INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW Medications for Obesity Management: Effectiveness and Value Final Evidence Report October 20, 2022 Prepared for Ma NEW ENGLAND m= CEPAC MESS COMPARATIVE EFFECTIVENESS PUBLIC ADVISORY COUNCIL Olnstitute for Clinical and Economic Review, 2022 ICER Staff and Consultants University of Illinois at Chicago Modeling Group Steven J, Atlas, MD, MPH Associate Professor of Medicine Harvard Medical School Director of Practice-Based Research and Quality Improvement Division of General Internal Medicine Massachusetts General Hospital Molly Beinfeld, MPH (Former) Senior Research Lead, Evidence Synthesis Institute for Clinical and Economic Review Victoria Lancaster, PharmD, MSc, MBA Health Technology Assessment Fellow Institute for Clinical and Economic Review Emily Nhan Research Assistant Institute for Clinical and Economic Review Ashton Moradi, PharmD, MS Health Economist Institute for Clinical and Economic Review David M. Rind, MD, MSc Chief Medical Officer Institute for Clinical and Economic Review Steven D. Pearson, MD, MSc President Institute for Clinical and Economic Review Francesca L. Beaudoin, MD, PhD, MS Senior Medical Advisor Institute for Clinical and Economic Review Kibum Kim, PhD Assistant Professor University of Illinois at Chicago Pei-Wen (Hilary) Lien, MSc PhD Candidate University of Illinois at Chicago Kanya Shah, PharmD, MS, MBA PhD Candidate University of Illinois at Chicago Daniel R. Touchette, PharmD, MA Professor, University of Illinois at Chicago Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research The role of the University of Illinois at Chicago is limited to the development of the cost-effectiveness model, and the resulting ICER report does not necessarily represent the views of the University of Illinois at Chicago. None of the above authors disclosed any conflicts of interest defined as more than $10,000 in health care company stock or more than $5,000 in honoraria or consultancies relevant to this report during the previous year from health care manufacturers or insurers. DATE OF PUBLICATION: October 20, 2022 How to cite this document: Atlas SJ, Kim K, Beinfeld M, Lancaster V, Nhan E, Lien PW, Shah K, Touchette DR, Moradi A, Rind DM, Pearson SD, Beaudoin, FL. Medications for Obesity Management: Effectiveness and Value; Final Evidence Report. Institute for Clinical and Economic Review, October 20, 2022. https://icer.org/assessment/obesity-management-2022/. Steven J. Atlas served as the lead author for the Report. Molly Beinfeld led the systematic review and authorship of the comparative clinical effectiveness section of this Report in collaboration with Victoria Lancaster and Emily ©lnstitute for Clinical and Economic Review, 2022 Page i Final Evidence Report - Medications for Obesity Management Nhan. Kibum Kim developed the cost-effectiveness model and authored the corresponding sections of the Report with assistance from Daniel R. Touchette, Pei-Wen Lien, and Kanya Shah. Development of the cost-effectiveness model was also assisted by Jessica Benitez-Burke and Lauren Lee. Ashton Moradi provided consultation on the cost-effectiveness analyses and developed the budget impact model. Francesca Beaudoin, David M. Rind, and Steven D. Pearson provided methodologic guidance on the clinical and economic evaluations. We would also like to thank Laura Cianciolo, Monica Frederick, and Foluso Agboola for their contributions to this Report. ©lnstitute for Clinical and Economic Review, 2022 Page ii Final Evidence Report - Medications for Obesity Management 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. There are no life science companies relevant to this review who participate in this program. For a complete list of funders and for more information on ICER's support, please visit https://icer.org/who-we-are/independent-funding/. For drug topics, in addition to receiving recommendations from the public, ICER scans publicly available information and also benefits from a collaboration with IPD Analytics, an independent organization that performs analyses of the emerging drug pipeline for a diverse group of industry stakeholders, including payers, pharmaceutical manufacturers, providers, and wholesalers. IPD provides a tailored report on the drug pipeline on a courtesy basis to ICER but does not prioritize topics for specific ICER assessments. About 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. New England CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. New England CEPAC 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 council members meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness and value of medical interventions. More information about 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 may differ in real-world practice settings. ©lnstitute for Clinical and Economic Review, 2022 Page iii Final Evidence Report - Medications for Obesity Management 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 Evidence 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/2022/03/ICER Obesity Stakeholder-List_030322.pdf Expert Reviewers Harold Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC Medical Director and President Louisville Metabolic and Atherosclerosis Research Center Clinical Associate Professor University of Louisville School of Medicine Louisville Metabolic and Atherosclerosis Research Center has received research grants from Allergan, Alon Medtech/Epitomee, Altimmune, Amgen, Boehringer Ingelheim, Eli Lilly, Novartis, NovoNordisk, Pfizer, and Vivus. Dr. Bays has served as a consultant/advisor for Altimmune, Amgen, and Boehringer Ingelheim. Joseph Nadglowski, Jr. President and Chief Executive Officer Obesity Action Coalition Joseph Nadglowski, Jr. has no personal financial relationships with any obesity-related industry. He is an employee of the Obesity Action Coalition (OAC) and OAC does receive funding from a wide- variety of obesity related industry including those providing behavioral, pharmaceutical, device, and surgical interventions. Fatima Cody Stanford, MD, MPH, MPA, MBA, FAAP, FACP, FAHA, FAMWA, FTOS Associate Professor of Medicine and Pediatrics Obesity Medicine Physician Scientist Equity Director, Massachusetts General Hospital Endocrine Division Massachusetts General Hospital and Harvard Medical School Dr. Stanford has received consulting fees and/or honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, GoodRX, Calibrate, and