ICER2 INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW Belimumab and Voclosporin for Lupus Nephritis: Effectiveness and Value Final Report April 16, 2021 Prepared for Ma NEW ENGLAND 4a ms CEPAC MESS = COMPARATIVE EFFECTIVENESS PUBLIC ADVISORY COUNCIL May 18, 2022: New evidence regarding treatments and therapies gets published on an ongoing basis. ICER reached out to patient and clinical experts and the relevant manufacturers 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. Olnstitute for Clinical and Economic Review, 2021 ese ie emote The University of Sheffield Modeling Group Jeffrey A. Tice, MD Professor of Medicine University of California, San Francisco Foluso Agboola, MBBS, MPH Director, Evidence Synthesis ICER Serina Herron-Smith, BS Research Assistant ICER Rick Chapman, PhD, MS Director of Health Economics Olena Mandrik, PhD, MSc Research Fellow School of Health and Related Research (ScHARR) The University of Sheffield Praveen Thokala, PhD, MASc Senior Research Fellow School of Health and Related Research (ScHARR) The University of Sheffield James Fotheringham, MD, PhD Consultant Nephrologist and Honorary Lecturer School of Health and Related Research (ScHARR) The University of Sheffield ICER Steven D. Pearson, MD, MSc President ICER The role of The University of Sheffield is limited to the development of the cost-effectiveness model, and the resulting ICER reports do not necessarily represent the views of The University of Sheffield. DATE OF PUBLICATION: April 16, 2021 How to cite this document: Tice JA, Mandrik O, Thokala P, Fotheringham J, Agboola F, Herron- Smith S, Chapman R, Pearson SD. Voclosporin and Belimumab for Lupus Nephritis: Effectiveness and Value; Evidence Report. Institute for Clinical and Economic Review, April 16, 2021. https://icer.org/wp-content/uploads/2020/11/ICER Lupus-Nephritis Final-Evidence- Report 041621.pdf Jeffrey Tice served as the lead author for the report and wrote the executive summary, background, other benefits, and contextual considerations sections of the report. Jeffrey Tice also led the systematic review and authorship of the comparative clinical effectiveness section with the support of Serina Herron-Smith and Belen Herce-Hagiwara. Foluso Agboola conducted the meta-analyses and network meta-analysis. Olena Mandrik and Praveen Thokala developed the cost-effectiveness model and authored the corresponding sections of the report with the support of James Fotheringham. Rick Chapman was responsible for the oversight of the cost-effectiveness analyses and developed the budget impact model. Steven Pearson provided methodologic guidance on the clinical and economic evaluations. We thank Professor Matt Stevenson from the University of Sheffield for his comments on the cost-effectiveness section. We would also like to thank Melanie Whittington, Maggie Houle, and Catherine Koola for their contributions to this report. Olnstitute for Clinical and Economic Review, 2021 Page i Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis 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 includes GlaxoSmithKline. 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 New England CEPAC The New England Comparative Effectiveness Public Advisory Council (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. The New England CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. The CEPAC Panel is an independent committee of medical evidence experts from across New England, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All Panel 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 New England CEPAC is available at https://icer.org/who-we-are/people/independent-appraisal-committees/new- england-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 and provider prescribing patterns may differ in real-world practice settings. Olnstitute for Clinical and Economic Review, 2021 Page ii Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis 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 draft report. None of these individuals is responsible for the final contents of this report, nor should it be assumed that they support any part of it. The report should be viewed as attributable solely to the ICER team and its affiliated researchers. For a complete list of stakeholders from whom we requested input, please visit: https://icer.org/wp-content/uploads/2020/12/ICER_Lupus-Nephritis Stakeholder-List_092920.pdf Expert Reviewers Kathleen Arntsen, BA President & CEO Lupus and Allied Diseases Association, Inc. Kathleen is the volunteer Board President and CEO of the Lupus and Allied Diseases Association, Inc. (LADA), an all-volunteer and patient-led 501(c)(3) non-profit organization. LADA receives funding from health care related organizations, including Aurinia and GSK, but members associated with LADA are not compensated. Dr. Michael Ward, MD, MPH Chief, Clinical Trials and Outcomes Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases No relevant conflicts of interest to disclose, defined as more than $10,000 in health care company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. Olnstitute for Clinical and Economic Review, 2021 Page iii Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Table of Contents EXECUTIVE SUIMMALY..........cccccccccccneeeeeeeseecccccccccceccecesseeeseeseseseeeeescsaaaacssssssssssssseseesseseseeseeeseeeeeeseeeeeeeneeess ES1 1. Background ..........::ccccccssccssersssseessesssscecessesenteeesessoesensssussnenecaeneeeecsensssesssoeeeessssorsessaeceeeeeeessenseesesserseness 1 2. Patient and Caregiver Perspectives ...........ssesccssssserccsessercecsesscccsssesneseseessesseseeseucescessucecesssneeseeeesnnseses 2 3. Comparative Clinical Effectiveness ...........cccsssssessssscssesssssccecsesseceeseeesenseesssseesessssceeeesesseneeeseesenssesesseeess 4 3.1. Methods Overview...........:sssscccscssscesseseecscesseesceesnsssneceeesescaesssesseessessenesnssensseseacescecaeassessensansseseae® 4 3.2. RESUItS ........essecceececeeececerseseseseeseecceesneesesesnssenssesseesseaeaeeaeecaeessessesssessenssessensaaecaeeeaeeaeesoessensseseeneae® 5 3.3. SUMMATrY ANd COMMENN ..........::sccccssssessesesssrsescssseecccsssnncesessuseeseseesnseecesanseeeessausecessarenseeessensetens 10 4. Long-Term Cost-EffectivenesSs............ccccssssssessssssssseessscesseceesscsenssseseessssussessessneessaneensseeeascuseesseseessssens 12 4.1. Methods Overview............cssccsccccescersssssesscescessesssneeeeeeecceceassesesesessoessaeeaessaesaaeeceeecesseseoeennenanse 12 4.2. Key Model Assumptions and IMput ...........:sccssscccssscesssressssseecssseecssecessnsecssneecsanseesaneessssesesssesesss 14 4.3. RESUITS .......ccssccscscsccstccscessesssccsssssscsesessessessesssssssessesesessesesasecessusssssessausonessusssecsnseaesetessesssseasoness 20 4.4 SUMIMALY AN COMMENL .......cccccssssescssessersccessscccesssssececsessenessreeseseeseuseusessesseeeesesseueessssssenecesessenes 26 5. Contextual Considerations and Potential Other Benefits or Disadvantages ...............:cccsesseseeeees 27 6. Health Benefit Price BENChmarkS ..........csccssssessscssscssssssesesseecseseeesssvsesosessescsessesenesseessesensesssssnsoneses 29 7. Potential Budget IMpact ............csscccccesssscrecsssscscesssssccccssssencessessacteesessenteesessenseseeseueeesessuereesssansecsesses 30 7.1. Overview of Key ASSUMPTIONS ...........scccesesssrsessesserceccescseceessneesesessseseesesseeeececsneeceesagnsettesssssesses 30 7.2. ROSUItS .......secceccecceeceeeeseeesseeseseceenecseeseeseesseseseseesueesnecsesececseesseeenssessoessesseceeceesneeaeeecessessseseeneanes 31 7.3 Access and Affordability Alert...........ssccccssssscceesessercecsssensesesssnnssesenseseesesseneeseeseesecesssenssteessanseeses 35 8. Summary of the Votes and Considerations for Policy .........cccssssesessersessessececeeseececeesscereneesnsseseesen 36 8.1 About the New England CEPAC Process ..........sscccsssccssscccsssccessnessnseessnsseesanenenanensnsaeassnseessasensneas 36 8.2 Voting RESUItS ............ccccccssssesssesssssseesseesssneeesseesessreeeseesensacensesssasssesessessussaesessceensaseeessesseesssseseees 38 8.3 Roundtable Discussion and Key Policy Implications .................:ccscccsssesssssessssseessseeesssseesseseessees 44 REFEFENCES .....csssesseeseccesccetcesescseessesseessesseessesssesssessessocsscessesceesoesesesoeassesssessesssesseesndecaeeedeeeacssssssssesseasaes 52 Supplemental Materials A. Background: Supplemental Information ...............::seceeesccscceseeeesseeeseeeseeesseeeneensaeeeceeesaeeesaeeesesenentaes 58 AL. Defimitions 0... eecccccescesseeseseneseaseececscecceseeeseeseessnseaeesaeeceescersesesessessoesaaeaaseaeeaseaeeecesseseseeeeseaese 58 A2. Potential Cost-Saving Measures in LUPUS Nephritis...........ccssscscccssserseccesserecsessereresesssensersssenees 59 B. Patient Perspectives: Supplemental Information. ..............cccccsccsssesseeeeseeeseeeseeesaeeeseeeeceeesseeeneeeeaeenas 60 BL. Methods.......ccecccccccscccccceessessseeseseeescecsecesssesssessseeessesaseeaseeeecdeessessseessoessseaanaesaeesaseedecdsesseasseeseneneas 60 Olnstitute for Clinical and Economic Review, 2021 Page iv Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis C. Clinical GUICE]INGS .......ccccccccccccssseesssssssesssssccccccccccessssssescesesececccccceteeseesesesesseseseecceececesecececersesesasaaaaanans 61 D. Comparative Clinical Effectiveness: Supplemental INFOrmation ,...........:cccsssccccessstcccessssereeeesssreeeees 65 D1. Detailed Methods ...........cssessssscssssssscssscseccsscsesssssssessesssessssesssvsnsossssesesessescsessescsescrsesesvansoaesaes 65 D2. Additional Clinical EVidence..............cssesssesssseseeesseseseseceeececssessessessenssessenssaseaeseaecseeeseeeeseseeseeeaes 74 D3. Heterogeneity and SUDZIOUPS...........cssesecssssecssssessstscessuecssseseessscecsnssessnsesssceessnesessuesesssesessneess 75 D4. Evidence Tables ........ccssssssssssssssssssscsesssscseccssssessesssessesenesssssssvsesossvsnsosessesesessesesescrseesssnssaesaes 76 D5. Supplemental MA and NMA Information............ccsscscccesssssressesseescecessercessesseseesessenstecessseneeseeses 94 D6. Ongoing StUCICS...........:.:ccccssersescsssstecccssssescessssceeeccssscecessescustseseeseeseesssseseesecseeeeseessuserserssenseteses 96 D7. Previous Systematic Reviews and Technology ASSESSMENHS .........csessssceccessttecesessneeerssssnseeens 101 E. Long-Term Cost-Effectiveness: Supplemental Information ...........::ccccssssccccesserecsesserecssessnensesssseeees 103 E1. Detailed Methods.......ccccsssssssccsssssssssccsesssccccccsesseessesseessesecesssesseassesseesesceesoeseesseesecsasseseeaeoese 103 E2. Model Inputs and ASSUMPTIONS ............csccssessesseeeessscccecnccaceeeeessseneeesesseeseneacaceeecaescceeeesessaesenees 105 E3. ROSUItS .......cseceeccecceeceeeeecerssessseesceeseeecessseeseseseesessaeaseenaeeececsaeeceaseessessoesseasaassaesaeeeaeeceeeeaeseseeseante 120 EA, Sensitivity ANalyses ...........cccsscscccesssssssssesceccessssucessessusessessensssevessnscessessusecsesseneeseesseseceesesseneeses 124 E5. Scenario AMAalySes.........sscccsessssssesssscsseccessccesesssssescessesceceesesseusesesesenesesessorsecuacaceeeneeseeeseesssseeseness 132 E6. Heterogeneity and SUDQrOUpS .............cc::sccesesessescessseeessssecsseceesssseesssesessneesssneensaeeeesuseessesesseess 139 E7. Model Validation .........cecssssssssssssssssescessecscesseeesesseessesecceaeeaesssessesesessesaaassassaaseceeceeecessoeseeenaase 139 F. Potential Other Benefits and Contextual Considerations ...........::..sssseseseeeeseseteeeeeseeeeeeecnesseeeeeeoeee 144 G. Potential Budget Impact: Supplemental Information ..............:cccsscccsesseeseeesseeesseeesseeeseseesssseess 146 H. Public COMMENHS.........eccceccescessesseeesensseeeeeeseesceecesssesseneseesenscecseeeceseeeseseoesseseaassaenanecceeeaeeceasseseeseaese 147 I. Conflict of Interest DiSClOSUIS ............ssceccssssesseseeseeenseseseaeeeaseaeecaeeeeeeseseoesseseaesanesaaeeaeeeeeenesseeeaenanse 154 Olnstitute for Clinical and Economic Review, 2021 Page v Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis List of Acronyms and Abbreviations Used in this Report ACR AD AE AHRQ ASP AZA BEM cl CNI CR CRR cyc eGFR EULAR evLYG ESRD GFR HCQ KDIGO KM LN LY MA MMF NA NMA NR NS OR PBO PERR PICOTS PR PRISMA PRR PSA QALY RCT RR SAE sc SLE SLICC USPSTF vcs WAC American College of Rheumatology Active disease Adverse event Agency for Healthcare Research and Quality Average sales price Azathioprine Belimumab Confidence Interval Calcineurin Inhibitor Complete response Complete renal response Cyclophosphamide Estimated glomerular filtration rate European League Against Rheumatism Equal value life-years gained End stage renal disease Glomerular filtration rate Hydroxychloroquine Kidney Disease: Improving Global Outcomes Kaplan Meier Lupus nephritis Life year Meta-analysis Mycophenolate mofetil Not applicable Network meta-analysis Not reported Not significant Odds ratio Placebo Primary efficacy renal response Population, Intervention, Comparator, Outcome, Timing, Setting Partial response Preferred Reporting Items for Systematic Reviews and Meta Analyses Partial renal response Probabilistic sensitivity analysis Quality adjusted life year Randomized control trial Risk ratio Serious adverse events Standard care Systemic lupus erythematosus Systemic Lupus International Collaborating Clinics United States Preventive Services Task Force Voclosporin Wholesale acquisition price Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page vi Executive Summary Systemic lupus erythematosus (SLE) is an autoimmune disease that affects between 300,000 and 1.5 million Americans.' It is more common in women (90% of diagnosed cases) and in non-Whites (four times higher prevalence in Black patients, two times higher prevalence in Hispanic patients). Approximately half of patients with SLE will be diagnosed with lupus nephritis (LN), characterized by inflammation in the kidney, proteinuria, and progressive kidney damage which can lead to kidney failure.23 LN typically presents in patients who are 20 to 40 years old*° and is the most common cause of death and disability in patients with SLE. In this report, ICER reviews belimumab, a parenteral b-lymphocyte inhibitor, and voclosporin, an oral calcineurin inhibitor, for the initial treatment of patients with LN. Each drug is added to standard induction therapy for LN which is high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide. The FDA approved belimumab on 12/17/2020 and voclosporin on 01/22/2021. Belimumab increases the complete renal response (CRR) and primary efficacy renal response (PERR) at two years compared with standard therapy alone, with benefits seen after the first year appearing stable at year two. At two years, the proportion of patients receiving < 5 mg of prednisone was greater in the belimumab group (36.8% versus 27.8%). There were no significant increases in adverse events or discontinuations compared with standard induction therapy for LN. Voclosporin nearly doubled the complete response (CR) and markedly increased the partial response (PR) at one year compared with standard therapy alone. The proportion of patients on low dose steroids was not reported, but all those with PR and CR were required to be taking low dose steroids. Adverse events were comparable to standard induction therapy for LN, but the FDA added a black box warning consistent with that of cyclosporin for possible serious infections and malignancies. Table ES1. Complete Response at One and Two Years Outcome (elit (-F-16 BAe RY (-F16) Belimumab CRR® 32.5% 30.0% Placebo CRR 25.5% 19.7% Voclosporin CR* 42.3% - Placebo CR 23.3% - * CR: Complete response from meta-analysis. Two-year data are not available. § CRR: Complete renal response at one year estimated from Figure 1 in the manuscript. See Supplement Section Ai for details on the small differences in the definition of CR and CRR. The most important uncertainty is how these short-term assessments of renal response translate into meaningful long-term outcomes for patients in whom SLE is a lifetime illness. In addition, the Olnstitute for Clinical and Economic Review, 2021 Page ES1 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC length of time these therapies are used prior to tapering them to standard maintenance therapy remains to be established. Because of inadequate representation of patients from communities of color in the development trials, the limited data available are highly uncertain and cannot be used to determine the relative effectiveness of either drug among different racial and ethnic groups. Table ES2 shows ICER's evidence ratings for the two therapies: Incremental or better - moderate certainty of a small or substantial net health benefit with high certainty of at least a small net health benefit (B+). Table ES2. Evidence Ratings aici (ee Teles Evidence Rating Adults with LN Belimumab + MMF/Corticosteroids or | MMF/Corticosteroids or B+ Cyclophosphamide/Corticosteroids Cyclophosphamide/Corticosteroids Voclosporin+ MMF/Corticosteroids MME/Corticosteroids Bt ICER performed cost-effectiveness analyses of the new drugs. The annual cost of belimumab for patients remaining on treatment was estimated to be $42,720 ($39,944 when including treatment discontinuation because of adverse events). Voclosporin annual costs for patients remaining on treatment were estimated to be $92,233 ($87,068 including adverse event-related discontinuation). The annual cost figure for voclosporin differs from the drug makers' announced net price due to their incorporation of estimated real-world discontinuation and lack of full adherence that occur for reasons other than treatment-related adverse effects. In the base case, the incremental cost-effectiveness ratio for belimumab was estimated to be approximately $90,000 per quality adjusted life year (QALY), and $78,000 per equal value of life years gained (evLYG). The corresponding results for voclosporin were approximately $149,000/QALY and $132,000/evLYG. In one-way sensitivity analyses, the incremental cost- effectiveness ratios were most sensitive to the monthly costs for patients with active kidney disease and the utilities for the active disease and complete response health states. In probabilistic sensitivity analyses, belimumab was cost effective at the $150,000/QALY threshold in 69% of the runs and voclosporin in 49% of the runs. To explore the potential for important differences in relative effectiveness across racial and ethnic subgroups, we performed a scenario analysis for Black patients, the most prevalent ethnic subgroup. We cannot stress enough that the results are highly uncertain due to the small numbers of Black patients in the available clinical trials and the lack of data on differences among subgroups in long term outcomes. For belimumab, the estimated cost-effectiveness for Black patients was worse than for White patients, whereas for voclosporin it was modestly improved. As noted, these results are highly uncertain. They should not guide clinical or policy decision-making but should be Olnstitute for Clinical and Economic Review, 2021 Page ES2 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC recognized as signaling how important it is for drug makers and clinical researchers to structure future clinical research to be able to examine the relative effectiveness of these treatments among the racial and ethnic groups that constitute the majority of patients with LN in the United States. The Health Benefit Price Benchmarks (HBPBs) 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 evLYG gained. We estimated that the HBPB for belimumab ranges from $45,000 to $61,000 and that the HBPB for voclosporin ranges from $72,000 to $101,000. There are other potential benefits and contextual considerations not fully captured in the economic model. These include potentially greater benefits of these therapies for Black patients, the high lifetime burden of illness of LN, the early age of onset of the disease, and the lack of FDA approved therapies for LN prior to the availability of these drugs. On the other hand, the assumed long-term benefits of these therapies are likely to be optimistic because we assume that patients with a partial response do as well as those with complete response, so the model may overestimate the benefits of belimumab and voclosporin. In conclusion, the evidence appears adequate to demonstrate that belimumab and voclosporin provide improved clinical outcomes for patients and may offer important benefits beyond those directly measured in clinical and cost-effectiveness analyses. Substantial uncertainty remains regarding the magnitude of the impact of short-term kidney function improvement on long-term outcomes that matter most to patients, such as progression to renal failure. Relative clinical benefits for Black patients and those from other racial and ethnic groups are not well defined from the existing clinical studies and deserves much greater focus in future research given the high unmet need in these communities. With these uncertainties in view, our modeling suggests that belimumab's estimated net price aligns well with its' estimated long-term added benefits for patients. These findings do not include consideration of potential broader benefits of belimumab on health for patients with LN. For voclosporin, its estimated net price produces a cost-effectiveness result at the upper end of commonly accepted ranges. The results of the cost-effectiveness analyses for both drugs are sensitive to important assumptions, and policymakers should also view the results in the context of important potential other benefits and contextual considerations related to new treatments for LN. The New England CEPAC's voting results from the March 26, 2021 public meeting aligned with the results summarized above. The CEPAC Council unanimously voted that the evidence was adequate to demonstrate that both belimumab and voclosporin, each when added to standard induction therapy, offered a net health benefit when compared to standard induction therapy alone. The majority of the Council assigned a high priority to the magnitude of lifetime impact for patients with LN as an important contextual consideration for policymakers as they make judgments about long- term value for money for these therapies. Finally, the majority of the Council judged belimumab to Olnstitute for Clinical and Economic Review, 2021 Page ES3 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC provide a "high" long-term value for money and voclosporin to provide an "intermediate" long- term value for money, at current pricing. At their net prices, approximately 80% (belimumab) and 35% (voclosporin) of eligible patients with LN could be treated in a given year before crossing the ICER potential budget impact threshold of $819 million per year. Testimony from clinical experts at the public meeting suggested that the ideal clinical uptake of these drugs would include the chance for nearly every patient to be on one drug or the other. Given that efforts to reach this clinical target would create a short-term potential budget impact that exceeds the threshold, ICER is issuing an access and affordability alert. Themes and recommendations from the public meeting include: e All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with lupus nephritis are introduced in a way that will help reduce health inequities. e Both belimumab and voclosporin are judged to be priced in reasonable alignment with estimates of their benefits for patients, and this consideration should guide payers to design coverage criteria that do not narrow coverage from the FDA label, although coverage criteria may define terms left indeterminate in the FDA label to assure appropriate use. e Manufacturers should commit to expanding their research, both before and after regulatory approval, to include adequate representation of patients with lupus nephritis from Black and other non-white populations. e Manufacturers should not seek to use common sense dosing algorithms as a tool to gain prolongation of their patents, thereby adding to future health care affordability concerns and reducing the headroom for future innovative therapies. e Specialty societies should work with regulators to standardize the primary outcome used in future pivotal trials of therapies for lupus nephritis. e Specialty societies should update their guidelines to include guidance on appropriate use of belimumab and voclosporin and commit the resources to update guidelines more frequently as evidence evolves. e Priority should be given to developing biomarkers that can guide the choice of therapy in lupus nephritis. e Larger observational studies describing the long-term outcomes following both complete and partial response are needed. Olnstitute for Clinical and Economic Review, 2021 Page ES4 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC 1. Background Systemic lupus erythematosus (SLE) is an autoimmune disease that affects between 300,000 and 1.5 million Americans.' It is more common in women (90% of diagnosed cases) and in non-Whites (four times higher prevalence in Black patients, two times higher prevalence in Hispanic patients). Approximately half of patients with SLE will be diagnosed with lupus nephritis (LN), a heterogenous disease characterized by inflammation in the kidney, proteinuria, and progressive kidney damage."? LN typically presents in patients who are 20 to 40 years old.*° The diagnosis is suspected when there is excess protein in the urine and made with a kidney biopsy. Within 15 years of the diagnosis, between 10% to 30% of patients with LN progress to end stage renal disease (ESRD), requiring dialysis or kidney transplantation.** The prognosis of patients with LN is worse in Black patients and Hispanic patients.27° Guidelines recommend induction therapy with high dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide, followed by maintenance therapy with MMF.1+?2 Unfortunately, fewer than half of patients with LN respond to current combination therapy, so there is a large unmet need for new therapies. The FDA recently expanded the indication for belimumab to include LN and is expected to approve voclosporin in early 2021 (Table 1.1). Belimumab is a parenteral b-lymphocyte inhibitor that is FDA approved for SLE; the manufacturer submitted an application to expand its indication to include LN on 7/29/20. Voclosporin is an oral calcineurin inhibitor that is reported to be safer than other calcineurin inhibitors (less kidney damage); the FDA approved voclosporin on 1/22/2021 for LN. Table 1.1. Interventions of Interest Intervention Brand Name (Generic Mechanism of Action Delivery Route deere] iat -maneyetrl acon Name) 10 mg/kg every 2 weeks x ' B-lymphocyte Benlysta (belimumab) . oo, Intravenous* 3 doses, then every 4 stimulator inhibitor k weeks Lupkynis™ (voclosporin) Calcineurin inhibitor Oral 23.7 mg twice daily mg: milligram, kg: kilogram *Belimumab is also available in a subcutaneous formulation, but that formulation has not been studied for the treatment of lupus nephritis Olnstitute for Clinical and Economic Review, 2021 Page 1 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 2. Patient and Caregiver Perspectives One important source to understand the patient perspective comes from a meeting convened in September 2017 by the Lupus and Allied Diseases Association, the Lupus Foundation of America, and the Lupus Research Alliance. The purpose of this meeting was to elicit the perspectives of patients living with lupus as part of the FDA's Patient Focused Drug Development Initiative. Insights from the meeting are summarized in the report Lupus: Patient Voices. In the report, patients with LN reported that the symptoms that most negatively affected their lives were fatigue (24%), joint and muscle pain (24%) and their kidney disease (21%). Among all patients with SLE the top three downsides of their current treatment were side effects (54%), the number of pills and other treatments taken each day (54%), and the cost of treatment (42%).*° From patient groups and other stakeholders, we heard how important it was to take into consideration the greater impact that LN has on communities of color. This input emphasized the importance of doing subgroup analyses in these patient populations. For example, progression to ESRD in Black LN patients is almost nine times greater than in White patients yet access to kidney transplantation is lower, and overall mortality from the condition is higher in Black patients and other non-White groups.