estimation in the SoC arm of the model to be consistent with recent national statistics on asthma mortality in the United States.*® We then applied the rate ratio reduction for severe exacerbations from pooled tezepelumab trials to estimate the incremental impact of indirectly reducing mortality. We acknowledge the possibility of a non-zero probability of death outside of hospital setting. However, given our model analysis was calibrated to the number of asthma-related deaths per year in the United States, any change to deaths outside of the hospital setting would have to coincide with re-calibration of the model outputs. In other words, our model analysis accounted for all annual estimated US asthma deaths despite only modeling a subset of overall asthma, and any change to the location of those deaths will likely influence the resources used (e.g., hospital costs) rather than the incremental difference in survival between treatment arms. Further research should identify specific probabilities of death from asthma exacerbations within and outside of the hospital setting in addition to direct mortality benefits from asthma biologic therapies to inform future modeling exercises. ©lnstitute for Clinical and Economic Review, 2021 Page 25 Final Report - Severe Asthma Return to Table of Contents Health utility for the day-to-day non-exacerbation health state was identified as a key influential input of biologic benefit with significant uncertainty. However, without reporting standard measures of utility scores from the trials, we relied on the AQLQ mapping algorithm to the EQ-5D. The resulting non-exacerbation state health utility values were slightly lower than our previous estimates. For the scenario analyses, multiple AQLQ estimates were submitted from manufacturers and estimated from various evidence sources. Given we compared each biologic in scenario analyses to SoC alone, we allowed for variation in the non-exacerbation state health utility values across biologics but kept SoC values fixed. We acknowledge that utility estimates are numerically different for different biologics, however, they are not statistically different. Further, differences in utility values between each biologic and SoC alone are all within a range of 0.03 - 0.06. Future research should focus on direct elicitation of validated health-related quality of life utility inputs in addition to mapping algorithms between the AQLQ and validated utility instruments The modified societal perspective may not be comprehensive. We included costs from lost productivity and time away from school from a recent 7 year US nationally representative population participating in the Medical Expenditure Panel Survey. The sample size of severe asthma was small, however, the relative reduction in lost productivity between severe and moderate asthma was similar to the relative impact of dupilumab versus SoC alone on missed work due to severe exacerbation events.>®* However, there are still gaps in the modified societal perspective analysis and those missing components can be found in the impact inventory table in the supplement. We updated the distribution of exacerbation categories using the most recent and best available real-world evidence on treatment for exacerbations from the CHRONICLE study. These estimates were another key driver of the model that are indirectly represented in the one-way sensitivity analysis and tornado diagram. This change produced greater cost offsets and greater improvements in QALYs. Future evidence should validate these findings to be consistent in other severe asthma populations. 4.4 Summary and Comment The base-case findings suggest that tezepelumab plus SoC provide clinical benefit in terms of gains in QALYs, LYs, and evLYs over SoC alone but do so with increased costs to the health system and society. For scenario analyses within the allergic and eosinophilic asthma populations, we find similar results to the base case. Threshold pricing suggests tezepelumab would meet $100,000 to $150,000 per QALY and per evLYG thresholds at a price range of approximately $9,000 - $12,100 per year. Model findings across all comparisons were sensitive to health-related quality of life improvements, severe asthma exacerbation risk of death, annualized exacerbation rates, and rate reductions in exacerbations from tezepelumab. ©lnstitute for Clinical and Economic Review, 2021 Page 26 Final Report - Severe Asthma 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 table below, with related information gathered from patients and other stakeholders. Contextual considerations relate to the relative priority that should be given to any effective treatment for severe asthma, while potential other benefits or disadvantages are judgments specifically about tezepelumab. Following the public deliberation on this report the appraisal committee will vote 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 Acuity of need for treatment of individual Death from asthma is uncommon, with about 3500 patients based on short-term risk of death or | deaths ascribed to asthma in the US in 2019.5 progression to permanent disability Asthma can progress over time. Maghnitude of the lifetime impact on Severe asthma can start at any age, and patients individual patients of the condition being with severe asthma have daily symptoms that treated interfere with nearly all activities and that markedly reduce quality of life. Other (as relevant) ©Institute for Clinical and Economic Review, 2021 Page 27 Final Report - Severe Asthma Return to Table of Contents Table 5.2. Potential Other Benefits or Disadvantages Potential Other Benefit or Disadvantage Relevant Information Patients' ability to achieve major life goals related to education, work, or family life Ability to achieve life goals for some patients is likely to be affected by frequency of asthma exacerbations, and so tezepelumab is likely to help some patients with these goals. However, daily symptoms are probably a more important factor interfering with achieving goals and the effect of tezepelumab on such symptoms is relatively small. Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Reduction of exacerbations in adolescents and adults is likely to reduce missed days of work for caregivers, however it is uncertain whether this effect would be large enough to importantly impact major life goals. Patients' ability to manage and sustain treatment given the complexity of regimen Intermittent injectable therapies may be easier to adhere to than inhalers and other daily asthma therapies. Tezepelumab is likely to extend the population of patients eligible for such injectable therapies. Health inequities Asthma disproportionately affects Black Americans and those living in urban centers. Although overall air quality has improved in the US over the past six decades and smoking rates have declined, socioeconomic disparities in pulmonary health have persisted or widened.>® ICER calculated that the Health Improvement Distribution Index, looking at the relative proportion of any health gains from treatment of asthma that go to Black Americans is 1.21. (See Supplement) Other groups, including Native Americans and Puerto Ricans are disproportionately burdened by asthma in the us.>® ©Institute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page 28 Return to Table of Contents Midwest CEPAC Votes At the public meeting, the Midwest CEPAC 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 new effective treatment for severe asthma, on the basis of the following contextual considerations: Contextual Consideration Ve.ry.low Loyv . Av.er?ge Hi.gh . Ve.ry .high Priority priority | priority | priority | priority Acuity of need for treatment of individual 0 1 5 7 1 patients based on the severity of the condition being treated Magnitude of the lifetime impact on 0 0 0 7 7 individual patients of the condition being treated A majority of the panel voted that a treatment for severe asthma should be given high priority relative to other diseases given its severe and chronic nature, while also noting the low risk of death attributable to asthma. The panel split between high priority and very high priority regarding the magnitude of lifetime impact on patients with severe asthma acknowledging both patient and clinical expert testimony regarding the lifetime impacts on daily quality of life. We heard about how severe asthma prevents patients from engaging in social activities, is associated with anxiety, depression, and other comorbidities, and that asthma exacerbations are both intermittent and unpredictable throughout a patient's lifetime. ©Institute for Clinical and Economic Review, 2021 Page 29 Final Report - Severe Asthma Return to Table of Contents What are the relative effects of tezepelumab versus standard-of-care alone on the following outcomes that inform judgment of the overall long-term value for money of tezepelumab? Potential Other Benefit or Major- Mlnor- No Mln-o.r Maj.o.r Disadvantage Negative | Negative Difference Positive | Positive Effect Effect Effect Effect Patients' ability to achieve majorlife | O 0 3 10 0 goals related to education, work, or family life Caregivers' quality of life and/or 0 0 4 10 ability to achieve major life goals related to education, work, or family life Health inequities 0 6 8 0 0 A majority of the panel voted that tezepelumab could have a potentially minor positive effect on patients' and caregivers' ability to achieve life goals related to education, work, or family life. We heard from patient experts that asthma is one of the most common reasons to miss school and work, and that tezepelumab's ability to reduce exacerbations can help eliminate the fear of hospitalizations and improve long-term ability to achieve major life goals, both for patients and their caregivers. About half the panel voted that tezepelumab would make no difference in reducing health inequities, while a plurality of panelists voted that tezepelumab would have a minor negative effect. Clinical expert testimony reinforced the disparities that exist across patient subgroups and the likelihood of a therapy like tezepelumab being very expensive, thereby creating inequities and concerns regarding access. Patient experts noted the concerns regarding access to specialist care for underserved communities and how the office-administered nature of tezepelumab could create barriers for families who have less flexibility in missing work to attend appointments. ®lInstitute for Clinical and Economic Review, 2021 Page 30 Final Report - Severe Asthma Return to Table of Contents 6. Health Benefit Price Benchmarks Health Benefit Price Benchmarks (HBPBs) for the annual cost of treatment with the intervention(s) are presented in Table 6.1 below. The HBPB for a drug is defined as the price range that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY or per evlY gained. At report posting, a list or net price was not available for tezepelumab and therefore we provide no discounts from WAC. We arrive at a HBPB range of approximately $9,000 - $12,100 per year. Table 6.1. Annual Cost-Effectiveness Threshold Prices for [Intervention(s)] Annual Prices Annual Price at Annual Price at Discount from Using... Annual WAC $100,000 $150,000 WAC to Reach Threshold Threshold Threshold Prices Tezepelumab plus SoC* QALYs Gained $9,000 $12,000 N/A evLYs Gained $9,200 $12,100 N/A WAC: wholesale acquisition cost; evLYG: equal value life year gained; QALY: quality-adjusted life year *Price is a placeholder based on net pricing of dupilumab and therefore we do not provide a discount from WAC Midwest CEPAC Votes Value votes were not taken at the public meeting because a net price for tezepelumab was not available. Page 31 Return to Table of Contents ®Institute for Clinical and Economic Review, 2021 Final Report - Severe Asthma 7. Potential Budget Impact 7.1. Overview of Key Assumptions Results from the cost-effectiveness model were used to estimate the potential total budgetary impact of tezepelumab for patients 12 years of age or older with severe uncontrolled asthma. We used an annualized placeholder price of $27,860 per treated patient per year and the three threshold prices (at $50,000, $100,000, and $150,000 per QALY) for tezepelumab in our estimates of budget impact. For this analysis, we assumed that all patients eligible for treatment with tezepelumab were currently uncontrolled and therefore received treatment with standard of care. Based on public comments received on our draft report we limited our estimated eligible patient population, by assuming that patients who currently receive a biologic for their asthma treatment are considered controlled and therefore were not eligible for tezepelumab for the purpose of this budget impact analysis. All costs were undiscounted and estimated over a five-year time horizon. This budget impact analysis included the estimated number of individuals 12 years of age and older with severe, uncontrolled asthma in the US who would be eligible for treatment with tezepelumab. Using this approach, we derived an estimate of 1.3 million patients in the US eligible for treatment with tezepelumab, based on 2019 data. Our estimate begins with prevalent cases of asthma in the US of 23.4 million for those 12 and older.>" From there, we assumed that about 9.5% of patients could be classified as having severe asthma (10% of adults and 5% of adolescents) arriving at approximately 2.2 million patients.>8° Of patients who are diagnosed with severe asthma, we assumed that 60.4% had severe asthma that remains uncontrolled, arriving at approximately 1.3 million patients.®62 We further assumed that 85% of patients with severe uncontrolled asthma are already eligible for available biologic therapy, and that 57% of those patients eligible for available biologic therapy are receiving a biologic. 535 Removing these patients from our eligible patient population, we arrived at approximately 695,000 patients eligible for treatment with tezepelumab. We assumed that 20% of these 695,000 million patients would initiate treatment in each of the five years, or approximately 139,000 patients per year. The aim of the potential budgetary impact analysis is to document the percentage of patients who could be treated at selected prices without crossing a potential budget impact threshold that is aligned with overall growth in the US economy. 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. ICER's methods for estimating potential budget impact are described in detail in the Supplement Section F. ©lnstitute for Clinical and Economic Review, 2021 Page 32 Final Report - Severe Asthma Return to Table of Contents 7.2. Results The average annual per patient total and net cost findings across the annualized placeholder price and the prices that achieve three different cost-effectiveness thresholds for tezepelumab are presented the Supplement Section F. Figure 7.1 illustrates the potential budget impact of treatment of the eligible population with tezepelumab, based on the annualized placeholder price, as well as the prices that achieve three different cost-effectiveness thresholds of $150,000, $100,000, and $50,000 per QALY compared to treatment with standard of care alone. Approximately 7.3% of the roughly 139,000 patients, or approximately 10,200 patients, could be treated each year without crossing the ICER budget impact threshold of $734 million per year over five years at the annualized placeholder price of $27,860. At the three threshold prices (approximately $11,927, $9,077, and $6,226 per year of treatment, respectively) 21.1%, 31.9% and 73.0% could be treated with tezepelumab without reaching the potential budget impact threshold, or approximately 29,400, 44,400, or 102,000 patients per year. Figure 7.1. Budgetary Impact of Tezepelumab in Patients with Severe Uncontrolled Asthma $30,000 Placeholder \ Price \ \ \ \ \ \ \ \ \ \ $20,000 \ \'\ .§ \' o \ -_ \ © \ S \ c \ c \ < % $150,000/QALY \ \ $10,000 S $100,000/QALY ~ " === ----- "SS0,000/QALY S0 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Patients Treated Without Crossing Bl Threshold ©Institute for Clinical and Economic Review, 2021 Page 33 Final Report - Severe Asthma Return to Table of Contents Assuming a placeholder price of $27,860 per year (at which only 7.3% of eligible patients could be treated), has the potential of creating a short-term potential budget impact that exceeds the potential threshold of $734 million per year. At the threshold price equal to achieving $150,000 per QALY, 21.1% could be treated without reaching the potential budget impact threshold. During the public meeting, we did not receive feedback related to the optimal utilization of tezepelumab, should it be approved. Therefore, ICER is not issuing an access and affordability alert. ©lnstitute for Clinical and Economic Review, 2021 Page 34 Final Report - Severe Asthma Return to Table of Contents 8. Policy Recommendations Following its deliberation on the evidence, the Midwest CEPAC engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on the use of tezepelumab. The policy roundtable members included 2 patient advocates, 1 clinical expert, 2 payers, and 2 representatives from the drug makers. 