Coral Health. ©lnstitute for Clinical and Economic Review, 2022 Page iv Final Evidence Report - Medications for Obesity Management Table of Contents ExX@CUtIVE SUMIMATLPY........ccccccesccessesssecsoesccasecessesenessaceconensseassensecnaceeassanensaessacanasesseesseeesesensnsneesseeeeeees ES1 1. BaCkgroun ...........cccesceseecesencceeneeneeceeeeseneeseneeaaecenensaeseesesaaaeeeneasaesenessaeaaeesescaeseeessaeaaeedenaeeeesensaeseeenens 1 2. Patient and Caregiver Perspectives ............:::cccssscceceseesencenessaceeeesenseeeenensaeeaeensaacasacseaaeeesaesaaeeeaseneaeeas 4 3. Comparative Clinical Effectiveness .............::cccccsssscecsssseseesessceeceesensrsesssseeseessesseeeeessuseseesaessueeenseseaeess 6 3.1. Methods Overview .........cecsecseeeseeseesneeseceneaneensessanseeaesecesesenesseeseeseecsasoeseseeesaeeseeseenseneeenseenes 6 Scope Of REVIOW ........:ccccccsccsecsesssecenssneeeeesseeseeeesseesenssssneesuessaeeeesessneeeesscueseeeesaneeeesesseseseassaeeeeessas 6 EVIDENCE BaSe...........eecesscessecesecesnersseeesneesanecsneseseeeusesseeesseecsssessessseeesanesenesenseesceesaesenssseatensnensaee® 6 3.2. RESUItS ......eseseeseseesseessnsesneeeseeesneesaeesseessenersceceaeeeseeesseeceeseeneeseeescesesneccesecscessseseaeesseneseesesnneees 13 Clinical Benefits .............eccseseeeseesseeeeneeeeeeeseeeecesecneessnessaessecseecaeeseesaeseacenseesesesesseesseesserseenseeeeeeees 13 HALIM .....ccscesccsesvenseeucnsecscceevoneeessnnessseseesonsessscuassosesesseesesaeeccenaesensueecnsessccsasseneaessanessensessoanseesanens 24 Subgroup Analyses and Heterogenceity..........scscccccccccssssssserscsccercesssssssseeesteesesesesssseauersesesesenseees 33 Uncertainty and ControverSies.........csccsscccscesssssssccccssecsesecsssessncenseesessessassceneesseesenesesanseneeensecesanes 33 3.3. SUMMary ANd COMMENL............:s:ccssccseececeesessscencessecsuceessansenceensenseacesssveenenssecensesssasserseessenseees 36 New England CEPAC Votes ..........sssssssersscccesssssssssnnenscecceseesssnscuenessesessseussneneesesecetsesessusenenerseeenees 40 4. Long-Term Cost Effectiveness ........sscscssccssesssssscrenesscersecsessseenecstecersesessceuacensestsesssseeeesteetteetsesssauen 41 4.1. Methods OVervView ......ccssccssesseesscecsrsescesecsesseassensecesecssscceesseasseasseeascdeesseeesseasseaseassesseeseneneees 41 Scenario ANalyS@S............c.cccccsescecceteececesenenseceeeeennaaeeseeeneneecnaaeaeeneaueaensesaaeseeenseaeeeesneaaeeseeenenentess 44 4.2. Key Model Assumptions and Input .............::cccsssscsceeessececeetenneeeeneaeneceensaeeeeensaceeeesessaeseeeeeaeees 45 Model ASSUMPTIONS. .............::cceesessceeeseeseceenensaceceeteaeeeneeasaeeesedeaeceeeseeenensaesaceesedeneeaentensaeeseaneneaes 45 4.3. RESUITS 00... cescccseeseesseessssennseceneceecseesscensceneeeeesseasseassecasecesesecasseasseassdasesseassesssesessseccsseceaeneees 50 Base-Case ReSUItS.........cccccsseesseeseecerecenssneesseesseessarsneneeeeecsesessessueseenesceseauesseessaceeeaetenseesseessaesaes 50 Sensitivity Analyses. .............:cescsceeceesecceenesseeceeeeeenceeeeeseeeceensaasaesesaaaeenseeaesenessaeeaeesenaaeeseeseaeeaease 51 Scenario ANalySes.............::cccceseeceeceeeseceeneeseeceeeneancecenseneaeceecsaaeaecnsaaaaeenessaeseeensaaeasasenaaeeesennaneaeass 52 Threshold AnalySes.........:cccccccccsssssssscccsescescessssssscsueescescesesesssceseeeseeseusuessancecesececsesssesssneceseeeecersss 54 Model Validation...........ccccssecsssessecenecenssesesseesseesseresensecneecaeecuessaeeecoeesonseaaessaeeseceeeaesenssesssesseessaes 54 Uncertainty and ControverSies...........csssscccccsssssccsssssscecsessneeeeessneesesessnseesseseseeessaceseesssseseeeasseess 55 4.4. SUMMATrY ANd COMMENL...........ccccsscscsceeccecccsssessnneccenceeacessesscnneceeecensessaensensceeecesseesssnnsreeeeeesesses 57 5. Contextual Considerations and Potential Other Benefits ............. ee eeeeeseeeseeseeeeesreeseeesseeseenersneres 58 New England CEPAC Votes ..........::::scscssseccessessssscenceseecssnseesassenceasseausasesassceneessesensasesasceeseessensesess 60 'Institute for Clinical and Economic Review,2022,-(itsti'é U*#*;*;*;*;"!;"CC#éR gO Final Evidence Report - Medications for Obesity Management 6. Health-Benefit Price BENCHimarkS ..........ccccsssseceseccccccceesecececcceccnnesesseeseaconseceseeesesecnacvseeseesssesnaceseens 61 New England CEPAC Votes ..........sssssssessssccessesssssnsenscescesevsssvsuaneneeccsssenseneneesesecesseseusnsnenseeeeenees 62 7. Potential Budget IMPpPact.............s:ccccccccsessssssccesecceseesuessssceeeeseccnesnesssneeceersecarsrsesenceaeeeceentesssssssessenens 63 7.1. Overview of Key ASSUMPTIONS .........cc::cccecesssssssccecsccseecesssessncessecsusaessassceneesseceesesssansenesensenssesss 63 7.2. RESUIES .......sccsssssssessseeesscsessssorsscensceseessssesnsesesscecsesssesecsnscsnsesecsssesosesseessessarsadssscenecenessseseessesoaees 64 Access and Affordability Alert ..........ccccccccssssssessrsccccesesssssscesecstcetscesssssseuacereessseseusuenensetesersesesenee 65 B. Policy RECOMMENCAIONS .........ssseccssecccessessssnscesecetcessesessceenarecescereensseagnasecenserseseseueesereettecessnseusneees 66 All Stakeholders... cee cesecessseeeseeeeneeceeecensnecesecneecenecseesseeseecseeaeesseeesscesseessaesenseeseeeseeesseseanseceeeeees 66 Manufacturers ..........eccceecseessseeesseeeesscesesaceeesceeeesaeeeesaeeessaeeecauaeessasenenseesneaseecaeeeeeueeesnaceeeasaesesaeeeenaaes 68 Clinicians and Clinical Societies ..........cccscsscsessecssescceesseesseeseeesetecessecssescseasenseesseessessseeseensecsssesenees 70 Patient OrganiZations ..................:cccssscsssssssssssssseseseesseseseseneeseesseeseeeeneeeeeeeeeeeeeseaeseeeeneseeaseeeeenaseaaenaas 71 Researchers/Regulators ..........cccsscccssssecsssseessseecsssecesseecesneeessssecsssneussaesesaeeesaeeeuseeeessanseessnseesenetessees 71 REFEFENCES .......eeecsescccessneeesaceeecneeeecseeecnaceecaeeeeneneesnaeeseaeessnaeensnaeeensueeesaeeeeauaeeqaosseenaeeseaaaecsanesennaateaes 73 Supplemental Materials A. Background: Supplemental Information ...........:::ccccccccssssssssescsscseecesecsssscecceeceescessesssneeseseesersssessees Al A1. Definitions... ee eeeeesseesseeenceeseecensseneecseeeneeeseesseeseonseeceeeeeeseeecsneseaesessessseesneeseeecnsesneeeeees Al A2. Potential Cost-Saving Measures in Obesity Management................::scccsssssssessssseeesesseseesnsseees A2 A3. FUtUre Therapies ........:cccssssssccsssssscssessssecssssnsecssssneesecssssnsescessauecesesssesessessrsacesssnsesestensessesessneees A2 B. Patient Perspectives: Supplemental INFOrmation ...........cccccccsesssseresersececeesesssecuserecetsesessnsenenereeesees Bi B1. Methods..........esesseessccsssccessesesseesseeceeecssseessensneecenessaeseonseaeaceneseeessecseneeeaeesseessetessaeseaeeesseesseeseaes B1 C. Clinical Guidelines .............ecsessscsseceeeceeeeenesseesseessceteseneseeesseesseeesseneseessesesseesaeeecnsecsesesnessnessenseeaeeees C1 Veterans' Health Administration/Department of Defense .............:cccscccsscsseesseceneeesneessseesneesnees C1 Canadian Clinical Practice Guideline...........ccscccscsssssesseseeesseessenseeeesencseesseesseeeseeeseceesseesseessseese C1 Endocrine SOCICtY.........s:ccccsscccsccssssssecsressecesccsssssseueessecessecesacseusearsecesacsesascenseesecessecesacsenseaesseaseess C2 National Institute for Health and Care Excellence ...........:.ccssccsssessecesecetsenseseeesseesseeneseseeneneneenes c3 D. Comparative Clinical Effectiveness: Supplemental Information..............:cccssscessseessseecesseeeeseeeeenaes D1 D1. Detailed Methods ..............eccescccesssceceesencceeesensaeeeseseaeceenseneaaeesaseaeeeenseneceeesenaaeaesaseneeeeeseneeeeeeneaes D1 PICOTS.......eeceeceeseeeseeeeeeceescenseeeneeseseaesseesaasenesseesseesaesseeeseseaesseeeaseeeesaeesesessecseeseceseeesseeaesiaesneesenentes D1 Data Sources and Searches. ........cccccsccesseesseessecenscesesesesseesseesseeseensecosecsnecsuesseneesoeecensecneseesseaeeeaes D5 Study Selection .......... ec ecseeceecessneeeeesecceceneeneecenensenaceeneaseeeceensansaesesaaaaeesencaeseeessaaeaseseusaeeesensaeeeeans D9 'Institute for Clinical and Economic Review,2022,-(iti'é'é U*;*;~;C;CC#CéR OE Final Evidence Report - Medications for Obesity Management Data Extraction and Quality AsSeESSMENIL.............ccc2cccccesssssecessssesecssssneeeecesanseesessnseesaesnseeeessness D9 Assessment of Level of Certainty in EViId@Nce............cccccsssssscssserceecsessssensnssceccesesessnsecenereececeesess D1i0 ASSESSMENT Of Bia .........cesesesseeseeecseeceseeesceecceecsnesenesecceesneesaeesseeseoesesnsecaeeesseeconeseeeseaeeesseesnseees D10 Data Synthesis and Statistical Analyses ............:ccsccsscccssssesesceccecseeseesesasnenneessensessasscneesseensenseeas D1i0 Supplemental NMA Method ..........ccssssccccssssesecesssnnecessssseseccessauecesesseesecsessnsecesussensessesoresecessenes D10 Supplemental NMA ReSUItS ........sscscccccccccssssssserereccesesscsnsssessestcesesesensnaeuauersestseseuseeeseteeteserseseses Dil D2. Additional Clinical EVid@Nnce .......cccccesseessceseccessessesssesseeseenseerseeesccssecseseserseanseseeseeseceesseesseaeees D16 EVIdeNce Base..........cseecsseccesseesseessecesececeeeesseesseeseeseaeecaueecsuseseesecesesenesseseaeessecssecseeaeteaeeseeeesseees D16 RESUITS ........:ccccessecceeessecceeeeessneeeeaesaeeseneensnecenesaeeecesnsaoeaesneaaaeeesessaeseeanaceeensessaeeneasncasentensneseeasens D20 HALIMS ....ssscsscensessernesevsseceensesseeceseccseeseusessecesessseaseetssenseesecaseesasensensaescsatsesusesseeeaseceneseentessseersonsas D35 D3. Evidence Tables........ccsccccsseesscesscessececessseseeesseaseessesseeseeecescsesseeesecssecsescceasseessecasearseneessenenseanee D39 D4. Ongoing Studies .............cccccssscccecsssssceesesseececesserseeesesceeeeassssnsenesesueeenssscesecsuseeeeeeesssansesesseensenss D83 D5. Previous Systematic Reviews and Technology AssesSMentts ............:::cccesesssseeeeeseeeesesseneeeens D89 E. Long-Term Cost-Effectiveness: Supplemental Information .............cccccesscecsseecesseeeeeneecesseeeesaeeneeaes E1 ET. Methods .........csesscessceeseceesseeeseeesseeseeeceseeesseneneecsnsseneeeaneesaeecsnesecessecseaeseaeessaeseecesseeseseeesseessnessees E1 Rationale for Not Including Certain Health States in the Base Case ...............:ccssssseessssseeeeseseees E1 IM PaCt INVENTOTSY 0... .cccecccnneeneneeeeneeeneeeneeeneeeeeeneneneneneeeeeneeeeeeneeseneneeenneesnecenensnensaesnecenenansasaenseenaags E1 Description Of EVLY Calculations. ............ccccccssecccsssecesseceesneeceseecesaeeessaesecsaceesnaeeesaeeensseeessaeensaaes E3 Target Population. .........scccccccsccssssssssscsseseesesssssscscsceuccersesesesssceseeeseesecssessanceceseceesesssessseeenseecersesess E3 Treatment Strategies... .ceccccsencsecceeeceneeeneeeeeeneeeneneeeeeneneceeeeneenseeseeennecenecenensnennecenecenesanssanenseenaags E4 E2. Model Inputs and ASSUMPTIONS ..............::ccccessesccecesseeseessssnscessesseeeensesceseeeaeseseeenesscesestsseeeesseaes E4 Model IMPuts.............ssssssssscsseccecssssssneceesserceseessssseuecerceseseseuseseueneececscsesuseucunnaseesesseseusnenenencesseeess E5 E3. RESUICS ........ccsesseesseesseesecceesssesseecseeeseeecssseseescseeecsessensseneecsnecsneesseesseeeceneeeceeseeeceeeseeseateessessensentes E9 Cost-Effectiveness Plane ...........ssccssceessseeseeeeneeseneesnseeeeseaseecoesceesseeseaneecanesseessecereeeseaeeesseesseeseeees E9 Undiscounted Base-Case ReSults..........scsssssssccssssssssesesssessseesssssesseeceesesesssessesssessssesnsseessnsoaess E9 Cumulative Incidence of Cardiovascular Conditions and Mortality ............cccsssssetssereecseeesenenee E11 E4. Sensitivity AMalyses ..........cssssecsssecccessessssesescccessestessssecssasecensersesssunscecesssesessaseeaeeecsentesessseseanees E13 One-Way Sensitivity Analysis...............cccccssssseccsssnscessessrseesessceeeeecsscesenseseessensssceseneeseseeeessseseees E13 Probabilistic Sensitivity Analysis .................ccsesceseeseesseeeeeesnenceetenseeeeeceneeecesescaeeeenennaeeetensenseeetees E16 E5. Scemario Analyses ........ccsccssssssesssecceeseesssscscsaccescestessnsceeuescecseessesnsensecesectsceessapeeeecereettesensssgenaees E19 'Institute for Clinical and Economic Review,2022, i (isti'é é;w;!;!;!