**> Disparities in outcomes between White and non-White LN patients persist even when adjusting for socioeconomic factors, signaling the possibility of both biological differences and the impact of systemic racism in the health care system and society.7® Patient groups also emphasized that each person is unique due to the heterogeneity and unpredictable course of the disease. Each patient has a different constellation of co-morbidities, demographics, living circumstances, and baseline medications. All of these play into the impact of LN on their lives and the potential for benefits and harms from new medications. Given the young age of onset of LN, the disease often has a huge negative impact on patients' ability to work, to have children, and to advance in their careers. It creates an emotional and financial burden to both the patient and caregiver and a huge economic burden for society to bear. Feedback from patients also highlighted the importance to them of reducing or eliminating the need for high-dose steroids because of side effects that often include mental health issues, weight gain and changes to appearance, and manifold significant long-term harms including increased risk for diabetes, osteoporosis, hypertension, infections, coronary artery disease, glaucoma, and cataracts. We also heard that we should be mindful of the outcomes of treatment that matter most to LN patients in addition to improving their kidney disease: to mitigate fatigue and reduce or eliminate joint and muscle pain. A final concern expressed by patients is the route of administration of therapies for LN. Given the COVID-19 pandemic, patients are understandably concerned about needing to come into infusion Olnstitute for Clinical and Economic Review, 2021 Page 2 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC centers for therapies that require intravenous infusion. Other factors that impact LN patients who receive intravenous infusions include treatment costs, child, and elder care, and in some geographic areas limited availability of infusion providers/centers and/or transportation challenges. In addition, the time and travel required to access kidney dialysis or infusion therapy is an impediment for many people. We also heard that utilization management payer policies such as step therapy restrictions present frustrations for both patients and their providers, particularly when patients are required to try and fail preferred treatments that can be ineffective or result in adverse reactions. They also highlighted issues with access to care in general and in particular for patients in communities of color and those who live in rural areas. ©Olnstitute for Clinical and Economic Review, 2021 Page 3 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 3. Comparative Clinical Effectiveness 3.1. Methods Overview Please see the Supplement Section D for details of the literature search, quality assessment, and the quantitative summary methods. Scope of Review This review compares the outcomes of adding belimumab or voclosporin to standard therapy with the outcomes of standard therapy alone for the treatment of adults with LN. The primary outcomes are complete and partial remission over one to two years of therapy and reductions in steroid use. Unfortunately, the drug makers did not measure fatigue or quality of life, and no data are available on longer-term progression to ESRD. Evidence Base The clinical evidence is summarized separately below for each drug because the pivotal trials for the two drugs differed markedly in populations studied, outcome definitions, and length of follow-up. Both drugs are added to standard induction therapy for LN (either MMF or cyclophosphamide in addition to high dose corticosteroids). Belimumab Our search identified one randomized trial of belimumab in patients with LN, the pivotal phase 3 trial BLISS-LN with outcomes at 104 weeks?', and two uncontrolled trial.1*?9 Detailed descriptions of the study designs can be found in Supplement Table D4.2. Voclosporin Our search identified two randomized trials of voclosporin in patients with LN: the pivotal phase 3 AURORA trial with primary outcomes measured at 52 weeks, and the 24-week phase 2b AURA-LV trial in which one arm received the same dose of voclosporin as in AURORA (Table 3.1). There was also one uncontrolled phase 2 trial (AURION).2°2° The full results of the AURORA trial have not yet been published. Detailed descriptions of the study designs can be found in Supplement Table D4.2. Olnstitute for Clinical and Economic Review, 2021 Page 4 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 3.1. Overview of Key Studies DUT 4 ar N Primary Outcome Belimumab BLISS-LN 446 104-week PERR Voclosporin AURA-LV 177 24-week CR Voclosporin AURORA 357 52-week CR CR: complete response; PERR: primary efficacy renal response Key Difference in the Clinical Trials. The primary differences in the study populations for the two drugs were that the AURORA trial excluded patients with an eGFR < 45 ml/min and required background therapy exclusively with MMF, whereas the BLISS-LN trial only excluded patients with an eGFR < 30 ml/min and allowed background therapy with either MMF or cyclophosphamide (Supplement Table D4.2). Approximately 26% of patients in the BLISS-LN trial received cyclophosphamide. Despite these differences, the patient populations in the two pivotal trials were otherwise quite similar (88% female, mean or median age 33, Black race 13-14% in both trials). The mean eGFR for patients at entry in the AURORA trial (91 ml/min) was slightly lower than that of patients in the BLISS-LN trial (100 ml/min) despite its exclusion of patients with low eGFR. Additional baseline characteristics for patients in all of the studies are in Supplement Table D4.3. There are several other important differences between the trials. The primary outcome for the AURORA trial was "complete response" (CR) at one year, while the primary outcome in the BLISS-LN trial was "primary efficacy renal response" (PERR) at two years. Apart from the time of assessment, the two outcomes differed in the degree of allowable proteinuria (CR UPCR < 0.5; PERR UCPR < 0.7) and CR required sustained, low dose or no corticosteroid use. Since the differences are small, it is reasonable to compare them at similar timepoints. There were also slight differences in the definitions used for complete response and partial response in the two trials (Supplement Section Ai describes the specifics for each definition). Lastly, the AURORA trial required a rapid taper of corticosteroids, which was not required in the BLISS-LN trial. 3.2. Results Clinical Benefits The primary outcomes that are used in the economic model are the complete renal response and partial renal response as defined in the clinical trials. The reduction in prednisone dose to 5 mg/day or less was measured in both trials. As noted, no measures of quality of life or patient reported outcomes such as fatigue, SF-36, EQ-5D, WHOQOL, SLEQOL, LupusQOL, or LupusPro were reported publicly or provided separately by the drug makers. ©Olnstitute for Clinical and Economic Review, 2021 Page 5 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Belimumab The key outcomes of the BLISS-LN trial are summarized in Table 3.2 below. At one year, the PERR for belimumab was approximately 10% greater than placebo, and, similarly, at two years both PERR and CRR for belimumab were about 10% greater than placebo. Table 3.2. Key Outcomes for Belimumab in BLISS-LN Placebo Belimumab Placebo Belimumab CRR 25.5%* 32.5%* 19.7% 30.0% i ee 35.4% 46.6% 32.0% 43.0% CRR: Complete renal response, PERR: Primary efficacy renal response. * The 12-month results are approximations read from Figure 1 in the NEJM publication.?" Figure 1 in the published results of the BLISS-LN trials shows that the proportion of patients having CRR and PERR increased over the first 40 to 48 weeks and remained relatively stable after that time. As can be seen in Table 3.3 above, the PERR decreased slightly between 12 months (52 weeks) and 24 months (104 weeks). The CRR results were not reported numerically at 12 months but were approximately 25% for the placebo group and 31% for the belimumab group mirroring the results of PERR. A unique outcome reported in the BLISS-LN trial was the time to a renal-related event or death, which included ESRD, doubling of the serum creatinine, increased proteinuria, or impaired kidney function. In atime to event analysis, the HR for this outcome was 0.51 (95% Cl 0.34-0.77) for belimumab compared with placebo. In an abstract presented in November 2020, the investigators reported on SLEDAI-S2K scores and prednisone dosage at 104 weeks follow-up.2" Patients randomized to belimumab had higher SLEDAI-S2K scores (62 versus 41, p=0.016) and a higher proportion of patients on 5 mg or less of prednisone (36.8% versus 27.8%, p=0.044). Voclosporin We performed a random effects meta-analysis of the AURA-LV and AURORA trials for complete and partial response at six and twelve months (Table 3.3 below). Detailed methods are shown in Supplement Section D1; detailed results in Supplement Section D5). The AURA-LV trial did not report PR at 12 months, so Table 3.2 includes PR from the AURORA trial at both six and twelve months. At one year, both the CR and PR for voclosporin was about 20% greater than placebo. ©Olnstitute for Clinical and Economic Review, 2021 Page 6 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 3.3. Meta-Analysis of Key Outcomes for Voclosporin Placebo Voclosporin Placebo Voclosporin MA Complete response 19.9% 32.9% 23.3% 43.2% MA Partial response 50.0% 70.9% S S AURORA Partial response 50.0% 70.4% 51.7% 69.8% MA: meta-analysis Exploratory Analysis Comparing Belimumab to Voclosporin As noted above, there were important differences in the studies of the two drugs in the study populations, co-interventions, and some of the outcomes. However, the differences in patient characteristics at baseline tended to favor belimumab (less proteinuria at baseline, better renal function at baseline [higher baseline eGFR], and longer follow-up for efficacy). We conducted a network meta-analysis comparing CRR at two years for belimumab to CR at one year for voclosporin (Supplement Section D1 for detailed methods, Section D5 for detailed results). In the NMA, there were no significant difference in CR between the two drugs when added to standard care, but the trend was for a greater proportion of patients to have a CR with one year of voclosporin compared with two years of belimumab (OR 1.62, 95% Cl 0.94 to 2.77, Supplement Table D5). Harms Belimumab In the BLISS-LN trial, SAEs were similar in the belimumab and placebo groups (25.9% versus 29.9%) as were adverse events thought to be related to treatment (55% versus 53%). Adverse events leading to treatment discontinuation were identical (13%). See Supplement Table D4.10 for additional details. Voclosporin In the AURORA trial serious adverse events (SAEs) were nearly identical in the voclosporin and placebo groups (20.8% versus 21.3%), as were adverse events thought to be related to treatment (4.5% in both groups). Adverse events leading to treatment discontinuation were less common in the voclosporin group (11.2% versus 14.6%). See Supplement Table D4.10 for additional details. Voclosporin carries a black box warning for serious infections and malignancies that may lead to hospitalization or death based on the experience with similar immunosuppressant therapies. Olnstitute for Clinical and Economic Review, 2021 Page 7 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Subgroup Analyses and Heterogeneity Because of inadequate representation of patients from communities of color in the development trials, the limited data available are highly uncertain and cannot be used to determine the relative effectiveness of either drug among different racial or ethnic groups. We present the results below for transparency and to signal the importance of re-orienting future research efforts so that adequate evidence can be generated to evaluate the relative safety and effectiveness of treatments among the patient groups that suffer the greatest burden of illness from LN in the United States. Belimumab In the BLISS-LN trial at 104 weeks, the point estimates for the odds ratio (OR) for PERR (2.24 versus 1.53) and CRR (2.16 versus 1.75) was nominally higher for Black patients than the point estimate for non-Black patients, but neither OR was statistically significant for Black patients, likely due to insufficient power as there were only 63 Black participants in the trial (four with CRR in the placebo group, six with CRR in the belimumab group). No p-values for interaction were reported. Heterogeneity was also seen among patients treated with belimumab based on their induction therapy. The PERR at 104 weeks was similar for patients receiving cyclophosphamide or MMF, but the OR for CRR in patients treated with cyclophosphamide was 1.07 (95% Cl 0.41 - 2.78) compared with 2.01 (95% Cl 1.19 - 3.38) for patients treated with MMF. Voclosporin In the AURORA trial, Black patients had a lower CR than White patients in the placebo group (15.8% versus 29.5%), which supports the evidence in the literature that Black patients have a worse response to standard induction therapy than White patients. In addition, Black patients had a higher CR than White patients among patients treated with voclosporin (46.2% versus 38.2%). This suggests that voclosporin may be more efficacious in Black patients, but no p-value for interaction was reported. However, the CR for voclosporin in White patients was non-significant (38.2% versus 29.5%, p =0.165), while it was significant in Black patients (46.2% versus 15.8%, p = 0.045) and Asian patients (41.5% versus 17.9%, p=0.005). There were only 45 Black participants in the trial, so these subgroup findings may be due to chance. ©Olnstitute for Clinical and Economic Review, 2021 Page 8 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Uncertainty and Controversies The most important uncertainty is how these short-term assessments of partial and complete renal response translate into meaningful long-term outcomes for patients. LN is a life-threatening, lifelong illness and the outcomes that matter most to patients are progression to ESRD or death. The available outcomes, limited to one to two-year response rates, are insufficient to demonstrate adequately the magnitude or durability of the long-term benefits of these novel therapies. It is also unclear from the available evidence how long therapy with these novel agents should continue. For voclosporin, in particular, there is the potential for a reduction in eGFR, which has been a significant limitation for other calcineurin inhibitors. Voclosporin is thought to be safer, but long-term data are lacking. There are concerns that voclosporin is suppressing proteinuria, without changing the underlying inflammation or altering the progression of LN. The studies have not reported on the impact of these novel therapies on fatigue, one of the most important outcomes to patients, nor are there any reports on the impact of these therapies on patients' quality of life or changes in functional status. And, importantly, LN disproportionately impacts non-White patients. As noted above, the number of non-White patients enrolled by drug makers in pivotal trials was too small to determine relative effectiveness of either drug across racial and ethnic groups. Olnstitute for Clinical and Economic Review, 2021 Page 9 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 3.3. Summary and Comment The ICER Evidence Rating Matrix is shown below in Figure 3.1. Full details are provided in the Supplement. Figure 3.1. ICER Evidence Rating Matrix Comparative Clinical Effectiveness High q Certainty oS o 3 > Wy vu $ & > Moderate 2 . < Certainty S 5 CG c ov a - Low Certainty Negative 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 C= "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 a small or substantial net health benefit, with high certainty of at least a small net health benefit C+ = "Comparable or Incremental" - Moderate certainty of a comparable or small net health benefit, with high certainty of at least a comparable net health benefit C- = "Comparable or Inferior" - Moderate certainty that the net health benefit is either comparable or inferior with high certainty of at best a comparable net health benefit C++ = "Comparable or Better" - Moderate certainty of a comparable, small, or substantial net health benefit, with high certainty of at least a comparable net health benefit P/1 = "Promising but Inconclusive" - Moderate certainty of a small or substantial net health benefit, small likelihood of a negative net health benefit = "Insufficient" - Any situation in which the level of certainty in the evidence is low Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page 10 Return to TOC Belimumab Belimumab added to standard therapy significantly increases the CRR and PERR at two years compared with standard therapy alone. The benefits were seen within the first year and remained stable between years one and two. There were no significant increases in adverse events or discontinuations due to adverse events compared with standard induction therapy for LN. Although the trials were two years in duration, this remains too short a time to provide high certainty of the magnitude or duration of long-term benefit. Hence, as with voclosporin, we judge that the comparative net health benefit of belimumab added to standard therapy is "incremental or better" (B+). Voclosporin Voclosporin added to standard therapy nearly doubled the CR and markedly increased the PR at one year compared with standard therapy alone. Adverse events were comparable to standard induction therapy for LN. However, other calcineurin inhibitors have adverse long-term renal effects, which would not have been evident in the relatively short clinical trials performed to date. Therefore, uncertainty remains as to whether the overall health benefits of voclosporin will prove to be substantial or incremental. Hence, at this time we have assigned a rating of "incremental or better" (B+) to the comparative net health benefit of voclosporin. Table 3.4. Evidence Ratings Sica § Comparator Evidence Rating Adults with LN Belimumab + MMEF/Corticosteroids or MMEF/Corticosteroids or B+ Cyclophosphamide/Corticosteroids Cyclophosphamide/Corticosteroids Voclosporin+ MMF/Corticosteroids MMEF/Corticosteroids B+ Olnstitute for Clinical and Economic Review, 2021 Page 11 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 4. Long-Term Cost-Effectiveness 4.1. Methods Overview The aim of the economic evaluation was to estimate the cost effectiveness of belimumab and voclosporin for patients with LN, with each drug compared to the standard of care as represented by the comparator arm in its own pivotal trial(s). The decision analytic model assumes progression of the disease through the patients' lifetimes (i.e., lifetime horizon), using a health care sector perspective in the base case. The model, based on response-to-treatment outcomes, consists of two parts: (a) a short-term interpolation model concordant with data from the trials; (b) a long-term (lifetime) model based on extrapolation using partitioned survival modeling. All patients start the short-term model in the active disease (AD) state. From the AD state, patients may transition to either complete response (CR), partial response (PR), end-stage renal disease (ESRD), or death (Figure 4.1). The base-case short-term model comprises three years for both belimumab and voclosporin. One-month probabilities up to the end of respective trial follow up times in the short-term model are informed by key trials: BLISS-LN for belimumab, and AURA-LV and AURORA for voclosporin. Based on clinical expert input, beyond the trial follow-up period, patients are assumed to stay in the same health states that they were in at the end of the trials (see Tables 4.2 and 4.3) until the end of the three years of the short-term model. The long-term model involves partitioned-survival modeling based on other benchmarks of longitudinal data on the outcomes of LN patients. ESRD-free survival for the different health states based on BLISS- LN categorized outcomes was estimated from Davidson et al. (2018). The proportion of ESRD events and deaths within the ESRD-free survival endpoint was estimated based on data from Chen et al. (2008), as these data are not reported in Davidson et al.(2018).®18 Utility and cost estimates for patients in the different health states were derived from multiple sources (reported in Section 4.2). The model estimated the total costs, quality adjusted life years (QALYs), and equal value of life years gained (evLYGs) by aggregating the cost/QALY/evLYG in each month depending on the proportion of patients in each health state. The details of the model are reported in Supplement Section E. Because of no reliable data to inform long-term disease progression by racial subgroups, the base-case model reflected ethnicity considerations by selecting the US source of data with large proportion of Black population.*® A scenario analysis was conducted with limited trial data reporting complete response in Black population. Neen Olnstitute for Clinical and Economic Review, 2021 Page 12 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure 4.1. Short-Term Model Structure response response AD: active disease, ESRD: end-stage renal disease Olnstitute for Clinical and Economic Review, 2021 Page 13 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 4.2. Key Model Assumptions and Inputs Our model includes several key assumptions reported in Table 4.1 below. The complete list of assumptions is reported in Supplement Section E2. Table 4.1. Key Model Assumptions a Tati Me) meta) derived from improved kidney function only Belimumab and voclosporin igre aL ML ol compared to standard therapies used in respective control arms and not to each other. In the long-term model, patients in CR and PR accrue costs and outcomes associated with time in AD before progressing to ESRD eva Tal MO we Lie Mm MeL Lh discontinue belimumab and voclosporin treatment at Li eM ae Me) mle ate) ae Tan) model (unless a serious adverse event leading to drug discontinuation occurred earlier) Patients in the AD state discontinue belimumab and voclosporin treatment at 18 months In the short-term model, treatment discontinuation due to adverse events (AEs) is included in the model Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis LN is a complication of SLE. Some treatments, such as belimumab, could affect not only LN, but also SLE progression. This model reconstructs the progression of LN only i.e., the model does not reflect broader benefits of treatments, for instance their impact on progression of SLE or other comorbidities. There are no head-to-head trials comparing belimumab and voclosporin. The designs of the trials, including the inclusion criteria, comparator arms, background therapy, definitions of outcomes, and study follow-up times are different, precluding comparison of the treatments to each other within the proposed framework. Clinical experts suggested that patients with CR and PR are likely to spend a period of time in AD before progressing to ESRD (rather than progressing directly to ESRD from CR or PR). AD is defined by a drop in eGFR level which is necessary to transition into ESRD. In the long-term model this was implemented by incorporating costs and outcomes for the time spent in AD rather than explicitly modeling this transition. The mean time spent in AD state before progressing to ESRD for patients with relapse is extracted from Hanly et al. (2016).2° There are no data to inform long-term treatment effects of belimumab and voclosporin, thus no additional effectiveness or costs related to belimumab and voclosporin treatment will be accumulated beyond the short-term model. In the base-case analysis, the short-term model time horizon is three years and assumes patients stay in the same health states that they were in at the end of the trials (see Tables 4.2 and 4.3) until the end of three years. As such, the patients in CR and PR states are assumed to receive treatment for the whole duration of three years, except for those who stop treatment earlier due to adverse events. There are no data to inform mean discontinuation time of belimumab and voclosporin for patients remaining in the AD state. Data from the AURORA and BLISS-LN trials suggest an additional clinical effect between 6-12 months of treatment. The selection of 18 months for discontinuation in the AD state is based on recommendations from clinical experts to account for the likelihood of longer than 3 years treatment time in clinical practice and so to mitigate potential underestimation of treatment duration in CR/PR states. We assume that in a real-life setting, the treatment discontinuation rate will be lower than in the trial settings because of no blinding (i.e., those patients who discontinued in the trial because of the assumed lack of efficacy would continue the treatment in real life). Given we assume patients in the AD state stop treatment at 18 months in the model, only treatment discontinuation to AEs is included in the model. Page 14 Return to TOC Costs of interventions for As there are no data available on time of patients' treatment patients who discontinued discontinuation due to AEs, we assume that the treatment discontinuation is Visaee) Sandi slasau-ecsarera | at the mid-point of the short-term model. For the patients who stop accumulated after the treatment due to AEs, the costs of interventions (belimumab and rualieleyeyieiaceyimedul-yiveyggeia-yeeny |) VOClOSsporin) are not accrued beyond 18 months (the midpoint of the short- model term model), though they still accumulate the costs related to their health state. Tapered steroid use In BLISS-LN, more patients were reported on low-dose steroids in treatment decreases costs and than comparator arms. In AURORA, steroid dose was tapered down to a Tal est MUL eM Om tals dose of 5 mg daily by week 8 and 2.5 mg daily by week 16. Costs of steroids short-term model and increments in utilities for patients on low-dose steroids are included in the short-term model. Inputs For belimumab, the proportion of patients reaching CR were extracted from the digitized curve from the BLISS-LN trial.?"? The proportions of patients reaching PR, ESRD, or death at the end of the trial follow-up of 104 weeks are reported in Table 4.2. Table 4.2. Outcomes from BLISS-LN Trial at 104 weeks Su Partial Renal Renal ESRD, % eee Response, % Belimumab . 0.0 104 weeks Placebo 19.7 17.0 0.4 0.9 ESRD: end-stage renal disease Definitions in BLISS-LN trial: Complete Renal Response (CRR): ratio of urinary protein to creatinine of <0.5, eGFR no worse than 10% below pre-flare value or 290 ml/min/1.73 m2with no use of rescue therapy. Partial Response: GFR no worse than 10% below baseline value or within normal range and at least 50% decrease in ratio of urinary protein to creatinine with one of the following: ratio of urinary protein to creatinine <1.0 if baseline ratio <3.0, or ratio of urinary protein to creatinine of <3.0 if baseline ratio >3.0; no treatment failure; and not complete renal response. Outcomes of voclosporin treatment were assessed using data from our meta-analysis of the AURA- IV and AURORA trials (see Section 3 "Comparative Clinical Effectiveness") for CR at 24 and 52 weeks and for PR at 24 weeks; for death and PR at 52 weeks, data from the AURORA trial were used (Table 4,3.). Olnstitute for Clinical and Economic Review, 2021 Page 15 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 4.3. Outcomes of Voclosporin from AURORA and AURA-LV Trials li Partial Renal ai Renal 5 1) 51D allah 3 Death¥, % AA Response**, % Response*, % 26.6 0.0 0.6 cee 43.2 52 weeks ESRD: end-stage renal disease Definitions in AURORA trial: Complete Renal Response (CRR): Decrease in UPCR to <0.5mg in two consecutive, first morning void urine specimens, eGFR >60ml/min per 1.73 m2 or no decrease of 220% of baseline eGFR on two consecutive occasions, No use of rescue therapy and presence of sustained low-dose steroids. Partial Response:2 50% decrease in urinary protein: creatinine ratio from baseline in the absence of rescue medication *Meta-analysis of AURA-IV and AURORA trials **Difference between PR/CR rates reported in AURORA trial and CR rate calculated in meta-analysis ***Not reported in AURORA trial, assumed as zero; ¥ AURORA trial As the clinical data are only reported at specific follow-up points, the proportions of patients in interim time cycles in the short-term model were estimated by applying linear interpolation to the data in Tables 4.2 and 4.3. We sought input from clinical experts and judged it highly plausible that both belimumab and voclosporin will be continued for a longer period than the duration of their pivotal trials. Based on expert input we assumed that belimumab and voclosporin will be used in patients in CR and PR states for three years before discontinuation (except for those stopping treatment earlier due to adverse events). For patients remaining in the AD state, we assumed that both drugs will be used for 18 months before treatment discontinuation. Based on the maintenance of response from year one to year two in the BLISS-LN trial, our model assumes that patients stay in the same health states that they are in at the end of the trials (see Tables 4.2 and 4.3) until the end of three years. That is, the probability of being in each model state (CR, PR, AD, ESRD) until the end of the short- term three-year model was considered to be same to as the last observation in the trials' follow-up (two years for belimumab and one year for voclosporin ). Also based on input from clinical experts, we also included treatment discontinuation due to AE in the model. We therefore assumed that 13% of patients taking belimumab and 11.2% taking voclosporin discontinue treatment due to AE in the short-term model. As there are no data from the trials to inform the time point for treatment discontinuation, this treatment discontinuation was assumed to happen at the midpoint of treatment duration (i.e., 18 months for both belimumab and voclosporin). Olnstitute for Clinical and Economic Review, 2021 Page 16 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC The long-term model used partitioned-survival modeling to estimate ESRD-free survival for the different health states (AD, CR, and PR) based on data from Davidson et al. (2018), with the proportion of ESRD events and deaths estimated based on data from Chen et al. (2008). The choice of sources in the long-term model was based on combined criteria of recent data, quality and quality of reporting, and representativeness to the US LN population (the cohort of patients in Davidson et al. included 53.4% Black patients). The structure of the partitioned survival model does not explicitly include the transition to AD state from CR/PR, however, patients with CR/PR are likely to spend some time in AD state before progressing to ESRD. As such, we assumed that patients with CR/PR spend 1.206 years in the AD state (defined as eGFR < 30 ml/min) before progressing to ESRD, based on SLICC data.?* An average life expectancy of 10 years (based on the difference between overall survival and ESRD free survival in the long-term model) was assumed for patients who were in ESRD at the end of the short term model. Details on the transitions from different health states, all model assumptions, data sources, and parametric distributions selected to extrapolate survival are presented in Supplement Section E2. The survival curves used in the base-case analysis for long-term extrapolation are presented in Figure 4.2 below, with further detail also provided in Supplement Section E2. The ESRD-free survival and overall survival are assumed to be the same across the PR and CR states. The face validity of the survival curves was confirmed by the clinical experts: in the CR/PR health states, the mean ESRD-free survival is 19.38 years, and the mean OS is 28.13 years while in the AD health state, the mean ESRD-free survival is 12.98 years, and the mean OS is 23.65 years. Olnstitute for Clinical and Economic Review, 2021 Page 17 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure 4.2. Survival Curves Used in the Long-Term Extrapolation Model 1.0 = - . XN - -CR/PR ESRD free survival 0.9 ; \ AD ESRD free survival 0.8 \ CR/PR Overall survival 0.7 \ AD Overall survival 0.6 t 2 > 0.5 3 wy 0.4 0.3 0.2 0.1 0.0 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 Time (in years) Both belimumab and voclosporin will be added on top of the standard therapy patients receive in the short-term model. Thus, the cost of standard therapy is not explicitly included in the model to avoid duplication as it is already reflected in the costs of health states. The analysis assessed IV belimumab with the dose of 10 mg per kilogram of body weight (based on the distribution of the body weights of the LN population retrieved from the literature)?