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 Recommendation 1 All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with severe asthma are introduced in a way that will help reduce health inequities. Asthma disproportionately affects underserved groups in the US including Black, Native American, and Puerto Rican populations. The trials of tezepelumab included mainly patients who were white or Asian. Multiple stakeholders highlighted that the high cost of biologic therapies can worsen disparities in accessing care. This may be due to lack of health insurance that limits access to specialists and the new therapies that they prescribe or high deductible payments that even for those with insurance may result in steep out of pocket costs. Additionally, the lack of research on tezepelumab in Black Americans raises questions about whether the results of clinical trials of tezepelumab apply to Black populations. We have particular concerns about generalizability to poorer urban settings where air quality may be lower, and we worry that the small numbers of Black Americans in these trials may reflect similarly low levels of people living in poorer urban settings. We also heard from patient groups that only 40% of patients with severe asthma are managed by an asthma specialist. To address these concerns: Manufacturers should take the following actions: e Set the price for new treatments for asthma in fair alignment with added benefits for patients. e Take steps necessary to include a more diverse patient population in clinical trials, including adequate number of patients with ethnic and racial backgrounds similar to the underlying population in the US with asthma. To accomplish this, manufacturers should engage with patient groups earlier in the design of trials to consider ways to maximize patient diversity. ©lnstitute for Clinical and Economic Review, 2021 Page 35 Final Report - Severe Asthma Return to Table of Contents Regulators: e The US FDA should develop guidelines requiring that clinical trials have appropriate diversity of the studied population so that manufacturers who work for such diversity are not disadvantaged by additional recruitment time/cost compared with manufacturers who do not seek this diversity. Pavers should take the following actions: e Create quality measures that assess whether therapies are being equitably distributed across insured patient groups. e Begin gathering data using these quality measures to inform future quality improvement activities. Clinical experts and clinical societies: e Develop expertise in diverse communities in the management of asthma such that providers outside of major medical centers can diagnose and appropriately treat or refer patients with severe asthma. e Management of severe asthma needs to be broadly improved, perhaps through some combination of centers of excellence and improved technologies to allow telehealth consultations from such centers. Patient groups: e Work to expand the involvement of disadvantaged and underrepresented patients in clinical trials either through their own work or in conjunction with PCORI. Medical journal editors: e Editors of leading journals should develop policies requiring that trials being considered for publication have adequate diversity of patients. ©lnstitute for Clinical and Economic Review, 2021 Page 36 Final Report - Severe Asthma Return to Table of Contents Payers Recommendation 1 Payers will need to consider subpopulations of people with severe asthma when designing coverage policies for tezepelumab and other biologics. For patients with eosinophilic asthma and/or allergic asthma there are a number of biologic therapies with proven efficacy in reducing exacerbations; coverage policies can take this into account when considering preferred initial options. For patients with neither eosinophilic nor allergic asthma who are not on chronic OCS, tezepelumab is the only biologic treatment that has demonstrated efficacy. Recommendation 2 For tezepelumab and other biologics for severe asthma, payers should meet criteria for fair access, including criteria related to cost sharing, clinical eligibility, step therapy, and provider gualifications. Several key examples of these criteria are shown below: Cost Sharing e Patient cost sharing should be based on the net price to the plan sponsor, not the unnegotiated list price. ¢ At least one drug in every class should be covered at the lowest relevant cost-sharing level unless all drugs are priced higher than an established fair value threshold. Coverage Criteria: General e Payers should offer alternatives to prior authorization protocols such as programs that give feedback on prescribing patterns to clinicians or exempt them from prior authorization requirements ("gold carding") if they demonstrate high fidelity to evidence-based prescribing. ¢ Payers should document at least once annually that clinical eligibility criteria are based on high guality, up-to-date evidence, with input from clinicians with experience in the same or similar clinical specialty. * Clinical eligibility criteria should be developed with explicit mechanisms that require payer staff to document using an open and transparent process that is readily accessible to the public that they have: ©lnstitute for Clinical and Economic Review, 2021 Page 37 Final Report - Severe Asthma Return to Table of Contents a. Considered limitations of evidence due to systemic under-representation of minority populations; and b. Sought input from clinical experts on whether there are distinctive benefits and harms of treatment that may arise for biological, cultural, or social reasons across different communities; and c¢. Confirmed that clinical eligibility criteria have not gone beyond reasonable use of clinical trial inclusion/exclusion criteria to interpret or narrow the FDA label language in a way that disadvantages patients with underlying disabilities unrelated to the condition being treated. Coverage Criteria: Specific Considerations e Age: Age criteria are likely to follow the FDA label for tezepelumab. Tezepelumab is likely to be approved for those 12 years of age and older. Payers should have efficient mechanisms for clinicians to seek coverage exceptions for patients with serious unmet need who are near the cutoff for the age necessary for coverage. o Clinical eligibility: Payers will likely use some combination of objective measures of disease severity and/or utilization of services for asthma derived from clinical guidelines or the eligibility criteria in pivotal clinical trials in determining who is eligible for tezepelumab. We did not hear concerns from clinical experts or the patient community about payers utilizing guidelines in making such determinations as long as they were using the most updated guidelines (typically GINA). For example, with currently available biologics, some payers have defined moderate-severe asthma using FEV1 criteria: If the member is 12 to 17 years of age, they have a pretreatment FEV1 < 90% predicted; if the member is 18 years of age or older, they have a pretreatment FEB1 of < 80% and FEV1 reversibility of at least 12% and 200 milliliters after albuterol (salbutamol) administration. Other payers have looked at utilization criteria to define the eligible patient population: Member has inadequate asthma control (e.g. hospitalization or emergency medical care visit within the past year) despite current treatment with both of the following medications at optimized doses: ©lnstitute for Clinical and Economic Review, 2021 Page 38 Final Report - Severe Asthma Return to Table of Contents a. High-dose inhaled corticosteroid b. Additional controller, or sustained-release theophylline e As noted above, repeated or prolonged need for oral corticosteroids suggests that it may be appropriate to initiate biologic therapy for asthma. Clinical experts advised that three months of frequent OCS treatment, such as on 50% of days, rather than six months as appears in some existing coverage policies, should be considered adequate to initiate biologic therapy. e Exclusion criteria: Although smoking was an exclusion criterion in clinical trials of tezepelumab, clinical experts advised that patients who smoke may also benefit from biologics and should not be excluded from coverage. e Duration of coverage and renewal criteria: It is not unreasonable for payers to seek attestation of benefit of expensive medications prior to renewing coverage for extended time periods. The first renewal is frequently required at six months. Renewal documentation procedures should be streamlined so that patients face no risk of interruption of their medication. Some payers may choose not to require any attestation given that patients and clinicians are likely to discontinue therapy that is not working. e Required switching: Biologic treatments are not easily interchangeable in an individual patient. Clinical experts therefore advised it is not clinically reasonable to require patients with severe asthma to switch biologic therapies when they change insurance plans. e Provider restrictions: Payers are likely to restrict prescribing of tezepelumab to asthma specialists such as pulmonologists and allergists. We heard from clinical experts that this is reasonable given frequent misdiagnosis and poor clinical management of severe asthma by non-specialists. However, to reduce disparities where access to specialists may be limited, payers should consider allowing prescribing by other providers in consultation with asthma specialists. ©lnstitute for Clinical and Economic Review, 2021 Page 39 Final Report - Severe Asthma Return to Table of Contents Step Therapy In order to justify step therapy policies extending beyond FDA labeling as appropriate, payers should ensure that: 1. The first-step therapy is clinically appropriate for all or nearly all patients and does not pose a greater risk of any significant side effect or harm; 2, Patients will have a reasonable chance to meet their clinical goals with first-step therapy; 3. Failure of the first-step drug and the resulting delay in beginning the second-step agent will not lead to long-term harm for patients; 4. Patients are not required to retry a first-line drug with which they have previously had adverse side effects or an inadequate response at a reasonable dose and duration. Payers should recognize that step therapy has generally not been used for biologic therapy in asthma. Individual biologic therapies frequently fail and so all options using different mechanisms of action should be available to patients with asthma. There are important subpopulations of patients with severe asthma for which certain treatments have clear indications. Only dupilumab has demonstrated reduction in steroid dose in OCS- dependent asthma, and only tezepelumab has shown efficacy in patients with severe asthma with an eosinophil count below 150 cells/pL. However, for eosinophilic asthma, there is no strong clinical rationale for first treatment among the available biologic treatment options or tezepelumab. Therefore, if large pricing differentials emerge among these agents, payers may have clinical justification to institute step therapy, as they have done in autoimmune conditions. If considered, such policies must meet all criteria for fair access, including those related to transparency and efficiency of implementation. Manufacturers and Payers Recommendation 1 Biologic therapies for asthma are expensive, prices should be reduced. At our public meeting, Sanofi expressed interest in aligning prices with benefits across different indications. This is a particular issue with their drug dupilumab, which ICER has judged to be priced fairly when used to treat atopic dermatitis. Systems and regulations in the US interfere with indication-specific pricing, but manufacturers should continue to seek innovative ways to accomplish such alignment. ©lnstitute for Clinical and Economic Review, 2021 Page 40 Final Report - Severe Asthma Return to Table of Contents Manufacturers of other biologic therapies for asthma should reduce their prices to align with their clinical benefits in asthma. Manufacturers should also continue to work with payers and policymakers to develop options to reduce the role that rebates play in supporting high list prices. Researchers and Patient Organizations Recommendation 1 Researchers looking at real world evidence in treatments of asthma should be aware of potential threats to validity, including selection bias. Since head-to-head trials of biologics are unlikely to be performed, there may be an interest by manufacturers, payers, and independent researchers in examining efficacy through the use of RWE. Given the apparently similar efficacy of biologics seen in randomized trials, issues of selection bias as well as differing comorbidities and other potential confounders are a threat to validity in such studies since biases within a data set could overwhelm small differences in efficacy. Specific areas require additional research e As discussed above, additional research is required to demonstrate the efficacy of tezepelumab in underserved and underrepresented populations. To the extent that such populations tend to live in urban settings and be exposed to particulates, the generalizability of the results of the clinical trials of tezepelumab is in doubt. e Research is needed on the development and use of biomarkers to allow better prediction of which patients will benefit from a given therapy such as tezepelumab. To the extent that manufacturers already have some such data, they should endeavor to promulgate and share their results rather than refusing to do so as occurred for this report when ICER asked for information on a specific subgroup treated with tezepelumab. e Quality of life instruments have been developed specifically for asthma. If patient groups or others feel that these instruments are not adequately capturing the benefits seen with new therapies, they should work with researchers to develop new measures that they trust. We note, however, that the manufacturer of tezepelumab collected multiple measures of quality of life, some of which have not been made publicly available, and could have analyzed these results in various ways to try to capture quality of life improvements if they felt that the published measures did not reflect the full benefits seen with tezepelumab. ©lnstitute for Clinical and Economic Review, 2021 Page 41 Final Report - Severe Asthma Return to Table of Contents OlInstitute for Clinical and Economic Review, 2021 Page 42 Final Report - Severe Asthma Return to Table of Contents References 10. 11. 12, 13. 14. 15. 16. 17. Centers for Disease Control and Prevention. Most Recent National Asthma Data. https://www.cdc.gov/asthma/most _recent national asthma data.htm. Published 2019. 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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. ©lnstitute for Clinical and Economic Review, 2021 Page 48 Final Report - Severe Asthma Return to Table of Contents Supplemental Materials ©Institute for Clinical and Economic Review, 2021 Page 49 Final Report - Severe Asthma Return to Table of Contents A. Background: Supplemental Information Al. Definitions Annualized Asthma Exacerbation Rate (AAER): The effect on AAER was the primary outcome of many trials. AAER was the rate of exacerbations, calculated on an annual basis. Asthma Control Questionnaire {ACQ): The ACQ is a seven-item questionnaire that includes five guestions on symptoms (ACQ-5), an additional question on rescue inhaler use (ACQ-6) and FEV4 (ACQ-7). Scores range from zero to six with higher scores indicating worse control and a change of 0.5 points being minimal clinical important difference. Asthma Quality of Life Questionnaire (AQLQ): the AQLQ is a 32-item questionnaire covering four domains (symptoms, activity limitation, emotional function, and environmental stimuli). It is scored from one to seven with higher numbers representing better quality of life. The minimally important difference is 0.5 points. FEVi1: The FEV: is the maximal volume of air that a person is able to blow out in one second. It is a measure of airflow obstruction in the lungs with lower values representing greater obstruction. Severe Asthma: Asthma that requires either OCS for >50% of the year or the combination of high dose ICS and a LABA or other controller medication (leukotriene inhibitor/theophylline) to maintain control. Asthma Exacerbation: An asthma exacerbation is generally defined as a worsening of asthma symptoms leading to treatment with systemic glucocorticoids for three or more days, an emergency department visit for where systemic glucocorticoids were administered, or hospitalization, but definitions varied somewhat across trials: e PATHWAY (Asthma exacerbation): Worsening of asthma symptoms that led to systemic glucocorticoid use or a doubling of a stable maintenance regimen of oral glucocorticoids for three or more days, an emergency department visit that led to systemic glucocorticoid treatment, or hospitalization e NAVIGATOR (Asthma exacerbation): Worsening of asthma symptoms that led to systemic glucocorticoid use for three or more consecutive days, an emergency department visit that resulted in the use of systemic glucocorticoids for three or more consecutive days, or hospitalization e LIBERTY ASTHMA QUEST (Severe asthma exacerbation): Deterioration of asthma leading to systemic glucocorticoid use for three or more days, an emergency department visit leading to treatment with systemic glucocorticoids, or hospitalization ©Ilnstitute for Clinical and Economic Review, 2021 Page Al Final Report - Severe Asthma Return to Table of Contents e LIBERTY ASTHMA VENTURE (Severe asthma exacerbation): Events leading to treatment with systemic glucocorticoids at 22 times the current dose of oral glucocorticoid for three or more days, an emergency department visit, or hospitalization e EXTRA (Clinically significant asthma exacerbation): Worsening of asthma symptoms requiring treatment with systemic corticosteroids e INNOVATE (Protocol-defined asthma exacerbation): Worsening asthma symptoms requiring systemic corticosteroid use for three or more days. For patients receiving long-term oral corticosteroids, an exacerbation was a 20 mg or more increase in the average daily dose of oral prednisone or a comparable dose of another systemic corticosteroid. Figure Al. Pathways Involved in Asthma with Type 2 Inflammation and Non-Type 2 Inflammation Inflammatory mechanisms and pathobiologic features leading to severe asthma Inflammatory mechanisms associated with granulocytic inflammation Tygllnflamahgn Non-type 2 inflammation - v AR e s s o : '-@Elrriténis;pdl[fitafits, microbes, and viruses ] "'v. 3 LAY AT = - ) \ - * [IL-3,4,5and 9 [-] "I? BLT Lipoxin L=t L v - l Modified with permission from Israel et al. 2017, Copyright Massachusetts Medical Society. Legend. Inflammatory, Immunologic, and Pathobiological Features Leading to Severe Asthma. Type 2 inflammation is most commonly initiated by the adaptive immune system on recognition of allergens through the actions of thymic stromal lymphopoietin (TSLP), which stimulates type 2 helper T (Th2) cells and innate lymphoid cells of group 2 (ILC2) to differentiate and produce the type 2 cytokines interleukin {IL) 4, IL-5, and IL-13. This differentiation depends on activation of the GATA3 transcription factor. These cytokines result in the production of IgE (through the action of IL-4) and subsequent activation of mast cells (which depend on stem cell factor and its receptor, KIT, for normal development and survival) and activation and recruitment of eosinophils through IL-5. IL- 13 acts on smooth muscle to induce hyperresponsiveness and remodeling; it also stimulates the epithelium to ©lnstitute for Clinical and Economic Review, 2021 Page A2 Final Report - Severe Asthma Return to Table of Contents increase cytokine production and stimulates mucus production. Mast cells produce multiple mediators and cytokines that cause airway smooth-muscle contraction, eosinophil infiltration, remodeling, and amplification of the inflammatory cascade through additional cytokine production (IL-3, IL-4, IL-5, and IL-9). Mast cells also synthesize prostaglandin D2 (PGD2), which stimulates upstream cells and eosinophils through its actions at the receptor known as CRTH2. The type 2 pathway can also be activated by factors such as infectious agents and irritants that stimulate the innate immune system through production of such cytokines as IL-33 (through its receptor ST2) and IL-25 (through its receptor IL-17RB), which in turn stimulate ILC2 and Th2 cells. The cytokines released in response to these agents can also activate non-type 2 pathways. Type 17 helper T (Th17) cells and their products can play a major role in attracting and stimulating neutrophils. The epithelium also produces cytokines that stimulate Th17 cells; in addition, it produces cytokines that directly stimulate neutrophils. These innate immune stimuli also activate type 1 helper (Th1) cells, which are more classically involved in host defenses against pathogens and can also stimulate neutrophils. In addition, some patients may have reduced ability to synthesize pro-resolving compounds such as lipoxins, which have a role in down-regulating neutrophilic inflammation and antagonizing effects of leukotrienes. Some patients with severe asthma may not have cellular evidence of activation of these pathways and are considered to have "paucigranulocytic" asthma. To produce clinical presentations of severe asthma, these phenotypic inflammatory patterns can induce or combine with any or several of the following: airway hyperresponsiveness, smooth-muscle hypertrophy, structural airway remodeling, or mucus secretion. Substances in yellow have been or are currently being targeted for treatment of severe asthma. ALX lipoxin A4 receptor, BLT2 leukotriene B4 receptor 2, CXCL8 CXC motif chemokine ligand 8, CXCR3 CXC chemokine receptor 3, GM-CSF granulocyte- macrophage colony-stimulating factor, TFG-p transforming growth factor B, and TNF-a tumor necrosis factor a. Table Al. Dosing Route and Administration for All Drugs Drug Dosing Mechanism Indication 70-280 mg SC | TSLP Patients with severe asthma with or without an Q4w eosinophilic phenotype, receiving ICS/LABA with or without OCS and additional controllers Tezepelumab Amgen/AstraZeneca Dupilumab (Dupixent®) 200-300 mg SC | Anti-IL-4Ra Age 212 years with moderate to severe asthma with an Sanofi/Regeneron Q2w eosinophilic phenotype or with OCS-dependent asthma . . 