~!"C~*#Cé ag Final Evidence Report - Medications for Obesity Management E6. Heterogeneity and SUDZrOUPS.............cccc:cccccsssseeessssseeecesssceseesesseseeessaceseeeessneeeesssanseseassnseeees E22 E7. Prior ECOMOMIC MOEIS..........scccsscsssccessescseccssccssesssseseseeessescsesseeescsusccseseseeseuseseesseeseseessersosesees E23 F. Potential Budget Impact: Supplemental Information ..............::sscseceseecsesesssseccseseceesesesesssscreeeeceraees Fi Methods ........seesecsscesseceseceesseeseseesseeccecessenseensseecneseenseaeaeseseseeseeessacseeaeecaeesseessansesaeeeaeeesseesseessaes F1 RESUItS......sccseccsssesscssesscsssccesnsscsnscsnsesscesesssensessseecnessssvscsnsesescseenseseevaeesneesesvaeesasentscsesaesseasaesonees F2 G. Supplemental Policy RECOMMENCAtIONS..........ccccccssesessssercseccecssesesseecesscescesssesenenaeeseeeteeseessnneenetes G1 PAYEMS.........ccccccccccccsssssceteecccsesaaneeeceeeneesaaaseeeeeeesseeaaaaeeeeeeseseeaaaeeeeeeeseeeaaeaneeeeeeeaesaaaaeeeeeeeessenaaneeseeeeeasas G1 H. Oral Comment SUMMALICS...........:ssecseeceesseesseesseeesseeceseeeseeesneesseeceanseaeeecoeeeseeseaeseaueseaeseacesseceseceneaes H1 I. Conflict of Interest DisClOSUIeS..........:ccsccesecessesseetseeeeeoeseseeesnensseeseoesecesesaeecaeeeeaeseaeeecoasesaeseaeseeceneatee I1 'Institute for Clinical and Economic Review,2022,-(isti'é;!;!;!OCOC*#@Rage'Vié Final Evidence Report - Medications for Obesity Management List of Acronyms and Abbreviations Used in this Report A1C ACC AHA AHRQ BMI Cl CPAP dL evLY FDA GLP-1 GIP HRQoL IBT IDS-SR IWQOL kg LDL m Mcs mg mmHg mmol/L n N NMA PCS PHQ-9 QALY SBP US USPSTF WAC Glycated hemoglobin American College of Cardiology American Heart Association Agency for Healthcare Research and Quality Body mass index Confidence interval Continuous positive airway pressure Deciliter Equal-value life year Food and Drug Administration Glucagon-like peptide-1 Glucose-dependent insulinotropic polypeptide Health-related quality of life Intensive behavioral therapy Inventory of Depressive Symptomatology Self-Report Impact of Weight on Quality of Life Kilogram Low density lipoprotein Meters Mental component summary Milligram Millimeter of mercury Millimoles per liter number Total number Network meta-analysis Physical component summary Patient Health Questionnaire Quality-adjusted life year Systolic blood pressure United States United States Preventive Services Task Force Wholesale acquisition cost Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page ix Executive Summary Obesity is a common chronic disease that increases the risk of other conditions such as diabetes mellitus, cancer, and heart disease as well as death." Individuals with overweight and obesity also face considerable social stigma that can have both direct (e.g., mental health, wellbeing) and indirect consequences (e.g., engagement with health care providers).? Body mass index (BMI, weight in kilograms/height in meters?) is commonly used to assess for obesity because it is easy to measure and correlates with body fat measurements.*" In 2015, the number of adults in the United States (US) with overweight or obesity was estimated to be 79 million and 70 million, respectively.©" The prevalence of obesity surpassed 40% of US adults in 2018,8 but among some racial and ethnic groups obesity is even more prevalent with higher proportions for Hispanic adults and highest proportions among non-Hispanic Black women.??° The direct medical costs attributable to obesity are staggering, estimated to be $260 billion in the US in 2016.71 Given the high of obesity and its many adverse clinical and cost consequences, cost-effective treatments for this chronic condition are imperative. Interest in medications to reduce weight and improve health in individuals with obesity has increased due to more non-surgical alternatives and data suggesting that newer medications have an acceptable safety profile and may be more effective in promoting weight loss. Limitations of medications for weight loss include side effects that lead to patient discontinuation, and weight regain when stopped. Under a chronic disease framework, clinical experts concluded that long- term anti-obesity medication use would likely be needed, particularly to prevent complications of obesity such as heart disease. This Report reviews four medications approved by the US Food and Drug Administration (FDA): semaglutide (Wegovy®, Novo Nordisk, June 2021), liraglutide (Saxenda®, Novo Nordisk, 2014), phentermine/topiramate (Qysmia®, Vivus, 2012), and bupropion/naltrexone (Contrave®, Currax Pharmaceuticals, 2014). Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1) receptor agonists that are also approved for diabetes mellitus and given by subcutaneous injection, whereas phentermine/topiramate and bupropion/naltrexone are combination oral agents that work via other mechanisms. Other promising therapies (e.g., tirzepatide) are still under investigation and are therefore not included in the scope of this review. For adults without pre-existing diabetes mellitus and either a BMI 230 kg/m? or 227 kg/m? with at least one weight-related comorbid condition (such as hypertension or dyslipidemia), the four interventions added to usual care all reduced body weight compared to usual care alone, which included standard diet and activity and lifestyle recommendations. Indirect mean and categorical weight loss reduction comparisons across the drugs as well as direct head-to-head evidence between two of the agents (semaglutide and liraglutide) suggest that semaglutide and phentermine/topiramate achieve greater weight loss than liraglutide and bupropion/naltrexone. Semaglutide and liraglutide improved blood sugar and blood pressure compared to usual care, but ©lnstitute for Clinical and Economic Review, 2022 Page ES1 Final Evidence Report - Medications for Obesity Management Return to Table of Contents how they compare to phentermine/topiramate and bupropion/naltrexone is less certain. In addition, none of these drugs have assessed long-term outcomes in adults without pre-existing diabetes mellitus, and thus there is uncertainty around long-term benefits such as cardiovascular morbidity and mortality. Adverse events were common among all interventions, but few serious harms were noted. All interventions had greater discontinuation due to adverse events than for placebo, though semaglutide appears to have lower rates than the other drugs. For all interventions, there is uncertainty about whether sustained weight loss leads to decreased clinical endpoints, and if weight regain occurs over time despite continued therapy. Given the strength of the evidence on weight loss outcomes in the trials and uncertainty around long-term outcomes for adults without pre-existing diabetes mellitus and with obesity or overweight with at least one comorbid condition, Table ES1 presents the ICER evidence ratings comparing each intervention with lifestyle modification to lifestyle modification alone and comparing semaglutide