> and low- dose voclosporin (oral administration) with the recommended dose of 23.7 mg twice a day. Costs of belimumab were estimated assuming all patients receive belimumab as IV administration (as it occurred in the BLISS-LN trial) and accounted for vial wastage. Cost associated with three doses of belimumab was used in the first month, and average number of monthly doses over a three-year period was used to estimate the monthly costs of belimumab beyond the first month. Voclosporin costs were assessed considering the average daily dose of 39.1mg (mean dose weighted to the duration of patients in AURORA trial) and the price per "wallet" (containing 60 capsules 7.9mg each) of $3,950 reported by the manufacturer. The mean rebate/discount of 22.5% was then applied to calculate our estimated net price for voclosporin. This approach produces an estimated net price different from that publicly announced by the drug maker for one reason: the drug maker factored in their own estimate of real-world patient noncompliance with treatment beyond discontinuation related to adverse events captured in the clinical trials. Although there is always some degree of lack of perfect adherence in the real world, we did not adopt the drug maker's price estimate because it would not have been applicable to the clinical benefits measured in the clinical trial and the drug wastage may not directly affect the treatment costs.?° Olnstitute for Clinical and Economic Review, 2021 Page 18 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 4.4. Key Model Inputs I ae (1 |= CPT ME Rec amc eet $9,811* ASP, FSS30-32 Monthly cost of Belimumab $3,560* ASP, FSS30-32 Based on the mean weighted daily dose, price per wallet (data of Aurinia) and assumed discount of 22.5% 0.8 Bexelius et al.?3 0.624 Bexelius et al., Mohara et al.3433 stan' Bartels-Peculis et al.?° Monthly cost of Voclosporin $7,686.10 42,510* > Hanly et al. & Barber et al.7836 Annual cost in AD health state Li et al.?" Medicare (data provided by the Annual cost in ESRD health state $120,920* Lupus Research Alliance) CR: complete response, PR: partial response, AD: active disease, ESRD: end stage renal disease ASP: Average sales price, FSS: Federal Supply Schedule *Based on Federal Supply Schedule as of November 7, 2020 * Costs are inflated to 2019 values Costs in CR, PR, and AD states used in the model were derived from US sources with cost adjustments applied using the U.S. and Canadian data in combination with expert opinion to yield the most appropriate real-world cost estimation. The mean all-cause health care costs per LN patient per year were reported as $45,469 in 2018 by Bartels-Peculis et al.(2020) based on data on 1,039 LN patients (median age, 47 years; 83% female) recorded in a health care claims database.** This claims database covers members in all 50 states in the US and Washington, DC, including approximately 10 million commercial members and 2.4 million Medicare Advantage members. The costs for CR, PR, and AD health states were estimated then using ratios between the different health states. The costs in the ESRD state were calculated as costs of people with LN, eligible for Medicare in 2016 based on ESRD alone or in combination with disability. The costs per health state are presented in the table above and further details are presented in Supplement Section E2. Given that quality of life outcomes were neither reported nor provided by the manufacturers, health state utility values were obtained from published literature, incorporating feedback from Olnstitute for Clinical and Economic Review, 2021 Page 19 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC clinical experts and patients. The model assumed that utility values in the CR state were equal to utility values of the population with SLE who have very low disease activity, based on data froma cohort of Swedish SLE patients.3? We estimated the utility values for patients in the PR, AD, and ESRD states by applying EQ-5D utility decrements compared to the CR state based on a cost-utility analysis from Thailand.*4 In the model, all utilities were capped at the general population utility for that age group (see Supplement Table E6 for details), to ensure they did not exceed the utilities of the general population. For patients who have therapy with low-dose steroids (< 5mg/day) or no steroids (< 2.5mg/day), we applied a positive increment in utilities and a reduction in costs to the proportion of patients in CR, PR, and AD states reported in corresponding steroid-use categories in the AURORA and BLISS-LN trials. More details on this analysis and sources are reported in Supplement Section E2. In the modified societal perspective analysis, indirect costs were also considered, which included costs of unemployment, absenteeism (temporary productivity loss), and caregiving. Further details on these non-medical costs are reported in Supplement Section E2. 4.3. Results Base-Case Results Tables 4.5 and 4.6 present the base-case results from the health care sector perspective for belimumab and voclosporin, respectively. The detailed results are presented in Supplement Tables E11 and E22. Table 4.5. Results for the Base Case for Belimumab Compared to Standard Care uta Erna Belimumab S 93,465 $929,962 11.666 17.861 11.740 Standard Care- $886,343 11.180 17.478 11.180 Belimumab : - $43,620 0.49 0.38 0.56 Incremental Cost- 589,663 $113,847 $77,835 aad eee tees QALY: quality-adjusted life year, evLYG: equal value life years gained Olnstitute for Clinical and Economic Review, 2021 Page 20 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 4.6. Results for the Base Case for Voclosporin Compared to Standard Care ieee TA Voclosporin $215,296 $928,486 12.640 18.408 12.770 Standard Care- $784,416 11.674 17.581 11.674 Voclosporin . - $144,070 0.97 0.83 1.10 Incremental Cost- $149,260 $174,250 $131,528 aod Y=) a=W t=] AL ek) QALY: quality-adjusted life year, evLYG: equal value life years gained Sensitivity Analyses To demonstrate effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors) or reasonable ranges to evaluate changes in cost per additional QALY. Probabilistic sensitivity analysis (PSA) was performed by jointly varying all model parameters, using 1,000 simulation runs. Due to the lack of data, the distributions used for costs and utilities in the PSA are assumed as mean values +10%. Tables 4.7 through 4.10 present the results of the PSAs. More details can be found in Supplement Section E4. Table 4.7. Probabilistic Sensitivity Analyses of Cost per QALY Gained for Belimumab Compared to Standard Care Cost Effective at Cost Effective at Cost Effective at $100,000 per $150,000 per $200,000 per QALY QALY QALY Belimumab 25.1% 51.6% 69.0% SC-Belimumab: Standard care for Belimumab, QALY: quality-adjusted life year Cost Effective at $50,000 per QALY Table 4.8. Probabilistic Sensitivity Analyses of Cost per QALY Gained for Voclosporin Compared to Standard Care Cost Effective at Cost Effective at Cost Effective at Cost Effective at Perey ky $100,000 per $150,000 per $200,000 per ' oy.VA QALY QALY 0.3% 11.3% 48.6% SC-Voclosporin: Standard care for Voclosporin, QALY: quality-adjusted life year Olnstitute for Clinical and Economic Review, 2021 Page 21 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 4.9. Probabilistic Sensitivity Analysis Cost per evLYG for Belimumab Compared to Standard Care Cost Effective at Cost Effective at Cost Effective at Cost Effective at ITOK OOo CH CeeMele yt CHET Kelo yt g YIU KOON sy-1e evLYG evLYG evLYG evLYG FEST 31.8% 62% 78.4% 86.3% SC- eit a Standard care for Belimumab, evLYG: equal value life years gained Table 4.10. Probabilistic Sensitivity Analysis Cost per evLYG for Voclosporin Compared to Standard Care Cost Effective at Cost Effective at Cost Effective at Cost Effective at TORO oy=1g $100,000 per $150,000 per Yio ele OMsy-Tg evLYG evLYG evLYG evLYG UCT a | Voclosporin*® = UT 21.1% 65.4% 89.3% SC-Voclosporin: Standard care for Voclosporin, evLYG: equal value life years gained Scenario Analyses We performed scenario analyses to identify the effect of alternative inputs and assumptions on the cost-effectiveness results. Tables 4.11 and 4.12 presents the results from the scenario analyses. Based on feedback from the patient groups and clinicians, we conducted a scenario analysis for the Black population (the most prevalent ethnic sub-group) using the values of CR in the Black population, as reported in the BLISS-LN and AURORA trials. However, these data on CR rates are highly uncertain due to the small sample sizes. Furthermore, due to lack of data, the rest of the model parameters were assumed to be the same for the Black LN population as overall LN population. Given the uncertainty in CR rates among Black population and the possibility that the PR rates, ESRD, death and the long-term survival is likely to differ between Black LN population and overall LN population, the results of these analyses ($156,093 per QALY gained for belimumab and $129,250 per QALY gained for voclosporin) should be treated with caution. The second scenario analysis included a modified societal perspective, considering the impact of LN on non-medical costs and patient productivity. We also performed additional scenario analyses using pessimistic assumptions for the long-term survival and utility values for CR/PR health states to understand the impact of these parameters on the cost-effectiveness results. These scenario analyses were thought to be useful in case the clinical experts believe that long term prognosis for those achieving response might not be as optimistic as assumed in the model. Scenario analyses were performed using lower survival (of 25.22 years overall survival and 14.49 years ESRD free survival) in CR/PR states, and another scenario analysis Olnstitute for Clinical and Economic Review, 2021 Page 22 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC OL 0} UINjaY siuuydan sndnq 40} uodsoj20, pue qewinuljag - Woday aduapiag jeuly €7 a8ed TZOZ 'MalAaY J1WOUI] pue /eI!UI|D 40 a3NIISUI® asuodsal a}a|dwod yD 'asuodsau jetwied :yq "ead ayl] paysnf{[pe-Ayjenb :A1vo AWO/6ST'S6TS - ATWO/6ZL'TZTS_--ATWO/LZT'ELTS ~-ATWO/106'S8TS AIWO/68€'LEZS A1VO/Z96'TELS Alvo/osz'evts (ETERS BLT ELT Sa By\ beh COLTS B reyes Tie) [=e] 0 uolesn TOO soueis _ " (0) ad eeni aes ae . ea Se Debs oe one ; BAIAdSJag |e}9190 ili PUEJVO RL t-3 aiid Wey NAL ET EAU Lesol-y| : BEY Non BLU Cy) aed ' het ase)-aseg L $}SO9 aAIZEUIO FUP ANT) : n sd BUJU evn ola el NU eels oP el 5 EIEN UL MOY PLATE ols ULOdso/POA 10} S}Nsay sIsSAjeUYY OLLUAIS ISIUIWI9I9Q "ZT FIGeL Jesh ayl| paysn[pe-Aqyjenb :ajyvo 'esuodsa jenied 'yd 'asuodsad 3}9|dWOd :yD AIO /OLt'ZvT$ - ATWO/SHZ'80T$_-ATVO/846'rTTS AIWO/ETT'OLTS AlV0/E0T'99$ Alvo/e99'68s (EERTTTER Chas MOUS) Pe ee EUR en) SETS e I synseu $9}e}s yyeay jo TIS el E IAPC MCR Ey MN Ve CCH RU MCE RCCIILE BSC elers PIONS OE Coo EYEE Lv SuizAjeuy OU APL ys INAS) PLU ey OMeUsIS asej-aseg QGewinullj9g JO} s}]/Nsoy sisAjeuy ONBUDIS JITSIUIW9)}9q "TT'p s/qel "Gq UOl}IES JUSWa|ddns ul payoda ae soleuads ay} jo sjle}ap ay] "say}e}s yyeay Jayjzo pue GYySy UsaMjeq SOl}eJ SOD UO pase UO!ZE[NI/e9 d}e}S YEaY JO }SOD aAIJEUJaYe Pasapisuod sasAjeue O|JeUaIS se] YL (Z2T'v a1qeL) Suljaqe| Snip uo paseq ajejs aseasip anijoe ul Sululewad Sjualjed JO} SyJUOW 9 }e ULJOdSO)DOA Jo JUAW}e<aJ} JO UO!ENUI]UODSIP pasap!suod sisAjeue OLeUAaIS "Gq UO!}I9S JUBWA/AdNs ul payoda aie soueuads ay} Jo sjlelap AYL *S}UGW}e91} YO JO} SOl}e4 SSBUBAI}IAJJa-]S09 |e]USWAIDU! PaseaiduU! SIedA € 0} B]e1S GY JO UO!JeINP ay} Bulseasdu| "Yd/HD Woy CYS 0} passaigoud oym japow Wa}-3uo] ay} Ul SyUaI}ed BSOU} JO} a}e}s GY JO UO!I}eINp JUaIAJJIP pasn sasAjeue Olieuads Jo dnoud yxau ay "ca NS Ul paplAoid ase sojseuads asay} UO sjleyap JaYyWNY *saze}s Yd/YD Ul (AJaAIIadsa '79°9 PUe ZZ'C JO) SAITIIIN JAMO] BuIsn UO}IeS JUeWA| Threshold Analysis Table 4.13. Threshold Analysis Results per QALY s Unit Price to | Unit Price to | Unit Price to | Unit Price to Net Price WAC per Xe (-\V-) Va al C\V-) Xela) Achieve Unit (mg) oes $50,000 per | $100,000 SUK EPR 8 QALY per QALY per QALY per QALY sas2 $426 S365 $8.33 $6.46 $3.58 QALY: quality-adjusted life year, WAC: wholesale acquisition cost Table 4.14. Threshold Analysis Results per evLYG Unit Price to | Unit Price to | Unit Price to | Unit Price to Net Price Achieve Achieve Achieve Achieve WAC per Uhiyia per Unit $50,000 per $100,000 $150,000 $200,000 evLYG per evLYG per evLYG per evLYG $4.26 $3.85 $5.27 $6.69 $8.11 ae $8.33 $6.46 $3.78 $5.42 $7.07 $8.71 evLYG: equal value life years gained, WAC: wholesale acquisition cost ae $4.52 Model Validation Several approaches were undertaken to validate the model, please see Supplement Section E7. First, preliminary methods and results were presented to manufacturers, patient groups, and clinical experts, with data inputs changed as needed and scenario analyses defined. Second, model input parameters were varied to evaluate the face validity of changes in results. As part of ICER's initiative for modeling transparency, we shared the model with interested manufacturers for external verification shortly after publishing the draft report for this review. The outputs from the model were validated against the trial and study data of the interventions as well as relevant observational datasets. Finally, the results were compared to other cost-effectiveness models in this therapy area. Uncertainty and Controversies Our analyses have important limitations. Most of these relate to the lack of availability of robust data and the assumptions required to overcome this. There is no long-term follow-up for either treatment, resulting in considerable uncertainty related to the prognosis of patients. We defined broad health states and assumed relationships between health states and ESRD-free and overall survival. Uncertainty in long-term outcomes was partially accounted for in sensitivity and scenario analyses that evaluated different assumptions. As there are no long-term data on the extrapolation of responses, the base-case analyses assume that these are sustained until death or ESRD. Olnstitute for Clinical and Economic Review, 2021 Page 24 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Treatment of LN may result to other clinical benefits for patients, not captured by the model (e.g., related to SLE management or other symptoms of chronic diseases, such as fatigue). The base-case analysis also did not consider analysis by ethnicity. For both belimumab and voclosporin, only complete response rates in ethnic minorities (i.e., Black population) at the end of the trials follow-up were reported. While these data were used in scenario analysis to assess cost effectiveness of therapies for the Black population, the results of this scenario should be interpreted with caution and should not be used in policy or reimbursement decisions, considering that trials were not powered for sub-group analyses (i.e., small samples, statistically non-significant results); no trial data were available on partial responses in Black population; and no data on long- term progression by ethnic subgroups were available. Studies on general populations and ethnic subgroups show that socio-economic status is a significant determinant of the prognosis and quality of life.22?9 Since race/ethnicity and income are strongly correlated (with Black and Hispanic subgroups being the poorest),"° using ethnicity-specific values would result in lower utility and life years gained for Black (comparing to White) patients which may result in worse cost-effectiveness findings in Black versus White populations, independent of the treatment effectiveness among these groups. Thus, only general (not ethnicity- specific) values were used in the base case so as not to disadvantage ethnic groups. We could not estimate disease progression parameters (e.g., transition probabilities) without access to individual patient data from the studies. As such, the data for the different interventions during the study period were used directly in the model to estimate short-term costs and outcomes. There were several structural assumptions in the model. As the model is based on a partitioned survival modeling approach, patients in PR/CR can only move into ESRD or death. Due to lack of data, movement into the health state AD from PR/CR is not modeled explicitly in the long-term model. However, additional costs and QALY decrements associated with time in AD for those who move from PR/CR into ESRD were included in the model. The long-term disease progression in the model was based on assessment of the cohort of LN patients using BLISS-LN criteria, which have the closest definition of the outcomes to those used in the trials.1* This modeling choice resulted in the same survival for CR and PR groups, likely leading to overestimation of cost effectiveness of belimumab and voclosporin treatments. Based on consultations with clinical experts, the model assumed continuation of treatments for up to three years for patients in CR and PR states and discontinuation of treatment within on average 18 months for patients remaining in AD state or for patients with adverse events. While it is likely that discontinuation rate in clinical practice is less than in the trials (because of the blinding), it is possible that more patients in AD state will discontinue the treatment early (because of the lack of Olnstitute for Clinical and Economic Review, 2021 Page 25 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC efficacy), and more patients in CR and PR states would continue treatment longer than it is currently considered in the model. Robust utility data were lacking for these populations. As such, we used utility data derived from several sources that were believed to be coherent. The base-case analyses were complemented with sensitivity and scenario analyses to explore the uncertainty in these values. 4.4 Summary and Comment For belimumab, our base-case results found that, at its current price, it meets traditional cost- effectiveness thresholds of $100,000/QALY. For voclosporin, at the net price, our base-case results found that it too meets traditional cost-effectiveness thresholds of $150,000/QALY. There is a higher uncertainty in cost effectiveness of voclosporin than in cost effectiveness of belimumab, though the differences in the trial's designs do not allow to have the direct comparison of both treatments. We also conducted scenario analyses to explore questions about the cost effectiveness in a Black population, using a modified societal perspective and pessimistic assumptions about long-term prognosis. Belimumab remains cost effective in scenario analyses with lower utilities and longer duration of AD state, while incremental cost-effectiveness ratio is above the threshold for voclosporin if longer duration of AD, lower long-term survival, or lower utilities in CR and PR states are assumed. Although there remains substantial uncertainty about whether the long-term benefits prove true, we believe that our base-case assessment of long-term benefits is the best starting point for a judgment of the value of treatments at this time. Olnstitute for Clinical and Economic Review, 2021 Page 26 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 5. Contextual Considerations and Potential Other Benefits or Disadvantages Our reviews seek to provide information on potential other benefits that treatments may offer to the individual patient, to caregivers, the delivery system, other patients, or the public. In particular, our goal is to highlight factors that would not have been considered or were incompletely captured as part of the evidence on comparative clinical effectiveness and cost effectiveness. These elements are listed in the tables below. Table 5.1. Contextual Considerations Contextual Considerations Relevant Information Acuity of need for treatment of individual The acuity of need due to the severity of the patients based on the severity of the condition condition in the near-term is low relative to more being treated rapidly progressive fatal conditions. Magnitude of the lifetime impact on individual The burden of LN over the lifetime is high given patients of the condition being treated its progression to ESRD. Olnstitute for Clinical and Economic Review, 2021 Page 27 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table 5.2. Potential Other Benefits or Disadvantages Potential Other Benefits or Disadvantages CWT aleeleenicoya Patients' ability to achieve major life goals related to education, work, or family life LN typically affects patients in their 20s and 30s and is the major cause of premature mortality in patients with SLE. In addition, patients with ESRD on dialysis have challenges with working. Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life ESRD is burdensome to caregivers as well as patients. Avoiding ESRD is likely to benefit caregivers. Patients' ability to manage and sustain treatment given the complexity of regimen Belimumab was given IV infusion in the pivotal clinical trial, but a SC formulation is available that is typically administered by the patient at home. The SC formulation may supplant the IV infusion in the real world, however it is more expensive that the IV formulation, it has not been studied in patients with LN, and was not modeled in this evidence report. Voclosporin is taken orally, twice a day. Health inequities LN disproportionately impacts non-White patients. Subgroup analyses for both belimumab and voclosporin suggest the potential for greater benefits in Black patients and have the potential to reduce historic disparities. Other (as relevant): Preservation of kidney function with treatments that are less teratogenic may improve the chances for both women and men to bear children Additional benefits beyond renal benefits Patient advocates and clinical experts noted the importance of this potential benefit given the preponderance of patients who are of child- bearing age and the clinical advice given to women with ESRD to avoid pregnancy. Reducing or eliminating the use of current treatments that can be teratogenic and cause infertility and miscarriages will also increase the ability of women and men with lupus to be parents. Belimumab carries an FDA indication for the treatment of SLE apart from its impact on lupus nephritis. These potential extra-renal benefits for patients with lupus nephritis have not been reported in peer reviewed publications, but may add to the cost effectiveness of belimumab. Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page 28 Return to TOC 6. Health Benefit Price Benchmarks Health Benefit Price Benchmarks (HBPBs) information for the annual cost of treatment (net of rebates) 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 evLYG gained. Using the broadest set of figures derived from these thresholds, we arrive at a HBPB for belimumab of $45,000 to $61,000; and for voclosporin the HBPB is $72,000 to $101,000. Table 6.1. Annual Cost-Effectiveness Threshold Prices for Belimumab and Voclosporin : : DIE XCoLe meee PVG Annual WAC Annual Price at Annual Price at eee ee $100,000 Threshold | $150,000 Threshold Prices Belimumab $41,614 $41,614 Voclosporin $119,011 $71,864 $92,539 22% to 40% $119,011 $77,439 $100,901 15% to 35% WAC: wholesale acquisition cost; evLYG: equal value life year gained; QALY: quality-adjusted life year No discount needed No discount needed $45,019 $48,398 $56,137 $61,205 Olnstitute for Clinical and Economic Review, 2021 Page 29 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 7. Potential Budget Impact 7.1. Overview of Key Assumptions We used results from the cost-effectiveness model to estimate the potential total budgetary impact of belimumab and voclosporin for the population of adults with Class III, IV, or V LN. Potential budget impact is defined as the total differential cost of using each new therapy rather than the relevant existing therapy for the treated population, calculated as differential health care costs (including drug costs) minus any offsets in these costs from averted health care events. All costs were undiscounted and estimated over a five-year time horizon. The analysis included the estimated number of individuals in the US who would be eligible for treatment. For this analysis, we assumed that the eligible population would include incident (new) cases of LN, who would be starting induction treatment and therefore eligible for the addition of either new medication, as well as those with prevalent disease who have relapsed and need additional therapy. Based on clinical expert opinion, we assumed that for every incident case, there would be approximately one relapse requiring new therapy, and used an estimate of eligible population that is twice the incident number. For LN, we used an estimated incidence of 6.9/100,000 persons from 2000-2004 US Medicaid data.1* Applying this proportion to the projected average US adult (age > 18 years) population from 2021-2025,*! we arrive at an estimate of approximately 18,300 individuals with LN. Of those with LN, an estimated 75% of patients have Class Ill, IV, or V LN.42 Applying this proportion to the estimated incident population with LN results in an eligible population of approximately 13,700 individuals. Assuming one prevalent relapse case per incident case doubles this estimate to approximately 27,400 eligible individuals. As these two treatments, if approved, would be launched within a short period of each other, we assumed that this eligible population would be split in equal proportions between the two interventions, or approximately 13,700 individuals per treatment. For the purposes of this analysis, we assume that all of these patients would be eligible to initiate treatment in the year of incidence or relapse, resulting in 13,700 eligible patients per year for each of the five years. For this analysis, we assumed that belimumab and voclosporin would be added on to standard of care (as defined above). 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. For reports begun in 2019-2020, the five-year annualized potential budget impact threshold that should trigger policy actions to manage access and affordability is calculated to be approximately $819 million per year for new drugs. ICER's methods for estimating potential budget impact are described in detail elsewhere.*? Olnstitute for Clinical and Economic Review, 2021 Page 30 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 7.2. Results Figure 7.1 illustrates the cumulative per-patient budget impact calculations for belimumab compared to standard of care, based on the annual price of $42,720 per year of treatment. The average potential budgetary impact for belimumab was approximately $47,200 per patient in year one, with cumulative net cost increasing in years two and three as treatment continues, reaching approximately $87,500, before decreasing somewhat in years four and five due to net savings as patients discontinue treatment and have lower total costs than in usual care. Additional net costs per year are presented along with cumulative net costs in Supplement Table G1. Figure 7.1. Cumulative Net Cost Per Patient Treated with Belimumab $100,000 $90,000 $80,000 $70,000 L $60,000 | $50,000 L $40,000 L $30,000 L $20,000 L $10,000 L so | 1 2 3 4 5 Olnstitute for Clinical and Economic Review, 2021 Page 31 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure 7.2 illustrates the cumulative per-patient budget impact calculations for voclosporin compared to standard of care, based on the net price of $92,233 per year of treatment. The average potential budgetary impact for voclosporin was approximately $87,200 per patient in year one, with cumulative net cost increasing in years two and three as treatment continues. As was seen with belimumab, net costs decreased somewhat in years four and five due to net savings as patients discontinue treatment and have lower total costs than in usual care. Additional net costs per year are presented along with cumulative net costs in Supplement Table Gi, Figure 7.2. Cumulative Net Cost Per Patient Treated with Voclosporin at Net Price $220,000 $200,000 $180,000 § $160,000 § $140,000 § $120,000 § $100,000 § $80,000 $60,000 $40,000 $20,000 | so | 1 2 3 4 5 Olnstitute for Clinical and Economic Review, 2021 Page 32 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure 7.3 illustrates the potential budget impact of belimumab treatment of the eligible population, based on the annual price of $42,720 per year, and the prices to reach $150,000, $100,000, and $50,000 per QALY (approximately $56,600, $45,400, and $34,200 per year of treatment, respectively) compared to the standard of care comparator. Approximately 80% of the approximately 13,700 eligible patients could be treated in a given year without crossing the ICER potential budget impact threshold of $819 million per year over five years. Approximately 59% of patients could be treated in a given year without crossing the potential budget impact threshold at the $150,000 per QALY threshold price, increasing to approximately 75% of the population at the $100,000 per QALY threshold price. All eligible patients could be treated at the $50,000 per QALY threshold price, reaching 97% of the potential budget impact threshold. Figure 7.3. Potential Budgetary Impact of Belimumab Treatment in Adults with Class Ill, IV, or V LN $80,000 $70,000 $60,000 ' $150,000/QALY eT $50,000 SA, « 4 $100,000/QALY~ ~@ ~ Base Case 40,000 seek - me, Annual Price $30,000 $20,000 $10,000 $O 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Patients Treated Without Crossing BI Threshold BI: budget impact, LN: lupus nephritis, QALY: quality adjusted life year ©Olnstitute for Clinical and Economic Review, 2021 Page 33 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure 7.4 illustrates the potential budget impact of voclosporin treatment of the eligible population, based on the net price ($92,233 per year of treatment), and the prices to reach $150,000, $100,000, and $50,000 per QALY (approximately $92,600, $71,900, and $51,200 per year of treatment, respectively) compared to the standard of care comparator. Approximately 35% of the approximately 13,700 eligible patients could be treated in a given year without crossing the ICER potential budget impact threshold of $819 million per year over five years at the net price. Similarly, nearly 35% of patients could be treated in a given year without crossing the potential budget impact threshold at the $150,000 per QALY threshold price, increasing to approximately 68% of the population at the $50,000 per QALY threshold price. Figure 7.4. Potential Budgetary Impact of Voclosporin Treatment in Adults with Class Ill, IV, or V LN $100,000 $150,000/QALY o Net Price ' $90,000 x $80,000 \ x x $70,000 '® $100,000/QALY $60,000 SS. ~ se. $50,000/QALY $50,000 ° Annual Price $40,000 $30,000 $20,000 $10,000 so 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Patients Treated Without Crossing BI Threshold BI: budget impact, LN: lupus nephritis, QALY: quality adjusted life year ©Olnstitute for Clinical and Economic Review, 2021 Page 34 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 7.3 Access and Affordability Alert Approximately 80% (belimumab) and 35% (voclosporin) of eligible patients with LN could be treated in a given year before crossing the ICER potential budget impact threshold of $819 million per year. Testimony from clinical experts at the public meeting suggested that the ideal clinical uptake of these drugs would include the chance for nearly every patient to be on one drug or the other. Given that efforts to reach this clinical target would create a short-term potential budget impact that exceeds the threshold, ICER is issuing an access and affordability alert. The purpose of an ICER access and affordability alert is to signal to stakeholders and policy makers that the amount of added health care costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services, creating pressure on payers to sharply restrict access, or causing rapid growth in health care insurance costs that would threaten sustainable access to high-value care for all patients. ©Olnstitute for Clinical and Economic Review, 2021 Page 35 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 8. Summary of the Votes and Considerations for Policy 8.1 About the New England CEPAC Process During New England CEPAC public meetings, the New England CEPAC Panel deliberates and votes on key questions related to the systematic review of the clinical evidence, an economic analysis of the applications of treatments under examination, and the supplementary information presented. Panel members are not pre-selected based on the topic being addressed and are intentionally selected to represent a range of expertise and diverse perspectives. Acknowledging that any judgment of evidence is strengthened by real-life clinical and patient perspectives, subject matter experts are recruited for each meeting topic and provide input to New England CEPAC Panel members before the meeting to help clarify their understanding of the different interventions being analyzed in the evidence review. The same clinical experts serve as a resource to the New England CEPAC Panel during their deliberation, and help to shape recommendations on ways the evidence can apply to policy and practice. After the New England CEPAC Panel votes, a policy roundtable discussion is held with the New England CEPAC Panel, clinical experts, patient advocates, payers, and when feasible, manufacturers. The goal of this discussion is to bring stakeholders together to apply the evidence to guide patient education, clinical practice, and coverage and public policies. Participants on policy roundtables are selected for their expertise on the specific meeting topic, are different for each meeting, and do not vote on any questions. At the March 26" meeting, the New England CEPAC Panel discussed issues regarding the application of the available evidence to help patients, clinicians, and payers address important questions related to the use of belimumab and voclosporin for lupus nephritis. Following the evidence presentation and public comments (public comments from the meeting can be accessed here), the New England CEPAC Panel voted on key questions concerning the comparative clinical effectiveness, comparative value, and potential other benefits and contextual considerations related to belimumab and voclosporin. These questions are developed by the ICER research team for each assessment to ensure that the questions are framed to address the issues that are most important in applying the evidence to support clinical practice, medical policy decisions, and patient decision-making. The voting results are presented below, along with specific considerations mentioned by New England CEPAC Panel members during the voting process. Olnstitute for Clinical and Economic Review, 2021 Page 36 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC In its deliberations and votes related to value, the New England CEPAC Panel considered the individual patient benefits, and incremental costs to achieve such benefits, from a given intervention over the long term. There are four elements to consider when deliberating on long-term value for money (see Figure 8.1 below): 1. Comparative clinical effectiveness is a judgment of the overall difference in clinical outcomes between two interventions (or between an intervention and placebo), tempered by the level of certainty possible given the strengths and weaknesses of the body of evidence. The New England CEPAC uses the ICER Evidence Rating Matrix as its conceptual framework for considering comparative clinical effectiveness. 