75-375 mg SC | Anti-IgE Age 26 years with moderate to severe persistent asthma ® Omalizumab (Xolair®) Q2W or Q4W* testing positive for perennial aeroallergen whose Genentech symptoms are inadequately controlled with ICS A2. Potential Cost-Saving Measures in Severe Asthma 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/wp- content/uploads/2021/03/ICER 2020 2023 VAF 013120-4-2.pdf). These services are ones that would not be directly affected by tezepelumab (e.g., reduction in exacerbations, ED visits, and hospitalizations), as these services will be captured in the economic model. Rather, we are seeking services used in the current management of asthma beyond the potential offsets that arise from a new intervention. During stakeholder engagement and public comment periods, ICER encouraged ©lnstitute for Clinical and Economic Review, 2021 Page A3 Final Report - Severe Asthma Return to Table of Contents all stakeholders to suggest services (including treatments and mechanisms of care) currently used for patients with asthma that could be reduced, eliminated, or made more efficient. No suggestions were received. ©lnstitute for Clinical and Economic Review, 2021 Page A4 Final Report - Severe Asthma Return to Table of Contents B. Patient Perspectives: Supplemental Information B1. Methods During ICER's scoping, open input, and public comment periods, we received public comment submissions from 8 stakeholders (two patient advocacy groups, three manufacturers, one clinical society, and two individuals) and participated in conversations with 12 key informants (three patient advocacy groups, four clinical experts, and four manufacturers, one individual). Some stakeholders played more than one role in our outreach. We also reviewed patient input received during prior ICER reviews of asthma in 2016 and 2018. The feedback received from written input and scoping conversations helped us to discuss the impact on patients described in Chapter 2 of the evidence report. ©lnstitute for Clinical and Economic Review, 2021 Page B1 Final Report - Severe Asthma Return to Table of Contents C. Clinical Guidelines Clinical practice guidelines for the treatment of severe asthma have been issued by several US and non-US-based organizations. These guidelines are summarized below. Global Initiative for Asthma (GINA)®® Launched in 1993 in collaboration with the National Heart, Lung and Blood Institute (NHLB), National Institutes of Health (NIH) and the World Health Organization (WHO), the GINA science committee conducts a systematic review each year to provide yearly updates on asthma management and prevention. Asthma severity is assessed based on the level of treatment required to control symptoms and exacerbations and can change over the course of a few months or years. GINA defines severe asthma as asthma that remains 'uncontrolled' despite optimized treatment with high dose ICS-LABA or that requires high dose ICS-LABA to prevent it from becoming "uncontrolled". GINA has several definitions to differentiate between uncontrolled, difficult-to-treat, and severe asthma. e Uncontrolled asthma: Poor symptom control and/or frequent exacerbations e Difficult-to-treat asthma: uncontrolled despite prescribing medium or high dose ICS with a second controller (usually LABA) or with a maintenance OCS, or that requires a high dose to maintain good symptom control and reduce risk of exacerbations. e Severe asthma: a subset of difficult-to-treat asthma that is uncontrolled despite adherence with maximal optimized high dose ICA_LABA treatment and management of contributory factors, or that worsens when high dose treatment is decreased The GINA guidelines detail a diagnosis and management pathway specifically for difficult-to-treat and severe asthma: 1. Adults and adolescents are diagnosed with difficult-to-treat asthma 2. Look for factors contributing to symptoms, exacerbations, and poor quality of life such as poor inhaler technique, suboptimal adherence, or comorbidities. 3. Optimize management including asthma education, modifying treatment, add-on non- biologic therapy, non-pharmacological interventions 4. If the asthma is still uncontrolled after 3 to 6 months, the patient is diagnosed with severe asthma ©lnstitute for Clinical and Economic Review, 2021 Page C1 Final Report - Severe Asthma Return to Table of Contents 5. Assess the severe asthma phenotype. A patient may have type 2 airway inflammation (blood eos 2150 cells/pl or FeNO 220 ppb or asthma clinically allergen-driven or need for maintenance OCS a. If a patient has type 2 inflammation, may consider adherence tests, increase ICS dose for 3-6 months or add-on type two biologic therapy with anti-IgE, anti- IL5/Anti-IL5R or Anti-IL4AR b. If apatientis not type 2, may continue to try to optimize management, avoid exposures (tobacco smoke, allergens) or consider add-on treatment with LAMA or azithromycin 6. Patient and their care team should continue to review their response and optimize management as needed American Thoracic Society (ATS) and European Respiratory Society (ERS)>*% The American Thoracic Society (ATS) and European Respiratory Society (ERS) provide recommendations for the management of severe asthma in adults and children in a 2020 update to their 2014 guidelines. The ATS-ERS Task Force defines severe asthma for patients ages six and up as asthma requiring high dose inhaled corticosteroids plus a second controller to prevent it from becoming "uncontrolled" or asthma that remains "uncontrolled" despite receiving this therapy. Uncontrolled asthma is defined as meeting at least one of four criteria: 1) Poor asthma control: Asthma Control Questionnaire (ACQ) Score >1.5 2) Frequent severe asthma exacerbations requiring two or more systemic corticosteroid bursts in the previous year 3) Serious exacerbations resulting in at least one hospitalization, ICU stay or mechanic ventilation in the previous year 4) Limited airflow: FEV1>80% predicted normal The Task Force recommends defining and diagnosing severe asthma using the following three steps: Step 1: Confirm a diagnosis of asthma and rule out "difficult-to-treat asthma". Severe asthma should only include patients with refractory asthma or those with comorbidities like severe sinus disease or obesity that are not yet fully treated. Patients with "difficult-to-treat asthma" should have their diagnosis confirmed and managed by a specialist for at least three months. Step 2: Distinguish severe asthma from moderate or mild asthma. Severe asthma patients require treatment with high dose inhaled corticosteroids and an additional controller like long acting $2- agonist (LABA), leukotriene modifier or theophylline and/or systemic corticosteroids. Those who ©lnstitute for Clinical and Economic Review, 2021 Page C2 Final Report - Severe Asthma Return to Table of Contents stopped this treatment due to lack of response after an adequate trial are also included in the definition of severe asthma. This definition does not include those with untreated severe asthma, however. Step 3: Distinguish controlled from uncontrolled severe asthma. Patients meeting any of the four criteria for "uncontrolled asthma" listed above while on high-dose therapy can be identified as having severe asthma. Patients who do not meet the criteria for uncontrolled asthma but worsen on tapered corticosteroids also meet the definition of severe asthma. For the treatment of severe asthma, the Task Force made the following recommendations with regard to biologic therapies: e Suggest using anti-IL5/IL5R therapies in adult patients with severe uncontrolled eosinophilic asthma, with a suggested eosinophil cut point of 2150 cells/pl. e Suggest using anti-1L4/13 therapy in adult patients with severe eosinophilic asthma (eosinophil cut point not stated) or severe corticosteroid-dependent asthma. e Suggest considering eosinophil cut point of 2260 cells/pl and FeNO 219.5 ppb to identify adults and adolescents with the greatest likelihood of response to anti-IgE therapy. ©lnstitute for Clinical and Economic Review, 2021 Page C3 Final Report - Severe Asthma Return to Table of Contents D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods PICOTS Population The population of focus for the review were adults and adolescents with severe asthma. Apart from the subpopulations described below (related to indications for the comparator therapies), we also examined efficacy in subgroups defined by: e Allergic vs. non-allergic asthma phenotypes e Eosinophil level e Race and ethnicity e Socioeconomic status e Age Interventions The full list of interventions is as follows: Tezepelumab (Amgen and AstraZeneca) Comparators We compared tezepelumab to: e Dupilumab (Dupixent®, Sanofi and Regeneron) in patients for whom dupilumab is indicated e Omalizumab (Xolair®, Genentech) in patients for whom omalizumab is indicated e Usual care (estimated by placebo arms of clinical trials) in all patients with severe asthma Outcomes A multistakeholder project launched in 2019 concluded that a core set of outcomes that should be measured in trials of therapies for severe asthma includes severe asthma exacerbation, change in asthma control, asthma-specific or severe asthma-specific quality of life, asthma-specific hospital stay or admission, and asthma-specific emergency department visits.5" ©Ilnstitute for Clinical and Economic Review, 2021 Page D1 Final Report - Severe Asthma Return to Table of Contents Although this core outcomes set was published after trials of the therapeutic agents subject to this review were conducted, the set helped inform outcomes that were sought as part of this review. The outcomes of interest are described in the list below. e Patient-Important Outcomes o Daily quality of life Daily symptoms (including nocturnal symptoms and impact on daily activities) Asthma control Asthma-related hospitalizations and emergency department visits Use/reduction in use of OCS Corticosteroid side effects Asthma exacerbations and severe exacerbations Missed time from school or work Mortality Adverse events including O 0O 0 0 0O 0O 0 O = Serious adverse events * Treatment-emergent adverse events = Adverse events leading to treatment discontinuation e Other Outcomes o Pulmonary function testing including forced expiratory volume in 1 second (FEV) o Adherence o Blood eosinophil levels Timing Evidence on intervention effectiveness and harms was derived from studies of at least 24 weeks duration. 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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 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. Table D1.2. Tezepelumab Search Strategies: EMBASE 'asthma'/exp ('tezepelumab' OR 'AMG 157' OR 'AMG157' OR 'AMG-157' OR 'MEDI 9929' OR 'MEDI9929' OR 'MEDI-9929' OR 'MEDI19929' OR 'MEDI 19929' OR 'MEDI-19929'):ti,ab #1 AND #2 ("animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT 'human'/exp #3 NOT #4 #5 AND [English]/lim #6 AND ('chapter'/it or 'comment'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it OR 'review'/it OR 'opinion'/it) N oo B~ (WN (R 8 | #6 NOT #7 Search ran on June 14, 2021 ©Ilnstitute for Clinical and Economic Review, 2021 Page D5 Final Report - Severe Asthma Return to Table of Contents Table D1.3. Tezepelumab Search Strategy: Ovid MEDLINE® Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily, Ovid MEDLINE and Versions® 1946 to Present 1 [ "asthma".ti,ab. ("tezepelumab" or "AMG 157" or "AMG157" or "AMG-157" or "MEDI 9929" or "MEDI9929" limit 5 to English language 2 or "MEDI-9929" or "MEDI19929" or "MEDI 19929" or "MEDI-19929").ti,ab. 3 |1land?2 4 | (animals not (humans and animals)).sh. 5 [3not4 6 7 6 and ("chapter" or "comment" or "editorial" or "letter" or "note" or "short survey" or "review" or "opinion").pt 8 [6not7 Search ran on June 14, 2021 Table D1.4. Dupilumab and Omalizumab Search Strategy: EMBASE 1 | 'asthma'/exp ('dupixent' OR 'dupilumab' OR 'REGN 668' OR 'REGN668' OR 'REGN-668' OR 'SAR 231893' OR 'SAR231893' OR 'SAR-231893'):ti,ab N ('xolair' OR 'omalizumab' OR 'rhuMAb-E25' OR 'RG3648' OR 'RG 3648' OR 'RG-3648' OR 'IGE 025' OR 'IGE025' OR 'IGE-025'):ti,ab #1 AND (#2 OR #3) ("animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT 'human'/exp #6 AND [English]/lim #7 AND ('chapter'/it or 'comment'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it OR 'review'/it OR 'opinion'/it) 3 4 5 6 | #4 NOT #5 7 8 9 #7 NOT #8 10 | #9 AND [randomized controlled trial]/lim 11 | #10 AND [2018-2021]/py Search ran on June 14, 2021 Table D1.5. Dupilumab and Omalizumab Search Strategy: Ovid MEDLINE® Epub Ahead of Print, In- Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily, Ovid MEDLINE and Versions® 1946 to Present 1 "asthma".ti,ab. ("dupixent" OR "dupilumab" OR "REGN 668" OR "REGN668" OR "REGN-668" OR "SAR 231893" OR "SAR231893" OR "SAR-231893").ti,ab. 3 ("xolair" OR "omalizumab" OR "rhuMAb-E25" OR "RG3648" OR "RG 3648" OR "RG-3648" OR "IGE 025" OR "IGE025" OR "IGE-025").ti,ab. 4 land(2or3) 5 (animals not (humans and animals}).sh. 6 4not5 7 limit 6 to English language 8 7 and ("chapter" or "comment" or "editorial" or "letter" or "note" or "short survey" or "review" or "opinion").pt ©lnstitute for Clinical and Economic Review, 2021 Page D6 Final Report - Severe Asthma Return to Table of Contents 9 7not8 10 | limit 9 to randomized controlled trial 11 | limit 10 to yr="2018-Current" Search ran on June 14, 2021 Figure D1. PRISMA flow Chart Showing Results of Literature Search for Severe Asthma 247 references identified 14 references identified through literature search through other sources v 232 references after duplicate removal 232 references screened 143 citations excluded 59 citations excluded 89 references assessed for 7 Study Design eligibility in full text 1 Population 1 Intervention 49 Outcomes 'L 2 Duplicates 29 total references 9 RCTs Y 0 references included in guantitative synthesis ©lnstitute for Clinical and Economic Review, 2021 Page D7 Final Report - Severe Asthma Return to Table of Contents 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 tezepelumab, dupilumab, and omalizumab using the clinicaltrials.gov database of trials. We scanned the site to identify studies completed more than two years ago that would have met our inclusion criteria and for which no findings have been published. For this review we did not find any evidence of publication bias for tezepelumab and dupilumab. However we identified three long term extension trials for omalizumab (NCT00109187, NCT00482508, and NCT00482248) that have not yet been published. Study Selection We performed screening at both the abstract and full-text level. Two investigators 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. Two investigators reviewed full papers and provided justification for exclusion of each excluded study. We also included FDA documents related to dupilumab and omalizumab. These included the manufacturer's submission to the agency, internal FDA review documents, and the transcript of Advisory Committee deliberations and discussions. All literature that did not undergo a formal peer review process is described separately. Our literature search identified 213 potentially relevant references (see Figure D1). After de- duplicating and screening titles and abstracts, 74 references were included for full-text screening. Final included studies were clinical trials in adults and or adolescents with severe asthma reporting on outcomes outlined in the PICOTS. 14 references relating to three RCTs of tezepelumab, four of dupilumab, and two of omalizumab met final inclusion criteria for abstraction. 13 additional references were included and abstracted from outside of our literature search, including submissions from manufacturers. Tezepelumab A total of 11 references relating to three RCTs®7-3! comparing tezepelumab to placebo met our inclusion criteria. Dupilumab A total of 13 references relating to three RCTs%!%7! and one phase 2b'® comparing dupilumab to placebo met our inclusion criteria. ©lnstitute for Clinical and Economic Review, 2021 Page D8 Final Report - Severe Asthma Return to Table of Contents Omalizumab A total of three references relating to two RCTs?*2?% and a pooled analysis'?> comparing omalizumab to placebo met our inclusion criteria. Quality of Individual Studies We used criteria published by the US Preventive Services Task Force (USPSTF) to assess the quality of RCTs and comparative cohort studies, using the categories "good," "fair," or "poor" (see Appendix Table F2)"® 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 RCTs. 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 RCTs. 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 RCTs, 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. Also note, we did not rate SOURCE in tezepelumab and TRAVERSE and VOYAGE in dupilumab as they were only available in grey literature with limited reporting of details prohibiting evaluation of the studies' quality. See Table D3.1 for the quality ratings. 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."*7> ©lnstitute for Clinical and Economic Review, 2021 Page D9 Final Report - Severe Asthma Return to Table of Contents Data Synthesis and Statistical Analyses Data on relevant outcomes were summarized in evidence tables (see Section D4) and synthesized qualitatively in the body of the review. D2. Additional Clinical Evidence Table D2.1. Biologic Therapies for Severe Asthma Drug Dosing Mechanism Indication 70-280 mg SC | TSLP Patients with severe asthma without an eosinophilic Q4w phenotype, receiving ICS/LABA with or without OCS and additional controllers Tezepelumab Amgen/AstraZeneca Dupilumab (Dupixent®) 200-300 mg SC | Anti-IL-4Ra Age 212 years with moderate to severe asthma with an Sanofi/Regeneron Q2w eosinophilic phenotype or with OCS-dependent asthma . . 