and the other interventions with lifestyle modification. Table ES1. Evidence Ratings for Treatment of Adults with Obesity Treatment Comparator Evidence Rating Semaglutide Lifestyle modification B+ Liraglutide Lifestyle modification B Phentermine/Topiramate Lifestyle modification C++ Bupropion/Naltrexone Lifestyle modification C+ Liraglutide C+ Semaglutide Phentermine/topiramate C+ Bupropion/naltrexone C++ Information about ICER's Evidence Rating Matrix may be found here. At current prices and with commonly accepted cost-effectiveness benchmarks, results suggest that phentermine/topiramate in addition to lifestyle modification is cost effective compared with lifestyle modification alone. The cost effectiveness of treatment of obesity with semaglutide or liraglutide in patients without diabetes mellitus exceeds commonly used thresholds. Bupropion/naltrexone is cost effective only at higher thresholds (see Table 4.5). The health-benefit price benchmark range for semaglutide is $7,500 to $9,800 per year; this would require a discount from the wholesale acquisition cost of 44-57%. In summary, among the agents we reviewed, greater weight loss was seen with semaglutide and with phentermine/topiramate; less weight loss was seen with liraglutide and with bupropion/naltrexone. Although few serious harms were noted for all the interventions, semaglutide may have lower rates of discontinuation and, along with liraglutide, may have additional cardiovascular benefits that extend beyond weight loss effects. Phentermine/topiramate is substantially less expensive than semaglutide and liraglutide, meets commonly accepted cost- effectiveness thresholds and is cost-saving when prescribed generically. Bupropion/naltrexone is ©lnstitute for Clinical and Economic Review, 2022 Page ES2 Final Evidence Report - Medications for Obesity Management Return to Table of Contents cost effective only at higher thresholds, but is cost effective when prescribed generically. Semaglutide requires substantial discounts from the wholesale acquisition cost to meet typical thresholds, but it is more effective, less burdensome, and more cost effective than liraglutide. Assuming semaglutide's current net price, approximately 0.1% of the 142 million patients across the US with overweight or obesity eligible for treatment with semaglutide could be treated within five years without crossing the Institute for Clinical and Economic Review potential budget impact threshold of $777 million per year. When these 142,000 patients initiate treatment in equal proportions over five years, only about 28,000 patients across the US could be treated per year without crossing the annual potential budget impact threshold, highlighting potential affordability and access considerations surrounding semaglutide. Therefore, at current pricing and projected continued uptake that is likely to exceed 28,000 patients per year in the US, semaglutide's short- term potential budget impact exceeds our threshold. Additional efforts at achieving affordability and access must be considered. Thus, we are issuing an access and affordability alert for semaglutide in the management of overweight and obesity. Appraisal committee votes on questions of comparative effectiveness and value, along with policy recommendations regarding pricing, access, and future research are included in the Report. Several key themes are highlighted below: e All stakeholders have an important role to play in ensuring that people living with obesity who are interested in weight loss have access to effective medications as a core benefit of health care insurance coverage. To achieve this goal, manufacturers should set the price for new treatments for obesity in proportion to their demonstrated benefit to patients and society, with moderation commensurate with residual uncertainty about long-term benefits and the large size of the potential population of people to be treated. Similarly, payers should ensure that pharmaceutical benefit designs developed in conjunction with employers and other plan sponsors ensure access to approved therapies among individuals with obesity. e All stakeholders should take steps that make effective treatment options for people living with obesity available in a way that will help reduce health inequities. To address these concerns, manufacturers should develop patient assistance programs at a level commensurate with other chronic disease conditions to support access to medications among racial and ethnic groups where the burden of obesity is particularly large, payer coverage is low, and inability to afford out-of-pocket payments is common. Likewise, payers should design coverage criteria that are sensitive to racial and ethnic variability in the clinical applicability of BMI thresholds to ensure that eligible beneficiaries from racial and ethnic groups particularly affected by obesity have access to effective therapeutic options. ©lnstitute for Clinical and Economic Review, 2022 Page ES3 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 1. Background Obesity is a common chronic disease that increases the risk of other conditions such as diabetes mellitus, hypertension, dyslipidemia, cancer, heart disease, and death.*" Individuals with overweight or obesity face a considerable social stigma that can make them feel judged, shamed, and ostracized, and can affect interactions with family, friends, and even health professionals.? Because obesity can start in childhood, the stigma can affect social interactions, educational development, relationships, and work.>* The net effect is that obesity can have a profound impact on all aspects of patients' lives and those of their families and caregivers. Obesity is defined by the World Health Organization as abnormal or excessive fat accumulation that presents a risk to a person's health."* While not optimal for assessing individuals with high or low muscle mass, body mass index (BMI, weight in kilograms/height in meters?) is commonly used to assess obesity because it is easy to reliably measure and correlates with body fat measurements.*" More than two-thirds of the United States (US) population have overweight (BMI 225) or obesity (BMI 230). The prevalence of obesity among adults has increased over time and was 40-45% in 2017-2018.2 Among children and adolescents, the prevalence of obesity is almost 20%.