2. Estimated incremental cost-effectiveness is the average incremental cost per patient of one intervention compared to another to achieve a desired "health gain," such as an additional stroke prevented, case of cancer diagnosed, or gain of a year of life. Alternative interventions are compared in terms of cost per unit of effectiveness, and the resulting comparison is presented as a cost-effectiveness ratio. Relative certainty in the cost and outcome estimates continues to be a consideration. As a measure of cost-effectiveness, the New England CEPAC voting panel follows common academic and health technology assessment standards by using cost per quality-adjusted life year (QALY), with formal voting on "long-term value for money" when the base case incremental cost-effectiveness ratio is between $50,000 per QALY and $175,000 per QALY. 3. Potential other benefits refer to any significant benefits or disadvantages offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that would not have been considered as part of the evidence on comparative clinical effectiveness. Examples of potential other benefits include better access to treatment centers, mechanisms of treatment delivery that require fewer visits to the clinician's office, treatments that reduce disparities across various patient groups, and new potential mechanisms of action for treating clinical conditions that have demonstrated low rates of response to currently available therapies. Other disadvantages could include increased burden of treatment on patients or their caregivers. For each intervention evaluated, it will be open to discussion whether potential other benefits or disadvantages such as these are important enough to factor into the overall judgment of long-term value for money. There is no quantitative measure for potential other benefits or disadvantages. 4. Contextual considerations include ethical, legal, or other issues (but not cost) that influence the relative priority of illnesses and interventions. Examples of contextual considerations include whether there are currently any existing treatments for the condition, whether the Olnstitute for Clinical and Economic Review, 2021 Page 37 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC condition severely affects quality of life or not, and whether there is significant uncertainty about the magnitude of benefit or risk of an intervention over the long term. There is no quantitative measure for contextual considerations. Figure 8.1. Conceptual Structure of Long-Term Value for Money Long-Term Value for Money 8.2 Voting Results Clinical Evidence 1. Given the currently available evidence, is the evidence adequate to demonstrate that the net health benefit of belimumab (Benlysta) plus standard induction therapy is superior to that provided by standard induction therapy alone? 12 votes 0 votes Comments: While there still remains uncertainty about the long-term outcomes of the treatment, the panel judged that the evidence was adequate to demonstrate that there was a net health benefit associated with belimumab plus standard induction therapy, as opposed to standard induction therapy alone. ©Olnstitute for Clinical and Economic Review, 2021 Page 38 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 2. Given the currently available evidence, is the evidence adequate to demonstrate that the net health benefit of voclosporin (Lupkynis™) plus standard induction therapy is superior to that provided by standard induction therapy alone? 12 votes 0 votes Comments: Similar to belimumab, there was uncertainty regarding the long-term outcomes of voclosporin, but the evidence ultimately swayed the panel to vote that there was a net health benefit associated with voclosporin plus standard induction therapy compared to standard induction therapy alone. Potential Other Benefits and Contextual Considerations When making judgements of overall long-term value for money, what is the relative priority that should be given to any effective treatment for lupus nephritis, on the basis of the following contextual considerations? 3. Contextual Consideration: Short-term risk of death for patients without treatment Very Low Priority Low Priority Average Priority lf amaa eye h ag Ta M altima elas] 4 votes 6 votes 2 votes 0 votes 0 votes Comments: Lupus nephritis is a chronic condition that does not indicate a short-term risk of mortality at time of diagnosis, leading the majority of the panel to vote very low or low priority on this contextual consideration. 4. Contextual Consideration: Magnitude of the lifetime impact on individual patients of the condition being treated Very Low Priority Low Priority Average Priority High Priority Tava am aCe a is 0 votes 0 votes 0 votes 4 votes 8 votes Comments: The patient advocates that participated in the meeting provided testimony regarding the significant lifetime burden of illness associated with lupus nephritis. The input from these patients persuaded the panel to vote that this contextual consideration carried high/very high priority. ©Olnstitute for Clinical and Economic Review, 2021 Page 39 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC What are the relative effects of belimumab versus standard induction therapy for lupus nephritis on the following outcomes that inform judgement of the overall long-term value for money of belimumab? 5. Belimumab: Patients' ability to achieve major life goals related to education, work, or family life Major Negative Wake Cet=e- eV) : Minor Positive Major Positive No Difference ac-teg Effect Effect Effect 0 votes 0 votes 2 votes 4 votes 6 votes Comments: The majority of the panel voted that belimumab would have a positive effect on a patient's ability to achieve major life goals. For those who voted no difference, this may be due to the fact that these benefits were already captured in the cost-effectiveness analysis. 6. Belimumab: Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Major Negative Minor Negative WT Tatoy mm xexy ah V(-) Major Positive Effect Sia ia is Effect alos 0 votes 0 votes 2 votes 7 votes 3 votes Comments: Patient advocates emphasized the importance of caregiver support during their treatment, leading the majority of the panel to vote that this consideration carries a minor positive effect. 7. Belimumab: Health inequities Major Negative Minor Negative Minor Positive Major Positive No Difference Effect ica Effect Sh aietes 0 votes 0 votes 2 votes 6 votes 4 votes Comments: Discussion around this voting question focused on society's goal to reduce health inequities. The CEPAC found belimumab to have a minor positive effect on reaching this goal, in particular for the Black, Hispanic, and Asian American communities, as lupus nephritis disproportionately affects these patients. Olnstitute for Clinical and Economic Review, 2021 Page 40 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 8. Belimumab: Preservation of kidney function improves the chances for patients to have children Major Negative Minor Negative Minor Positive Major Positive No Difference Effect Sh aK=tog iia ha =tou 0 votes 0 votes 2 votes 5 votes 5 votes Comments: The majority of the CEPAC found belimumab to have a positive effect on this contextual consideration, as the toxicity of standard induction therapy can have detrimental effects on a woman's ability to become pregnant and carry a baby safely to term. It was also noted that this consideration was particularly important due to the significant population of young women that are affected by lupus nephritis. What are the relative effects of voclosporin versus standard induction therapy for lupus nephritis on the following outcomes that inform judgement of the overall long-term value for money of voclosporin? 9. Voclosporin: Patients' ability to achieve major life goals related to education, work, or family life Major Negative Minor Negative Minor Positive Major Positive No Difference Effect Effect iia a i=fal 0 votes 0 votes 2 votes 5 votes 5 votes Comments: Similar to the discussion surrounding belimumab, voclosporin was deemed by the panel to have a positive effect on patients' major life goals compared to standard induction therapy. 10. Voclosporin: Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Major Negative Minor Negative Minor Positive Major Positive No Difference actos io iia Siete 0 votes 0 votes 2 votes 7 votes 3 votes Comments: The panel heard from patients that voclosporin may have more positive impact on caregivers, as it is an oral treatment, as opposed to infusion. Olnstitute for Clinical and Economic Review, 2021 Page 41 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 11. Voclosporin: Health inequities Major Negative Minor Negative Minor Positive Major Positive No Difference Effect Effect iia Sh acelos 0 votes 0 votes 1 vote 7 votes 4 votes 12. Voclosporin: Preservation of kidney function improves the chances for patients to have children Major Negative Minor Negative Minor Positive Major Positive No Difference Effect ae iis Sh aetas O votes 0 votes 2 votes 5 votes 5 votes Long-Term Value for Money 13. Given the available evidence on comparative effectiveness and incremental cost- effectiveness, and considering other benefits, disadvantages, and contextual considerations, what is the long-term value for money of treatment at current pricing with belimumab versus standard induction therapy? Low Long-Term Value for Intermediate Long-Term Value High Long-Term Value for Money at Assumed Price bie) mV elaL=\ are ACLU Lille dg o(-) Money at Assumed Price 1 vote 2 votes 9 votes Comments: The incremental cost-effectiveness ratio for belimumab using the base case was $89,663 per QALY. While the base case presented an optimistic scenario, the economic model presented a high probability for the drug to be cost effective. The participating patient and clinical experts also discussed the cost savings from reduction in long-term use of steroids. Considering all these factors, a majority of the CEPAC to vote that belimumab presents with a high long-term value for money at assumed price. Olnstitute for Clinical and Economic Review, 2021 Page 42 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 14. Given the available evidence on comparative effectiveness and incremental cost- effectiveness, and considering other benefits, disadvantages, and contextual considerations, what is the long-term value for money of treatment at current pricing with voclosporin versus standard induction therapy? Low Long-Term Value for Intermediate Long-Term Value High Long-Term Value for Coa areL ACTA T alte Md (oC) for Money at Assumed Price Money at Assumed Price 1 vote 7 votes 4 votes Comments: The incremental cost-effectiveness ratio for voclosporin using the base case and the health sector perspective was $149,000 per QALY, falling modestly when calculated from the societal perspective. The same potential other benefits and contextual considerations that applied to belimumab were considered important for voclosporin, and the majority of the CEPAC panel found voclosporin to have intermediate long-term value for money at the estimated net price. Olnstitute for Clinical and Economic Review, 2021 Page 43 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 8.3 Roundtable Discussion and Key Policy Implications Following its deliberation on the evidence, the New England CEPAC Panel engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on belimumab and voclosporin for lupus nephritis to policy and practice. The policy roundtable members included two patients, two clinical experts, two payers, two representatives from pharmaceutical manufacturers, and one representative from a patient advocacy organization. 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. The names of the Policy Roundtable participants are shown below, and conflict of interest disclosures for all meeting participants can be found in Appendix |. Table 8.1 Policy Roundtable Members Names aH iC-ee Tae -VaileLaeda) President & CEO, Lupus and Allied Diseases Association, Inc. Linda Goler Blount, MPH President & CEO, Black Women's Health Imperative Christele Felix, BS Chief Operating Officer, LupusChat Investigator and Professor of Medicine, The Feinstein Institutes for Medical Research, Northwell Health Kathleen Arntsen, BA Meggan Mackay, MD, MS Vice President, Pharmacy Clinical and Specialty Jay McKnight, PharmD, BCPS . . Strategies, Humana Pharmacy Solutions Senior Vice President, Medical and Clinical Affairs, Simrat Randhawa, MD, MBA . . Aurinia Pharmaceuticals, Inc. Professor of Medicine and Pathology, Ohio State University Wexner Medical Center Bernard Rubin, DO, MPH Medical Director, GlaxoSmithKline Emily Tsiao, PharmD Clinical Pharmacist, Premera Blue Cross Brad Rovin, MD The roundtable discussion was facilitated by Dr. Steven Pearson, MD, MSc, President of ICER. The main themes and recommendations from the discussion are organized by audience and summarized below. Olnstitute for Clinical and Economic Review, 2021 Page 44 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC All Stakeholders All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with lupus nephritis are introduced in a way that will help reduce health inequities. People from diverse racial and ethnic backgrounds are at a higher risk of developing lupus and lupus nephritis. Unfortunately, patients from these communities are also at a higher risk of not receiving adequate education about their condition, face a longer time between diagnosis to initiation of any therapy, and are often late to receive guidance regarding new treatment options. All stakeholders should accept and act upon their responsibility to address these disparities. e Manufacturers should engage with a variety of people from diverse communities to help inform the design and implementation of clinical trials, ensure that patients enrolled in pivotal trials are fully representative of people of color and those from less advantaged backgrounds, and should commit to designing trials that capture the comprehensive set of patient outcomes that matter most to patients. It is important that manufacturers not engage the same limited number of individuals to provide input and represent the trials from early design stages through post-marketing roles as ambassadors. e Payers should engage with people from diverse LN patient groups and with clinical experts in order to infuse coverage policies with sensitivity to the way that different treatments may offer distinct advantages or disadvantages for people based on their social background and living situation. In addition, out-of-pocket financial burden should be scaled to ensure that patients can afford the many drugs that they are frequently required to take for SLE and LN. Health plans should also consider establishing an internal quality assessment measure to seek to maximize the percent of eligible patients with LN who are on belimumab or voclosporin and demonstrating adherence to their medication. e Patient advocacy groups for people with LN should seek to represent diverse perspectives, requiring outreach to patients who are often not engaged by academic health systems, manufacturers, or other policymakers. Patient groups should collaborate with organizations and people in diverse communities to help build the trust needed to empower all patients and caregivers. e Clinicians should follow the principle of shared decision-making to ensure that the values of patients with diverse needs and perspectives on risks and benefits of different treatments are at the heart of all treatment decisions. ©Olnstitute for Clinical and Economic Review, 2021 Page 45 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Payers Both belimumab and voclosporin are judged to be priced in reasonable alignment with estimates of their benefits for patients, and this consideration should guide payers to design coverage criteria that do not narrow coverage from the FDA label, although coverage criteria may define terms left indeterminate in the FDA label to assure appropriate use. Given the significant uncertainty that remains about the longer-term safety and effectiveness of belimumab and voclosporin for lupus nephritis, it is reasonable for payers to use prior authorization as a component of coverage. Prior authorization criteria for both drugs should be based on clinical evidence and input from clinical experts and patient groups. The process for authorization should also be clear, accessible, efficient, and timely for providers. Perspectives on specific elements of cost sharing and coverage criteria within insurance coverage policy are discussed below. Relevant Fair Access Design Criteria set out in ICER's previous work are included. Cost Sharing e Patient cost sharing should be based on the net price to the plan sponsor, not the unnegotiated list price. e = If all drugs in a drug class are priced so that they represent a fair value, it remains reasonable for payers to use preferential formulary placement with tiered cost sharing to help achieve lower overall costs. 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. e Payers should document at least once annually that clinical eligibility criteria are based on high quality, up-to-date evidence, with input from clinicians with experience in the same or similar clinical specialty. e 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: ©Olnstitute for Clinical and Economic Review, 2021 Page 46 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Considered limitations of evidence due to systemic under-representation of minority populations; and 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 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. If the initial request for coverage is denied, access to a peer-to-peer call should be rapid. Management of lupus nephritis is urgent. In many clinicians' experience, access to peer-to- peer calls is onerous and prolonged. Peer to peer calls facilitate the communication of individual patients' unique clinical characteristics and need for therapy. The physician peer should be knowledgeable in the management of lupus nephritis. If the peer-to-peer call results in the patient receiving the clinician's recommended drug, there should not be a requirement for the renewal review to occur in a short timeframe such as six months, annually is more reasonable. Drug-Specific Considerations: Belimumab FDA Label: Adult patients with active LN who are receiving standard therapy. Coverage Criteria Diagnosis: Clinical experts advised that renal biopsy is routine for diagnosis but that it would not be reasonable to require a repeat biopsy if one had been previously done within the previous six-month to two-year period. In particular, repeat biopsies are not necessary in the setting of an acute flare of LN in a patient with prior biopsy-proven disease. Clinical experts noted that in some cases the diagnosis seems clear based on worsening proteinuria and/or extra-renal disease, and that some patients may have co-morbidities making biopsy more dangerous, therefore payers may consider having no biopsy requirement or a rapid pathway for medical exceptions. Patient Eligibility Criteria: Patients should be receiving standard therapy, which consists of concomitant treatment with corticosteroids and MMF or cyclophosphamide. Successful treatment may allow patients to minimize or even eliminate steroid use. Exclusion Criteria: Patients who had failed both MMF and cyclophosphamide induction, and patients with eGFR < 30 were excluded from the BLISS-LN pivotal trial. However, clinical experts did not believe that eGFR < 30 should be used as a rigid exclusion given that this test Olnstitute for Clinical and Economic Review, 2021 Page 47 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC result should be viewed in the context of renal biopsy results. Payers may receive requests for dual therapy with belimumab and voclosporin. Although there are pathophysiological arguments for dual therapy, clinical experts agreed that studies are needed to evaluate the outcomes of dual therapy before routine consideration within clinical practice. e Duration of Therapy and Renewal of Coverage: Because belimumab appears to have no risk of nephrotoxicity, and because it may be useful in addressing other symptoms of SLE, payers may opt to require no demonstration of benefit or time limit on initial coverage. Physician attestation of a response to therapy of at least a 50% reduction in proteinuria after 6 to 12 months of therapy is a reasonable consideration. e Provider Criteria: The therapy should be prescribed by a rheumatologist or nephrologist with expertise in LN or, at minimum, access to consultation with an expert. Virtual consultation with a SLE expert at a Lupus Center of Excellence should be supported. Step Therapy There is no other treatment that could be considered a first-step treatment prior to eligibility. Drug-Specific Considerations: Voclosporin FDA Label: Adult patients with LN in combination with a background immunosuppressive therapy regimen...If the patient has not experienced therapeutic benefit by 24 weeks, consider discontinuation...Consider risks and benefits of treatment beyond one year. Coverage Criteria e Diagnosis: Clinical experts advised that renal biopsy is routine for diagnosis but that it would not be reasonable to require a repeat biopsy if one had been previously done within the previous six-month to two-year period. In particular, repeat biopsies are not necessary in the setting of an acute flare of LN in a patient with prior biopsy-proven disease. Clinical experts noted that in some cases the diagnosis seems clear based on worsening proteinuria and/or extra-renal disease, and that some patients may have co-morbidities making biopsy more dangerous, therefore payers may consider having no biopsy requirement or a rapid pathway for medical exceptions. e Patient Eligibility Criteria: Patients should be receiving standard therapy, which consists of concomitant treatment with corticosteroids and MMF. Successful treatment may allow patients to minimize or even eliminate steroid use. e Exclusion Criteria: Given the FDA label language, payers are likely to restrict coverage if eGFR < 45. However, clinical experts advised that concomitant renal biopsy results may suggest the possibility for patient benefit even with eGFR below this level. Payers may receive requests for dual therapy with belimumab and voclosporin. Although there are Olnstitute for Clinical and Economic Review, 2021 Page 48 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC pathophysiological arguments for dual therapy, clinical experts agreed that studies are needed to evaluate the outcomes of dual therapy before routine consideration within clinical practice. e Duration of Therapy and Renewal of Coverage: Given the FDA label language, based on the potential for nephrotoxicity with prolonged use, physician attestation of a response to therapy of at least a 50% reduction in proteinuria after 6 to 12 months of therapy is not unreasonable. Current data support one year of therapy, but clinical experts and some trial data suggest that longer treatment duration may be appropriate in individual patients. e Provider Criteria: The therapy should be prescribed by a rheumatologist or nephrologist with expertise in LN or, at minimum, access to consultation with an expert. Virtual consultation with a SLE expert at a Lupus Center of Excellence should be supported. Step Therapy There is no other treatment that could be considered a first-step treatment prior to eligibility. Manufacturers Manufacturers should commit to expanding their research, both before and after regulatory approval, to include adequate representation of patients with lupus nephritis from Black and other non-white populations. We heard over and over about the poor outcomes in non-white populations, but the pivotal trials of both therapies did not represent the race/ethnicity distribution of LN in the United States nor were the race/ethnicity subgroups large enough to make meaningful conclusions about the relative efficacy of the therapies in Blacks and other non-white populations. Manufacturers should commit to performing the research needed to help inform more personalized, tailored care for patients from these communities. Manufacturers should not seek to use common sense dosing algorithms as a tool to gain prolongation of their patents, thereby adding to future health care affordability concerns and reducing the headroom for future innovative therapies. The addition of a dosing algorithm to the patent protection for voclosporin significantly extended the time during which no generic competition will be possible. This approach of capitalizing upon a dosing algorithm found to lead to improved outcomes makes financial sense for an individual drug maker but creates greater access barriers to care over time for patients with LN and others due to the additional costs seen with drugs that face no generic competition. Manufacturers serious about a long-term commitment to patients will contribute to future innovation and affordability by Olnstitute for Clinical and Economic Review, 2021 Page 49 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC resisting the temptation to monetize dosing algorithms, especially those that appear self-evident to clinicians. Specialty Societies Specialty societies should work with regulators to standardize the primary outcome used in future pivotal trials of therapies for lupus nephritis. The primary outcome in the pivotal trial of belimumab changed five years after the study began recruiting participants, was a novel measure, and did not correspond to any of the outcomes measured in the pivotal trial of voclosporin. This makes it challenging for clinicians and guideline developers to use the evidence to guide the choice of therapy for patients. There is a substantial evidence base describing short term measures that predict long term good outcomes in lupus nephritis. One of those measures should be defined as the standard primary outcome. Specialty societies should update their guidelines to include guidance on appropriate use of belimumab and voclosporin and commit the resources to update guidelines more frequently as evidence evolves. Payers typically base coverage policy on specialty society guidelines. The first two therapies specifically approved by the FDA to treat lupus nephritis are now available for clinicians to prescribe. However, current US rheumatology and nephrology guidelines have not been updated to guide appropriate use of the therapies. In addition, the guidelines should directly address the heterogeneity in the presentation and clinical course of LN by race/ethnicity. Finally, given the likelihood that the FDA will approve several additional new therapies for LN in the next few years, guideline developers should build in a mechanism to update their guidelines annually (e.g., living guidelines). The specialty societies need to examine their conflict-of-interest policies to ensure appropriate input from clinicians familiar with the latest data. Researchers Priority should be given to developing biomarkers that can guide the choice of therapy in lupus nephritis. Many different immunosuppressive therapies are tried in succession when the initial therapy fails to control the disease. There is currently no rationale strategy to guide therapy as there are no biomarkers that predict a good response with one therapy or a poor response with another therapy. This leads to a process of trial and error on the background of declining renal function than can no longer be recovered. Biomarker guided therapy promises to be more effective and less toxic. ©Olnstitute for Clinical and Economic Review, 2021 Page 50 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Larger observational studies describing long-term outcomes following both complete and partial response are needed. The available US studies have overlapping survival curves for patients with complete response and those with partial response to therapy. This does not have face validity. Robust evidence on the time to ESRD and the time to death are needed in order to model the impact of treatment of LN over time. Given the heterogeneity of the disease by race/ethnicity, there should be adequate numbers of patients studied to capture differences in disease trajectory by race/ethnicity. These longitudinal observational studies could also capture the side effects of both corticosteroids and non-steroidal immunosuppressive medications. oF ek This is the first ICER review of belimumab and voclosporin for the treatment of lupus nephritis. Olnstitute for Clinical and Economic Review, 2021 Page 51 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC References w 10. 