75-375 mg SC | Anti-IgE Age 26 years with moderate to severe persistent asthma ® Omalizumab (Xolair®) Q2W or Q4W* testing positive for perennial aeroallergen whose Genentech symptoms are inadequately controlled with ICS ICS: inhaled corticosteroids, IgE: immunoglobulin E, IL: interleukin, LABA: long-acting beta agonists, mg: milligram, OCS: oral corticosteroids, Q2W: every other week, Q4W: every four weeks, SC: subcutaneous * dosing and frequency determined by serum total IgE level and body weight Table D2.2. Overview of Key Studies Drug Trials N Outcomes PATHWAY 550 AAER at 52 weeks, change form baseline in pre-BD FEV1, ACQ-6, AQLQ Tezepelumab | NAVIGATOR 1061 | AAER at 52 weeks, change form baseline in pre-BD FEV1, ACQ-6, AQLQ SOURCE 150 | Reduction in OCS use without losing asthma control at 48 weeks, AAER Change from baseline in pre-BD FEV1 at 12 and 24 weeks, AAER, time to Phase 2b 776 severe exacerbation during treatment, ACQ-5, AQLQ Dupilumab AAER at 52 weeks, change from baseline in pre-BD FEV1, severe QUEST 1902 . . e exacerbations leading to hospitalization, loss of asthma control VENTURE 210 | Reduction in OCS use without losing asthma control at 24 weeks EXTRA 850 | AAER at 48 weeks, AQLQ, rescue medication use Omalizumab Clinically significant asthma exacerbations at 24 weeks, quality of life, INNOVATE 484 hospitalization/emergency department visits, rescue medication use AAER: annualized asthma exacerbation rate, ACQ: Asthma Control Questionnaire, AQLQ: Asthma Quality of Life Questionnaire, FEV1: forced expiratory volume in one second, OCS: oral corticosteroids, Pre-BD: prebronchodilator Trials of Tezepelumab We identified three phase 3 RCTs of tezepelumab in severe asthma.5"3! The trials are described in detail below and additional details can be found in Evidence Table D4.3. NAVIGATOR and PATHWAY have been published and the data for these trials are informed by the clinical trial report, conference posters and data on file from Amgen. SOURCE is not yet published and the information provided is informed by data provided by Amgen and a conference abstract. ©Ilnstitute for Clinical and Economic Review, 2021 Page D10 Final Report - Severe Asthma Return to Table of Contents PATHWAY The PATHWAY trial was a multicenter, double-blind, placebo-controlled phase 2 RCT evaluating the efficacy and safety of three doses of tezepelumab compared to placebo. Patients were randomized 1:1:1:1 to tezepelumab 70 mg (N =138), 210 mg (N = 137), or 280 mg (N = 137) or to placebo (N = 138) once every 4 weeks for 52 weeks. The 550 included patients were 18 to 75 years of age with asthma that was uncontrolled despite taking medium to high dose inhaled corticosteroids with LABA. Patients had a history of at least two asthma exacerbations requiring systemic glucocorticoid treatment or at least one severe exacerbation leading to hospitalization in the year prior to trial entry. Patients had prebronchodilator forced expiratory volume in 1 second (pre-BD FEV;) values between 40% and 80% of the predicted normal value and a six-item Asthma Control Questionnaire score of at least 1.5. At baseline, treated patients were mean 51.6 years old, 65.6% female, and predominantly white (91.6%) with a mean asthma control score (ACQ-6, range 0-6) of 2.68 and a mean quality of life score (AQLQ, range 1-7) of 4.14.% Additional baseline characteristics can be found in Evidence Table D4.3. The primary endpoint was the annualized rate of asthma exacerbations (AAER) per patient-year at week 52. Key secondary endpoints included change from baseline in pre and postbronchodilator FEV1, ACQ-6 score, AQLQ score, asthma symptom score, and the annualized rate of severe asthma exacerbations at week 52. The primary endpoint as well as changes in prebronchodilator FEV1, ACQ-6, and AQLQ were assessed in subgroups according to blood eosinophil count and allergic status. NAVIGATOR The NAVIGATOR trial was a 52-week, phase 3, multicenter, double-blind RCT that compared the efficacy and safety of tezepelumab (210 mg) to placebo subcutaneously every 4 weeks in 1061 patients. Included patients were 12 to 80 years of age with physician diagnosed asthma and had to have receive medium or high-dose inhaled glucocorticoids for at least 12 months before screening and an additional controller medication. Enrolled patients also had a morning pre-BD FEV less than 80% of normal value (<90% for adolescents) during run-in and a postbronchodilator FEV; of at least 12% before or during the run-in period. Patients also had to have at least two asthma exacerbations defined as worsening of asthma symptoms that led to hospitalization, an emergency department visit that resulted in the use of systemic glucocorticoids in the 12 months before informed consent. Patients who had received biologic treatment (marketed or experimental) could be included in the last dose had been administered more than four months prior or more than five half-lives before screening. Patients were randomized 1:1 to either tezepelumab {N=529) or placebo (N=532) with a mean age of 49.6, of which 36.5% were male, 62.2% were white, and the mean pre-BD FEV; at baseline was 62.7.7 Additional baseline characteristics can be found in Evidence Table D3.3. ©Institute for Clinical and Economic Review, 2021 Page D11 Final Report - Severe Asthma Return to Table of Contents The primary endpoint was the AAER over 52 weeks in the overall patients. This endpoint was also assessed in patients with a baseline eosinophil count of less than 300 cells per microliter. Secondary endpoints include change from baseline in pre-BD FEV1, ACQ-6, and AQLQ. SOURCE The SOURCE trial is an ongoing phase 3, multicenter, parallel group RCT that is evaluating the effect of tezepelumab (210 mg) to placebo subcutaneously every 4 weeks on oral corticosteroid (OCS) dose reduction in adults with OCS-dependent asthma. Eligible patients much be receiving OCS as an asthma treatment prior to screening (6 months), taking a stable dose (7.5-30 mg) of prednisone daily prior to screening (1 month) as well as a medium to high dose ICS for prior to screening (12 months). Patients receiving medium dose ICS must have had their dose increased to a high dose for at least 3 months prior to screening. Eligible patients also had to be taking a LABA with or without an additional controller medication three months before screening and patients on additional maintenance asthma controller medications were permitted to enter the study if use had been documented for at least three months or a biologic if the wash out period of 4 months or 5 half- lives was completed. Patients also had to at least one asthma exacerbation in the 12 months before screening. Patients were enrolled 1:1 to tezepelumab (N= 74) or placebo {N= 76) with a mean age of 53.4 years, 62.7% female patients, 20.19% Black or African-American, with a mean pre-BD FEV1 of 1.575 liters.2 Additional baseline characteristics can be found in Evidence Table D3.3. The primary endpoint is percentage reduction from baseline in OCS dose at week 48 (defined as 90- 100%, 75- <90%, 50- <75%, 0- <50%, or no change or increase). Secondary endpoints include AAER, proportion of patients with 100% reduction on OCS dose and change from baseline in pre-BD FEV:. ©Ilnstitute for Clinical and Economic Review, 2021 Page D12 Final Report - Severe Asthma Return to Table of Contents Table D2.3. Key Trials of Tezepelumab Trial Arms Key Baseline Characteristics PATHWAY Tezepelumab 70 mg (N = 138) Age, mean years: 51.6 Tezepelumab 210 mg (N = 137) Female, %: 65.6 Tezepelumab 280 mg (N = 137) Black, %: 3.5 Placebo (N = 138) Pre-BD FEV1 (L), mean: 1.85 Pre-BD FEV:1 (% predicted), mean: 59.4 AQLQ, mean: 4.14 ACQ-6, mean: 2.68 NAVIGATOR Tezepelumab 210 mg (N = 528) Age, mean years: 49.5 Placebo (N = 531) Female, %: 63.5 Black, %: 5.8 Pre-BD FEV:1 (L), mean: 1.8 Pre-BD FEV1(% predicted), mean: 62.8 AQLQ, mean: 3.9 ACQ-6, mean: 2.8 SOURCE Tezepelumab 210 mg (N = 74) Age, mean years: 53.4 Placebo (N = 76) Female, %: 62.7 Black, %: 20.2 Pre-BD FEV:1(L), mean: 1.57 Pre-BD FEV1 (% predicted), mean: NR AQLQ, mean: 2.47 ACQ-6, mean: 2.47 Key Trials of Dupilumab We identified three RCTs of dupilumab in severe asthma.®'81% The trials are described in detail below and additional details can be found in Evidence Table D2.4. QUEST and VENTURE have been published and the data for these trials are informed by the clinical trial report and conference posters. TRAVERSE is not yet published and data for this trial is informed by conference abstracts. Phase 2b The Phase 2b trial was a 24-week double-blind, placebo-controlled dose-ranging RCT evaluating the efficacy and safety of dupilumab in adults with uncontrolled persistent asthma. Included patients were over the age of 18 years with a diagnosis of asthma for at least a year while receiving medium to high dose inhaled corticosteroids plus LABA for at least one month prior to screening. Patients were also required to have at least one systemic corticosteroid burst therapy, hospitalization, or emergency visit requiring systemic steroid treatment in the year prior. The 776 enrolled patients were randomized 1:1:1:1:1 to dupilumab 200 mg every 4 weeks (N = 154), 300 mg every 4 weeks (N =157), 200 mg every 2 weeks (N = 150), 300 mg every 2 weeks (N = 157), or placebo (N = 150). Across the two dupilumab arms dosing once every 2 weeks (the FDA recommended dosing schedule) and the placebo arm, patients were mean 49.2 years of age, 65.2% female, predominantly white (77.8%).18 Additional baseline characteristics can be found in Evidence Table D2.4. ©Ilnstitute for Clinical and Economic Review, 2021 Page D13 Final Report - Severe Asthma Return to Table of Contents The primary endpoint was change from baseline in FEV; (liters) in patients with at least 300 eosinophils per microliter at week 12. Secondary endpoints were change in FEV: at 24 weeks, AAER, asthma symptom score, ACQ-5, and AQLQ. LIBERTY ASTHMA QUEST The LIBERTY ASTHMA QUEST trial was a 52-week phase 3 RCT that compared the efficacy of dupilumab to placebo in patients with moderate-to-severe asthma. Patients enrolled were 12 years of age or older with diagnosed persistent asthma for 12 months or more (according to GINA guidelines) and on current treatment with medium-to-high dose inhaled glucocorticoid with up to two additional controllers. Patients enrolled also had a pre-BD FEV1 of <80% of the normal volume (<90% for adolescents), an ACQ-5 score of 1.5 or higher, and worsening asthma in that last year that lead to hospitalization, emergency medical care, or treatment with systemic glucocorticoids for three days or more. Patients were randomized 2:2:1:1 to 200mg dupilumab (N= 631) or matched placebo 1.14 ml (N= 317) or 300mg dupilumab (N= 633} or matched placebo 2.00 ml (N= 321) with an average mean age 47.9 years, 62.9% female, average pre-BD FEV; at baseline of 1.78 liters, and average ACQ-5 score of 2.76.% Additional baseline characteristics can be found in Evidence Table D3.4. The primary endpoints were annualized rate of severe exacerbation events during the 52-weeks and the absolute change from baseline in pre-BD FEV1 at week 12. Secondary endpoints include percent change in pre-BD FEV; at 52 weeks, and severe asthma exacerbation resulting in hospitalization or emergency department visit. LIBERTY ASTHMA VENTURE LIBERTY ASTHMA VENTURE is a 24-week double-blind, placebo-controlled, phase 3 RCT assessing the efficacy and safety of dupilumab in patients with oral glucocorticoid-dependent severe asthma. The 210 included patients were older than 12 years of age with physician-diagnosed asthma receiving treatment with systemic glucocorticoids for at least 6 months prior to trial entry and high dose inhaled glucocorticoids with up to two controllers for at least 3 months. Patients were randomized 1:1 to 300 mg of dupilumab (N =) or matched placebo (N =) every two weeks. Overall, enrolled patients were mean 51.3 years of age, 60.5% female, and had an average ACQ-5 score of 2.50.%° Additional baseline characteristics can be found in Evidence Table D2.4. The primary endpoint was the change in the oral glucocorticoid dose without losing asthma control from baseline to week 24. Key secondary endpoints are a reduction of at least 50% in oral glucocorticoid dose and the proportion of patients with the maximum possible reduction in oral glucocorticoid dose. Other secondary endpoints were the annualized rate of severe exacerbations and change from baseline in pre-BD FEV1and the ACQ-5 score at week 24. ©Ilnstitute for Clinical and Economic Review, 2021 Page D14 Final Report - Severe Asthma Return to Table of Contents LIBERTY ASTHMA TRAVERSE LIBERTY ASTHMA TRAVERSE is an ongoing, single-arm, 96-week, open-label extension study evaluating the long-term efficacy, tolerability, and safety of dupilumab added on to standard of care in adults and/or adolescents. TRAVERSE enrolled 1,902 patients who had participated in the previous dupilumab asthma studies (DRI, EXPEDITION, QUEST, or VENTURE). Baseline characteristics are not currently available, however key outcomes of interest include treatment- emergent adverse events, AAER, change from baseline in pre-BD FEV1, ACQ-5, and AQLQ. Subgroups of interest in this study includes patients with blood EOS of 2300, 2150, and FeNO 225ppb. Table D2.4. Key Trials of Dupilumab Trial Arms Key Baseline Characteristics Phase 2b* Dupilumab 200 mg Q2W (N = 150) | Age, mean years: 49.2 Dupilumab 300 mg Q2W (N = 157) Female, %: 65.2 Placebo (N = 158} Black, %: 4.9 Pre-BD FEV1(L), mean: 1.8 Pre-BD FEV1{% predicted), mean: 60.8 ACQ-5, mean: 2.74 AQLQ, mean: 4.02 LIBERTY ASTHA QUEST Dupilumab 200 mg (N=631) Age, mean years: 47.9 Placebo 1.14 ml {(N=317) Female, %: 62.9 Dupilumab 300 mg (N= 633) Black, %: NR Placebo 2.00 ml (N=321) Pre-BD FEV: {L), mean: 1.78 Pre-BD FEV:1{% predicted), mean: 58.4 ACQ-5, mean: 2.76 AQLQ, mean: NR LIBERTY ASTHMA VENTURE | Dupilumab 300 mg (N = 103) Age, mean years: 51.3 Placebo (N = 107} Female, %: 60.5 Black, %: NR Pre-BD FEV:{L), mean: 1.58 Pre-BD FEV:1{% predicted), mean: 52.2 ACQ-5, mean: 2.5 AQLQ, mean: NR LIBERTY ASTHMA TRAVERSE NA NA: not available, Q2W: once every two weeks * Baseline characteristics exclude the dupilumab Q4W 200 mg and 300 mg arms Key Trials of Omalizumab We identified two phase 3 RCTs of omalizumab in severe allergic asthma.?>?> The trials are described in detail below and additional details can be found in Evidence Table D3.5. EXTRA and INNOVATE have been published and the data for these trials are informed by the clinical trial report and a conference abstract. OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page D15 Return to Table of Contents EXTRA EXTRA was a 48-week, prospective, multicenter, double-blind, placebo-controlled phase 3 RCT assessing the efficacy and safety of omalizumab in patients with inadequately controlled, severe allergic asthma. Patients were randomized to either omalizumab with dosing based on body weight and total serum IgE level, minimum 0.0008 mg/kg per IgE (IU/mL) Q2W or 0.0016 mg/kg per IgE (IU/mL) Q4W (N = 427) or placebo (N = 421) for 48 weeks. Included patients were between 12 and 75 years of age with at least one year of severe allergic asthma and uncontrolled despite use of high dose ICS and LABAs. Patients also had at least one asthma exacerbation during the 12 months prior to the trial. At baseline, patients were mean 44.5 years of age, 65.8% female, majority white (74.4%) with an AQLQ score of 4.0.%> Additional baseline characteristics can be found in Evidence Table D3.5. The primary endpoint was the rate of asthma exacerbations during the 48-week treatment period. Secondary endpoints were change in asthma symptom severity score, mean puffs per day of rescue medication, and overall asthma-related quality of life (AQLQ). INNOVATE The INNOVATE trial was a 28-week, multicenter, randomized, double-blind phase 3 RCT comparing the efficacy, safety, and tolerability in omalizumab versus placebo in patients with persistent severe allergic asthma. Eligible patients were 12 to 75 years old with a positive skin prick test to 21 perennial aeroallergen they might be exposed to during the study, severe persistent asthma requiring regular treatment with beclomethasone dipropionate {BDP) or LABA, an FEV of 240 to <80% of predicted normal value, and at least two severe asthma exacerbations requiring systemic corticosteroids, or one severe exacerbation requiring hospitalization or emergency room treatment, in the past 12 months. Additional asthma medications such as theophylline's or oral b agonists were allowed if taken regularly starting at least 4 weeks prior. Patients were randomized 1:1 to omalizumab (N= 209) or placebo (N= 210) with a mean age of 43.3, 66.6% female, 6.7% Black, and mean AQLQ score of 3.9.2 Additional baseline characteristics can be found in Evidence Table D3.5. The primary endpoint was severe exacerbation rate, however due to baseline differences in exacerbation history, a post hoc adjustment was made and included in the analysis. Additional secondary endpoints were emergency visits for asthma, AQLQ, and change from baseline in pre-BD FEVi. ©Ilnstitute for Clinical and Economic Review, 2021 Page D16 Final Report - Severe Asthma Return to Table of Contents Table D2.5. Key Trials of Omalizumab Trial Arms Key Baseline Characteristics EXTRA Omalizumab (N = 427) Age, mean years: 44.5 Placebo {N = 421) Female, %: 65.8 Black, %: 20.8 Pre-BD FEV:1{L), mean: NR Pre-BD FEV:1{% predicted), mean: 64.9 ACQ-5, mean: NR AQLQ, mean: 4.0 INNOVATE Omalizumab (N = 209) Age, mean years: 43.3 Placebo (N = 210) Female, %: 66.6 Black, %: 6.7 Pre-BD FEV:1{(L), mean: NR Pre-BD FEV:1{% predicted), mean: 61.3 ACQ-5, mean: NR AQLQ, mean: 3.9 ACQ: Asthma Control Questionnaire, AQLQ: Asthma Quality of Life Questionnaire, FEV1: forced expiratory volume in one second, L: liters, N: total number, NR: not reported, pre-BD: prebronchodilator Clinical Outcomes of Tezepelumab Daily Symptoms and Quality of Life In Additional Tezepelumab Doses In PATHWAY at 52 weeks, the reductions in ACQ-6 from baseline in the low dose (70 mg every four weeks) and high dose (280 mg every four weeks) arms were similar to those seen in the intermediate dose of tezepelumab (low: -1.17; diff 0.26, 95% CI -0.01 to 0.52} and (high: -1.22, diff 0.31, Cl1 0.04 to 0.58); both smaller than the MCID. The improvement in AQLQ in the low dose arms was not statistically significantly different from placebo (1.12 vs 0.97; diff 0.14, CI-0.13, 0.42) but the improvement in the high dose arm was (1.32 vs. 0.97, diff 0.34, CI 0.0, 0.63; P=0.017).5 Annualized Asthma Exacerbation Rate (AAER) in Additional Tezepelumab Doses In PATHWAY at week 52, the AAER was statistically significantly lower with tezepelumab as compared to placebo in both the low (0.27 vs. 0.72; rate ratio [RR] 0.38, 95% Cl 0.25 to 0.58) and high dose arms (0.23 vs. 0.72; rate ratio [RR] 0.34, 95% Cl 0.21. to 0.53).