° The total number of adults with overweight was estimated at 79 million with another 70 million estimated to have obesity in 2015, and with half the US population projected to have obesity by 2030.°" The prevalence of obesity varies among racial and ethnic groups, being higher for Hispanic adults and highest among non-Hispanic Black women.?° Screening adults for obesity is recommended by the US Preventive Services Task Force.*© Given the prevalence of obesity and its impact on health, the direct medical costs of obesity are staggering, estimated to be $260 billion in the US in 2016." The financial impact of obesity on individuals includes not only direct medical costs but also indirect costs of lower wages and greater work loss and disability.*"78 The stigma of obesity lies in societal perceptions that attribute the problem to an individual's inability to control caloric intake and physical activity. However, it is recognized that energy balance dysregulation is the result of interactions among complex genetic factors associated with the body's mechanisms that control energy balance and contribute to developing obesity.?°° An individual's lifestyle is also impacted by societal, economic, and cultural factors, which have contributed to the rise in obesity. This complexity supports the idea that treating obesity and its consequences must consider the potential range of causes that contribute to any one individual with obesity. The goal of therapy for obesity is to broadly prevent, treat, or reverse its complications, including its impact on quality of life.2+2? Patients cite a variety of reasons for wanting to lose weight including improved health, self-esteem, and body image. Treatments to promote weight loss are intended to improve health and prevent the health risks associated with obesity (e.g., diabetes, hypertension, dyslipidemia, heart disease, cancer, fatty liver, osteoarthritis, sleep apnea) and ultimately improve ©lnstitute for Clinical and Economic Review, 2022 Page 1 Final Evidence Report - Medications for Obesity Management Return to Table of Contents quality of life and longevity.*?3 Observational studies support an association between weight loss and reductions in mortality.' Initial weight loss treatments focus on lifestyle interventions that variably combine healthful nutrition, increased physical activity, and behavioral modifications.247° Though helpful for some, weight loss is usually modest and regaining weight over time occurs in the vast majority of individuals. Earlier generation medications also had modest effects on weight loss, and some were found to pose significant health risks. The introduction of surgical procedures to promote weight loss demonstrated that, for severe obesity, significant weight loss was possible and was associated with decreased weight-related complications.°?' This supports the notion that successfully managing obesity as a chronic condition can lead to long-term health benefits. For individuals who have not achieved desired weight loss with lifestyle changes, there are multiple pharmacotherapy options indicated to promote weight loss and prevent complications of obesity. Pharmacotherapy is often considered first-line before more invasive weight loss techniques are considered (e.g., bariatric surgery). Currently, approved medications by the US Food and Drug Administration (FDA) include the single agents: phentermine (1959), orlistat (Xenical®, H2 Pharma, 2007), liraglutide (Saxenda®, Novo Nordisk, 2014), and semaglutide (Wegovy®, Novo Nordisk, June 2021), and the combination drugs: phentermine/topiramate (Qysmia®, Vivus, 2012) and bupropion/naltrexone (Contrave®, Currax Pharmaceuticals, 2014). Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1) receptor agonists that are also approved for diabetes mellitus due to their effect in stimulating insulin production. Their weight loss effect is mediated in part by decreasing hunger and delaying gastric emptying.?? Both are given by subcutaneous injection with liraglutide administered daily and semaglutide weekly. The other FDA-approved medications are administered by mouth and taken daily. Because orlistat results in modest weight loss and causes intestinal side effects, it is less commonly used for initial medication management and is not reviewed in this Report. Phentermine is an amphetamine-like medication that suppresses appetite and is approved for short-term use (less than 12 weeks). It is also available in combination with topiramate, a carbonic anhydrase inhibitor used to treat seizures. The combination of bupropion and naltrexone works in the brain to decrease hunger.*® Bupropion is an inhibitor of norepinephrine and dopamine and is an antidepressant and anti-anxiety medication. Naltrexone is an opioid antagonist and blocks the effect of opioid pain medications. Since phentermine, topiramate, bupropion, and naltrexone are available as single agents, clinicians may also use them "off label" alone and in various combinations for weight loss. There are a host of other more invasive treatments including endoscopic surgical procedures and devices placed into the stomach to promote early satiety. Though these may also be used for individuals who have not achieved desired weight loss with lifestyle changes, patients and experts felt that the limited time duration of weight loss and/or invasive nature of these procedures would make them less comparable to medications that could be taken for longer periods. ©lnstitute for Clinical and Economic Review, 2022 Page 2 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Practical issues in using medications for weight loss are modest weight reduction, potential side effects, long-term safety, durability of treatment effect, and concerns about insurance coverage. Consequently, there is a need to understand the comparative benefits and costs of the newer branded medications for individuals interested in weight loss after not achieving their goals with initial lifestyle modification. Because semaglutide appears to promote greater weight loss than other FDA-approved medications, there has been considerable interest among patients and providers despite being administered as an injection and more costly. Finally, a number of newer medications that promote weight loss are being investigated. An oral version of semaglutide has been approved for the treatment of diabetes mellitus and is under investigation for use in weight loss. Another medication, tirzepatide, is both a