11. 12. 13. 14. 15. 16. 17. Genetics Home Reference. Systemic Lupus Erythematosis. National Institute of Health. https://ghr.nim.nih.gov/condition/systemic-lupus-erythematosus Published 2020. Updated 8/17/2020. Accessed 8/30/2020, 2020. Albuquerque BC, Salles VB, Tajra RDP, Rodrigues CEM. Outcome and Prognosis of Patients With Lupus Nephritis Submitted to Renal Transplantation. Sci Rep. 2019;9(1):11611. Jaryal A, Vikrant S. Current status of lupus nephritis. Indian J Med Res. 2017;145(2):167-178. Carls G, Li T, Panopalis P, et al. 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Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Reckers-Droog VT, van Exel NJA, Brouwer WBF. Looking back and moving forward: On the application of proportional shortfall in healthcare priority setting in the Netherlands. Health policy (Amsterdam). 2018;122(6):621-629. Versteegh M, Corro Ramos |, Buyukkaramikli NC, Ansaripour A, Reckers-og V, Brouwer W. Severity-Adjusted Probability of Being Cost Effective. PharmacoEconomics. 2019;37(9):1155- 1163. Ottersen T, Forde R, Kakad M, et al. A new proposal for priority setting in Norway: Open and fair. Health policy (Amsterdam). 2016;120(3):246-251. Wetering E, Stolk E, van Exel J, Brouwer W. Balancing equity and efficiency in the Dutch basic benefits package using the principle of proportional shortfall. The European Journal of Health Economics. 2013;14(1):107-115. Stolk EA, Donselaar Gv, Brouwer WBF, Ja JVB. Reconciliation of Economic Concerns and Health Policy: Illustration of an Equity Adjustment Procedure Using Proportional Shortfall. PharmacoEconomics. 2004;22(17):1097-1107. iDBC - iMTA Disease Burden Calculator [computer program]. 2020. Page 56 Return to TOC Supplemental Materials Olnstitute for Clinical and Economic Review, 2021 Page 57 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC A. Background: Supplemental Information A1. Definitions Table A.1. Classification of Lupus Nephritis Class | Minimal Mesangial LN Class Il Mesangial Proliferative LN Class Ill Focal LN (<50% glomeruli) Il (A) Active Lesions Ill (A/C) Active and Chronic Lesions Ill (C) Chronic Lesions Class IV Diffuse LN (250% glomeruli) IV (S) Diffuse Segmental IV (G) Diffuse Global IV (A) Active Lesions IV (A/C) Active and Chronic Lesions IV (C) Chronic Lesions Class V Membranous LN Class VI Advanced Sclerosed (290% glomeruli) Complete Response (CR) in voclosporin trials : UCPR of < 0.5 mg/mg, eGFR = 60 mL/min/1.73 m2, or no confirmed decrease from baseline in eGFR of > 20% with the presence of sustained, low dose steroids and no administration of rescue medication. Partial Response (PR) in voclosporin trials : >50% decrease in UPCR from baseline with the presence of sustained, low dose steroids and no administration of rescue medication. Primary Efficacy Renal Response (PERR) in belimumab trial: UPCR<0.7, estimated glomerular filtration rate (eGFR) was not more than 20 percent (%) below the pre-flare value or 260 and was not a treatment failure. Complete Renal Response (CRR) in belimumab trial: UPCR<0.5, eGFR not more than 10% below the pre-flare value or 290 and was not a treatment failure. Renal event in belimumab trial: progression to end stage renal disease, doubling of serum creatinine from baseline, renal worsening, or renal-related treatment failure. ©Olnstitute for Clinical and Economic Review, 2021 Page 58 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC A2. Potential Cost-Saving Measures in Lupus Nephritis ICER includes in its reports information on wasteful or lower-value services in the same clinical area that could be reduced or eliminated to create headroom in health care budgets for higher-value innovative services (for more information, see https://icer.org/our-approach/methods- process/value-assessment-framework/). These services are ones that would not be directly affected by therapies for Lupus Nephritis (e.g., reduction in ESRD, kidney transplant), as these services will be captured in the economic model. Rather, we are seeking services used in the current management of LN beyond the potential offsets that arise from a new intervention. During stakeholder engagement and public comment periods, ICER encouraged all stakeholders to suggest services (including treatments and mechanisms of care) currently used for patients with LN that could be reduced, eliminated, or made more efficient. No suggestions were received and no Choosing Wisely recommendations apply. ©Olnstitute for Clinical and Economic Review, 2021 Page 59 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC B. Patient Perspectives: Supplemental Information B1. Methods During ICER's scoping, open input, and public comment periods, we received public comment submissions from nine stakeholders (four patient advocacy groups, three manufacturers, one clinical society, and one individual) and participated in conversations with 17 key informants (five patient advocacy groups, seven clinical experts, one clinical society, two health plans, and two manufacturers). Some stakeholders played more than one role in our outreach. We also reviewed Lupus: Patient Voices, which summarizes a national meeting eliciting the perspectives of patients living with lupus, including those with LN. The feedback received from written input and scoping conversations helped us to discuss the impact on patients described in Chapter 2 of the draft evidence report. Olnstitute for Clinical and Economic Review, 2021 Page 60 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC C. Clinical Guidelines American College of Rheumatology (ACR) 2012 Guidelines for Screening, Treatment, and Management of Lupus Nephritis?" The ACR convened a Core Executive Panel to review existing treatment guidelines for lupus nephritis (LN), which was achieved by conducting a systematic literature review and developing various clinical scenarios. The recommendations for treatment of LN were subsequently determined by a Task Force Panel's review of this work and vote on most appropriate interventions and treatment. The guidelines advise on the management of Lupus Nephritis based on histologic classification, described below. Class | and Il The Task Force Panel recommends that generally, histologic classes | and II of LN do not require immunosuppressive treatment. Class Ill and IV The recommendation for classes II and IV are aggressive therapy with glucocorticoids and immunosuppressants. This indicates a recommended 2-3 grams of MMF daily + glucocorticoids, or administration of intravenous cyclophosphamide (CYC) + glucocorticoids. Class V It is recommended that when combined with classes III and IV, class V patients should be treated with the recommended therapies to treat classes III and IV alone. Patients with class V "Pure Membranous" LN should begin treatment on 0.5 mg/kg of prednisone, plus 2-3 grams MMF daily. Class VI In cases of class VI LN, it is recommended that patients forgo immunosuppressive agents and prepare for renal replacement therapy. Treatment of LN in Patients who are Pregnant There are various treatment recommendations for pregnant patients, depending on the severity and activity of disease. In patients with previous LN but no indication of active systemic or renal disease, it is not necessary to treat with nephritis medication. It is recommended that patients with mild disease activity be placed on hydroxychloroquine (HCQ), as this will likely decrease SLE activity Olnstitute for Clinical and Economic Review, 2021 Page 61 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC during pregnancy. If the patient presents with clinically active nephritis or significant extrarenal disease activity, the treating clinician should provide glucocorticoids, at a dose of their discretion. If necessary, azathioprine (AZA) can be added to treatment, but should not exceed 2 mg/kg in pregnant women. Guidelines for Induction and Maintenance Therapy It is recommended that all SLE patients with nephritis indications be treated with HCQ as background therapy. Induction therapy is recommended for the first six months of treatment, followed by maintenance therapy. For patients who respond to induction therapy, it is recommended that maintenance therapy includes AZA or MMF. If a patient fails to respond to the first six months of induction therapy, the guidelines suggest that the treating clinician switch the immunosuppressive agent (from MMF to CYC, or CYC to MMF) and treat the patient for three days with IV pulses of glucocorticoids. European League Against Rheumatism (EULAR) 2019 Update of the Joint European League Against Rheumatism and European Renal Association - European Dialysis and Transplant Association (EULAR/ERA-EDTA) Recommendations for the Treatment of Lupus Nephritis™ The EULAR/ERA-EDTA guidelines were published in 2012 to advise on the management and treatment of individuals with LN. These recommendations were updated by EULAR in 2019 and were informed by health professionals and patients in order to incorporate the most recent evidence and available treatments. EULAR recommends treatment options based on the 2003 classification system of LN. For classes | and Il, it is recommended that patients are treated with HCQ. Stage Ill LN recommendations include a background therapy of HCQ, as well as immunosuppressive agents combined with glucocorticoids. These immunosuppressive agents include MMF, mycophenolate acid, low-dose intravenous cyclophosphamide, or MMF plus calcineurin inhibitors (tacrolimus or cyclosporin A). The recommended treatment for class IV and V patients is the same as class III, although rituximab should also be considered as a treatment option for immunosuppression. It is recommended that stage VI patients are only treated with HCQ. Along with treatment recommendations based on disease classification, the EULAR guidelines propose additional overarching principles and general recommendations based on the current available evidence. For patients with indications of kidney involvement, biopsy should be considered, and the International Society of Nephrology/Renal Pathology Society classification system should be used to assess the results. Olnstitute for Clinical and Economic Review, 2021 Page 62 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Ultimately, the goal of treatment is to preserve kidney function, and induction and maintenance will depend on the patient's class of nephritis and response to treatment. If a patient improves after the initial six-month induction period, it is recommended that the patient receives immunosuppression with MMF or azathioprine (AZA), plus prednisone for three to five years. Ifa patient does not respond to induction therapy, the physician may use their discretion and suggest an alternative initial treatment or consider treatment with rituximab. For women who plan to become pregnant, treatment with MMF should be stopped at least six months prior to conception. While it is fine to continue taking certain drugs, such as HCQ, prednisone, AZA, or calcineurin inhibitors, it is recommended that pregnant patients are assessed by a multidisciplinary clinical team every four weeks. Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis Chapter 12: Lupus Nephritis" This Chapter of the Kidney International Supplements outlines treatment recommendations for children and adults with LN. Any SLE patient with indications for kidney involvement, proteinuria, hypertension, or active urine sediment should be considered for a kidney biopsy to confirm the presence of LN. The KDIGO treatment recommendations are based on the histological classifications of LN, described below. This article suggests that all classes of LN patients are treated with HCQ unless there are clinical contraindications to doing so. Class | It is recommended that class | patients be treated based on extrarenal indications of lupus, as class | LN does not present with kidney manifestations or suggest long-term damage to kidney function. Class Il Patients with class II LN should be treated based on proteinuria levels. For those who have proteinuria measures of < 1 gram/day, treatment should be based on extrarenal indications of lupus. It is recommended that patients with proteinuria > 3 grams/day are treated with corticosteroids or calcineurin inhibitors (CNIs). ©Olnstitute for Clinical and Economic Review, 2021 Page 63 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Class Ill and IV Initial therapy of corticosteroids plus cyclophosphamide or mycophenolate mofetil (MMF) is recommended for the treatment of class III and IV patients. If during the first three months of induction therapy the patient presents with exacerbated symptoms of LN, it is recommended that the treating physician consider an alternative initial therapy or an additional kidney biopsy. Class V For patients with class V LN, normal kidney function, and non-nephrotic levels of proteinuria, it is recommended that treatment be dictated by extrarenal manifestations of SLE. Treatment should also include antiproteinuric and antihypertensive medication. Patients with pure class V LN and nephrotic proteinuria should be treated with corticosteroids plus immunosuppression with cyclophosphamide, MMF, CNI, or azathioprine (AZA). Indications for Induction Therapy and Maintenance Patients with class Ill and IV LN should undergo six months of initial induction therapy and should be considered for transition into maintenance therapy, contingent on the clinical success of initial therapy. For patients who respond to induction, it is suggested that immunosuppressive therapy is tapered after one year of remission. Immunosuppression should only be continued in maintenance therapy for patients who achieve only partial remission. Olnstitute for Clinical and Economic Review, 2021 Page 64 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods Population, Intervention, Comparators, Outcomes, Timing, and Settings Framework (PICOTS) Population The population of focus for the review is adult patients with Class Ill, IV, or V LN ages 18 and older. Interventions The full list of interventions is as follows: e Belimumab (Benlysta) plus standard therapy (defined below) e Voclosporin plus standard therapy Comparators Data permitting, we intend to compare belimumab and voclosporin to standard therapy, defined as mycophenolate mofetil (MMF) plus corticosteroids or cyclophosphamide plus corticosteroids. Outcomes The outcomes of interest are described in the list below. e Patient-Important Outcomes o Complete renal remission (normal renal function) at one year* Maintenance of remission Reduction in corticosteroid dose (steroid sparing) Reduction in renal flares Prevention of chronic kidney disease Dialysis Renal transplant Fatigue Joint and muscle pain Childbearing potential 0 000€0UC~COWUlCUCOUlUCO Olnstitute for Clinical and Economic Review, 2021 Page 65 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Timing (e) Adverse events (AEs) including = Significant adverse events = Adverse events leading to drug discontinuation = Infections =" Acute renal failure " Diabetes =" Hypertension =" Nephrotoxicity =" Neurotoxicity (encephalopathy, tremors, headache, seizures) = Progressive multifocal leukoencephalopathy (PML) =" Hypersensitivity reactions = Infusion reactions =" Depression = Suicide =" Gastrointestinal (nausea, diarrhea) =" Death Other Outcomes Oo 0000UC~UWUC-C~CNUCUCUOWUCUCOUCONCOCOCO CON Renal response Partial renal response Duration of complete renal response 24-hour urine protein excretion (<0.25, 0.25-3.0, >3.0 g/day) Change in creatinine Change in estimated glomerular filtration rate (eGFR) The proportion of patients with eGFR >90, 60-89, 30-59, 15-29, <15 Change in urine protein creatinine ratio (UPCR) The proportion of patients with UPCR by categories Change in serum albumin Change in complement levels Change in ANA level Change in DS DNA level Change in Quality of Life SELENA-SLEDAI score Evidence on intervention effectiveness will be derived from studies of at least 24 weeks duration and evidence on harms from studies of at least 24 weeks duration, though studies of at least one- year duration are preferred. Olnstitute for Clinical and Economic Review, 2021 Page 66 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Settings All relevant settings will be considered. 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Sey yar '(ZT way aas) JUawssasse java] aWO0dINO Aue 'ajqeyiene JI 'pue Apnys ydea Jo Seiq JO ySI4 UO eJeP JUaSaIq = GT. UIYUM Seiq JO 4SIy *SUO!}EUD BUY} apiAojd pue (poluad dn-moj|oO} 'SODId 'azIs Apnis "3°d) payes1X9 d1aM e}ep YIIYM JOJ SdI¥SsuayeVeYD JUaSsaid 'Apnys y9ed 4104 = BT. eJRLYP ES LS LAU WAN LIP LS "WweIZeIP MO|} e YUM Ajjeap! 'a8e 1s yoea je SUOISNJOXa JO} SUOSedJ YUM 'MaIAdJ JY} Ul PapnNjoul pue 'AyIqISI[a 10J Passasse 'pauaadS SaIpNys JO SJaqUUINU BAIN = /T uol}ajas Apnis = Sway 3SIP}224D Data Sources and Searches Procedures for the systematic literature review assessing the evidence on new therapies for Lupus nephritis followed established best research methods.**"© We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.4" The PRISMA guidelines include a checklist of 27 items, which are described further in Appendix Table A1. 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- review.org/methodology/icers-methods/icer-value-assessment-framework-2/grey-literature- policy/). Where feasible and deemed necessary, we also accepted data submitted by manufacturers "in-confidence," in accordance with ICER's published guidelines on acceptance and use of such data (https://icer-review.org/use-of-in-confidence-data/). Olnstitute for Clinical and Economic Review, 2021 Page 70 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Table D2. Search Strategies for EMBASE lupus nephritis'/exp 2 | ('lupus erythematosus nephritis' OR 'nephritis, systemic lupus erythematosus' OR 'lupoid nephritis' OR 'lupus kidney'):ti,ab 3 | #lor#2 4 | voclosporin'/exp 5 | ('isa 247' OR 'isa247' OR 'luveniq' OR 'Ix 211' OR 'Ix211'):ti,ab 6 | #40OR #5 7 | belimumab'/exp 8 | ('benlysta' OR 'lymphostat b'):ti,ab 9 | #70OR#8 10 | #6 OR #9 11 | #3 AND #10 12 | ('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp) NOT 'human'/exp 13 | #11 NOT #12 14 | #13 AND [English]/lim 15 | #14 AND ('chapter'/it OR 'editorial'/it OR 'letter' /it OR 'note'/it OR 'short survey' /it) 16 | #14 NOT #15 Table D3. Search Strategies for OVID 1 | Exp Nephritis, Lupus/ 2 | ("Lupus Nephritides" or "Lupus Glomerulonephritis" or "lupus nephritis").ti,ab 3 1or2 4 | (voclosporin or ISATX247 or "ISA 247" or "ISA-247" or "ISA(TX)247").ti,ab 5 | ("BEL-114333" or BEL114333 or "HGS-1006" or HGS1006 or "LymphoStat-B" or "GSK-1550188" or GSK1550188 or Benlysta or belimumab).ti,ab 6 | 4or5 7 | 3and6 8 | (addresses OR autobiography OR bibliography OR biography OR case reports OR clinical trial, phase | OR comment OR congresses OR consensus development conference OR dictionary OR directory OR duplicate publication OR editorial OR encyclopedia OR festschrift OR guideline OR interactive tutorial).pt 9 | 7nots8 10 | animals not (humans and animals).sh. 11 | 9not 10 12 | limit 11 to English language 13 | remove duplicates from 12 Olnstitute for Clinical and Economic Review, 2021 Page 71 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure D1. PRISMA Flow Chart Showing Results of Literature Search for Belimumab and Voclosporin 570 references identified 8 references identified through literature search through other sources v 544 references after duplicate removal 544 references screened 503 citations excluded 23 citations excluded - ~~ - Tm 41 references assessed for 3 Population eligibility in full text 4 Intervention 6 Study Design 6 Outcomes vy 6 Duplicates 3 Cannot locate full-text 18 total references 4 RCTs 3 references included in quantitative synthesis Olnstitute for Clinical and Economic Review, 2021 Page 72 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Study Selection We performed screening at both the abstract and full-text level. A single investigator screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. One investigator reviewed full papers and provided justification for exclusion of each excluded study. Data Extraction and Quality Assessment We used criteria published by the US Preventive Services Task Force (USPSTF) to assess the quality of 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. Olnstitute for Clinical and Economic Review, 2021 Page 73 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC 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 (see Appendix D).*9°° 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 belimumab and voclosporin 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. The primary concern is the lack of peer-reviewed, published data for the AURORA trial. Data Synthesis and Statistical Analyses Data on relevant outcomes were summarized in evidence tables (see Appendix Table D4) and synthesized quantitatively and qualitatively in the body of the review. We evaluated the feasibility of conducting a quantitative synthesis by exploring the differences in study populations, study design, analytic methods, and outcome assessments for each outcome of interest. Based on data availability, we conducted random effects pairwise meta-analyses for low dose voclosporin using two randomized trials2°?35 on the following outcomes: CR at 24 weeks, CR at 48/52 weeks, and PR at 24 weeks. The AURA-LV trial did not report PR at 48/52 weeks. We calculated risk ratios (RRs) and their respective 95% Cls using the Mantel-Haenszel method. We assessed heterogeneity using the Cochran q test and the 12 statistic. In an exploratory analysis, we also created a network to compare the complete response rate of voclosporin at one year to that of belimumab at two years.** All NMAs were conducted in a Bayesian framework with random effects on the treatment parameters using the gemtc package in R.>+ The outcomes were all binary and were analyzed using a binomial likelihood and logit link.>? League tables were presented for the treatment effects (odds ratio [OR]) of each intervention versus each other and versus placebo along with 95% credible intervals (95% Crl). Due to inconsistent or limited reporting of data, other outcomes are described without summary Statistics across studies. D2. Additional Clinical Evidence All clinical evidence is described in the main report. Olnstitute for Clinical and Economic Review, 2021 Page 74 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC D3. Heterogeneity and Subgroups The primary source of heterogeneity was anticipated to be race/ethnicity as non-White patients typically present with more severe LN that progresses more rapidly. Other subgroups of interest include sex and the background immunosuppressive therapy for LN (MMF, cyclophosphamide). When available, we present the information for those subgroups. 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Supplemental MA and NMA Information Figure D2. MA of Complete Response at 48/52 Weeks. Voclosporin (VCS) versus Placebo (PBO) vcs PBO Study Events Total Events Total Risk Ratio RR 95%-Cl Weight AURA-LV 44 89 21 BB -+- 207 [1.35;3.18] 36.0% AURORA fhe 41 178 -=- 1.77 (1.28; 2.44] 64.0% Random effects model 268 266 1.87 [1.45; 2.42] 100.0% Heterogeneity: /* = 0%, 17 = 0, p =0.57 0.5 1 2 95% Cl: 95% confidence interval, |2: |-squared, RR: risk ratio, t2: between-study-variance estimator Figure D3. MA of Complete Response at 24 Weeks. Voclosporin (VCS) versus Placebo (PBO) vcs PBO Study Events Total Events Total Risk Ratio RR 95%-Cl Weight AURALV 29 «89 17 88 |__## 4.69 [1.00;2.84] 32.4% AURORA 58 179 36 178 -=- 1.60 [1.12; 2.30] 67.6% Random effects model 268 266 a 1.63 [1.21; 2.19] 100.0% Heterogeneity: |" = 0%, 1 = 0, p = 0.87 05 4 2 95% Cl: 95% confidence interval, |2: |-squared, RR: risk ratio, t2: between-study-variance estimator Figure D4. MA of Partial Response at 24 Weeks. Voclosporin (VCS) versus Placebo (PBO) vcs PBO Study Events Total Events Total Risk Ratio RR 95%-Cl Weight AURA-LV 64 89 44 88 144 [1.12; 1.84] 33.6% AURORA 126 179 89 178 1.41 [1.18; 1.68] 66.4% Random effects model 268 266 1.42 [1.23; 1.64] 100.0% Heterogeneity: /" = 0%, 1 = 0, p = 0.89 95% Cl: 95% confidence interval, |2: |-squared, RR: risk ratio, t2: between-study-variance estimator Olnstitute for Clinical and Economic Review, 2021 Page 94 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Figure D5. NMA figure Voclosporin Belimumab Pp De Placebo Belimumab vs. placebo study: BLISS-LN Voclosporin vs. Placebo studies: AURA-LV & AURORA Table D5. NMA Results of Complete Renal Response (Fixed Effect model): Odds Ratio (95% Credible Interval) Voclosporin 1.62 (0.94, 2.77) 2.57 (1.77, 3.75) Belimumab 1.59 (1.08, 2.34) Placebo Table D6. NMA Results of Complete Renal Response (Random Effect model): Odds Ratio (95% Credible Interval) Voclosporin 1.65 (0.36, 8.02) 2.62 (1.07, 6.76) Belimumab 1.59 (0.45, 5.55) Placebo Olnstitute for Clinical and Economic Review, 2021 Page 95 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC OL 0} UINjaY siquydean sndnq Jo} ulsodsoj20, pue qewinuljag - Wodey aouapiag jeuly 96 aed TZOZ 'Ma!AaY I1WOUOIJ pue [ed1UI| JOJ a1NySU|@ -ljue) auljaseq uolsnjul '(49 U99-a]8uls) je JUaSoud qewixniy °Z juawusisse 0202 salpoqiqueojne FS 9AI}9e 'aJaNaS - uolyeaful jayjesed EN Salton lrg 4340190 JUeAa|aJ aSeas|p sisouseip 3S - qewnuwi|ag 'T 'paziwopues - 71S ul uolejnpowounwuy| :AJeWLd $0 uoIJONpay - uolsnjou| jeyUawWadxy "EUOIUSAJAU| ESS RFC SPCIULS qewnuljag elajIeg/SNIIA/SWUSIUeSIO BAI] SUISN SBUIDIeA - SdAl}da0e1]U0D ayenbape sulsn jou 'Sulpaay jseaig "WUeUdaId - quaijyed 0} 4sI1 paseasoul UUM pa}eld0sse UO!IPUOD jedIPaW Auy - quejdsues Aaupiy pauueld - sisAjelp |euay - Apnys Aq pauqiyoid 9TZ :}UaW]|O1Ua SW} POO}/SUOI}EIIPaW BUIye} SjUal}ed - jenjoy uoisn|oxq L@Z 7}UaWy|O1Ua GL-8T a8y - payewiysy V9VLESEOLON sjuawssasse Apnjs $0 uolzesnp 3ulunp jed1Sojoyeway JIN 8ubje} ANUIyUOD 0} BuUly|IM JUa!Ied - *'juawusisse 'Du| SjedIyNadeWeY, elULINY pue jediwaysoiq Apnis jajjesed dulyNoy - T VYOUNV U! 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Previous Systematic Reviews and Technology Assessments We identified two previous systematic reviews - one reviewing immunosuppressive treatments for lupus nephritis and one reviewing the renal effects of belimumab. These reviews are summarized below. Tunnicliffe DJ, Palmer SC, et al. Immunosuppressive Treatment for Proliferative Lupus Nephritis. Cochrane Review."' Cochrane researchers conducted a systematic review of immunosuppressive treatments for use in adults and children with biopsy-proven class Ill, IV, V+Ill and V+VI lupus nephritis. In total, 74 studies were included in the review with 67 studies on induction therapy and nine studies on maintenance therapy. The included studies evaluated treatments such as cyclophosphamide, mycophenolate mofetil (MMF), azathioprine, and tacrolimus used alone or with MMF. The 67 included studies that focused on induction therapy ranged from 2.5 to 48 months (median 12 months) in duration and enrolled 4791 participants in total. The main results reported by CADTH concluded that MMF plus corticosteroids may lead to increased complete disease remission (RR: 1.17, 95% Cl: 0.97 to 1.42; I? = 0%) compared to cyclophosphamide at six months as well as the stabilization of kidney function (RR: 1.05, 95%CI: 0.94 to 1.17; I? = 0%) although the certainty in the evidence is low. Researchers also reported that tacrolimus plus MMF may improve the induction of complete renal remission at six months (RR: 2.38, 95% Cl: 1.07 to 5.30; |? = 57) as well as the induction of stable kidney function (RR 1.78, 95%CI: 1.40 to 2.26; I? = 0%) though the generalizability is low because the majority of patients included in the study are Asian. The nine studies reporting on maintenance therapy ranged from 6 to 36 months in duration and enrolled 767 participants. Researchers concluded that Azathioprine probably increased renal response (RR 1.75, 95% Cl: 1.20 to 2.55; I? = 0%) versus MMF but there was no difference in other outcomes like injection or alopecia, according to the review. Sciascia S, Radin M et al. Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: A systematic review. 2017.°° The identified systematic review summarizes the potential effect of belimumab on renal parameters in patients with systematic lupus erythematosus (SLE) focusing on those with lupus nephritis (LN). 