° Pulmonary Function Tests The key secondary outcome is change from baseline in prebronchodilator FEV (pre-BD FEV1). The minimum clinically important difference (MCID) for FEV1 is considered to be 0.1 liters (100-200 mL).' In PATHWAY, the least-squares mean change from baseline in pre-BD FEV: at week 52 statistically improved in the 210 mg tezepelumab arm compared to placebo (0.08L vs. -0.06L; diff 0.13, 95% ClI 0.03 to 0.23; P=0.009). A dose response in pre-BD FEV1 was seen across the three tezepelumab ©Institute for Clinical and Economic Review, 2021 Page D17 Final Report - Severe Asthma Return to Table of Contents doses, with all improvements being statistically significant. Patients with eosinophilic asthma (baseline EOS 2300 cells/uL) on 210 mg of tezepelumab also experienced higher pre-BD FEV; than those on placebo (0.11 vs -0.10; diff 0.21; CI 0.06 to 0.35). For those with baseline ESO 2150, EOS <150 and <300 cells/uL, however, the difference between any tezepelumab dose and placebo was smaller than the MCID.53! See Table D2.6 for more details. In NAVIGATOR at 52 weeks, the mean change from baseline in pre-BD FEV1 was statistically greater for patients on tezepelumab compared to placebo (0.23L vs. 0.09L; Diff 0.13; CI: 0.08 to 0.18; P<0.001). Patients on tezepelumab also had a clinically greater change in the baseline EOS 2150 (0.28 vs. 0.11 diff 0.17; CI: 0.11 to 0.23) and 2300 (0.37 vs. 0.14; diff 0.23; Cl: 0.15 to 0.31) subgroups compared to placebo. Patients on tezepelumab with baseline EOS <150 and <300 also had greater change versus placebo, but the difference was smaller than the MCID (diff 0.03 and 0.07).7 See Table D2.6 for more details. The NAVIGATOR trial investigators did not report on post-BD FEV1. Data are not yet available on pulmonary function tests in SOURCE. Table D2.6. Pulmonary Function Test Results in Tezepelumab Grou Trial Pre-BD FEV1 (L), LS Mean (SE) Post-BD FEV1 (L), LS Mean (SE) P PBO TEZ 210mg PBO TEZ 210mg Overall PATHWAY -0.06 (NR) 0.08 (NR) -0.06 (NR) 0.10 (NR) NAVIGATOR 0.23 (0.02) 0.09 (0.02) NR NR PATHWAY -0.10 (NR) 0.07 (NR) NR NR EOS 2150 NAVIGATOR 0.11 (0.02) 0.28 (0.02) NR NR PATHWAY -0.01 (NR) -0.02 (NR) NR NR EOS <150 NAVIGATOR 0.07 (0.04) 0.10 (0.04) NR NR 05 >300 PATHWAY -0.10 (NR) 0.11 (NR) NR NR EOS 2 NAVIGATOR 0.14 (0.03) 0.37 (0.03) NR NR EOS <300 PATHWAY -0.04 (NR) 0.01 (NR) NR NR NAVIGATOR 0.06 (0.02) 0.13 (0.02) NR NR BD: bronchodilator, EOS: blood eosinophil count, FEV1: forced expiratory volume in one second, L: liters, LS: least- squares mean, NR: not reported, PBO: placebo, SE: standard error, TEZ: tezepelumab Hospitalization and Emergency Department (ED) Visits In PATHWAY, patients on 210 mg of tezepelumab experienced fewer AAER leading to hospitalizations or ED visits than placebo (0.7 vs 3.6; diff 0.15 CI: 0.04, 0.58).5 In NAVIGATOR, AAER requiring hospitalization or ED visits for patients on tezepelumab was lower compared to placebo (0.06 vs. 0.28; RR: 0.21; Cl: 0.12 to 0.37)." Tezepelumab also prolonged time to first exacerbation requiring hospitalization or ED visits (RR: 65%; HR: 0.35) and reduced asthma- related hospitalization (3.2% vs. 7.0%) compared to placebo." ©lnstitute for Clinical and Economic Review, 2021 Page D18 Final Report - Severe Asthma Return to Table of Contents 0OCS-Dependent Patients Of the 100 patients receiving maintenance oral corticosteroids (mOCS) during NAVIGATOR (tezepelumab, n= 49, placebo, n= 51), tezepelumab-treated patients had lower AAER compared to placebo (2.12 vs. 2.94; RR: 28%; Cl: -26 to 59). Tezepelumab-treated patients also had clinically greater improvement compared to placebo in pre-BD FEV1 (0.29 vs. 0.02; diff 0.27; Cl: 0.1 to 0.44) and numerically greater improvements in ACQ-6 (-0.85 vs. -1.50; diff 0.65; Cl: 0.22 to 1.08) and AQLQ (0.81 vs 1.32; diff 0.50; Cl: 0.4 to 0.97).77 Clinical Outcomes of Dupilumab Pulmonary Function Tests In the phase 2b trial at week 12, a statistically significant improvement in pre-BD FEV1 was seen in the overall population for both 200 mg Q2W (0.20L; CI: 0.11 to 0.28); P<.001) and 300 mg Q2W (0.16L; Cl: 0.08 to 0.25; P<0.0002) versus placebo. In patients with 2300 EOS at baseline, the LS mean change in pre-BD FEV1 for 200 mg Q2W was 0.26 (Cl: 0.11 to 0.40); p = 0.0008) and 0.21 (Cl: 0.06 to 0.36; P=0.0063) for the 300 mg Q2W dose.!® At week 12 in LIBERTY ASTHMA QUEST, dupilumab had a statistically greater improvement in in Pre- BD FEV: versus matched placebo in both the low dose (0.32 vs. 0.18; diff 0.14; P<0.001) and high dose (0.34 vs. 0.21; diff 0.13; P<0.001) arms.® In patients with EOS 2300 at baseline, 300 mg Q2W dupilumab had a statistically significant improvement in pre-BD FEV; versus matched placebo (0.22 vs. 0.47; diff 0.24; Cl: 0.16 to 0.32; P<0.001). The 200 mg Q2W dose also improved pre-BD FEV versus matched placebo (0.21 vs. 0.43; diff 0.21; Cl: 0.13 to 0.29). This trend in improvement continued for low dose in the EOS 2150 to <300 (0.28 vs. 0.17; diff 0.11) and <150 groups (0.19 vs. 0.13; diff 0.06), however high dose dupilumab had no difference in improvement compared to matched placebo in the 2150 to <300 group (0.25 vs. 0.25).2° The improvements in pre-BD FEV; sustained through week 52 for both doses. Patients on high dose dupilumab had a mean improvement of 0.35 (diff 0.13; Cl: 0.08 to 0.19) and low dose had an improvement of 0.36 (diff. 0.20; CI: 0.14 t0 0.25).7® See Table D2.7 below for additional timepoints and subgroup data on QUEST pulmonary function tests. ©Ilnstitute for Clinical and Economic Review, 2021 Page D19 Final Report - Severe Asthma Return to Table of Contents Table D2.7. Pulmonary Function Tests in LIBERTY ASTHMA QUEST Group Change in Pre-BD FEV1, LS Mean Change in Post-BD FEV1, LS Mean Low dose High Dose Low Dose High Dose PBO | DUP PBO DUP PBO | DUP PBO DUP Week 12 Overall 0.18 0.32 0.21 0.34 0.01 0.15 0.04 0.14 EOS 2150 0.19 0.26 0.23 0.37 0.01 0.19 0.04 0.17 EOQS 2300 0.21 0.43 0.22 0.47 0.04 0.29 0.07 0.27 Week 52 Overall 0.16 0.36 0.22 0.35 -0.04 0.15 0.01 0.14 EOS 2150 0.15 0.40 0.23 0.39 -0.04 0.20 0.01 0.16 EOS 2300 0.17 0.47 0.23 0.48 -0.01 0.29 0.03 0.25 Data from LIBERTY ASTHMA QUEST and Castro 2020 ERJ.'®8 BD: bronchodilator, DUP: dupilumab, EOS: blood eosinophil count, FEV1: forced expiratory volume in one second, LS: least-squares, PBO: placebo In LIBERTY ASTHMA VENTURE, dupilumab-treated patients had a statistically significant improvement in Pre-BD FEV1 compared to placebo (0.01 vs. 0.22; diff 0.22; Cl: 0.09 to 0.34; P<0.001).° Hospitalization and Emergency Department (ED) Visits In the Phase 2b study, no data on hospitalizations or emergency department visits were reported. In LIBERTY ASTHMA QUEST, rates of asthma-hospitalizations were lower in the low dose dupilumab arm versus matched placebo (0.035 vs. 0.065). Data on the high dose arm and matched placebo is not available.?® In LIBERTY ASTHMA VENTURE, no data on hospitalizations or emergency department visits were reported. Oral Corticosteroid-Dependent Patients In LIBERTY ASTHMA VENTURE, a greater percentage of patients taking 300 mg Q2W dupilumab achieved a 290% reduction in oral glucocorticoid dose at 24 weeks (55.3% vs. 30.8%). Dupilumab at 300mg Q2W also had a greater percentage of patients achieve 275% (68.9% vs. 39.3%), 250% (79.6% vs. 53.3%) and 20% (86.4% vs. 68.2%). Dupilumab 300 mg Q2W also had a greater proportion of patients no longer requiring OCS at week 24 compared to placebo (OR: 2.74; Cl: 1.47 to 5.10; P= 0.002.° Subgroups In a post hoc analysis of the phase 3 QUEST study,?° patients across the high type 2 biomarker subgroup of EOS 2300 cells/uL had lower AAER (range: 0.16 to 0.65) compared to placebo (range: 0.86 to 2.35). Patients with EOS 2300 cells/pL also showed improvements in lung function ©Ilnstitute for Clinical and Economic Review, 2021 Page D20 Final Report - Severe Asthma Return to Table of Contents compared to placebo as measured by pre-BD FEV1 (200 mg dupilumab: diff 0.30; Cl: 0.21 to 0.39; 300 mg dupilumab: diff 0.25; Cl 0.16 to 0.33). Patients with EOS 2150 cells/uL experienced a slightly smaller improvement in pre-BD FEV: (200 mg dupilumab: diff 0.25; Cl: 0.18 to 0.32; 300 mg dupilumab: diff 0.15; CI 0.09 to 0.22). Patients with EOS 2150 and FeNO 225 at baseline had a greater benefit in pre-BD FEV1 than the overall population versus matched placebo in the 200 mg dupilumab dose (diff 0.33; Cl: 0.24 to 0.43) and the 300 mg dupilumab dose (diff 0.26; Cl: 0.17 to 0.35) arms."® In a post hoc analysis of QUEST patients who met the criteria for allergic asthma (as defined by the eligibility criteria used by physicians for omalizumab), high dose and low dose dupilumab patients had a greater reduction in annualized severe exacerbation rate (high dose: 46% and low dose: 37%) compared to matched placebo at week 52. Reductions in AAER also occurred in both doses versus placebo in the EOS 2150 (55% vs. 42%) and EOS 2300 (62% and 57%) groups."® Patients in QUEST who did not meet the criteria for allergic asthma saw similar reductions across both doses versus placebo (overall: 60% and 45%; EOS >150: 71% and 63%; EOS >300: 75% and 71%)."° See the point estimates in Table D2.8 below. In pre-BD FEV; at week 12, QUEST allergic asthma patients had significant improvement for both doses of dupilumab (diff 0.13 and 0.16, respectively) versus placebo. Similar results occurred in non- allergic patients on dupilumab {low dose: 014 vs. high dose: 0.09). ACQ-5 score had improvements for allergic patients on dupilumab (high dose: -0.26 vs. low dose: -0.28) at week 24. Non-allergic patients on low dose dupilumab had a significant improvement in ACQO-5 (0.44; Cl: 0.22 to 0.65; P<0.001) versus matched placebo and high dose had a nominal improvement versus matched placebo (0.08; Cl: 0.12 to 0.29).7° Table D2.8. Additional Data for Allergic and Non-Allergic Patients in LIBERTY ASTHMA QUEST Group Allergic Annualized Severe Exacerbation Rate (estimate, 95%Cl) Status PBO 1.14 ml DUP 200 mg PBO 2.0 ml DUP 300 mg Overall 0.74 (0.57 t0 095) | 0.46 (0.38t0 0.57) | 0.97 (0.77 to 1.24) | 0.53 (0.43 to 0.65) EOS 2150 Allergic 0.86 (0.64 to 1.15) | 0.52(0.39t0 0.64) | 1.05(0.80to 1.40} | 0.47 (0.37 to 0.61) EOS 2300 0.89 (0.64 to 1.25) | 0.38 (0.28t0 0.54) | 1.15 (0.84 to 1.59) | 0.44 (0.32 to 0.60) Overall 1.07 (0.82to 1.42) | 0.43(0.35t0 0.55) | 0.92 (0.70to 1.20) | 0.51 (0.40 to 0.65) EOS 2150 A'I\I':r';'ic 1.23(0.90to 1.70) | 0.36(0.26 t0 0.48) | 1.02 (0.75 to 1.40) | 0.38 (0.28 to 0.50) EOS 2300 1.38(0.95t01.99) | 0.34(0.231t00.50) | 1.28 0.89 to 1.86) 0.37(0.26 to 0.53) 95%Cl: 95% confidence interval, DUP: dupilumab, EOS: blood eosinophil count, PBO: placebo, mg: milligram, ml: milliliter OInstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page D21 Return to Table of Contents Clinical Outcomes of Omalizumab Pulmonary Function Tests In EXTRA and INNOVATE, pre-BD FEV1 in liters was not assessed. Hospitalization For omalizumab-treated patients in INNOVATE, rates of total emergency visits were lower than placebo (0.24 vs. 0.43; RR 0.56; Cl: 0.32 to 0.97). Omalizumab also had lower rates for hospital admissions (0.06 vs. 0.12), emergency room visits (0.04 vs. 0.06) and unscheduled doctor visits (0.13 vs. 0.24).2 Supplemental Harms For a complete list of all harms, please see Evidence Tables D3.13 to D3.17. Table D2.9. Select Pooled Harms from Key Studies Drug Trial AEs SAEs :;:;atter:':::; Discontinuation | Mortality rezepelumab | PATHWAY® 251(60.9) | 40(9.7) 3(0.7) 56 (13.6) 1(0.2) NAVIGATOR | 836(78.9) | 125(11.75) NR 93 (8.8) 2(04) Phase 2b 358 (77.6) 32(7) NR 30 (6.5) 05 Dupilumab | QUEST 1550 (81.7) | 157(8.3) NR 228 (12.0) 8(0.4) VENTURE 133 (63) 15 (7.5) NR 7(3.5) 0(0) ormalisama |EXTRA 668 (79.9) | 84(9.9) NR 177 (20.8) 3(0.7) INNOVATE 356(73.8) | 66(13.7) 51(10.5) 52 (10.7) NR AEs: adverse events, NR: not reported, SAEs: serious adverse events. All data are pooled estimates and presented as n (%). * Includes 70 mg, 210 mg, and 280 mg doses of tezepelumab T Serious treatment-related adverse event ¥ Overall discontinuation § Adverse event-related mortality ©Ilnstitute for Clinical and Economic Review, 2021 Page D22 Final Report - Severe Asthma Return to Table of Contents S]USIUO) JO 9|gE] 0} uImay €20 d8ed BLUYISY 2J3A3S - }Joday |euld TTOC 'M3IA9Y dlWOU0d3] pue |edjul|) JO} 91NUISUIQ uonendw Ijdiynwi i 'seanseaw pa1eadss Yyim [3pow SPIYS-PIXIW SAHININ '|2POW S19343-PaxiW (AN 'WOpUERS 18 SUISSIW JYYIA 'PJEMIO) PILIIED UOIIBAIDSGO IS8 4D0T pood IN SOA S9A ON SaA S3A S9A S9A SaA JLVAONNI pooon AN SSA SOA ON SaA S9A SOA S9A SaA vilxa gewnzjjew pood IN SSA SOA ON S9A S3A SOA S9A SOA JUNINIA pood NYNIN SOA SOA ON SaA S3A SOA S9A SoA 15Ino gewnjidng pood UVIN PUe 4301 SSA S9A ON S9A S9A S9A S9A S9A YOLVDIAVN pood WIN pue ¥viN SSA S9A ON S9A S9A SOA S9A SeA AVMHLVd gewn|adazal Suney - sishjeuy PUEA Suinuoday S3wWoN0 UOIJUBAIB| Suipung dn-mojjo4 sdnaio 03 yeouddy 1e9.11-0) SIUSWIRINSEON awoonnQ | jouomuyaq | jouonmuyaqg | JoyeSnsaau| |enuaJsap aiqesedwion |euy 41sdsn -uoljudu| SAINDI|IS e3) e' Jwusned -UoN Ayjenp Apnis 'T°€q ajqeL sId|qel 90UapIAg €A S1U9U0) JO 3|qe] O} uin3ay ¥¢a a8eq BWYISY o19A3S - 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Previous Systematic Reviews and Technology Assessments We identified two ongoing health technology assessments by the National Institute for Health and Care Excellence (NICE) of tezepelumab and dupilumab and one assessment of omalizumab by the Canadian Agency for Drugs and Technologies in Health (CADTH). We also identified and summarized the most recent and relevant systematic reviews of dupilumab and omalizumab in patients with severe asthma below. NICE Technology Assessments Tezepelumab for treating severe asthma [I1D3910] NICE is currently conducting an appraisal of the clinical and cost effectiveness of tezepelumab in people with severe asthma inadequately controlled by standard therapy. Comparators in the draft scope include dupilumab, omalizumab, reslizumab, benralizumab, and mepolizumab. The expected publication date is to be confirmed. Dupilumab for treating severe asthma [1D1213] NICE is currently conducting an appraisal of the clinical and cost effectiveness of dupilumab in people older than 12 years with severe asthma inadequately controlled by standard therapy. NICE recommends dupilumab as an add-on maintenance therapy for severe asthma patients with type 2 inflammation marked by a blood eosinophil count of at least 150 cells/uL, a fractional exhaled nitric oxide of at least 25 parts per billion, and a history of at least 4 exacerbations in the prior year. Recommended dosing starts at 400 mg and then tapers to 200 mg every other week and should be stopped if the rate of severe exacerbations does not decrease by at least 50% after 12 months of treatment. The expected publication date is November 18, 2021. Omalizumab for treating severe persistent allergic asthma [TA278] NICE evaluated omalizumab for the treatment of severe persistent allergic asthma in 2013. They recommend it as an option for treating severe persistent allergic IgE mediated asthma as an add-on to optimized standard therapy in people aged 6 and older who need continuous or frequent treatment with oral steroids (four or more courses in the previous year). Optimized standard therapy includes inhaled high-dose corticosteroids, long-acting beta agonists leukotriene receptor antagonists, theophylline, oral corticosteroids, and smoking cessation. CADTH Technology Assessments Omalizumab Treatment for Adults and Children with Allergic Asthma: A Review of the Clinical Effectiveness, Cost-Effectiveness, and Guidelines ©Institute for Clinical and Economic Review, 2021 Page D64 Final Report - Severe Asthma Return to Table of Contents CADTH conducted a review of omalizumab treatment for adults and children with allergic asthma in 2015. They published a summary with a critical appraisal. They concluded that omalizumab decreases the risk of asthma exacerbations in patients with moderate to severe allergic asthma inadequately controlled by standard therapies. They acknowledged that one evidence-based guideline recommended its use for the treatment of individuals aged 6 and older who had severe persistent confirmed allergic IgE mediated asthma as an add on to optimized standard therapy for those who need frequent treatment with oral corticosteroids. Previous Systematic Reviews Agache |, Song Y, Rocha C, et al. Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma. Allergy. 2020 May;75(5):1058-1068. Through a systematic review, investigators identified three randomized controlled trials (RCTs) of dupilumab in patients with severe, uncontrolled asthma to assess its efficacy and safety. The 2735 included patients across the three trials (LIBERTY ASTHMA QUEST, VENTURE, and the Phase 2b study) were ages twelve and older with severe asthma uncontrolled by ICS or OCS plus two additional controllers. In this population, dupilumab decreased the annualized rate of severe exacerbations with high certainty of evidence compared to placebo across all trials (IRR: 0.51, 95% Cl 0.45-0.59) with no difference between the 200 mg and 300 mg doses. In the subgroup of patients with high blood eosinophil count (>300 cells/uL) the rate of severe exacerbations decreased significantly more than those with <300 cells/pL (IRR: 0.63 vs. 0.35; p = 0.001). The pooled ACQ-5 score in the three RCTs showed improvement in asthma control with dupilumab compared to placebo, although not by the minimally important difference (MID) of 0.5. The pooled result of the two RCTs that evaluated AQLQ was similar, showing improvement with dupilumab versus placebo but again not reaching the MID. As for safety, investigators determined with moderate certainty that dupilumab increases drug-related adverse events at 24 weeks. Additionally, pooled analysis showed with high certainty that dupilumab reduces the percentage use of OCS (reaching the MID) and rescue medication (without reaching the MID) as compared to placebo and improves FEV; at 24 weeks (without reaching the MID). Overall, this systematic review concludes that as an add-on treatment in patients with severe, uncontrolled asthma using ICS plus a second controller, dupilumab reduces the rate of asthma exacerbations and use of OCS; somewhat improves asthma control, quality of life, and FEV1; but may increase short-term drug-related adverse events. ©Ilnstitute for Clinical and Economic Review, 2021 Page D65 Final Report - Severe Asthma Return to Table of Contents Henriksen DP, Bodtger U, Sidenius K. et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020. 16(49) Investigators conducted a systematic review to assess the efficacy of omalizumab in patients with severe allergic asthma. 