GLP-1 receptor agonist and also a glucose-dependent insulinotropic polypeptide receptor agonist, and has been approved for treatment of diabetes mellitus. Data on weight loss with tirzepatide have been published,!? and these results are discussed in Supplement A3. Table 1.1. Interventions of Interest inhibitor Intervention Mechanism of Action Delivery Route Prescribing Information Semaglutide GLP-1 receptor agonist Subcutaneous 2.4 mg once weekly Liraglutide GLP-1 receptor agonist Subcutaneous 3 mg once daily : . Sympathomimetic amine/ . Phentermine/Topiramate GABA receptor modulation Oral 7.5-15 mg/46-92 mg daily Bupropion/Naltrexone Opioid antagonist/NE and DA Oral 32 mg/360 mg daily CA: carbonic anhydrase, DA: dopamine, GABA: gamma-aminobutyric acid, GLP-1: glucagon-like peptide-1, mg: milligram, NE: norepinephrine Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 3 Return to Table of Contents 2. Patient and Caregiver Perspectives Discussions with individual patients and patient organizations identified important insights and perspectives. Common themes emphasized included: the considerable physical and mental burden on patients with obesity; the broad recognition that the social stigma associated with obesity can begin at a young age and affect an individual throughout their life; the need for better treatment options; the impact on all aspects of life including education, work and social/family relationships; the importance of measuring treatment outcomes that are most meaningful to patients; and the affordability of increasingly expensive treatments that may not be covered by health insurance. Patients and clinicians emphasized that obesity is a serious, chronic disease with important health consequences affecting both physical and mental well-being. Individuals with obesity are at increased risk of chronic health conditions such as high blood pressure or cholesterol, diabetes mellitus, heart disease, sleep apnea, arthritis, immobility, depression, and cancer. As a result, obesity is associated with reduced disease-free life and increased risk of premature death." Despite these risks, patients and advocates said that societal biases further the perception that those living with obesity are not able to make the personal lifestyle choices to manage weight. This simplistic focus on "blame the patient" overlooks considerable evidence that the causes of obesity are complex and multifactorial. The resulting social stigma associated with obesity is widely felt by individuals with obesity, begins at a young age, and affects individuals throughout their lives. This stigma and bias can lead to anxiety, depression, and behaviors that make self-care harder, and may impact willingness to engage with health care providers around weight loss and the consequences of obesity. We also heard that there are diverse perspectives about obesity that broadly reflect the many individuals with obesity and the variety of underlying factors that contribute to obesity and its management. Though many individuals with obesity are interested in weight loss, the cycle of weight loss and gain, the many "fad" diets and treatments that offer unrealistic expectations, and the cost of treatments that are often not covered by health insurance all impact perceptions about weight loss. We heard some advocate more for efforts focused on managing the medical issues associated with obesity, especially for those individuals who have suffered through failed treatments, weight cycling, and the psychological harms associated with such prior experiences. Even among those more interested in weight-neutral treatment efforts, there was recognition that more can be done in the health care system to reduce the stigma of obesity and better support individuals interested in weight loss treatment. Patients and patient organizations identified that the impact of obesity is particularly high among women and individuals from certain racial and ethnic groups. For example, the prevalence of obesity is higher for Hispanic adults and highest among non-Hispanic Black women.??° Moreover ©lnstitute for Clinical and Economic Review, 2022 Page 4 Final Evidence Report - Medications for Obesity Management Return to Table of Contents disparities in access to health care and treatments for obesity may exacerbate the morbidity and mortality associated with obesity across racial and ethnic groups. It was also highlighted that trials of interventions for obesity need to ensure a diversity of individuals from different racial and ethnic backgrounds. Patients and clinicians highlighted that there is a need for new therapeutic options for individuals with obesity who are interested in weight loss treatments, particularly for individuals who have not responded to lifestyle treatments or who responded but then regained lost weight over time. They emphasized that no one treatment is a panacea, and this reflects the various underlying mechanisms that contribute to obesity as well as the benefits and harms associated with all therapies. Given the wide variety of treatments available for those interested in weight loss treatment, they supported focusing on medical therapies for those who have not responded to lifestyle interventions and are interested in additional treatments. Though patients may also consider invasive surgical and other device interventions while also considering the use of medical therapies, patients felt that many individuals had treatment preferences that made direct comparison of medical and non-medical therapies less important. This also reflected increased interest in medications that provide substantial weight loss to an increasing percentage of users, with weight reduction that is becoming comparable to results associated with some bariatric procedures. Patients and clinicians also reported that individuals with obesity commonly use medications approved in combination products for weight loss but available as individual drugs in an off-label manner. This reflected that they often saw this route as minimizing side effects when starting treatment and being less costly for patients given the higher costs of approved combination medications that are often not covered by insurers. The net effect is that many patients end up on a combination of medications, but not always using the approved combination products. There was also recognition that the addition of medications, such as the GLP-1 receptor