11 total articles were included: 1 post-hoc analysis of a randomized control trial, four observational studies, and six case reports all reporting the effect of belimumab on renal parameters in patients with LN. From a total of 2004 identified patients with SLE, 326 (16.3%) had LN at baseline and of those, 234 (71.8%) were being treated with belimumab (10 mg/kg). Olnstitute for Clinical and Economic Review, 2021 Page 101 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC Of the 234 LN patients being treated with belimumab, 129 (55.1%) showed improvements in renal parameters including renal flare, renal remission, and/or renal organ disease improvement assessed by SELENA-SLEDAI, SLEDAI-2K, BILAG, and/or SLAM indexes. Comparing LN patients receiving belimumab versus placebo, those receiving belimumab achieved a higher percentage of renal remission (68.1% versus 58.7%, chi-square value = 4.9814, p = 0.025) and a shorter median time to renal remission (139.5 versus 167 days). From the included randomized trails, adding belimumab to standard of care increased rate of renal remission by 10% compared to placebo. As for rate of renal flare, LN patients receiving belimumab had a lower rate (1.95% versus 3%, chi-square value = 1.8742, p = 0.17) although this difference was not statistically significant. Given the evidence from the 11 included studies, investigators determined that it is not possible to make definitive recommendations for the off-label use of belimumab for LN. However, the published evidence supports the continued investigation of belimumab in treating LN. Olnstitute for Clinical and Economic Review, 2021 Page 102 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC E. Long-Term Cost-Effectiveness: Supplemental Information E1. Detailed Methods Table E1. Impact Inventory Included in This Analysis Notes on Sources (if Tt Mem tual srt from [...] Perspective? quantified), Likely (Add additional domains, as relevant) | Health Care Magnitude & Impact (if Sector not) Formal Health Care Sector Longevity effects xX X Health . . Health-related quality of life effects X X Outcomes Adverse events X X Paid by third-party payers X X : Paid by patients out-of-pocket O O Medical Costs . Future related medical costs Oo oO Future unrelated medical costs Oo oO Informal Health Care Sector Patient time costs NA O Health-Related ; ; ; oon Unpaid caregiver-time costs NA oO osts Transportation costs NA oO Non-Health Care Sector Labor market earnings lost NA X Cost of unpaid lost productivity due to se " Productivity illness Cost of uncompensated household NA Oo production ' Future consumption unrelated to ery aay ey ad (oya NA O health : : Cost of social services as part of Social services . : NA oO intervention Number of crimes related to NA q Legal/Criminal intervention Justice Cost of crimes related to intervention NA | Impact of intervention on educational NA q achievement of population Cost of home improvements, . NA O remediation ©lnstitute for Clinical and Economic Review, 2021 Page 103 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC ate Ce (ere M MwA Ly Notes on Sources (if aT yeRey a alta from [...] Perspective? quantified), Likely (Add additional domains, as relevant) | Health Care Magnitude & Impact (if Sector not) Production of toxic waste pollution b G u NA Oo intervention Other impacts (if relevant) NA NA: not applicable Adapted from Sanders et al.°? Target Population The population of focus for this economic evaluation includes adult SLE patients with Class Ill, IV, or V LN. The model uses a mean start age of 35 years assuming patients' characteristics (gender and age) are similar to the population described in Davidson et al. (2018) study.78 Treatment Strategies The list of interventions for LN was developed with input from patient organizations, clinicians, manufacturers, and payers on which treatments to include for LN. The full list of interventions is as follows: e Belimumab (Benlysta®, GlaxoSmithKline), IV, 10 mg/kg of body weight, plus standard therapy e Voclosporin (Aurinia), oral, mean daily dose of 39.1 mg a day, plus standard therapy For belimumab, the comparator was standard therapy, defined as IV CYC or oral MMF, IV dose of steroids (500-1000 mg), and then oral prednisone (0.5 to 1.0 mg/kg per day). For voclosporin, the comparator was standard therapy, defined as oral MMF, IV dose of steroids (500-1000 mg), then oral steroids 20-25 mg daily tapered down to 5 mg daily by week 8 and 2.5 mg daily by week 16. ©lnstitute for Clinical and Economic Review, 2021 Page 104 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC E2. Model Inputs and Assumptions Our model includes several key assumptions stated below. Table E2. Assumptions of Short-Term and Long-Term Modeling LN is a complication of SLE. Some treatments, such as belimumab, could affect not only LN, but also SLE progression. Since this model reconstructs the progression of LN only, it is not able to reflect broader benefits of treatments, for instance their impact on progression of SLE or other comorbidities. There are no head-to-head trials comparing belimumab and voclosporin. The designs of the trials, including the inclusion criteria, comparator arms, background therapy, definitions of the outcomes, and the study follow-up times are too different, precluding comparing the treatments to each other. There are no long-term data on survival for patients on belimumab and voclosporin. Also, there is no clinical reason why response achieved by one treatment will have different survival to response achieved on a different treatment. Thus, long-term modeling was based on survival analyses of LN patients, conditional on achieving AD, CR, and PR at the end of each trial.1® The data from Davidson et al. (2018) only report on ESRD-free survival, but not ESRD and death separately. As such, the proportion of ESRD events and deaths in the model was estimated based on data from Chen et al. (2008), which reported KM curves for ESRD-free survival and overall survival separately. Clinical experts suggested that patients with CR and PR are likely to spend a period of time in AD before progressing to ESRD (rather than progressing directly to ESRD from CR or PR). AD is defined by a drop in eGFR level which is necessary to transition into ESRD. This was implemented in the long-term model by incorporating the costs and outcomes for the time spent in AD rather than explicitly modeling this transition. The time spent in AD state was extracted from Hanly et al. (2016). There are no data to inform long-term treatment effects of belimumab and voclosporin, thus no additional effectiveness or costs related to belimumab and voclosporin treatment were accumulated beyond the short-term model. In the base-case analysis, the short-term model time horizon is three years Olnstitute for Clinical and Economic Review, 2021 Page 105 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis assuming patients stay in the same health states that they were in at the end of the trials (see Tables 4.2 and 4.3) until the end of 3 years. There are no data to inform mean discontinuation time of belimumab and voclosporin used for LN treatment for patients remaining in AD state. Data from AURORA and BLISS-LN trials suggest an additional clinical effect between 6-12 months of treatment. The time of 18 months for AD state is selected to account for underestimation of treatment duration in CR/PR states, as it was informed by clinicians. The adverse events reported in both trials were comparable in the intervention and comparator arms (i.e., neither belimumab nor voclosporin treatment resulted in more adverse events than standard therapy). There was no agreement among physician experts regarding the belimumab drug forms that are going to be prescribed to LN patients. Since only IV drug form was used in the BLISS-LN trial, costs of belimumab in vials were used in the base-case analysis. Based on the prescribing information for belimumab and the feedback from clinical experts, the modeling considered drug wastage in calculating the annual cost of belimumab treatment. Both voclosporin and belimumab are assumed to be added on to standard care (i.e., MMF for voclosporin, and MMF or CYC for belimumab). Therefore, the costs of these therapies are assumed to be the same between the standard care and intervention arms for their respective comparisons. Given the costs of standard care are already included in the health state costs, these are not incorporated separately, to avoid double counting. As there are no data is available on time of patients' treatment discontinuation due to AEs, we assume that the treatment discontinuation is at the mid-point of the short-term model (i.e., 18 months for both belimumab and voclosporin). For the patients who stop treatment due to AEs, the costs of interventions (belimumab and voclosporin) were not accrued beyond the midpoints of short-term model, although they still accumulated the costs related to their health state. In BLISS-LN, more patients were reported on low-dose steroids in treatment than comparator arms. In AURORA, steroid dose was tapered down to a dose of 5 mg daily by week 8 and 2.5 mg daily by week 16. Costs of steroids and increment in utilities for Olnstitute for Clinical and Economic Review, 2021 Page 106 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis a 1 - patients on low-dose steroids were included in the short-term model.?3 There is no evidence on how the steroid dosages change after Low-dose steroid use in the trials does not treatment with belimumab or voclosporin is discontinued. Thus, affect costs in the long-term model. the impact of low-dose steroids was limited to the duration of treatment with belimumab and voclosporin. Model Inputs Clinical Inputs In the short-term model, the proportion of patients who remain in CR, PR, AD, and ESRD were calculated by the linear interpolation of data from the clinical trials. The proportions of patients reaching CR in the BLISS-LN trial?" were extracted from the digitized curve which reports the proportions of patients achieving CR over time. The proportions of patients reaching PR, ESRD, or death at the end of the trial follow-up (104 weeks), were used in the short-term model to estimate the proportions in interim time cycles. Table E3. Outcomes on Belimumab from BLISS-LN Trial Partial Renal pyr) Time Complete Renal Response, % ESRD, % Response, ia % 104 30.0 17.5 0.0 0.4 weeks 19.7 17.0 0.4 0.9 ESRD: end-stage renal disease Definitions in BLISS-LN trial: Complete Renal Response (CRR): ratio of urinary protein to creatinine of <0.5, eGFR no worse than 10% below pre-flare value or 290 ml/min/1.73 m2with no use of rescue therapy. Partial Response: GFR no worse than 10% below baseline value or within normal range and at least 50% decrease in the ratio of urinary protein to creatinine with one of the following: ratio of urinary protein to creatinine <1.0 if baseline ratio <3.0, or ratio of urinary protein to creatinine of <3.0 if baseline ratio >3.0; no treatment failure; and not complete renal response. Outcomes of voclosporin treatment were assessed using the data from a meta-analysis of the AURA-IV and AURORA trials (see Section 3 "Comparative Clinical Effectiveness") for CR at 24 and 52 weeks and for PR at 24 weeks; for death and PR at 52 weeks, data from the AURORA trial were used. Olnstitute for Clinical and Economic Review, 2021 Page 107 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E4. Outcomes on Voclosporin from AURORA and AURA-LV Trials Partial RX -Yar-|| Complete Renal Response*, % ESRD***, % Death¥, % Response**, % Placebo 23.3 28.4 0.0 2.8 ESRD: end-stage renal disease Definitions in AURORA trial: Complete Renal Response (CRR): Decrease in UPCR to <0.5mg in 2 consecutive, first morning void urine specimens, eGFR >60ml/min per 1.73 m2 or no decrease of 220% of baseline eGFR on 2 consecutive occasions, No use of rescue therapy and presence of sustained low-dose steroids Partial Response:2 50% decrease in urinary protein: creatinine ratio from baseline in the absence of rescue medication * Meta-analysis of AURA-IV and AURORA trials; **Difference between PR/CR rates reported in AURORA trial and CR rate calculated in meta-analysis; ***Not reported in AURORA trial, assumed as zero; ¥ AURORA trial. 43.2 26.6 0.0 0.6 ST Treatment Duration Considering the plausibility that both of the drugs will be used longer than the duration of the trials, it was assumed that belimumab and voclosporin will be used in patients in CR and PR states for three years before discontinuation, based on consultations with clinical experts. For patients remaining in AD state, we assumed that both drugs will be used for 18 months before treatment discontinuation. In the model, the patients are assumed to stay in the same health states that they were in at the end of the trials (see Tables E3 and E4) until the end of three years. That is, the probability of being in each model state (CR, PR, AD, ESRD) after the end of the trials' follow-up (two years for belimumab and one year for voclosporin) in the short-term three-year model was considered to be same as the last observation in the trials. Discontinuation due to adverse events In the model, based on consultations with clinical experts, treatment discontinuation due to AE was considered, to reflect the clinical practice of patients staying longer on the therapies than in trial settings. Based on the data from the phase III (BLISS-LN and AURORA) trials, 13% in the belimumab arm of BLISS-LN and 11.2% in the voclosporin arm of AURORA discontinued due to AEs. As such, these proportions (13% in belimumab arm and 11.2% in voclosporin arm) were assumed to discontinue treatment in the short-term model. As there are no data from the trials to inform the time point for treatment discontinuation, this treatment discontinuation was assumed to happen in the model at the midpoint of treatment duration (i.e., 18 months for both belimumab and voclosporin). Olnstitute for Clinical and Economic Review, 2021 Page 108 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Long-term Extrapolation The inputs for long-term extrapolation were common for both treatments, and as such are presented together. The long-term model used partitioned-survival modeling to estimate ESRD-free survival for the different health states (AD, CR, and PR) based on data from Davidson et al. (2018), with the proportion of ESRD events and deaths estimated based on data from Chen et al. (2008).®78 The structure of the partitioned survival model does not include the AD state, calculating the costs and benefits for the proportion of people without ESRD, with ESRD, and those who died. Since patients do spend some time in AD state (and ignoring this would lead to lower costs, higher benefits, and so more favorable cost-effectiveness ratio for the drugs), we added the costs and utilities relevant for AD state for those patients who progress to ESRD. It was assumed that patients spend 1.206 years in the AD state (defined as eGFR < 30 ml/min) before progressing to ESRD, based on SLICC data."8 As there are no data on long-term LN progression in patients receiving belimumab or voclosporin treatments, the base-case analysis assumed that long-term disease progression depends only on whether patients achieve CR, PR, or AD at the end of the short-term model (and not the treatment received). The long-term probability of remaining alive without ESRD, conditional on being in AD, CR, and PR health states at the end of the trials, was modeled by fitting survival curves to the digitized published Kaplan-Meier (KM) data.?® The probability to remain without ESRD or death was obtained from the KM curves for CR, PR, and AD states defined by mBLISS-LN criteria; these criteria were selected as having definitions more close to those used in both of the trials (Table E5).17202223 Olnstitute for Clinical and Economic Review, 2021 Page 109 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E5. Definitions of the Outcomes in Different Studies Davidson et al. (2018) AURORA Occurrence of estimated creatinine clearance within the normal range Urinary protein:creatinine ratio < 0.5. Urinary protein:creatinine ratio < 0.5. eGFR that was no worse than 10% below the pre-flare value or >90 ml per minute per 1.73 m2 No use of rescue therapy. Decrease in UPCR to <0.5 mg in 2 consecutive, first morning void urine specimens eGFR >60ml/min per 1.73 m2 or no decrease of >20% of baseline eGFR on 2 consecutive occasions No use of rescue therapy and presence of sustained low-dose steroids lete Renal Remissi Study and Reference Al Ul ad Partial Remission /Response /Response Creatinine clearance of no more than 10% below the baseline value or within normal range; 2 50% decrease in urinary protein:creatinine ratio to < 1.0 (if the baseline ratio were < 3.0) or < 3.0 (if the baseline ratio was > 0.3). eGFR no worse than 10% below baseline value or within normal range; Decrease in urinary protein:creatinine ratio with one of the following: ratio <1.0 if baseline ratio was < 3.0 or <3.0 if the baseline ratio was >3.0; No receipt of prohibited (rescue) therapy resulting in treatment failure > 50% decrease in urinary protein:creatinine ratio from baseline in the absence of rescue medication Because of the substantial overlap in the survival curves for patients remaining in PR and CR reported by Davidson et al. (2018), patients in these states were assumed to have the same ESRD- free survival. The KM data were digitized, and individual data were reconstructed using the methods described in Guyot et al. (2012).®° The characteristics of the cohort used in the Davidson et al. (2018) study defined the approach for data extrapolation. The analysis was based on the Hopkins Lupus Cohort which had the average follow-up time per patient of 6.4 years and drop-out rate of approximately 10% per year.* Considering the large loss to follow-up, small number of events, and clinical plausibility of observed data informed by the clinical experts (i.e., the implausibility of not having a single ESRD/death event in multiple years of follow-up among patients with AD), the digitized KM curves were truncated to the last event: 3.8 years for AD and nine years for PR/CR curves. Olnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page 110 Return to ToC Different parametric distributions were fitted to these survival data, with the best-fitting curves identified based on a combination of visual inspection, fit statistics such as Akaike information criteria (AIC)/Bayesian information criteria (BIC), and clinical plausibility. Given very similar AIC (53- 55 for all except an exponential distributions of PR/CR curves and 100-102 for all distributions of AD curves) and BIC (53-55 for all except exponential distributions of PR/CR curves and 102-106 for all except gengamma distributions of AD curves) values between the different curves, clinical plausibility was the key factor in determining the selection of the parametric distributions for extrapolation. For each health state, a single parametric distribution was selected to calculate the proportion of the cohort remaining alive without ESRD each year. Weibull distribution for AD (Figure E1) and lognormal for CR/PR (Figure E2) were selected, based on the feedback from clinical experts considering similarity in AIC/BIC for most of the distributions applied. Figure E1. ESRD-Free Survival Probabilities with Different Extrapolation Approaches for Patients in AD State = \ - exponential { Weibull , Gompertz \ log normal «2 | \ | log logistic ° gamma -- generalised gamma o g 2 a € $ t s+ oO a w % *\, ® a | = o ~ =. ° a aa oS T T 0 20 40 60 60 Time (years) Olnstitute for Clinical and Economic Review, 2021 Page 111 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Figure E2. ESRD-Free Survival Probabilities with Different Extrapolation Approaches for Patients in CR/PR State 1.0 ty = co oT - 2 s $+ G Oo p=] oo a & Ss o< 5s °° a -- exponential \ nw Weibull aa Gompertz log normal log logistic gamma Ts 2 generalised gamma- --- T T T 0 20 40 60 80 Time (years) Mortality The monthly probability of death in the short-term model was estimated from interpolation of the trial data assuming a constant hazard between time points. In the long term model, the probability of deaths over time in the CR, PR and AD health states was estimated based on the digitized published KM data from Chen et al.(2008) which reports both ESRD-free survival and overall survival.® An average life expectancy of 10 years was assumed for patients who were in ESRD at the end of the short term model, based on the difference between overall survival and ESRD-free survival in the long-term extrapolation. To retrieve clinically plausible predictions for the CR, PR and AD health states, a multi-stage approach was utilized. First, the published KM curves reporting ESRD-free survival (either ESRD or death) and overall survival were digitized and reconstructed. Then, the proportions of deaths and ESRD events over time were estimated from the predictions of survival at each month up to the time of the last follow-up for the patients with AD, CR, and PR. Beyond the last observation in the KM curves reported by Chen et al. (2008), the proportions were estimated by assuming 100% mortality of population at age 100 to interpolate the ESRD-free survival and the overall survival reported by Chen et al. (2020). These proportions of deaths versus ESRD events over time were applied to the ESRD-free survival curves estimated based on data from Davidson et al. (2018).78 Olnstitute for Clinical and Economic Review, 2021 Page 112 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC The predictions on mortality in the LN population in CR/PR and AD states were validated by clinical experts. The survival curves used in the base-case analysis for long-term extrapolation are presented in Figure E3. The ESRD free survival and overall survival is assumed to be the same between PR and CR states. In the CR/PR health states, the mean ESRD-free survival is 19.38 years, and the mean overall survival is 28.13 years, while in the AD health state, mean ESRD-free survival is 12.98 years, and the mean overall survival is 23.65 years. Figure E3. Survival Curves Used in the Long-Term Extrapolation Model 1.0 = . \ - -CR/PR ESRD free survival 0.9 : . \ AD ESRD free survival 08 \ CR/PR Overall survival 0.7 \ AD Overall survival 0.6 = = 5 05 3 w 0.4 0.3 0.2 O.1 0.0 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 Time (in years) Adverse Events Costs or disutilities for AEs were not explicitly included in the model, as the impact of AEs related to standard therapy on costs and utilities were reflected in the values assigned to each health state (CR, PR, AD, and ESRD). Also, similar rates of AEs in treatment and comparator arms were reported in the AURORA and BLISS-LN trials, so no AEs related to interventions were included additionally in modeling. Utilities Health state utilities used in the model were derived from published literature. No US-specific preference-based utility values for LN states (CR, PR, and AD), reflecting the total health utility and measured on zero to one or zero to 100 scales, were found in the literature, and no data on utilities have been provided by the manufacturers. Olnstitute for Clinical and Economic Review, 2021 Page 113 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Previous cost-effectiveness models in LN have assumed that the quality of life of patients in CR is similar to that of the general population. The cost-effectiveness model of Wilson et al. (2007) assumed utilities of one for CR®, and a CEA in Thailand reported EQ-5D values for CR of 0.94, comparable to utilities for a healthy population in the US.3*°? However, given the potential for other complications from underlying SLE, clinical experts and patient groups suggested that it is implausible that the utility values for LN patients would be as high as general population utilities. Thus, the model assumed that utility values in the CR state are equal to utility values of the population with SLE who have very low disease activity. As such, the utility values for patients in CR were assumed to be the same as for individuals who scored 0-9 points on Systemic Lupus Activity Questionnaire in a cohort of 182 Swedish patients (0.8+0.16).39 We estimated the utility values for patients in the PR, AD, and ESRD states by applying utility decrements compared to the CR state. A cost-utility analysis of alternative drug regimens for newly diagnosed severe LN patients in Thailand?' reported utility values of 0.94 for CR, 0.85 for PR, 0.764 for AD, and 0.689 for ESRD. These values were used to estimate utility decrements in our model by subtracting the corresponding decrements from the utility value for the CR state: 0.09 for PR, 0.176 for AD, and 0.251 for ESRD. The utility values in this study were calculated based on 216 observations conducted on 18 patients (mean age 40), enrolled in four tertiary care hospitals in Thailand. The utility values for the ESRD state that are reported by Mohara et al. (2014) are comparable to the mean EQ-5D score for ESRD dialysis patients younger than 65 years in a cohort of North American dialysis patients® and to the EQ-5D scores among patients with CKD on dialysis reported in a systematic review by Cooper et al. (2020) [0.44-0.78 in US, Canadian, UK, and international studies].° In the model, all utilities were capped at the general population utility for that age group (see Table E6), to ensure they did not exceed the utilities of the general population. Olnstitute for Clinical and Economic Review, 2021 Page 114 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E6. General Population Utility Values Utilities Related to Steroid Use Patient representatives and clinical experts advised that the benefits to patients of reduced steroid use should be recognized as an important potential benefit of treatment. The short-term model therefore included an incremental gain in utilities related to low-dose steroid and no steroid use. Since no measured utilities were provided by the manufacturers, these utility adjustments were based on published literature and expert clinical opinion. The preferred option to include the increment in utilities associated with lower steroid use was to use the mean difference in steroid use in treatment and comparator arms for both drugs; however, no data on mean steroid use in the voclosporin AURORA trial was provided. Thus, in the short-term model for belimumab, we used the minimum relative increment in utilities for the proportion of patients on low-dose steroids (<5 mg) in the BLISS-LN trial.?" In the short-term model for voclosporin, for both treatment and comparator arms, no increment in utilities was applied during the first eight weeks of the trial, an increment related to low-dose steroid use was applied from week 8 to 16, and an increment related to no steroid use from week 16 onwards. We reflected the possible impact of low-dose corticosteroid use by using a utility increment, which was estimated as equal to the average of the increment measured using the five-item EQ-5D instrument (which showed no increment in utilities related to low-dose steroid use) and a visual analog scale (VAS) EQ-5D in a cohort of patients in Sweden.*3 In addition, an increment in EQ-5D utility for no steroid use, from the same study, was applied (Table E7). Olnstitute for Clinical and Economic Review, 2021 Page 115 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E7. Utility Values for Health States Increment in Utilities Tixeceytsaim mene a(t Baseline for Low-Dose ola ered ena M TL) Steroids No Steroids 0.80 0.025 0.09 0.71 0.025 0.09 0.62 0.025 0.09 0.55 0.025 0.09 AD: active disease, CR: complete response, ESRD: end-stage renal disease, PR: partial response 33,34 Economic Inputs Drug Acquisition Costs Average sales price (Table E8) was used to calculate the costs of belimumab. Since no body weight was reported in the published BLISS-LN trial, the annual cost calculation included the distribution of body weights of the LN population from the literature (with mean weight of 65.92 kg) to estimate the dosage of belimumab (assuming 10mg/kg as in BLISS-LN).*"°" It was assumed that all patients receive belimumab as intravenous administration, as in the BLISS-LN trial. Assuming a standard deviation of 10 kg around the mean weight, including drug wastage resulted in mean dose of 690 mg in the base-case analysis. This mean dose was multiplied by the unit cost ($46.84 per 10 mg) to get the cost per dose of $3,198. An additional administration cost of $72.18 was added for each administration of belimumab (assuming all patients receive belimumab as intravenous administration as in the BLISS-LN trial). In the first month for belimumab, the costs included three doses to reflect the treatment schedule for belimumab in the BLISS-LN trial, resulting in belimumab treatment costs of $9,811 for the first month. Beyond the first month, the cost per dose was multiplied by the average number of monthly doses over a three-year period, based on dosage from the BLISS-LN trial (one dose each 28 days), to estimate the monthly cost of belimumab as $3,560. Voclosporin costs were assessed considering the average daily dose of 39.1mg (mean dose weighted to the duration of patients in AURORA trial) and the price per wallet (containing 60 capsules 7.9mg each) of $3,950 reported by the manufacturer. The mean discount of 22.5% was used to calculate the net price for voclosporin. Olnstitute for Clinical and Economic Review, 2021 Page 116 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E8. Drug Cost Inputs UN Da Tle Mean Monthly Interventions Administration 10mg Drug Cost EY ei el aa ELS $72.18 $46.84 $4.26 $3,560* *Average sales price (ASP) + 6% markup * WAC provided by the GSK +For belimumab, mean monthly costs are based on weight distribution in population (mean weight 65.92 kg). §For voclosporin, mean monthly costs are based on average monthly dose of 39.1mg, price per wallet of $3,950 reported by the manufacturer, and 22.5% discount rate. . Costs of Health States A review of the literature identified multiple sources on costs of LN; however, there were no sources reporting costs split out for being in the AD, CR, and PR model states. The modeling approach considered here used data from the literature sources in combination with expert opinion to yield the most appropriate real-world costs estimation. The base-case analysis estimated the costs for each health state using total mean all-cause health care costs (medical and pharmacy costs) per LN patient per year as a starting point, then applying cost ratios between the different health states. The mean all-cause health care costs per LN patient per year were reported as $45,469 in 2018 by Bartels-Peculis et al.(2020) based on data on 1,039 LN patients (median age, 47 years; 83% female) recorded in a health care claims database.