22 published papers were identified in adults with severe asthma treated with omalizumab including 12 randomized controlled trials. From five RCTs with data on reduction in annual exacerbations, omalizumab was favorable with an absolute risk reduction of 37% compared to placebo. As for improvement in asthma control, data from five studies of 2287 patients showed a statistically significant improvement in ACQ and ACT scores, although the improvements were below the minimal clinically important difference (MCID) of 0.5 points. Statistically significant improvements in AQLQ above the MCID of 0.5 were seen in four studies of 1852 patients on omalizumab compared to placebo. Safety was assessed from 13 studies and was not significantly different in terms of serious adverse events between omalizumab and placebo groups. Overall, evidence quality was low for important outcome measures due to evolving definitions of severe asthma, however omalizumab appears safe and demonstrates significant reductions in exacerbation rate and OCS dose. The effect on lung function, asthma control and quality of life remains uncertain. More studies on patients with true, severe asthma are needed. ©Institute for Clinical and Economic Review, 2021 Page D66 Final Report - Severe Asthma Return to Table of Contents E. Long-Term Cost-Effectiveness: Supplemental Information El. Detailed Methods Table E1. Impact Inventory Type of Impact Included in This Analysis from [...] Notes on Sources Sector (Add additional domains, as Perspective? ,('f quantlflfed), Likely Magnitude relevant) Health Societal | & Impact (if not) Care Sector Formal Health Care Sector Health Longevity effects X X Outcomes Health-related quality of life X X effects Adverse events X X Medical Costs | Paid by third-party payers X X Paid by patients out-of-pocket O O Future related medical costs O O Future unrelated medical costs O O Informal Health Care Sector Health- Patient time costs NA O Related Costs | Unpaid caregiver-time costs NA O Transportation costs NA O Non-Health Care Sector Productivity Labor market earnings lost NA X Cost of unpaid lost productivity NA X due toillness Cost of uncompensated household | NA O production Consumption | Future consumption unrelated to NA O health Social Services | Cost of social services as part of NA O intervention Legal/Criminal | Number of crimes related to NA O Justice intervention Cost of crimes related to NA O intervention ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page E1 Return to Table of Contents Education Impact of intervention on NA O educational achievement of population Housing Cost of home improvements, NA O remediation Environment | Production of toxic waste pollution | NA O by intervention Other Other impacts (if relevant) NA O NA: not applicable Adapted from Sanders et al®? There are multiple definitions of moderate and severe asthma and some definitions have evolved over time. The Global Initiative for Asthma (GINA) defines severe asthma as a type of difficult-to- treat asthma that is 1) uncontrolled despite management of modifiable disease factors and despite adherence to maximally optimized high dose ICS-LABA treatment, or 2) asthma that worsens when high dose treatment is decreased.? The European Respiratory Society (ERS)/American Thoracic Society (ATS) Management of Severe Asthma guideline defines severe asthma as asthma that requires or remains uncontrolled despite treatment with high dose ICS plus a second controller medication and/or OCS. In scenario analyses, we estimated cost-effectiveness estimates in two main subgroups: 1) allergic asthma and 2) eosinophilic asthma. These analyses compare relevant agents in each indication versus SoC (i.e., placebo arms of clinical trials). E2. Model Inputs and Assumptions Health State Utilities Health state utilities were derived from publicly available literature and/or manufacturer submitted data and applied to health states. The 2018 review used the St George's Respiratory Questionnaire (SGRQ) instrument and mapping algorithm. The AQLQ was measured across all biologics in this review which include the sub-group analyses in allergic and eosinophilic asthma whereas the SGRQ was not measured across all biologics. While the SGRQ was administered in tezepelumab trials, the utility values from both mapping algorithms produce similar differences in utility between tezepelumab plus SoC and SoC alone (<0.01 difference in utility for non-exacerbation health state). Further, when using the AQLQ mapping instrument, the non-exacerbation health state utility value at baseline is consistent with recent cost-effectiveness publications on other biologic therapies in asthma.% Given a dearth of data on the utility associated with an asthma-related ED visit, we assumed the mid-point between the values for hospitalization and oral steroid burst events. We assigned the pre-post decrement in utilities observed in Lloyd et al. for exacerbation-related events. Two weeks ©lnstitute for Clinical and Economic Review, 2021 Page E2 Final Report - Severe Asthma Return to Table of Contents duration was assumed for all exacerbation health states, consistent with the model cycle. Although an oral steroid burst or ED visit does not typically last two weeks, the stress and anxiety related to these events may remain over a two-week period. Severe asthma flare-ups are commonly treated through prescribed bursts of oral corticosteroids (OCS), ranging in intensive treatment periods from five days to two weeks. While consistent use of OCS is associated with a greater likelihood of side effects, we note that there is a distinction between chronic OCS use and a steroid burst.%>% The disutility of chronic OCS for the proportion of patients using >5 mg of prednisone daily or its equivalent (-0.023)°" will be assumed to be equivalent to the disability-adjusted life years (DALYs) that were weighted by the proportion of chronic oral corticosteroid user who developed the following adverse events: type 2 diabetes, myocardial infarction, glaucoma, cataracts, ulcer, osteoporosis, and stroke. Table E2.2 displays the disutilities present in the model. This disutility for chronic OCS use is assumed to not apply for those individuals who are able to reduce their chronic OCS use to at or below 5 mg. Table E2.1. Asthma Patient-Reported Outcome Response and Non-Exacerbation Utility Characteristic Tezepelumab plus SoC SoC (placebo arm) Source Asthma Patient-Reported Pooled PATHWAY and Outcome Measure AQlQ AQLQ NAVIGATOR trials®' Asthma Patient-Reported Pooled PATHWAY Outcome Mean Change 0.34 (0.17, 0.49) Reference :ZS:"G TOR trialsasf;d Difference vs. SoC (95% Cl) Non-Exacerbation Mean Health State Utility for Biologic plus SoC vs. SoC Pooled PATHWAY and Alone (95% CI for 0.788 (0.774, 0.801) 0.75 NAVIGATOR trials®? tezepelumab mean difference vs. placebo) Cl: confidence interval, SoC: standard of care Table E2.2. Disutilities Characteristic Disutility Source Steroid Burst* -0.1 Lloyd et al. 20072 ED Visit* -0.15 Lloyd et al. 200752 and assumption Hospitalization* -0.20 Lloyd et al. 200752 Chronic Oral Corticosteroid Use** -0.023 Norman et al. 2013%' *2-week duration **Lifetime duration ©lnstitute for Clinical and Economic Review, 2021 Page E3 Final Report - Severe Asthma Return to Table of Contents Drug Utilization Treatment Regimen Table E2.3 indicates inputs corresponding to the regimen for the specific intervention. Table E2.3 also includes findings for tezepelumab as compared to SoC alone on the proportion of patients who are on oral corticosteroids at the end of the study, generally from oral steroid sparing studies (i.e., SOURCE). Consistent with prior ICER reports, we assumed 100% compliance and adherence to biologic add-on therapy.3*3" Given that the model does not include progressive aspects of the disease and given the treatment benefits are held constant over time, changes to the compliance/adherence assumption are not thought to greatly impact the results. Table E2.3. Treatment Regimen Characteristic Tezepelumab Omalizumab Dupilumab Treatment Dose 210 mg every 4 weeks 75-3?5mg every 2 to 4 weeks 200mg or 300mg (vial wastage included) every 2 weeks Route of Administration Subcutaneous injection Subcutaneous injection Su?:jl;ii?::us Cost Inputs All costs used in the model were updated to first quarter of 2021 US dollars or the most recently available data using the health care component of the personal consumption expenditure index, in accordance with the ICER Reference Case. Drug Costs Treatment Costs and Details The unit cost for each intervention is reported in Table E2.4. We used estimates of net price from the SSR Health database for dupilumab. The net price for omalizumab was provided to us by the manufacturer using the following statement, "average annual net cost of treatment for adults with allergic asthma (Q1 Jan - Mar 2021) based on average utilization of 2.85 units of 150 mg prefilled syringe per month. Methodology intended to represent an average prescribed dosing. Net cost assumption is an average cost reflecting all price concessions given to customers, and inclusive of all statutory discounts and rebates. This calculation is an estimate for the purposes of financial modeling. Cost treatment per patient varies as dosing depends on age, weight, IgE level and pricing differs by provider and payer (commercial insurance or government program)."®® Further, threshold prices will be calculated at the three cost-effectiveness thresholds (550,000, $100,000, and $150,000 per QALY gained). ©lnstitute for Clinical and Economic Review, 2021 Page E4 Final Report - Severe Asthma Return to Table of Contents Treatment-related costs (SoC and asthma biologics) will be assigned by treatment scenario for all living health states {exacerbation and non-exacerbation states). Table E2.4. Drug Costs Drug WAC per Dose Discount from WAC Net Price per Dose Net Price per Year Tezepelumab Placeholder based on Dupilumab WAC Placeholder based on Dupilumab WAC Placeholder based on Dupilumab net Placeholder based on Dupilumab net price price price price Dupilumab (300mg) $1601.70 | 33.1%* $1071.50 $27,859.88 Omalizumab . 5%t . . (150mg) $1162.34 | 27.5% $784.56 $26,832.00 WAC: wholesale acquisition cost *SSR Health, LLC, was used for estimating discount from wholesale acquisition cost +The net-price/year provided by Genentech was used for estimating the discount from whole sale acquisition cost (data on file)®® Non-Drug Costs Table E2.5 details the health care utilization costs that were used in the model. Unit costs for health care utilization were the same across different treatments and populations. Unit costs for health care utilization are consistent with the previous 2018 review. Unit costs for asthma-related hospital stays, emergency department (ED) visits, and exacerbations requiring an OCS burst were estimated using a cohort of 222,817 US patients with asthma from the Clinformatics DataMart Multiplan dataset. Costs were estimated for 30-day periods after an exacerbation and were summarized as mean health care cost per exacerbation and inflated to the most recent available evidence on inflation up to early 2021 US Dollars. The annual cost of SoC in an incremental analysis compared to SoC alone has an approximate incremental difference of $0. We assumed the same annualized cost of SoC from the prior 2018 ICER review and consistent with Whittington et al. 2018. The chronic use of oral corticosteroids likely results in adverse clinical events and their associated costs. We assumed that doses of daily oral corticosteroids above 5 mg were potentially harmful to the patient in terms of adverse events and could impact day-to-day living. Annual US costs associated with an individual using oral corticosteroids chronically above the 5 mg dose level was $8,326. This annual estimate compared chronic oral steroid users to asthma patients who did not use oral steroids. The cost associated with biologic administration is also displayed in Table E2.5. We assume that four office visits each year would be associated with standard of care. Therefore, administration ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page E5 Return to Table of Contents costs were assigned to the listed therapies in Table E2.3 for each administration in a year above four. Societal Perspective Inputs A recent nationally representative cross-sectional analysis of the Medical Expenditure Panel Survey (MEPS) from 2010 - 2017 provided indirect cost inputs for the modified societal perspective (Table E2.8).53 We made the assumption that patients would benefit from biologic treatment enough that indirect costs would be consistent with moderate asthma rather than severe asthma. We operationalized this reduction through a multiplier that reduced indirect costs each cycle. This reduction in indirect cost was consistent with an analysis by Corren et al. from 2019 which found significant reductions in lost time at work from initiating dupilumab.?" The MEPS analysis includes both school or work in their cost calculations over a seven year period in a nationally representative population. ©lnstitute for Clinical and Economic Review, 2021 Page E6 Final Report - Severe Asthma Return to Table of Contents Table E2.5. Health Care Utilization Cost Inputs Health Care Cost Category Unit Cost Source Exacerbation-Related Steroid Burst (SD) $1,604 ($2,738) Suruki et al. 2017%° Exacerbation-Related ED Visit (SD) $2,161 ($2,869) Suruki et al. 2017%° Exacerbation-Related Hospitalization (SD) $9,442 ($7,568) Suruki et al. 2017%° Annual Cost for SoC (95% interval) $6,494 (85,297, $7,827) Whittington et al. 2018*° Annual Cost of Long-Term Oral Corticosteroid Tezepelumab (assumed to be self- administered after loading dose) 46 Use with Adverse Events (SD assumed) 28,326 (38,326) Lefebvre et al. 2017 Office Visit Treatment Administration for Subcutaneous Office-Administered $74 Physicians' Fee and Coding Guide (HCPCS code 99213)% Scenario Analysis Inputs Table E2.6. Key Inputs for Eosinophilic Asthma Scenario Analysis Parameter Tezepelumab plus SoC Dupilumab plus SoC SoC Alone Annualized Exacerbation Rate, end of study (95% Cl) 1.91 (95% Cl: 1.63, 2.23) Rate Ratio for Exacerbations Resulting in Steroid Burst (without ED visit or 0.38 (95% Cl: 0.29, Alone Pooled PATHWAY hospitalization) (95% ClI for biologic 0.52) AlC Reference group mean difference vs. placebo) Rate Ratio for Exacerbations Resulting in ED Visit (without hospitalization) 0.38 (95% CI: 0.29, AlC Reference group {95% ClI for biologic mean difference 0.52) vs. placebo) Rate Ratio for Exacerbations Resulting in Hospitalization (95% ClI for biologic 0.38 (95% CI: 0.29, AIC Reference group . 0.52) mean difference vs. placebo) Non-Exacerbation Mean Health State Utility for Biologic plus SoC vs. SoC 0.80 0.75 Pooled PATHWAY Sources and NAVIGATOR Academic in and NAVIGATOR Subgroup = 150 confidence;*® Subgroup = 150 cells/pL cells/pL ©lnstitute for Clinical and Economic Review, 2021 Page E7 Final Report - Severe Asthma Return to Table of Contents Table E2.7. Key Inputs for Allergic Asthma Scenario Analysis Parameter Tezepelumab plus SoC Omalizumab plus SoC SoC Alone Annualized Exacerbation Rate, end of study (95% Cl) 1.82 (95% Cl: 1.54, 2.16) Rate Ratio for Exacerbations Resulting in Steroid Burst (without ED visit or hospitalization) (95% CI for biologic mean difference vs. placebo) 0.39 (95% Cl: 0.29, 0.54) 0.52 (95% Cl: 0.37, 0.73) Reference group Rate Ratio for Exacerbations Resulting in ED Visit (without hospitalization) (95% CI for biologic mean difference vs. placebo) 0.39 (95% Cl: 0.29, 0.54) 0.397 (95% Cl: 0.19, 0.82) Reference group Rate Ratio for Exacerbations Resulting 0.39(95% ClI: 0.29, 0.16 (95% Cl: 0.06, Alone in Hospitalization {95% CI for biologic 0.42) Reference group . 0.54) mean difference vs. placebo) Non-Exacerbation Mean Health State Utility for Biologic plus SoC vs. SoC 0.79 0.78 0.75 Sources Pooled PATHWAY and NAVIGATOR Allergic Subgroup Bousquet et al. 2005; Normansell et al. 2014 Pooled PATHWAY and NAVIGATOR Allergic Subgroup Table E2.8. Key Inputs for Modified Societal Perspective Analysis Category Mean Source Incremental Indirect Costs per Person per $1000 Song et al. 202053 Year (Severe asthma vs. no asthma) Multiplier for Biologic Impact on Indirect 0.32 Song et al. 2020°3; equivalent to comparison Costs per Year between severe and moderate asthma E3. Results Description evLYG Calculations The cost per evLYG 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 evLYG. 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.1°! 2. For each cycle (Cycle 1) 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 (ALYG). ©lnstitute for Clinical and Economic Review, 2021 Page E8 Return to Table of Contents Final Report - Severe Asthma 3. We sum the product of the life years and average utility (cumulative LYs/cumulative QALYs) for Cycle | 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, we use the conventional utility estimate for that Cycle I. 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 evLYG is the incremental difference in evLY between the intervention and the comparator arms. Description Health Improvement Distribution Index Calculations (Results presented in Chapter 5) The Health Improvement Distribution Index identifies a subpopulation that has a higher prevalence of the disease of interest and therefore, creates an opportunity for proportionately more health gains within the subpopulation. This opportunity may be realized by achieving equal access both within and outside the identified subpopulation to an intervention that is known to improve health. The Health Improvement Distribution Index is defined as the disease prevalence in the subpopulation divided by the disease prevalence in the overall population. For example, if the disease prevalence was 10% in poor Americans whereas the disease prevalence across all Americans was 4%, then the Health Improvement Distribution Index would be 10% / 4% = 2.5. For interventions known to increase health in this disease and that accomplish equal access across the entire population, poor Americans would receive 2.5 times the health improvements as compared to the same sized group of Americans without regard to economic status. Health Improvement Distribution Indexes above 1 suggest that more health may be gained on the relative scale in the subpopulation of interest when compared to the population as a whole. This statistic may be helpful in characterizing a treatment's contextual considerations and potential other benefits. For this evaluation, asthma disease prevalence (2019) among black adults was 9.7% whereas the asthma disease prevalence (2019) among all US adults was 8.0%. Therefore, the Health Improvement Distribution Index for black adults equals 9.7% / 8.0% = 1.21. ©lnstitute for Clinical and Economic Review, 2021 Page E9 Final Report - Severe Asthma Return to Table of Contents E4. 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 plausible parameter ranges). Figure E4.1 presents the tornado diagram resulting from the one-way sensitivity analysis for tezepelumab plus SoC versus Soc alone. Key drivers of cost-effectiveness estimates include the utility for non-exacerbation state for tezepelumab plus Soc and SoC alone, severe asthma exacerbation risk of death, annualized exacerbation rate for SoC alone, and exacerbation rate ratio for tezepelumab plus SoC. Probabilistic sensitivity analyses were also be performed by jointly varying multiple model parameters over at least 1,000 simulations, then calculating 95% credible range estimates for each model outcome based on the results. Figure E4.1. Tornado Diagrams Utility for non-exacerbation state - tezepelumab plus SoC I Severe asthma exacerbation risk of death N [ Exacerbation rate ratio - Tezepelumab plus SoC I Annualized exacerbation rate - SoC I Cost for hospitalization -_ Cost for steroid burst . Cost of non-exacerbation state per cycle - 50C alone ur Utility for steroid burst m Cost for EDvisit I 5300,000 $350,000 $400,000 5450,000 5500,000 $550,000 $600,000 ncremental $/QALY *Grey shade indicates lower input's impact on the cost-per-QALY estimate whereas black shade indicates higher input's impact ©lnstitute for Clinical and Economic Review, 2021 Page E10 Final Report - Severe Asthma Return to Table of Contents Table E4.1. Tornado Diagram Inputs and Results for Tezepelumab plus Standard of Care vs. Standard of Care Alone Lower ICER Upper ICER | Lower Input Upper Input Utility for non-exacerbation state - tezepelumab plus SoC > 341,148 | 5 588,362 0.77 0.81 Severe asthma exacerbation risk of death S 313,035 | S 534,167 0.001 0.019 Exacerbation rate ratio - Tezepelumab plus SoC $ 411,511 | $ 461,178 0.27 0.50 gsguallzed exacerbation rate - $ 407276 | § 453716 1.58 208 Cost for hospitalization S 420,282 | $ 439,063 $6,872 $12,413 Cost for steroid burst S 423,603 | $§ 436,191 $1,167 $2,109 Cost of non-exacerbation state $ 426010 | & 434108 $22.38 $40.42 per cycle - SoC alone Utility for steroid burst S 427,539 | $ 433,179 0.64 0.66 Cost for ED visit S 428865 | $ 431,640 $1,573 $2,841 Table E4.2. Results of Probabilistic Sensitivity Analysis for Tezepelumab plus Standard of Care vs. Standard of Care Alone Tezepelumab plus SoC SoC Alone Incremental Mean Credible Mean Credible Mean Credible Range Range Range $662,000 - $188,000 - $452,000 - Total Costs $697,000 $736,000 $228,000 $272,000 $469,000 $483,000 Total 15.00 14.69 - 13.90 13.35- 1.10 0.70-1.60 QALYs 15.31 14.19 $431,000 $302,000 - ICER $647,000 ©lnstitute for Clinical and Economic Review, 2021 Page E11 Final Report - Severe Asthma Return to Table of Contents Figure E4.2. Probabilistic Sensitivity Analysis Results: Cost-Effectiveness Clouds $500,000 ) 1 8 o o o o $480,000 $470,000 $460,000 $450,000 Incremental Costs (2021 US Dollars $440,000 o $430,000 0.25 0.75 1.25 1.75 2.25 Incremental QALYs This panel presents cost-effectiveness clouds from the probabilistic sensitivity analysis. E5. Scenario Analyses Scenario Analysis 1 Scenario analysis 1 includes results specific to an allergic asthma population. We relied on pooled baseline data from NAVIGATOR and PATHWAY to estimate cost-effectiveness estimates for tezepelumab plus SoC versus SoC alone within the allergic sub-population (see Table E3.1). Separately we estimated cost-effectiveness estimates for omalizumab plus SoC versus SoC alone using the same baseline allergic asthma inputs. Specific to tezepelumab plus SoC, cost-effectiveness estimates were still above commonly cited cost-effectiveness thresholds and were slightly higher than the base-case estimates mainly due to a lack of differentiation of exacerbation rate ratios across categories of exacerbations (i.e., mild, moderate, severe). ©lnstitute for Clinical and Economic Review, 2021 Page E12 Final Report - Severe Asthma Return to Table of Contents Table E5.1. Scenario Analysis Results Cost per QALY Cost per Life Year Cost per evLY Treatment Comparator Gained Gained Gained ;zzcepe'"mab Plus | ¢ ¢ alone $455,000 $1,950,000 $448,000 g;':a"'"mab Plus | ¢ ¢ alone $492,000 $1,371,000 $479,000 *Placeholder price for tezepelumab assumed the same net pricing for dupilumab Scenario Analysis 2 Scenario analysis 2 includes results specific to an eosinophilic asthma population. We relied on pooled baseline data from NAVIGATOR and PATHWAY to estimate cost-effectiveness estimates for tezepelumab plus SoC versus SoC alone within the eosinophilic asthma sub-population (see Table E5.2). Separately we estimated cost-effectiveness estimates for dupilumab plus SoC versus SoC alone using the same baseline eosinophilic asthma inputs. Specific to tezepelumab plus SoC, cost- effectiveness estimates were still above commonly cited cost-effectiveness thresholds and were very similar to the base-case estimates. From the draft report, cost per QALY gained and cost per evlLY gained for dupilumab plus SoC versus SoC alone decreased from a change in the non- exacerbation health state utility value. The utility value increased through an academic-in- confidence submission that updated the previous AQLQ value used in the draft report. Table E5.2. Scenario Analysis Results Cost per QALY Cost per Life Year Cost per evLY Treatment Comparator Gained Gained Gained ;szce"e'"mab Plus | ¢ alone $386,000 $1,854,000 $382,000 SD:g""mab Plus | ¢0c alone $426,000 $1,713,000 $419,000 *Price is a placeholder based on net pricing of dupilumab Scenario Analysis 3 Table E5.3 presents the results from a modified societal perspective that included productivity losses from both missed school and work. See Table E2.8 for unit costs. Cost-effectiveness results were still above commonly cited cost-effectiveness thresholds when including the impact of tezepelumab on lost productivity. ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page E13 Return to Table of Contents Table E5.3. Scenario Analysis Results SoC Cost per QALY Cost per Life Year Cost per evLY Treatment Comparator Gained Gained Gained Tezepelumab plus SoC alone $424,000 $1,458,000 $416,000 *Price is a placeholder based on net pricing of dupilumab E6. Heterogeneity and Subgroups We estimated costs and health outcomes among two relevant subgroups: allergic asthma and eosinophilic asthma. The results for these scenario analyses are available in section E5 of this supplement and describe differences in costs and health outcomes among these subgroups. We also considered additional subgroups such as steroid dependent patients and populations within urban and rural settings. However, at the time of this report posting we are not aware of evidence that would provide inputs for the economic model in these subgroups. E7. Model Validation Model validation followed standard practices in the field. We tested all mathematical functions in the model to ensure they were consistent with the report (and supplemental Appendix materials). We also conducted sensitivity analyses with null input values to ensure the model was producing findings consistent with expectations. Further, independent modelers tested the mathematical functions in the model as well as the specific inputs and corresponding outputs. Model validation was also conducted in terms of comparisons to other model findings. We searched the literature to identify models that were similar to our analysis, with comparable populations, settings, perspective, and treatments. Prior Economic Models The current ICER model's structure is based on prior asthma model structures including ones developed by Campbell et al. and reviewed in McQueen et al., including the prior ICER report on asthma biologics.3®*! Since the 2018 review, we found one relevant original research publication in uncontrolled asthma by Sullivan et al. Additionally, there have been two NICE appraisals for benralizumab and dupilumab that are relevant to this ICER review. Sullivan et al. assessed omalizumab plus SoC from a US payer perspective using real-world evidence from PROSPERO.%* Results suggested over a lifetime, omalizumab add-on therapy was associated an increase in QALYs and costs and met the commonly cited cost-effectiveness threshold of $100,000 per QALY. Inputs such as exacerbations at baseline and mortality were similar or the same as our analysis. However, ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page E14 Return to Table of Contents the non-exacerbation health state utility difference between omalizumab plus SoC versus SoC alone from Sullivan et al. suggest pre-post (uncontrolled) differences close to 0.20 whereas our current and past reviews have a non-exacerbation state utility difference range of 0.03 - 0.06 observed in trial environments. As discussed in the main report, response rates in the SoC arms of trials can be high and therefore, raise concern of real-world analyses that do not include a control group. Differences between our current modeling analysis and our past 2018 analysis include updates to the proportion of exacerbations resulting in steroid bursts, ED visits, and hospitalizations, asthma- related excess mortality, and the use of the AQLQ mapping instrument to estimate the non- exacerbation state utility value for each arm of the model. First, the 2018 review used a variety of sources to arrive at proportions of exacerbations resulting in steroid bursts, ED visits, and hospitalizations of 90%, 5%, and 5%, respectively. Recent evidence from the CHRONICLE study suggests a different distribution of 79%, 9%, and 14% for exacerbations resulting in steroid bursts, ED visits, and hospitalizations, respectively. CHRONICLE is a prospective real-world study of US patients with confirmed severe asthma not controlled by high-dose inhaled corticosteroids and additional controllers.® In CHRONICLE, they were able to identify the distribution of exacerbation categories by setting (e.g., ED or hospital) for patients receiving biologics, maintenance systemic corticosteroids, and not receiving biologics or systemic corticosteroids. In the model we used the distribution of exacerbations from the cohort not receiving biologics or systemic steroids for the SoC alone arm. We then applied the rate ratio reductions for these exacerbation categories from the tezepelumab pooled NAVIGATOR and PATHWAY trials. Given the distribution of visits shifts towards more ED visits and hospitalizations as compared to our previous review, there is more opportunity to increase quality of life and life years, and reduce costs as compared to the SoC arm. Second, as discussed in the main report, asthma mortality was calibrated to be consistent with recent United States estimates on asthma deaths. This calibration was done to ensure our previous estimates on asthma mortality stayed consistent with currently available evidence from the United States. This change was necessary largely because of the distribution shift of exacerbations from CHRONICLE described above. Finally, we relied on the AQLQ mapping instrument which is a shift away from the SGRQ from the last review. The resulting non-exacerbation state health utility values were slightly lower than our previous estimates, shifting the incremental cost-effectiveness ratios upward, assuming all else equal. ©lnstitute for Clinical and Economic Review, 2021 Page E15 Final Report - Severe Asthma 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 each new therapy rather than relevant existing 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. The potential budget impact analysis included individuals ages 12 years and older with severe uncontrolled asthma who are eligible for treatment with tezepelumab. To estimate the size of the potential candidate populations for treatment, we applied a "funnel-based" approach for which we used inputs for the US population size,'% prevalence estimates for severe asthma,*'-%° the proportion of patients whose asthma remains uncontrolled,5-%? and the proportion of patients who are not currently receiving asthma treatment with a biologic.63%* Using this approach we derived an estimate of approximately 695,000 individuals eligible for treatment with tezepelumab. We assumed that 20% of these patients would initiate treatment in each of the five years, or approximately 139,000 patients per year. ICER's methods for estimating potential budget impact are described in detail elsewhere and have recently been updated.*®'% 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. Briefly, we evaluate a new drug that would take market share from one or more drugs, and calculate the blended budget impact associated with displacing use of existing therapies with the new intervention. In this analysis, we assumed that tezepelumab would displace current treatments with standard of care within the eligible patient population. 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 ©lnstitute for Clinical and Economic Review, 2021 Page G1 Final Report - Severe Asthma Return to Table of Contents 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 (GDP) +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 2021-2026, therefore, 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. Results Table F1 illustrates the per-patient budget impact calculations in more detail, based on the annualized placeholder price ($27,860 per year) and the prices to reach $150,000, $100,000, and $50,000 per QALY for tezepelumab ($11,927, $9,077, and $6,226 per year, respectively) compared to standard of care alone. Table F1. Per-Patient Average Annual Total and Average Net Cost over a Five Year Time Horizon Average Annual Per Patient Total and Net Cost Placeholder Price | $150,000/QALY | $100,000/QALY | $50,000/QALY Tezepelumab $36,000 $20,300 $17,500 $14,700 Standard of Care $12,000 $12,000 $12,000 $12,000 Difference (Net) $24,000 $8,300 $5,500 $2,700 QALY: quality-adjusted life year Figure F1 illustrates the health care system perspective cumulative per-patient budget impact calculations for tezepelumab compared to standard of care alone, based on the placeholder annualized price of $27,860 per year of treatment. The average potential budgetary impact for tezepelumab was approximately $24,500 per patient in year one, with the cumulative net cost increasing in years two through five as treatment continues, reaching approximately $120,000 by the end of the five-year horizon. The annual net cost decreased in each subsequent year to approximately $24,000 in year five. ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page G2 Return to Table of Contents Figure F1. Cumulative Net Cost per Patient with Tezepelumab for Five Years at an Annual Placeholder Price of $27,860 per Year $140,000 $120,000 $100,000 $80,000 $60,000 $40,000 $20,000 I $0 : 1 2 3 4 5 ©Institute for Clinical and Economic Review, 2021 Page G3 Final Report - Severe Asthma Return to Table of Contents G. Public Comments This section includes summaries of the public comments prepared for the Midwest CEPAC Public Meeting on November 19. These summaries were prepared by those who delivered the public comments at the meeting and are presented in order of delivery. A video recording of all comments can be found here. Conflict of interest disclosures are included at the bottom of each statement for each speaker who is not employed by a pharmaceutical manufacturer. Andrew Lindsley, MD, PhD Asset Lead, Medical Director, Amgen Amgen and AstraZeneca recognize that severe asthma is a devasting, chronic disease that causes significant morbidity and mortality for affected patients, persistent stress to care-providers and high costs to the US medical system and society at-large. Following more than a decade of clinical study, we are excited to have developed tezepelumab as a potential new treatment option. Following ICER's evaluation of tezepelumab, Dr. Andrew Lindsley (Amgen, US Medical Affairs) was invited to deliver oral comments at the Midwest CEPAC meeting. Dr. Lindsley's comments, as summarized below, highlight three central concerns with the report. 1. The asthma mortality rate used in the ICER report is inaccurate and underestimates asthma mortality. 2. ICER's evidence rating for tezepelumab's net health benefit significantly understates the clear statistical superiority of tezepelumab to standard of care as demonstrated by rigorous clinical trial data. 3. The report undervalues the clinically meaningful changes seen in patient-reported outcomes with tezepelumab. These inaccuracies adversely affect ICER's cost-effectiveness calculation, undervalue tezepelumab's ability to help patients, and may adversely affect patient access to this innovative new treatment. The first major point is that ICER's use of a mortality rate estimate (mortality risk per asthma hospitalization) does not align with observed asthma patients' death rates. There is almost a 3-fold underestimation of the risk of death among patients hospitalized with asthma between ICER's model versus data from the U.S. Center for Disease Control (for the period 2018 and 2019). ©Institute for Clinical and Economic Review, 2021 Page G1 Final Report - Severe Asthma Return to Table of Contents Mortality rate is a fundamental driver in ICER's model. Underestimating asthma-associated deaths limits the external validity of ICER's model and makes the model's results less representative of expected real-world outcomes. Furthermore, ICER's underestimation of the mortality risk of asthma hospitalizations leads to substantial overestimation of the cost per QALY for tezepelumab. The second major point is that ICER's proposed C++ confidence rating of tezepelumab's net health benefit understates the certainty provided by robust tezepelumab clinical trial data. The NAVIGATOR phase-3 trial rigorously evaluated tezepelumab's efficacy and safety as an add-on therapy in subjects with uncontrolled asthma managed with high intensity standard of care (SOC) therapy. In this well-powered phase-3 trial, all of the primary and key secondary endpoints were achieved by exceeding the 95% certainty-level. These endpoints included exacerbation reduction, lung function, symptom control and health-related quality of life measurements. Amgen, AstraZeneca and other stakeholders, including the American Thoracic Society (as per their public comments) believe that an evidence rating of at least "B+", denoting moderate certainty of small or substantial health benefit, is far more consistent with the available clinical data. To be clear, the available evidence does not support the conclusion that tezepelumab only offers a comparable net health benefit when weighed against SOC treatments. The third major point underscores the meaningful changes in patient-reported outcomes seen in tezepelumab clinical trials. One of the biggest drivers for ICER's model is the changes in patient daily quality of life. In the NAVIGATOR study, the proportion of treatment responders was higher in the tezepelumab arm than the placebo group for all patient-reported outcomes. NAVIGATOR data generated using the St. George's Respiratory Questionnaire (SGRQ) , a well-validated and FDA recognized instrument for measuring quality of life in patients with respiratory disease, was particularly compelling and unfortunately undervalued by ICER. As with other patient-reported outcomes, a higher proportion of patients had an SGRQ response in the tezepelumab group than in the placebo group. Importantly, the mean improvement in SGRQ at the population level also exceeded the minimal clinically important difference (MCID). These results further underscore the meaningful impact that tezepelumab treatment can provide to patients living with severe uncontrolled asthma. We appreciate the open dialogue with ICER and other stakeholders during this review process and during the Midwest CEPAC meeting. Given the shortcomings outlined above, we believe ICER's revised report undervalues tezepelumab and its ability to help patients. We respectfully ask that these written comments be included in the final ICER report to ensure a balanced view of the findings and limitations. Dr. Lindsley is a full-time employee of Amgen. ©Institute for Clinical and Economic Review, 2021 Page G2 Final Report - Severe Asthma Return to Table of Contents Kyle Hvidsten, MPH Head, Health Economics & Value Assessment, Sanofi Thank you to members of the Midwest CEPAC and our colleagues from ICER for this opportunity. My name is Kyle Hvidsten and | am the Head of the Sanofi Genzyme Health Economics and Value Assessment Group. | am joined by my colleague Dr Megan Hardin who is a Pulmonologist and a member of the Sanofi Genzyme Medical Organization. We are both pleased to participate in today's discussion. Dupilumab is a fully human monoclonal antibody that inhibits interleukin-4 and 13 signaling by specifically binding to the interleukin-4 R alpha subunit shared by these receptor complexes. Dupilumab's unique mechanism of action leads to suppression of type 2 inflammation including broad activity against multiple type 2 effector cells such as B cells, eosinophils and IgE. Dupilumab has been approved in the US as an add-on maintenance treatment of patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. Dupilumab is also approved in the US for patients six years and older with uncontrolled moderate-to-severe atopic dermatitis and adults with inadequately controlled chronic rhinosinusitis with nasal polyposis. We first engaged the Midwest CEPAC in 2018 as a part of ICER's review of biologic therapies for the treatment of moderate