*° This claims database covers members in all 50 states in the US and Washington, DC, including approximately 10 million commercial members and 2.4 million Medicare Advantage members. The costs of being in AD, CR, and PR were calculated as the following. First, the cost of the ESRD state was calculated using relationships between costs for patients with ESRD and without ESRD, compared to overall LN costs. These ratios were estimated as 1.95 and 0.69 respectively from Li et al. (2009).3"7 Then the costs of being in AD, CR, and PR were calculated from the proportional costs of ESRD and different eGFR states reported by Barber et al. (2019). Although their eGFR categories do not correspond exactly with the definitions of response states in the model, clinical experts suggested that the cost ratios for ESRD and eGFR states retrieved from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort are a reasonable approximation.2®*° As such, it was assumed that costs in eGFR >60 ml/min are equal to those in CR (=0.075*ESRD costs), eGFR 30-60 ml/min to PR (=0.078*ESRD costs), and eGFR < 30 ml/min to AD (=0.406*ESRD costs). The calculated costs of each state in the model, inflated to 2019, are reported in Table E9. Olnstitute for Clinical and Economic Review, 2021 Page 117 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Considering that patients in ESRD state qualify for Medicare coverage, cost in ESRD state then was calculated as costs of people with LN, eligible for Medicare in 2016 based on ESRD alone or in combination with disability. Table E9. Costs of Each Model State* Annual Costs, USS Complete response $7,871 Partial response $8,185 Active disease $42,510 $120,920 *Costs are inflated to 2019values Costs of Steroids A reduction in costs related to lower steroid drug cost use was assigned to each model state in the short-term model, using price data from the Redbook." It was calculated that the mean annual cost of oral prednisone with dose of 10 mg/day is $169; the cost of 5 mg/day and 2.5 mg/day were assumed to be one-half and one-quarter of the 10 mg/day cost, respectively. Indirect Costs Indirect costs included costs of unemployment, absenteeism (temporary productivity loss), and caregiving. The costs of absenteeism were estimated from data specific to LN patients, while the other costs were estimated from similar populations, as described below. In the absence of data on US indirect costs for each LN state (CR, PR, AD, and ESRD), data on patient unemployment and productivity loss associated with caregiving were retrieved from a study of the societal economic burden of autosomal dominant polycystic kidney disease (ADPKD) in the US in 2018 (Table E8). Considering that eGFR level is an indicator of kidney function, based on clinical advice we assumed that CKD 1-3 (eGFR 230 ml/min) corresponds to the CR/PR states in the model and CKD 4-5 (eGFR < 30 ml/min) to the AD state in the model. We assessed the unemployment rate related to LN by subtracting from the unemployment to population ratio in each health state (CR, PR, AD, ESRD) the unemployment to population ratio in the US, based on data from Cloutier et al. (2020). The cost of absenteeism because of LN symptoms was assigned to the proportion of the employed population, applying data from a six-month longitudinal survey of SLE patients in the US.® Garris et al. (2013) reported the work hours missed weekly due to SLE by severity of symptoms (assessed as self-perceived disease activity). We estimated these costs assuming that patients in the CR/PR state Olnstitute for Clinical and Economic Review, 2021 Page 118 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC have mild symptoms, patients in AD state have moderate symptoms, and patients in ESRD state have severe symptoms. The costs of caregiving were calculated using the data reported by Cloutier et al. (2020), estimating on average 3.1, 27.0, and 46.7 hours of caregiving annually for patients with CKD stages 1-3 (assumed equal to CR/PR), CKD stages 4-5 (assumed equal to AD), and ESRD, respectively.© In addition, the incremental direct health care costs associated with caregiving were also included in the costs of caregiving. The indirect costs were calculated by multiplying the time on unemployment, absenteeism among those who are employed, and time spent caregiving, with the mean earnings (estimated as weighted average of the proportions of men and women in Davidson et al., and their respective wages extracted from data from the Bureau of Labor Statistics 2020"°) and adding the additional health care costs associated with caregiving. The estimated indirect costs are presented in Table E10. The model considered productivity losses for population up to the retirement age and costs of caregiving for the population lifetime. Table E10. Indirect Costs (Societal Perspective) Estimated Using Median Earnings Unemployment Cost $3,199 $11,220 $19,623 VeRO $1,766 $2,764 $3,038 Productivity Loss and Additional Direct Health Care Costs $175 $793 $1,496 Associated with Caregiving Total Indirect Costs $5,140 $14,777 $24,157 CR: complete response, PR: partial response, AD: active disease, ESRD: end state renal disease *2020 data. Description of 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. 15. 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." 16. For each cycle (Cycle |) 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). Olnstitute for Clinical and Economic Review, 2021 Page 119 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC 17. 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. 18. If no life years were gained using the intervention versus the comparator, we use the conventional utility estimate for that Cycle I. 19. The total evLY is then calculated as the cumulative sum of QALYs gained using the above calculations for each arm. 20. 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. E3. Results Tables E11 and E12 present the base-case results from the health care sector perspective. Table E11 presents the results for belimumab, while Table E12 presents the results for voclosporin. The total costs in the belimumab arm were approximately $930,000 , which is higher than the total costs in the standard care arm of around $886,000. However, the belimumab arm has higher QALYs, LYs and evLYGs (11.67 QALYs, 17.86 LYs, and 11.74 evLYGs respectively) compared to the standard care arm (11.18 QALYs, 17.48 LYs, and 11.18 evLYGs respectively). This resulted in an incremental cost per QALY gained of approximately $90,000, an incremental cost per LY gained of $114,000 for belimumab compared to standard care, and incremental cost per evLYG of approximately $78,000. Table E11. Discounted Base-Case Results for Belimumab versus Standard Care: Health Care Sector Perspective tll OTT ee oe QALYs ne PRC} Costs, $ $93,465 $929,962 11.666 17.861 11.740 Standard Care $886,343 11.180 17.478 11.180 Incremental Incremental Incremental Titers] Ook Ca) : QALYs iA evLYG Belimumab vs. Standard Care $43,620 0.49 0.38 0.56 Cost per QALY Cost per Life Cost per EYE eM CML ela lac MO] a2) Gained, $ Year Gained, $ evLYG, $ $89,663 $113,847 $77,835 Olnstitute for Clinical and Economic Review, 2021 Page 120 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC The total costs in the voclosporin arm were approximately $929,000, which is higher than the total costs in the standard care arm of around $784,000. However, the voclosporin arm has higher QALYs, LYs and evLYGs (12.64 QALYs, 18.41 LYs, and 12.77 evLYGs respectively) compared to the standard care arm (11.67 QALYs, 17.58 LYs, and 11.67 evLYGs respectively). This resulted in an incremental cost per QALY gained of approximately $149,000 an incremental cost per LY gained of $174,000 for voclosporin compared to standard care, and incremental cost per evLYG of approximately $132,000. Olnstitute for Clinical and Economic Review, 2021 Page 121 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E12. Discounted Base-Case Results for Voclosporin versus Standard Care: Health Care Sector Perspective Treatment Total Costs, $ Costs, $ Standard Care - $784,416 Incremental Incremental Titel geyantsyale-) : Incremental Costs, $ Voclosporin vs. Standard Care fey. NRG NG evLYG $144,070 Cost per Life Cost per QALY : Cost per : : Year Gained, Voclosporin vs. Standard Care Gained, $ evLYG, S 3 $149,260 $174,250 $131,528 Olnstitute for Clinical and Economic Review, 2021 Page 122 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Results from Undiscounted Analysis Tables E13 and E14 present the undiscounted base-case results from the health care sector perspective for belimumab and voclosporin, respectively. Table E13. Base-Case Undiscounted Results for Belimumab versus Standard Care: Health Care Sector Perspective Dols artes e ace ct Bgl dal yan9 Beet 1-019 Health Total Costs, mie Cost/LY Costs, $ § (oor 7 Ley-1N ' Cost/evLYG, Care Costs, . Gained, Gained, $ $ $96,443 $1,627,622 $1,724,065 18.307 28.677 18.443 $43,079 $48,858 $36,545 Standard é - $1,691,480 $1,691,480 17.551 28.010 17.551 - - - are Table E14. Base-Case Undiscounted Results for Voclosporin versus Standard Care: Health Care Sector Perspective Non- eee Beh 4 rut Total Health QALYs | LYs | evLYG | Cost/QALY | Cost/LY | Cost/evLYG, Costs, $ : Costs, $ are Gained,$ | Gained, $ k) Costs, $ $223,549 $1,459,278 $1,682,827 19.694 29.623 19.933 $92,255 $98,563 $79,420 Standard ean - $1,546,212 $1,546,212 18.213 28.237 18.213 - - - Olnstitute for Clinical and Economic Review, 2021 Page 123 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC E4. Sensitivity Analyses Sensitivity Analyses Results for Belimumab To demonstrate effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors) or reasonable ranges to evaluate changes in cost per additional QALY. For the belimumab versus standard care comparison, the results of sensitivity analyses demonstrate high certainty in cost effectiveness of this treatment (Figure E4 and Table E15). Figure E4, Tornado Diagram for One-Way Sensitivity Analyses of Belimumab versus Standard Care Monthly costs of AD health state* [$3000, $7000] (I Utility in CR health state* [0.72, 0.9] Hm Utility in AD health state [0.6, 0.7] Zz W@ICER for Upper Input Monthl ts of CR health stat 500, $1000 onmny costs © ealth state [$ ° = @ICER for Lower Input Monthly costs of ESRD health state* [S6000, $12000] Y | | Utility in PR health states* [0.63, 0.79] | $50,000 $100,000 $150,000 $200,000 $250,000 Incremental Costs per QALY *Lower input corresponds to higher incremental cost-effectiveness ratio and vice versa. Olnstitute for Clinical and Economic Review, 2021 Page 124 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E15. Tornado Diagram Inputs and Results for One-Way Sensitivity Analyses of Belimumab versus Standard Care Lower ICER | Upper ICER aya a Input Utility in PR health states* [0.63, 0.79] $90,766 $88,589 0.63 0.79 Monthly costs of ESRD health state* $103,025 $83,359 $6,000 $12,000 HUSA) Monthly costs of CR health state [$500, $83,759 $102,691 $500 $1,000 $1000] Utility in AD health state [0.6, 0.7] $86,106 $103,155 0.6 0.7 Utility in CR health state* [0.72, 0.9] $113,403 $76,975 0.72 0.9 Monthly costs of AD health state* [$3000, $104,283 S-3,515 $3,000 $7,000 $7000] *Lower input corresponds to higher incremental cost-effectiveness ratio and vice versa. Table E16 presents the results of the probabilistic sensitivity analysis (PSA). Due to the lack of data for many inputs, the distributions used for costs and utilities in the PSA are mean values +10%. Table E16. Results of Probabilistic Sensitivity Analysis for Belimumab versus Standard Care Credible : Credible Credible Range Range tay) Total Total 934,663 896,233, 23,007, > (> S 886,305 ($845,508, $927,103) $48,357 (> Costs $973,093) $73,708) Total 11.700 (11.310, 11.192 (10.795,11.589) 0.51 - (0.30,0.71) ey NG 12.089) ($90,106, - - - - 95,269 ce > $100,371) Figure E5 presents cost-effectiveness clouds (i.e., the scatterplot of costs vs. QALYs) from the probabilistic sensitivity analysis (PSA) for belimumab and standard care. Olnstitute for Clinical and Economic Review, 2021 Page 125 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Figure E5. Cost-Effectiveness Clouds for Belimumab and Standard Care $1,100,000 $1,050,000 $1,000,000 $950,000 $900,000 $850,000 Costs $800,000 $750,000 $700,000 @ Belimumab $650,000 @ Standard care $600,000 10.000 10.500 11.000 11.500 12.000 12.500 13.000 13.500 14.000 QALYs Figure E6 below presents the cost-effectiveness acceptability curve for belimumab versus standard care. At a threshold of $50,000/QALY, belimumab had 25% chance of being cost-effective, a 52% chance of being cost-effective at a threshold of $100,000/QALY and a 69% chance of being cost- effective at a threshold of $150,000/QALY. Olnstitute for Clinical and Economic Review, 2021 Page 126 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Figure E6. Cost-Effectiveness Acceptability Curve for Belimumab versus Standard Care == Belimumab 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Probability of being cost-effective compared to BSC 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 Threshold Olnstitute for Clinical and Economic Review, 2021 Page 127 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Sensitivity Analyses Results for Voclosporin To demonstrate effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors) or reasonable ranges to evaluate changes in cost per additional QALY. For the voclosporin versus standard care comparison, key drivers of uncertainty included monthly costs and utility values in the CR and AD health states (Figure E7 and Table E17). Figure E7. Tornado Diagram for One-Way Sensitivity Analyses of Voclosporin versus Standard Care Monthly costs of AD health state* [$3000, $7000] Po Utility in CR health state* [0.72, 0.9] im Utility in AD health state [0.6, 0.7] Po W@ICER for Upper Input Monthly costs of CR health state [$500, $1000] i @ ICER for Lower Input Monthly costs of ESRD health state* [S6000, $12000] i Utility in PR health states* [0.63, 0.79] il $50,000 $100,000 $150,000 $200,000 $250,000 Incremental Costs per QALY *Lower input corresponds to higher incremental cost-effectiveness ratio and vice versa. Olnstitute for Clinical and Economic Review, 2021 Page 128 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E17. Tornado Diagram Inputs and Results for One-Way Sensitivity Analyses of Voclosporin versus Standard Care a ee ee ao Wyeaess ee Utility in PR health area one states* [0.63, 0.79] $146,446 $152,177 . , Monthly costs of ESRD health state* [S6000, $6,000 $12,000 $12000] $155,550 $146,293 Monthly costs of CR health state [$500, 0.72 0.9 $1000] $144,203 $167,907 state [0.6, 0.7] ' $127,235 ' ' Utility in CR health $143,404 $162,185 ee a Monthly costs of AD health state* [S3000, $3,000 $5,000 $7000] $161,649 $70,306 *Lower input corresponds to higher incremental cost-effectiveness ratio and vice versa. Table E18 presents the results of the probabilistic sensitivity analysis (PSA). Due to the lack of data, the distributions used for costs and utilities in the PSA are mean values +10%. Table E18. Results of Probabilistic Sensitivity Analysis for Voclosporin versus Standard Care (efg=telle) (<1 Credible (of gto) (=) DET) eax) Range ($895,716, ($746,628, ($121,013, S 928,107 $783,688 S 144,419 $960,498) $820,748) $167,826) (12.252, (11.309, 12.641 11.680 0.96 (0.76, 1.16) 13.029) 12.051) 145,690, - - - - S 150,334 (> $154,958) Olnstitute for Clinical and Economic Review, 2021 Page 129 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Figure E8 presents cost-effectiveness clouds (i.e., the scatterplot of costs versus QALYs) from the probabilistic sensitivity analysis (PSA) for voclosporin and standard care. Due to the lack of data, the distributions used for costs and utilities in the PSA are mean values +10%. Figure E8. Cost-Effectiveness Clouds for Voclosporin and Standard Care $1,100,000 $1,050,000 $1,000,000 $950,000 $900,000 $850,000 Costs $800,000 $750,000 $700,000 @ Voclosporin $650,000 @ Standard care $600,000 10.000 10.500 11.000 11.500 12.000 12.500 13.000 13.500 14.000 QALYs Olnstitute for Clinical and Economic Review, 2021 Page 130 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Figure E9 below presents the cost-effectiveness acceptability curve for voclosporin versus standard care. At a threshold of $50,000/QALY, voclosporin had 0.3% chance of being cost-effective, a 11.3% chance of being cost-effective at threshold of $100,000/QALY and a 48.6% chance of being cost- effective at threshold of $150,000/QALY. Figure E9. Cost-Effectiveness Acceptability Curve for Voclosporin versus Standard Care 1 Voclosporin 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Probability of being cost-effective compared to BSC 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 Threshold Olnstitute for Clinical and Economic Review, 2021 Page 131 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC E5. Scenario Analyses We performed scenario analyses to identify the effect of alternative inputs and assumptions on the cost-effectiveness results. Tables E19 and E20 present the results from a scenario analysis taking a modified societal perspective, which includes costs of unemployment, absenteeism (temporary productivity loss), and caregiving, along with patient QALYs, LYs, and health care costs. Table E19 presents the results for belimumab, while Table E20 presents the results for voclosporin. Table E19. Base-Case Results for Belimumab versus Standard Care: Modified Societal -- = r | tmerementaResuts | eK otal Costs ' Ae Vc) QA Cost/QALY feria ee Gained, $ Gained, $ $1,126,351 11.666 17.861 11.740 $66,103 $83,933 $57,383 ee Standard Care $1,094,193 11.180 17.478 11.180 = : 2 Table E20. Base-Case Results for Voclosporin versus Standard Care: Modified Societal er - ee Reb hoi VN INC en ay (ee cy yey hg ony] h ' Cost/evLYG, $ Gained, $ Gained, $ Cou $1,095,833 12.640 18408 12.770 $131,962 $154,055 $116,285 - Care $968,460 11674 17.581 11.674 - - - Olnstitute for Clinical and Economic Review, 2021 Page 132 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E21 and E22 present the results from a scenario analysis utilising CR rates in Black population in BLISS-LN and AURORA trials. Table E21 presents the results for belimumab, while Table E22 presents the results for voclosporin. Table E21. Scenario Analysis Results Assuming CR Rate Specific to Black population in BLISS-LN Otol ee Results Treatment | Treatment Total YN RG Costs Health Costs eal evLYG ee a a Cost/evLYG feline ts Gained CET =fe) Belimumab $87,884 $891,396 979,280 11.243 17.585 11.305 $156,093 $187,230 $132,893 Standard - $924,124 $924,124 10.890 17.290 10.890 - - (er) g-) Trial Table E22. Scenario Analysis Results Assuming CR Rate Specific to Black Population in AURORA Non- Tivtesiatalee Bates Treatment | Treatment Costs alia) Ueto | ChING a6 ci AC) Cost/QALY | Cost/LY , ; Cost/evLYG Care Costs Gained Gained Trial VEEEEeT §©- $215,296 $713,045 $928,341 12.681 18.408 12.809 $129,250 $173,633 $115,869 Standard - $784,781 $784,781 11.570 17.581 11.570 - - Care Olnstitute for Clinical and Economic Review, 2021 Page 133 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Tables E23 and E24 present the results from a scenario analysis assuming lower survival (of 25.22 years overall survival and 14.49 years ESRD-free survival) in the CR and PR states. These scenario analyses were thought to be useful in case the clinical experts believe that long-term survival for those achieving response might not be as optimistic as assumed in the model. Table E23 presents the results for belimumab, while Table E24 presents the results for voclosporin. Table E23. Scenario Analysis Results Assuming Lower Survival in CR/PR Health States for Belimumab versus Standard Care: Health Care Perspective = = Maa onet Miter elects reatment | Treatment (oye) Costs el b aay (eteea cy ele BS evLYG | Cost/QALy | Cost/LY , ' Cost/evLYG Care Costs Gained Gained $93,465 $888,150 $981,615 10.991 17.221 11.036 $170,113 $233,207 $149,514 Belimumab Standard - $926,225 $926,225 10.665 16.983 10.665 - - - (er) g-) Table E24. Scenario Analysis Results Assuming Lower Survival in CR/PR Health States for Voclosporin versus Standard Care: Health Care Perspective telat eee Treatment | Treatment Total Cost/QALY | Cost/LY Costs teria) Costs alah a habe é say eet i , Cost/evLYG Care Costs ale als Claleyreye) § $215,296 $789,086 $1,004,382 11.649 17.466 11.739 $237,389 $281,114 $210,105 Stale lae| - $840,567 $840,567 10.959 16.884 10.959 - - - (er) g-) Olnstitute for Clinical and Economic Review, 2021 Page 134 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Tables E25 and E26 present the results from a scenario analysis assuming lower utilities (of 0.72 and 0.64, respectively) in the CR and PR states. These scenario analyses were thought to be useful in case the clinical experts believe that long term QoL for those achieving response might not be as high as assumed in the model.3*3 Scenario analyses were performed using Table E25 presents the results for belimumab, while Table E26 presents the results for voclosporin. Table E25. Scenario Analysis Results Assuming Lower Utilities in CR and PR Health States for Belimumab versus Standard Care: Health Care Perspective . . ue - itt a alent cs aes ota Costs Pela Pee a Di al ad aden 97°18 TL PORE N = Care Costs Gained Gained $93,465 $836,497 929,962 11.212 17.861 11.298 $114,948 113,847 $93,770 - $886,343 886,343 10.833 17.478 10.833 - - - Care Table E26. Scenario Analysis Results Assuming Lower Utilities in CR and PR Health States for Voclosporin versus Standard Care: Health Care Perspective Non- Tikes eels Octal ala Cost/QALY | Cost/LY Costs edb) CAS ie SOAS i / Cost/evLYG Gained Gained Care Costs Voclosporin $215,296 $713,190 $928,486 11.959 18.408 12.126 $185,904 $174,250 $152,969 Sit lilerlae| - $784,416 $784,416 11.184 17.581 11.184 - - - ler] g-) Olnstitute for Clinical and Economic Review, 2021 Page 135 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Tables E27 and E28 present the results from scenario analyses assuming longer duration of AD state among those patients who progressed to ESRD and had a relapse in the long-term model. The scenario analyses were performed to address the concern of clinical experts that the time patients with relapse remain in AD state before progressing to ESRD may be longer than in the base-case analysis. Table E27 presents the results for belimumab, while Table E28 presents the results for voclosporin. Table E27. Scenario Analysis Results Assuming Longer Duration of AD State for Patients with Relapse who Progressed to ESRD: Belimumab rd atau eee MNc=t-h tele a yl deal an Total Costs Telia) Costs BAS) BUA KS Cost/QALY | Cost/LY , : Cost/evLYG Care Costs Gained Gained AD duration: 2 years $93,465 $838,812 $932,278 11.525 17.861 11.599 $97,156 $115,221 $83,560 Belimumab Sit liteklae| $888,132 $888,132 11.071 17.478 11.070 - - - (er) g-) AD duration: 3 years $841,729 $935,194 11.347 17.861 11.421 $108,245 $116,951 $91,843 Belimumab $93,465 Seater lee] $890,385 $890,385 10.933 17.478 10.933 - - - ler] g-) AD duration: 5 years $847,561 $941,026 10.992 17.861 11.065 $138,501 $120,412 $113,345 Belimumab $93,465 Standard - $894,891 $894,891 10.658 17.478 10.658 a 2 2 (er) g) Olnstitute for Clinical and Economic Review, 2021 Page 136 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E28. Scenario Analysis Results Assuming Longer Duration of AD State for Patients with Relapse who Progressed to ESRD: Voclosporin r r Non- a ee Results Lae Dla ota VR ai Costs Health Costs alah hae Cost/QALY mane < ae Care Costs Gained a AD duration: 2 years $215,296 $716,593 $931,889 12.432 18408 12.562 $159,038 $175,317 $139,168 Voclosporin Sitlieklae| $786,936 $786,936 11.521 17.581 11.521 ler] g) AD duration: 3 years $215,296 $720,878 $936,174 12.171 18.408 12.301 $173,127 $176,661 $149,992 Voclosporin Standard $790,111 $790,111 11.327 17.581 11.327 - - - Care AD duration: 5 years $215,296 $729,448 $944,744 11.648 18.408 11.778 $209,393 $179,349 $176,888 Voclosporin Standard - $796,459 $796,459 10.940 17.581 10.940 a ° 2 ler] g-) Table E29 presents the results from scenario analyses assuming treatment discontinuation at 6 months for patients remaining in active disease state on voclosporin treatment. Table E29. Scenario Analysis Results Assuming Treatment Discontinuation at 6 Months for Voclosporin versus Standard Care: Health Care Perspective . . ue - ee Results ETc ota Costs Pela Costs BN bebe Ke Lo Or ey EN Te Care Costs Gained Gained $188,813 $713,190 12.640 18.408 12.770 $121,823 $107,350 Voclosporin $902,003 $142,218 Sit iteklae| $784,416 11.674 17.581 11.674 - - - Care $784,416 Olnstitute for Clinical and Economic Review, 2021 Page 137 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Tables E30 and E31 present the results from scenario analyses assuming alternative costs of health states calculation based on cost ratios between ESRD and other health states (data in confidence). The ratio of costs in the complete and partial responses to ERSD was calculated as 0.164072514, and the ratio of costs in active disease to ERSD was calculated as 0.302691815. Table E30. Scenario Analysis Results Assuming Alternative Costs of Health States Calculation for Belimumab versus Standard Care: Health Care Perspective . . ls - Mitte sat sub elas ae taah ota Costs Pela ee a Diet dee nea 97°) TL Pen ETN = Care Costs Gained Gained ; $93,465 $882,355 11.666 17.861 11.740 $142,470 $123,676 Belimumab $975,820 $180,897 Sie llerlae| S- $906,511 11.180 17.478 11.180 - - - Care $906,511 Table E31. Scenario Analysis Results Assuming Alternative Costs of Health States Calculation for Voclosporin versus Standard Care: Health Care Perspective oy ats Incremental Results Treatment | Treatment Total Cost/QALY | Cost/LY Costs Health Costs en f5 Die aah i : i Cost/evLYG Gained Gained Care Costs : $215,296 $817,371 12.640 18.408 12.770 $195,159 $171,973 Voclosporin $1,032,667 $227,832 St aler-lae| S- $844,295 $844,295 11.674 17.581 11.674 - - - (er) g) Olnstitute for Clinical and Economic Review, 2021 Page 138 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC E6. Heterogeneity and Subgroups It is likely that LN progression will differ by ethnicity," and modeling using SLICC data which considered ethnicity was our preferred approach. However, the manufacturers did not provide the requested data that would have allowed us to implement this modeling approach. As such, the model did not consider differing probabilities of disease progression by ethnicity. The scenario analysis considered complete response rate in Black population according to BLISS-LN and AURORA trials data; however, because of the substantial limitations of these data, these results should be considered with extreme caution. The cost values in the long-term model were independent of ethnicity. The distribution of patients in Medicaid by ethnicity shows a higher percentage of Black than White population.3"73 This would result in differences in health state costs by ethnic sub-group because Medicaid costs differ from costs on private insurance. '? To avoid the potential ethical implications of valuing health states differently for certain groups, the analysis assumed average costs independent of ethnicity. The model also did not consider utility values of health states by ethnicity. Studies on general populations and ethnic subgroups show that socio-economic status is a significant determinant of the quality of life.3239 Since race/ethnicity and income are strongly correlated,"° using ethnicity- specific utilities could result in lower utility values for Black (compared to White) patients in the CR state, while similar utilities for Black and White population in the ESRD state.© This could result in worse cost-effectiveness findings in Black versus White populations, independent of the treatment effectiveness among these groups. Thus, only general (not ethnicity-specific) utility values were used in the study, so as to avoid potentially disadvantaging ethnic groups with lower utility values. E7. Model Validation Several approaches were undertaken to verify and validate the model. Model verification followed standard practices in the field. We tested all mathematical functions in the model to ensure they were consistent with the report (and supplemental materials). Model input parameters were varied to evaluate the face validity of changes in results. 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. For model validation, preliminary methods and results were presented to manufacturers, patient groups, and clinical experts, with data inputs changed as needed and scenario analyses defined. As part of ICER's initiative for modeling transparency, we shared the model with interested manufacturers for external verification shortly after publishing the draft report for this review. The Olnstitute for Clinical and Economic Review, 2021 Page 139 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC outputs from the model were validated against the trial and study data of the interventions as well as any relevant observational datasets. 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. Our model results were compared to other cost-effectiveness models in this therapy area. Prior Economic Models Three models compared cost effectiveness of alternative drug regimens for LN patients in the past ten years (Table E27).93%74 All three identified models (one for US and two for Asian countries) used the response/remission structure to reflect the disease progression. None of the models evaluated the cost effectiveness of either belimumab or voclosporin, with Kim et al. (2019) assessing cost effectiveness of tacrolimus, while Mohara et al. (2014) and Nee et al. (2015) assessed the cost effectiveness of multiple standard regiments of LN treatment. Only Kim et al. (2019) provided the definitions of the outcomes used, which were defined according to the 2012 Clinical Practice Guideline on Glomerular Diseases." None of the previous models considered ethnical diversity of the LN population, with the other US model by Nee et al. (2015) modeling the population reflecting demographic and ethnicity in trials (i.e. underrepresented Black population).? The study of Davidson et al. (2018) applied in this modeling, gives an advantage of more accurate representation of ethnicity in LN population in the US. While Nee et al. (2015) used life-time horizon to calculate the costs, only therapy costs incurred during the first 3-years were considered in the analysis.? The other model with the lifetime horizon, by Kim et al. (2019), included the cost of maintenance treatment until the patient relapsed."* These assumptions differ from the current model assuming that (a) even if progressed, patients would not stop the standard treatment (rather would change the treatment scheme), and (b) chronic LN condition would require patients to have standard therapy over their lifetime. Two Asian models used comparable utility values to this model.3*4 Nee et al. (2015) combined utility values from sources of different origin and applying different measurement scales, as a result the utility value of patients on dialysis (ESRD) in Nee's et al. model was higher than the utility value of the relapse state (0.67 versus 0.60). To accurately reflect an impact of LN development on quality of life (i.e., a more advanced state has lower utility values), this model used adjustment to utility values instead of combining the utility values from multiple sources. The previous cost-effectiveness models predicted accumulating 9.4-9.7,34 11.3-11.5," and 14.2- 15.10 QALYs for patients treated with standard therapies in comparison to 11.2 - 11.7 QALYs on Olnstitute for Clinical and Economic Review, 2021 Page 140 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC standard treatment predicted by this model. The difference between this and the other US model can be explained by the approach to utility values described above. The prior cost-effectiveness models predicted total costs for patients on standard treatment (converted to USD inflated to 2019 values) in the ranges $48-121k," $174-180k,** and $669-677k.? The total lifetime costs on the standard care in this model were equal to $784-886k. Considering that the US model of Nee et al. (2015) applied maintenance costs only for three years, the predictions of the two models may be considered comparable. Olnstitute for Clinical and Economic Review, 2021 Page 141 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table E27. Comparison of the Modeling Studies in Lupus Nephritis ae Horizon Author Definitions cial alas Population gets Dalby SeLTe Therapies Tay ada) and Values (Year) , TCL iT ays CR: return of serum creatinine to baseline, plus a Inducti AD decline in nduction hase: (start), UPCR to (1) patients 2 -_ CR, PR, <500 mg/g with focal or EQ-5D from decision , ; : ESRD, PR: 9 scenarios for diffuse Mohara et al.: Kim et tree . eas . . . . (1) 20 y - . . kidney stabilization induction and proliferative CR-0.940, PR- 1 China Maintena . (2)3m ert) nce transplan (425%) or maintenance LN (Class III-V) (3) 3% 0.850, AD - hase: t, post- improveme __ therapies (2) mean age ° 0.764, ESRD - F ' kidney nt of serum at baseline - 0.689 Markov _. transplan creatinine, 18y model t but not to the baseline, plus a 250% decrease in UPCR Baseline (i.v. CYC . 1 - iv. CYC) +3 (1) Newly Ne r Measured EQ- ifetime AD comparators for diagnosed 5D (216 IM fel iele . . . (2) 6m . (start), induction and active severe patients) : CR- aetal. . Markov No . . for the Y1 Thailand CR, PR, oo. maintenance LN patients 0.940, PR - Es model definitions . and 12m ESRD, therapies (CYC > (2) mean age 0.850, AD - (2013) . . afterwar death AZA, i.v. CYC > at baseline - d 0.764, ESRD - 40 0.689 MMF and MMF - ly (3) 3% low-dose MMF) Remissio . 3-year (1) patients n (start), . . maintenance with VAS froma relapse . . : . regimens (MMF proliferative Dutch requiring (1) Nee et vs. AZA) [assumed LN _. reference: Markov MMF, No . Lifetime _. al.? US <a patients do not (2) range 20-40 remission - model relapse definitions ; (2) 12m (2015) requirin need y (reflecting (3) 3% 0.70, relapse - ove 3 immunosuppressi demographic/ . 0.6; TTO ESRD - ESRD ve agents after ethnicity in 0.67 ' this time trials death ) Olnstitute for Clinical and Economic Review, 2021 Page 142 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC cis Author (Year) Cola 3% model Trial- el based (start), and US . CR, PR, partitione . ESRD, d-survival death model pY=y Tai atey ae CR: UPCR <0.5, eGFR no worse than 10% below pre- flare value or 290 ml/min/1.73 m2with no use of rescue therapy. PR: GFR no worse than 10% below baseline or within normal range and at least 50% decrease in UPCR with UPCR <1.0 if baseline ratio <3.0, or UPCR <3.0 if baseline ratio >3.0; no treatment failure; and not CR. Compared Therapies Belimumab vs. standard therapy; Voclosporin vs. standard therapy Population (1) Newly diagnosed LN patients (2) mean age at baseline - 35y. Horizon Cycle Length Eolas (1) Lifetime (2) 1m (3) 3% Utility Sources and Values EQ-5D score in Swedish population; an impact of disease severity on EQ-5D is adjusted using Mohara et al. data: CR -- 0.8, PR--O.71, AD- 0.624, ESRD - 0.549 States: AD: Active disease; CR: Complete remission; PR: partial remission; ESRD: End-stage renal disease; Treatments: AZA: Azathioprine; CYC: cyclophosphamide; MMF: mycophenolate mofetil; Other abbreviations: eGFR: glomerular filtration rate (assessment of renal function); ICER: incremental cost-effectiveness ratio; LE: lupus erythematosus; LN: lupus nephritis; TTO - time trade-off, QALY: quality-adjusted life-years. ©lnstitute for Clinical and Economic Review, 2021 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page 143 Return to ToC F. Potential Other Benefits and Contextual Considerations QALY Shortfalls One important contextual consideration to consider is the argument that society should give preference to treatments for patients with more severe conditions," and that giving priority to treatments according to "lifetime burden of illness" or "need" best represents the ethical instincts of a society or other decision-makers.'"°"" To inform this contextual consideration, ICER provides empirical results for the absolute QALY shortfall and proportional QALY shortfall. The absolute QALY shortfall is defined as the total absolute amount of future health patients with a condition are expected to lose without the treatment that is being assessed."* The ethical consequences of using absolute QALY shortfall to prioritize treatments is that conditions that cause early death or that have very serious lifelong effects on quality of life receive the greatest prioritization. Thus, certain kinds of treatments, such as treatments for rapidly fatal conditions of children, or for lifelong disabling conditions, score highest on the scale of absolute QALY shortfall. The proportional QALY shortfall is measured by calculating the proportion of the total QALYs of remaining life expectancy that would be lost due to untreated illness."2®° The proportional QALY shortfall reflects the ethical instinct to prioritize treatments for patients whose illness would rob them of a large percentage of their expected remaining lifetime. As with absolute QALY shortfall, rapidly fatal conditions of childhood have high proportional QALY shortfalls, but the highest numbers can also often arise from severe conditions among the elderly who may have only a few years left of average life expectancy but would lose much of that to the illness without treatment. For this population of adults with SLE and Class Ill, IV, or V LN, the absolute shortfall was estimated to be 21.2 QALYs, with a proportional shortfall of 0.55, representing a loss of 55% of total quality- adjusted life expectancy (QALE) relative to individuals without the condition. To provide some anchoring of these results, we also present a league table of absolute and proportional QALY shortfalls for a variety of conditions from prior ICER reports (Table F1), using a burden of disease calculator developed by Dutch investigators (https://imta.shinyapps.io/iDBC/) that allows for calculation of absolute and proportional QALY shortfalls under different assumptions." ©lnstitute for Clinical and Economic Review, 2021 Page 144 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Table F1. League Table of Absolute and Proportional QALY Shortfalls for Selected Conditions a cea wl eked cy From iDBC tool®* Total Undiscounted : Absolute Proportional Shortfall Shortfall Condition QALYs with Standard of Care NATE Ole AV or V LN Cystic Fibrosis Secondary Progressive Multiple Sclerosis Hemophilia A Mcrae lae Major Depression Moderate-to-Severe 40 Ulcerative Colitis BCG-Unresponsive 72 80 4.9 5.7 0.54 High-Risk NMIBC QALY: quality-adjusted life year Olnstitute for Clinical and Economic Review, 2021 Page 145 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC G. Potential Budget Impact: Supplemental Information Table G1. Cumulative Net Cost Per Patient Treated with Belimumab or Voclosporin at Net Prices Over a Five-Year Time Horizon Belimumab Voclosporin Additional Costs per : Additional Costs per ' : CUTE Lai -meokg ' COTE L ti =m ekg NT euler Livi) | Year (Non-Cumulative) $47,223 $47,223 $87,153 $87,153 $26,511 $73,734 $69,084 $156,237 $13,779 $87,513 $51,828 $208,065 -$3,918 $83,595 -$5,408 $202,657 -$3,990 $79,605 -$5,522 $197,135 Olnstitute for Clinical and Economic Review, 2021 Page 146 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC H. Public Comments This section includes summaries of the public comments prepared for the New England CEPAC Public Meeting on Friday, March 26, 2021. These summaries were prepared by those who delivered the public comments at the meeting and are presented in order of delivery. Three speakers did not submit summaries of their public comments. 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. Bernard Rubin, DO, MPH Medical Director, GlaxoSmithKline My name is Bernie Rubin, and | am a rheumatologist and medical director in GlaxoSmithKline's immuno-inflammation therapy area. Speaking on behalf of my GSK colleagues, | thank ICER for the opportunity to make public comments on their review of lupus nephritis treatments, including GSK's belimumab. We also thank the ICER staff for their collegial interactions over the past 7 months and acknowledge the substantial effort that went into this assessment. During my 30-year career as a practicing rheumatologist prior to joining GSK, | regularly saw both the catastrophic sudden onset of lupus nephritis in my patients, as well as the equally devastating slowly progressive kidney inflammation that can occur in patients with SLE. In either case, the onset of lupus nephritis disrupted their lives, affecting their well-being, work, home life, and interpersonal relationships. Even in the best of circumstances, only half of lupus nephritis patients achieve remission, subjecting those who do not reach this milestone to slowly progressive kidney failure and potential dialysis; thus, highlighting the desperate need for new treatments. GSK is committed to delivering high value, high quality treatments to patients and we remain committed to the lupus community with the recent FDA approval of IV and subcutaneous belimumab for the treatment of lupus nephritis. The findings of the ICER evaluation of lupus nephritis treatments support the value of belimumab as a cost-effective therapy. However, limitations and uncertainties remain with ICER's assessment, including the following key elements: First, lupus nephritis is a complex disease that is difficult to model: At the core of every economic model is the assumption that the model is a simplification of a complex world. GSK is concerned that ICER's lupus nephritis economic model may not sufficiently capture the true and complex patient journey; thereby underestimating the value of interventions aimed at improving the lives of lupus nephritis patients. Models should seek to appropriately Olnstitute for Clinical and Economic Review, 2021 Page 147 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC account for all benefits that medicines have in this disease to the extent possible. GSK urges ICER to acknowledge this limitation, both in its final report and the executive summary. Second, it is critical to capture the entire range of treatment benefits: GSK appreciates ICER's scenario analysis that accounted for the societal perspective when determining cost per QALY for belimumab. However, GSK believes that it does not fully account for the health-related quality of life and symptom burden of lupus nephritis on productivity and day-to- day activities, which extend to patients' family members, caregivers, friends, and employers. GSK once again urge ICER to acknowledge this point as a limitation to the model, both in its final report and the executive summary. Lastly, | would like to take this opportunity to provide additional suggestions, as ICER develops its final report: 1. Model outcomes should be reported as ranges, rather than point estimates, in order to reduce confusion among lay readers. 2. Releasing the complete model methodology to avoid the perception of an opaque process. Given the many stakeholders involved, trust is ICER's most valued asset. 3. Model limitations should be considered by CEPAC, and later by ICER, not only in the body and appendix of the final report, but also in the executive summary, which will be read by a much wider audience. Consideration of these suggestions will provide both CEPAC and ICER with the opportunity to educate the public on the broader field of value assessment, rather than just the two drugs included in this review. To conclude, GSK again acknowledges ICER's effort in conducting this assessment. We value collaboration with all stakeholders. Our company is committed to delivering high value, high quality treatments and welcome ICER's lupus nephritis evaluation. This evaluation supports the value of belimumab as a cost-effective therapy offering patients with the devastating disease of lupus nephritis the potential to access much needed, innovative medications. Thank you for your time and the opportunity to comment on behalf of GSK. Dr. Rubin is a full-time employee of GlaxoSmithKline. Olnstitute for Clinical and Economic Review, 2021 Page 148 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Eric Turowski, MBA Vice President of Market Access, Aurinia Pharmaceuticals, Inc. Lupus Nephritis (LN) is a rare, life-threatening disease with historically no FDA-approved therapies until late 2020. If poorly controlled, LN can lead to permanent and irreversible tissue damage within the kidney, resulting in kidney failure. Treating LN is a race against the clock. A single flare causes irreversible damage. Unfortunately, LN disproportionately impacts underserved patients in Black, Asian and Hispanic communities: these patients, in particular, will benefit from effective and safe oral medications. Aurinia has been dedicated to bringing voclosporin to patients for ~20 years through research, investment, and development. We have spent significant time engaging with patients, caregivers, advocacy organizations and healthcare providers, and we have heard them continue to vocalize the devastating impact of uncontrolled LN. Throughout our launch preparations, we invested in cost- effectiveness modeling and analysis to help us determine an appropriate price for LUPKYNIS. This price is consistent with the total value LUPKYNIS brings to patients, providers, and the healthcare system. Our priority and focus for LUPKYNIS is to provide all LN patients access to this potentially life-changing and life-saving medicine that offers genuinely unique clinical value demonstrated in our clinical trial program: ° Patients on LUPKYNIS were 2.7 times more likely to achieve a Complete Response at one year, with comparable adverse events and in the presence of low dose steroids vs. the current standard of care alone. * Proteinuria is the single best predictor of positive long-term outcomes, and LUPKYNIS reduced proteinuria twice as fast as the standard of care alone. ° LUPKYNIS displayed consistent efficacy across racial and ethnic subgroups. * Regarding ICER's modeling in this assessment, we wish to point out that the assumption regarding LUPKYNIS's treatment duration is not consistent with the vast amount of research we have conducted with rheumatologists and nephrologists. ° ICER assumes that patients who do not achieve a Complete or Partial Response will remain on treatment for an average of 18 months. Considering the significant negative ramifications of LN, we do not expect HCPs will accept failure for an average of 18 months with a product they know, on average, shows a therapeutic benefit well before that timeframe. ° LUPKYNIS is very efficient at reducing the primary treatment goal - proteinuria; thus, physicians can quickly identify a therapeutic benefit or lack thereof. Olnstitute for Clinical and Economic Review, 2021 Page 149 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC e Based on these points, a 6-month average duration for non-responders is a much more reasonable assumption. This change alone produces roughly a 20% reduction in LUPKYNIS's cost per QALY and meaningfully enhances its cost-effectiveness. Aurinia appreciates the thorough analysis ICER has conducted, and the time patients, advocates, and healthcare providers have contributed to the Evidence Report. We are pleased that all parties agree about the historical unmet clinical needs of LN patients. Based on the clinical evidence, LUPKYNIS is a cost-effective therapy with unique and crucial clinical value that should be made broadly available to the patients and providers treating Lupus Nephritis. Eric is a full-time employee of Aurinia Pharmaceuticals, Inc. Dina Thachet, BS, CCLS Patient Advocate, Lupus and Allied Diseases Association, Inc. ICER Community-- Thank you for allowing me to share my perspective. I'm a patient advocate with SLE/LN-IV representing Lupus and Allied Diseases Association. When | was 19, | began having vague symptoms including fatigue, weight loss, blood in my urine, etc. Despite many tests, doctors couldn't find the cause. | was repeatedly misdiagnosed and often, my symptoms were dismissed. A year later, | was diagnosed with severe endometriosis and needed an emergency laparoscopy. The surgeon prescribed birth control pills to regulate my cycle and the day | took the first pill, | landed in the ER with meningitis and an E. Coli intestinal infection. They treated me for eleven days and sent me home. | was back in the ER within thirty minutes. After a rheumatology consult, | was diagnosed with SLE. The pill was the trigger. | was hospitalized for another three weeks in a full-blown flare with CNS, pericarditis, pleurisy, etc. After a biopsy, | was diagnosed with stage 4 nephritis, with kidney function at approximately 7 to 9%. During those three weeks, | was pronounced clinically dead 3 times, and then given a 5-year prognosis. That was 27 years ago. Needless to say, here | am. | immediately started taking high-dose steroids and inmmunosuppressives--while most of the inflammation resolved, the nephritis remained. | began monthly chemotherapy treatments for 1.5 years, and several years later, for another 1.5 years. I've been on steroids and immunosuppressives for the entire 27 years, and am now experiencing long-term side effects, including osteopenia, pre- diabetes, and Gl issues. That said, |'d actually like to focus on the impact of lupus treatments on quality of life, specifically the impact on reproduction and parenthood. The majority of us diagnosed with lupus are of child- bearing age, many of whom one day wish to be parents. That matters. Current treatments are toxic Olnstitute for Clinical and Economic Review, 2021 Page 150 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC and many have a detrimental impact on fertility, the ability to get pregnant and safely carry a pregnancy to term, and to have a healthy baby. For those who are able to become parents, lupus fatigue combined with treatment side effects can make even basic child-rearing and daily life difficult. All of this adds insult to injury when we are already dealing with diminished quality of life. Our hopes, dreams, and desire to be parents are just as important as our physical health, and should be factored into the treatment plan. Those diagnosed today deserve treatment options that have little to no impact on fertility, and/or fertility preservation options with guaranteed insurance coverage. Unfortunately, | wasn't given that consideration. 27 years ago, | was told that | would and should never get pregnant and that if | were to, that | and the baby would likely die. | was 20. | felt hopeless and terrified to allow that dream to rekindle. Until it did. | worked with my rheumatologist and the MFM team to make sure | was stable enough to even consider pregnancy, and weighed the lupus- related risk factors. | began working with an RE, but numerous procedures failed. Testing showed that my ovarian reserve was scientifically equivalent to zero--a result of the chemotherapy treatments. | was devastated. While we continued to explore our options, it became increasingly difficult to maintain hope. In addition to depression and isolation, we suffered a tremendous financial burden on top of the ongoing financial burden of lupus treatments, even with really good insurance. This threatened our ability to consider continued fertility options as well as other options, such as adoption or surrogacy, and depleted our savings. | would be remiss to not point out that all of this would be even more challenging, if not impossible, for anyone who is uninsured, underinsured or on public aid, which many with lupus are due to not being able to work. All told, | experienced over 13 years of fertility challenges and heartbreaking losses. But mine is a story of resilience and hope. I'm thrilled to share that | was finally able to get pregnant. At the age of 43, while high-risk, and far from easy, | carried a full-term pregnancy and | am the proud mother to our little miracle, Isla. She is the biggest blessing of our lives. My deepest desire is that those diagnosed with lupus nephritis are able to access and afford treatments that allow them to become parents, if that's what they want. At minimum, we deserve to have hope, and these new LN treatments can give us that. Dina has no financial conflicts of interest to disclose. Olnstitute for Clinical and Economic Review, 2021 Page 151 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC Toni Grimes, MS Patient with Lupus, Lupus Foundation of America This month marks 14-years that | have been living and thriving with lupus. Fourteen years ago, | had no idea what lupus was let alone the unmet needs for lupus specific medications. This is an amazing time for lupus nephritis with regards to patients and providers having options for more personalized medicine for patients like myself. | was diagnosed in 2007 at the height of my military career as an Army officer who was about to deploy to Iraq. After having trouble breathing, | was diagnosed with a pleural effusion. | underwent a thoracentesis to draw the fluid off my lung. The biopsy resulted in a positive ANA and this began my "ologist" journey. After 16 vitals of blood begin drawn, | was officially diagnosed with lupus. This was a rarity because it takes on average 6 years to get diagnosed and | was diagnosed in one month, basically the timeframe of my follow up appointment. Two months after diagnosis my lung collapsed after a second thoracentesis. | had surgery to repair my lung the day my unit deployed to Iraq and six months post-op | deployed to Afghanistan instead. While deployed | was having a lot of lower left flank pain. After passing out multiple times in front of my Soldiers due to the pain and mental health issues from my deployment | was medevacked back to the States. Three months after returning home | was diagnosed with lupus nephritis - that left flank pain turned out to be stage III kidney disease and eventually stage IV. | was extremely fortunate to be serving my country at the time of my diagnosis because | didn't have to worry about the cost of my medical care, and | didn't have to worry about taking sick leave or missing a paycheck. | remember switching from Cellcept to Cytoxan. | was taking six pills a day and | had just received a 90-day supply when my nephrologist changed my treatment plan because of low response. | remember her mentioning that one of her patients was unable to get one Cellcept pill a day because her insurance didn't want to cover it, but | had just received 540 pills. That patient's insurance would rather deny her 1-pill a day and allow her kidneys and quality of life to suffer. Because of her lack of access to treatment she would have a higher probability of going on dialysis and hope to get on a kidney transplant list. This was so asinine to me, but due to my situation | unlimited access to care and she did not. That was in 2008. In 2009 | was diagnosed with fibromyalgia. In 2010 | was in the fight of my life. | was diagnosed with neuropsychiatric lupus and psychosis along with my Post Traumatic Stress Disorder. After being hospitalized for six-months in a semi-vegetive state | had to learn how to walk, talk and write again. This ultimately ended my career. In February 2011 was | medically retired from the Army with 19 years, 2 months, and 29 days of service. When | took off my uniform, | replaced it with another one....a purple lupus cape. And this began my advocacy journey. Our journeys are very unique because lupus is like a fingerprint, no two lupus warriors are the same. This is why it is so important for lupus nephritis patients and providers to have treatment Olnstitute for Clinical and Economic Review, 2021 Page 152 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC options. When | was diagnosed with lupus nephritis there were no lupus specific drugs, | was using drugs meant for cancer patients, organ transplant recipients and high dose steroids, which to this day | am still suffering from its side effects seven years after my last dose. | had to make a hard decision to take these drugs during my childbearing ages. These choices were heartbreaking and continue to haunt me because of their horrible side effects | was not able to be the mother that | wanted to be. Fast forward 13-years we have two drugs specific for lupus nephritis. When | retired in 2011, | attended my first Lupus Advocacy Summit in DC and Benlysta just received FDA approved as the first and only biologic specific drug for lupus. Now in my lifetime we have two more FDA approved drugs specific for lupus nephritis. This gives me a ray of hope and warms my heart that there's more to come. It's important for the right patients to be included in clinical trials so more personalize medicine can be used because lupus is like a fingerprint. | know our feedback and experiences are critically important with regards to research development. | hope to have more treatment options to choose from and personalized medicine. Thank you for allowing me to share my voice. Toni has no financial conflicts of interest to disclose. Olnstitute for Clinical and Economic Review, 2021 Page 153 Final Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to ToC |. Conflict of Interest Disclosures Tables I1 through |3 contain conflict of interest (COI) disclosures for all participants at the March 26" Public meeting of the New England CEPAC. Table I.1. ICER Staff and Consultants and COI Disclosures ICER Staff and Consultants Rick Chapman, PhD, MS, Director of Health Economics, ICER* Olena Mandrik, PhD, PharmD, MSc, Research Fellow, The University of Sheffield* James Fotheringham, MD, PhD, Consultant Nephrologist and Honorary Lecturer, The University of Sheffield Steven D. Pearson, MD, MSc, President, ICER* Belen Herce-Hagiwara, BA, Research Assistant, ICER* Praveen Thokala, PhD, MASc, Senior Research Fellow, The University of Sheffield* Serina Herron-Smith, BA, Research Assistant, Evidence Synthesis, ICER* Jeffrey A. Tice, MD, Professor of Medicine, University of California, San Francisco* Maggie Houle, BS, Program and Event Coordinator, ICER* Melanie Whittington, PhD, MS, Associate Director of Health Economics, ICER* Catherine Koola, MPH, Program Manager, ICER* *No conflicts of interest to disclose, defined as individual health care stock ownership in any health plan or pharmaceutical, biotechnology, or medical device manufacturers, or any health care consultant income or honoraria from health plans or manufacturers. Table |.2. New England CEPAC Panel Member Participants and COI Disclosures Participating Members of CEPAC Robert Aseltine, PhD, Professor and Chair, UCONN Health* Greg Low, RPh, PhD, Director, MGPA Pharmacy Quality and Utilization Program, Massachusetts General Hospital* Rena Conti, PhD, Associate Professor, Boston University* Eleftherios Mylonakis, MD, PhD, FIDSA, Professor, Alpert Medical School of Brown University* Marthe Gold, MD, MPH, Senior Scholar, New York Academy of Medicine* Stephanie Nichols, PharmD, BCPS, BCPP, FCCP, Associate Professor, University of New England College of Pharmacy* Megan Golden, JD, CEO, Mission: Cure* Jeanne Ryer, MSc, EdD, Director, NH Citizens Health Initiative* Rebecca Kirch, JD, Executive Vice President of Policy and programs, National Patient Advocate Foundation* Jason Schwartz, PhD, Assistant Professor of Health Policy, Yale School of Public Health* Stephen Kogut, PhD, MBA, RPh, Professor, University of Rhode Island College of Pharmacy* Jason Wasfy, MD, MPhil, Medical Director, Mass General Physicians Organization* *No conflicts of interest to disclose, defined as individual health care stock ownership (including anyone in the member's household) in any company with a product under study, including comparators, at the meeting in excess of $10,000 during the previous year, or any health care consultancy income from the manufacturer of the product or comparators being evaluated. Olnstitute for Clinical and Economic Review, 2021 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Page 154 Return to TOC Table 1.3. Policy Roundtable Participants and COI Disclosures Policy Roundtable Participant ee Mm Ret , . LADA receives funding from health care related Kathleen Arntsen, BA, President & CEO, Lupus and Allied _ . . _. . _. organizations, including Aurinia and GSK, but members Diseases Association, Inc. associated with LADA are not compensated. Linda Goler Blount, MPH, President & CEO, Black Women's | BWHI's Rare Disease Diversity Coalition receives Health Imperative sponsorship from Aurinia Pharmaceuticals, Inc. Christele Felix, BS, Chief Operating Officer, LupusChat No financial conflicts of interest to disclose. Meggan Mackay, MD, MS, Investigator and Professor of Dr. Mackay participates in industry-sponsored clinical trials Medicine, The Feinstein Institutes for Medical Research, for lupus nephritis and is reimbursed for subjects recruited Northwell Health and followed. Jay McKnight, PharmD, BCPS, Vice President, Pharmacy Clinical and Specialty Strategies, Humana Pharmacy Dr. Jay McKnight is a full-time employee of Humana. Solutions Simrat Randhawa, MD, MBA, Senior Vice President, Medical | Dr. Simrat Randhawa is a full-time employee of Aurinia and Clinical Affairs, Aurinia Pharmaceuticals, Inc. Pharmaceuticals, Inc. Dr. Brad Rovin is involved in several trials of novel therapeutics for lupus nephritis and is a consultant on the Brad Rovin, MD, Professor of Medicine and Pathology, Ohio i i 2 . . . medical/scientific advisory boards to design trials for these State University Wexner Medical Center therapeutics. His organization receives less than 25% funding from pharmaceutical companies for clinical trials. Bernard Rubin, DO, MPH, Medical Director, Dr. Bernard Rubin is a full-time employee of GlaxoSmithKline GlaxoSmithKline. Emily Tsiao, PharmD, Clinical Pharmacist, Premera Blue Dr. Emily Tsiao is a full-time employee of Premera Blue Cross Cross. Olnstitute for Clinical and Economic Review, 2021 Page 155 Evidence Report - Belimumab and Voclosporin for Lupus Nephritis Return to TOC