to severe asthma associated with type 2 inflammation. During this review, ICER rightly emphasized the importance of demonstrating the long-term safety and effectiveness of asthma therapies. As ICER noted in its November report, we have completed a two-year open label extension study of almost three thousand adult and adolescent patients. When combined with the patients who had previously participated in the phase 3 trial, this represents up to three years of exposure to dupilumab. This trial demonstrated a safety profile generally consistent with the one- year trials and this extension study demonstrated sustained reduction in exacerbation rates and, importantly, an improvement in lung function and asthma control. As noted in ICER's report, dupilumab significantly reduced oral corticosteroid or "OCS" dose compared to placebo in patients with severe OCS-dependent asthma and it is the only biologic therapy to have an indication for patients with OCS-dependent asthma. Sanofi appreciates and fully agrees with ICER's efforts to draw attention to the significant health inequalities that exist in the US as they disproportionally impact African-Americans and LatinX suffering from asthma. Specifically, we commend ICER's development of the Health Improvement Distribution Index and we look forward to seeing it used in future reviews. We see the HIDI as an important approach to calling attention to historically underserved patient populations where safe and effective ©Institute for Clinical and Economic Review, 2021 Page G3 Final Report - Severe Asthma Return to Table of Contents interventions can produce disproportionate health gains based on the increased prevalence of disease relative to the general population. We share ICER''s recognition of this important and urgent issue and we are currently engaged in similar initiatives to ensure that we are working to improve the health and lives of all patients equally. At Sanofi, our clinical studies do not exclude participants based on minority status, gender, sexual orientation, or age. We are also working to enhance the selection of trial sites to include more diverse, population-dense communities and to involve more diverse investigators with the goal of further increasing minority participation in our trials. Lastly, dupilumab's price was established prior to its approval for the treatment of moderate to severe asthma. As we discussed during the New England CEPAC meeting this past July, this price was established through Sanofi's Pricing Policy where we set a clear rationale that includes, among other considerations, a holistic assessment of our medicine's value and it reflects our commitment to affordable access for patients. It is also worth noting that this price aligned with ICER's determination of the value-based price for dupilumab in atopic dermatitis and is in line with other asthma biologics. Since dupilumab's launch we have only made modest and predictable price increases in line with our Policy for responsible pricing. This is reflected in the fact that along with dupilumab, no other Sanofi medicine has ever been included in ICER's annual list of products that have taken "unsubstantiated price increases." Thank you again for the opportunity to participate in today's meeting and in the important process that began in May. Dr Hardin and | look forward to answering your questions. Kyle Hvidsten is a full-time employee of Sanofi. Kenneth Mendez President & CEO Asthma and Allergy Foundation of America My experience has been that there can be confusion in the patient community when ICER evaluates a new therapy before the FDA approves that therapy. The press will cover a pre-FDA approved and the public will read these reports assuming that ICER's findings are a judgement on a therapy's efficacy before the FDA makes its final determination. In addition, without a declared price from the manufacturer, the discussion about value is uniformed. I'd like to address the voting questions. ICER's executive summary says Tezepelumab evidence shows that there are benefits: (from pg 13 of the report): ©Institute for Clinical and Economic Review, 2021 Page G4 Final Report - Severe Asthma Return to Table of Contents "On balance, we rate the net health benefit of Tezepelumab added to standard-of-care therapy without biologics, compared with standard-of-care therapy alone in adults and adolescents with severe, uncontrolled asthma as "Comparable or Better" (C++)." In reading the first voting question, the answer should be "yes". However, for questions #2-#4 | believe they are misleading when comparing tezepelumab with dupilumab.To ask a simple yes no guestion for net health benefits forces an answer that is out of context on how these treatments work. Let's assume you've got Advil and Tylenol when you need to treat someone for a headache. Some people find that ibuprofen also known as Advil works better than acetaminophen also known as Tylenol, but others find that Tylenol works better than Advil. This may relate to the underlying pathway causing the headache. In a similar way, there are different pathways that lead to asthma, and in some blocking a certain pathway may work, but in another person this same pathway may not be active and blocking it has no effect. This speaks to the importance of phenotyping asthma and using that information to inform the choice of biologic. Without this, comparing biologics is a bit like comparing Tylenol and Aduvil. It's misguided to approach asthma management as "one-size-fits-all," Considering the heterogeneity of people with asthma is essential to improving and personalizing asthma care. If you don't consider an individual's specific circumstances, this could contribute to racial and ethnic disparities in asthma outcomes. As you consider questions 5-7, please keep in mind the patient voices that will speak after me. 3,500 people die each year from asthma, and it is one of the most challenging chronic conditions for Americans. Climate change and its impact on air quality adds further challenges to those living with asthma. Making new treatments available for the asthma community is a high priority. Continuing to questions 8-13, since Tezepelumab is not yet approved by the FDA and there is no price on it, answering these questions 8-12 is premature. These questions are misleading, and I'd encourage the CTAF to rephrase these questions before you vote. But it does appear that Tezepelumab can have major positive effects for some. | applaud ICER for highlighting the continuing disparities in asthma. AAFA published a report last year which was an update to an asthma disparities report we did 15 years ago. The gaps still remained the same: Black Americans are still 3x more likely to die from asthma, ¢ 5x more likely to be treated in an emergency room, » Black women have the highest mortality rate of any demographic group. ©Institute for Clinical and Economic Review, 2021 Page G5 Final Report - Severe Asthma Return to Table of Contents ¢ Puerto Ricans have the highest rate of asthma prevalence compared to any other racial or ethnic group in the US ¢ Regional data shows that American Indian and Alaska Native populations are twice as likely to experience asthma symptoms every day. ICER staff rightly points out that health gains from a successful treatment, like Tezepelumab, could have consistent benefits across racial subgroups and would provide proportionally greater benefit to Black Americans. ICER notes that clinical trials have not adequately enrolled Black Americans. We agree with ICER that we need more diversity in clinical trials and appreciate ICER identifying this in the revised report. But ICER should find a way to quantify whether disparities in the burden of a given disease mean that an "average" effectiveness has different implications for different groups. There remains a large unmet need for therapies that substantially improve daily quality of life in patients with severe asthma and we look forward to seeing the outcome of FDA's review on this therapy. Tezepelumab uses a new mechanism of action and does represent a promising new treatment. I'd like to introduce you to Monique and Javon a family we've followed in our AAFA community and to whom we've provided support. | hope their video shows the challenges of living with asthma and finding the right treatment. AAFA receives funding from pharmaceutical manufacturers, PARMA, and PCMA. Kenneth has equity interests in Abbott Labs and AbbVie in excess of $10,000. Monique Cooper Patient Advocate, Caregiver My name is Monique Cooper and | am not only a parent of a severe asthmatic but | to have asthma. Hi, am Javan Allison and | was diagnosed with Asthma at the age of two. Living with asthma has been a journey that we never thought we would go through. Javan was born a premature baby with several complications. At two months old, | noticed his first breathing difficulties. His skull was moving rapid in and out as he was wheezing. | took him to the emergency room where they diagnosed him with bronchitis. Javan has always been a hyper kid struggling with anxiety and adhd which played a small part of him having asthma attacks. We didn't know how serious it was until he was two years old. One typical day when Javan was 4 he was having fun being with family members, but he was also around environmental things that triggered his allergies. We picked Javan up and ran a few errands with him. We noticed how weak he was. He was notable to walk on his own. His dad and I first thought it was signs of wanting to be picked up but then he started coughing. We reached home ©Institute for Clinical and Economic Review, 2021 Page G6 Final Report - Severe Asthma Return to Table of Contents and Javan didn't even make it down the hallway before passing out on the floor. We immediately rushed him to the hospital where they told us that he was in distress. This is when we realized how serious this was. This was also his first of many ICU stays. Throughout this journey we have had good days and bad days, but on both days, we are affected the same. Although he is having some great days now at the age of 13, we take off or leave early from work and school to see his pulmonologist on a bi-weekly basis. We make sure we stay on routine with his medications. Pump first thing in the morning, pump at night before bedtime, make sure we cover all allergies, so they won't trigger asthma. Javan plays sports and it is always a fear with the what ifs. What if it's too hot and he gets exhausted and can't breathe, what if the activities are too much for him to handle? Before and after practice and game days, he takes the emergency inhaler to make sure his airways stay functioning for him. On his worst days, we take off from work and he's home from school due to being hospitalized after having attacks. Every year up until he reached middle school, Javan would have a good first week of school, attending every day. When we reach that second to third week, the complications would start. He would get sick with asthma, and either be in the hospital and or home for days to weeks at a time, delaying him in his education. While in the hospital we wouldn't know if he's getting better up until the very last hour of being discharged because of our villain (What we like to call asthma) that likes to come and sneak back into Javan's lungs. When Javan was 10 years old, Javan was having a typical asthma day with difficulty breathing, and on the nebulizer every 4 to 6 hours. That day, February 17th, 2018, changed our lives when Javan wrote on the bathroom fogged mirror "HELP ME". He didn't have the strength to yell out to me while | was in the shower. We rushed him to the hospital barely making it. That day, it took everything in him to breathe. The doctors were trying to figure out why when giving him the proper medication for asthma, would everything else stop working functionally. Blood pressure low and then high, airways closing more and more, oxygen low. This nurse came in and noticed him from previous emergency visits and gave suggestions that saved Javan's life. He stayed in ICU for a week. Overtime his symptoms gotten better and Javan has not had a hospital stay since. When it comes to things | would like to enjoy and be a part of, sometimes it saddens Me. For instance, he can't be around dogs because he is allergic to them and that's a trigger. We can't travel to states during time of high pollen season and where it is snowing or cold and then travel back to Florida where it is hot in that same time frame. Javan has had over 50 hospital visits due to asthma and several overnight ICU stays. Some families may not know how serious it is, it causes death if you don't take precautions to this disease. This experience is one experience where you don't take life for granted. No financial conflicts to disclose. ©Institute for Clinical and Economic Review, 2021 Page G7 Final Report - Severe Asthma Return to Table of Contents Brenda Young Patient Expert, Allergy and Asthma Network Volunteer My name is Brenda Young & | was diagnosed with asthma as a child but in 2010 | took a turn for the worse. Since then, | have been hospitalized over 20 times. | have been in the ICU too many times to count and the fear of death haunts me on a daily basis, This disease has robbed me of a normal, meaningful life. My only hope is continued research and treatments beyond my "frenemy--- prednisone." Prednisone has totally changed my appearance and made me feel like | was literally going crazy." The bizarre thing is the drug that is keeping me alive and breathing is also the cause of so many terrible side effects---osteoporosis, diabetes and glaucoma, just to name a few." My story is a common one unfortunately. Over 90,000 US patients are on chronic OCS and recent studies indicate they are at 30% greater likelihood to suffer adverse side effects and have higher rates of ER visits, hospitalizations, and comorbidities. | have gained weight and my face is swollen. | have tried the other severe asthma biologics & anaphylaxes, so currently there is no treatment option for me beyond prednisone. The toll on me and my family is unspeakable. All | really want is to be by my daughter's side as she raises her own children. No financial conflicts to disclose. ©Institute for Clinical and Economic Review, 2021 Page G8 Final Report - Severe Asthma Return to Table of Contents H. Conflict of Interest Disclosures Tables H1 through H3 contain conflict of interest (COI) disclosures for all participants at the November 19 Public meeting of the Midwest CEPAC. Table H1. ICER Staff and Consultants and COI Disclosures ICER Staff and Consultants* Foluso Agboola, MBBS, MPH, Vice President of Serina Herron-Smith, BA, Senior Research Assistant, ICER Research, ICER Jon Campbell, PhD, MS, Senior Vice President for Health Economics, ICER Monica Frederick, Senior Program and Event Coordinator, ICER Noemi Fluetsch, MSc, MPH, Research Assistant, Health Economics, ICER Eric Gutierrez, MPH, Statistical Analyst, University of Colorado Anschutz Medical Campus Belen Herce-Hagiwara, BA, Research Assistant, ICER Steven D, Pearson, MD, MSc, President, ICER *No relevant conflicts of interest to disclose, defined as more than $10,000 in healthcare company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. Cat Koola, MPH, Associate Director, Patient Engagement, ICER R. Brett McQueen, PhD, Assistant Professor University of Colorado Anschutz Medical Campus Ashton Moradi, PharmD, MS, Health Economist, ICER David M. Rind, MD, MSc, Chief Medical Officer, ICER Table H2. Midwest Panel Member Participants and COI Disclosures Participating Members of Midwest CEPAC Eric Armbrecht, PhD* Associate Professor, Saint Louis University Center for Health Outcomes Research, School of Medicine and College for Public Health & Social Justice Alan Balch, PhD* Chief Executive Officer, Patient Advocate Foundation, National Patient Advocate Foundation Kurt Vanden Bosch, PharmD* System Formulary Manager, St. Luke's Health System, Idaho Angela Brown, MPH* Chief Executive Officer, St. Louis Regional Health Commission (RHC) Aaron Carroll, MD* Professor of Pediatrics, Associate Dean for Research Mentoring; Director, Center for Health Policy and Professionalism Research and the Center for Pediatric and Adolescent Comparative Effectiveness Research at the Indiana University School of Medicine ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Heather Guidone, BCPA* Program Director, Center for Endometriosis Care (CEC) Jill Johnson, PharmD* Professor, Department of Pharmacy Practice, University of Arkansas for Medical Sciences College of Pharmacy Tim McBride, PhD* Co-Director, Center for Health Economics and Policy Professor, Brown School, Washington University in St. Louis Reem Mustafa, MD, MPH, PhD* (Chair) Associate Professor of Medicine, Division of Nephrology and Hypertension, and Director, Outcomes and Implementation Research, University of Kansas Medical Center Rachel Sachs, JD, MPH* Associate Professor of Law, Washington University in St. Louis Page H1 Return to Table of Contents Don Casey, MD, MPH, MBA* President, American College of Medicine (ACMQ) Sneha Dave, BA* Executive Director, Health Advocacy Summit (HAS) Stuart A. Winston, DO* Cardiologist in the Sub-Specialty of Cardiac Electrophysiology, St. Joseph Mercy Health System Physician Lead: Patient Experience, Quality Improvement Integrated Health Associates, St. Joseph Mercy Health System Timothy Wilt, MD, MPH* Professor of Medicine, Core Investigator, and Staff Physician at the Minneapolis VA Center for Chronic Disease Outcomes Research, University of Minnesota School of Medicine *No relevant conflicts of interest to disclose, defined as more than $10,000 in healthcare company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. Table H3. Policy Roundtable Participants and COI Disclosures Policy Roundtable Participant Mindy Bauer, PharmD, Associate Director, Clinical Pharmacy, IPD Analytics Melanie Carver, Chief Mission Officer, Asthma and Allergy Foundation of America Kyle Hvidsten, MPH, Head, Health Economics & Value Assessment, Sanofi Tony R. Vancauwelaert, MD, FAAFP, Executive Medical Director, Enterprise Medical Operations - Pharmacy, Health Care Services Corporation Michael E. Wechsler, MD, Professor of Medicine, Director of NJH Cohen Family Asthma Institute, National Jewish Health Tonya Winders, MBA, President & Chief Executive Officer, Allergy & Asthma Network David Zimmer, BS, MBA, Vice President US Value and Access, Amgen Conflict of Interest Dr. Bauer is a full-time employee of IPD Analytics. AAFA receives funding from Pharmaceutical manufacturers, PhRMA, and PCMA. Kyle Hvidsten is a full-time employee of Sanofi. Dr. Vancauwelaert is a full-time employee of Heath Care Services Corporation. Dr. Wechsler has received consulting fees and honoraria from the following health care companies: AstraZeneca, Amgen, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Regeneron, and Sanofi. Tonya Winders serves as a speaker & advisor to AstraZeneca, Amgen, GSK, Novartis, Sanofi, Regeneron & ALK Abello. The Allergy & Asthma Network receives funding from healthcare companies for unbranded disease awareness, education, advocacy & research. David Zimmer is a full-time employee of Amgen. ©lnstitute for Clinical and Economic Review, 2021 Final Report - Severe Asthma Page H2 Return to Table of Contents