agonists, represents a step forward in the magnitude of weight loss achieved, but they do not work for everyone, and the weight loss achieved is still less than that seen for bariatric surgery for many individuals. Finally, it is acknowledged that most patients will require chronic use to maintain the weight loss achieved, not unlike the need to use medications to manage diabetes mellitus, but there was concern about the safety of long-term use and the willingness of individuals to remain on therapy for many years, especially if it requires considerable out-of-pocket costs to the individual. ©lnstitute for Clinical and Economic Review, 2022 Page 5 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 3. Comparative Clinical Effectiveness 3.1. Methods Overview Procedures for the systematic literature review assessing the evidence on semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone for the management of obesity are detailed in Section D1 of the Supplement. Scope of Review We reviewed the clinical effectiveness of the medications plus lifestyle interventions compared to placebo plus lifestyle interventions. For studies evaluating multiple doses or combinations of the medications, we reviewed only the FDA-approved dose and/or combination for the obesity indication. Lifestyle interventions were variably defined in the clinical trials as interventions ranging from diet and exercise counseling to intensive behavioral therapy (IBT) and meal replacement programs. We sought evidence on weight loss outcomes, including percentage weight loss from baseline and proportion of participants achieving 5%, 10%, or 15% body weight loss as well as patient-important outcomes, including functional status, health-related quality of life (HRQoL), and weight regain. We also sought evidence on changes in glycated hemoglobin (A1C), systolic blood pressure (SBP), low density lipoprotein (LDL), and waist circumference. The full scope of the review is available in Section D1 of the Supplement. Evidence Base Semaglutide Evidence informing our review of semaglutide for obesity management was derived from five of the STEP trials. STEP 1, STEP 2, STEP 3, STEP 5, and STEP 8 were selected as studies of interest due to their study design, relevant population, and length of follow-up.2?** Additional studies of semaglutide are described in Section D2 and Tables D8, D13, and D19 in the Supplement. STEP 1, STEP 2, and STEP 5 evaluated subcutaneous semaglutide 2.4 mg plus lifestyle intervention versus placebo plus lifestyle intervention.2"7°324 STEP 2 also evaluated subcutaneous semaglutide at 1.0 mg, but we only reviewed evidence for the subcutaneous semaglutide 2.4 mg as it is the approved dose for obesity treatment (Table 3.3).2° STEP 3 evaluated subcutaneous semaglutide 2.4 mg plus IBT versus placebo plus IBT (Table 3.1).32 STEP 8 evaluated subcutaneous semaglutide 2.4 mg plus lifestyle intervention versus subcutaneous liraglutide 3.0 mg plus lifestyle intervention, and compared both to placebo plus lifestyle intervention.?> STEP 8 was open label due to dosing differences between semaglutide and liraglutide, however, active treatment groups were double- blinded to whether they were receiving the intervention or comparable placebo (Table 3.1). ©lnstitute for Clinical and Economic Review, 2022 Page 6 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Participants in STEP 1, 3, 5, and 8 included adults with BMI 230 kg/m? or 227 kg/m with at least one weight-related comorbid condition (Table 3.1).293134 History of type 1 or type 2 diabetes mellitus or HbA1C equal to or above 6.5% were exclusion criteria for these trials. Participants in STEP 2 included adults with BMI of 227 kg/m? diagnosed with type 2 diabetes mellitus and excluded individuals with renal disease (Table 3.3).°° Participants in STEP 1, 3, 5, and 8 trials were of similar age and baseline weight and BMI.293+34 Participants in STEP 2 who had diabetes mellitus were somewhat older, had lower BMI, and were less likely to be female or White.®° Baseline characteristics for the STEP trials are outlined in Tables 3.1 and 3.3. Outcomes were assessed at week 68 for all STEP trials except STEP 5, which evaluated outcomes at weeks 52 and 104. STEP 4, which was a withdrawal study, was not included in the base evidence review or network meta-analysis (NMA) due to differences in study design and baseline weight loss during a run-in dose escalation period.?? However, we did review its unique data regarding weight regain. See additional information regarding this trial in Section D2 of the Supplement. Table 3.1. Overview of Key Trials of Semaglutide for the Management of Obesity??3233° STEP 1 STEP 3 STEP 5 STEP 8 Study Arms PBO SEM PBO SEM PBO SEM PBO SEM LIR N 655 1,306 204 407 152 152 85 126 127 Monthly counseling, . Monthly counseling, | Monthly counseling, . : Low calorie meal . oo. Lifestyle reduced-calorie . reduced-calorie reduced-calorie diet, . : : replacement diet for : : . : Intervention | diet, and increased _ diet, andincreased | and increased physical . - 8 weeks and IBT visits . - oe physical activity physical activity activity Mean Age, | 47 46 46 46 A7 47 51 «| 48 49 Years Female 76 73.1 88.2 77.4 74.3 80.9 77.6 | 81 76.4 Gender, % Baseline Weight, ke 105.2 105.4 103.7 106.9 106 108.8 | 102.5 | 103.7 Baseline BMI, ke/m? 38 37.8 37.8 38.1 38.5 38.8 37 37.2 wae White, | 76 74.5 775 75.4 93.4 92.8 70.6 | 746 | 74.8 , eDiabetes, | 44> | 45.4 52.9 48.2 46.4 40 | 341 | 354 IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, NR: not reported, PBO: placebo, SEM: semaglutide Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 7 Return to Table of Contents Liraglutide Evidence informing our review of liraglutide for obesity management was derived from six of the SCALE Phase III randomized trials, which evaluated subcutaneous liraglutide 3.0 mg versus placebo.*7"© STEP 8, described previously, is included in the liraglutide evidence analysis as well.3° Additional studies of liraglutide are described in Section D2 and in Tables D8, D13, and D19 of the Supplement. SCALE (Maintenance), SCALE (Sleep Apnea), SCALE (Obesity and Pre-Diabetes), and SCALE (Type 2 Diabetes) evaluated subcutaneous liraglutide 3.0 mg plus lifestyle intervention versus placebo plus lifestyle intervention.*7"° SCALE (IBT) and SCALE (Insulin) evaluated subcutaneous liraglutide 3.0 mg plus IBT versus placebo plus IBT.**4* Participants in SCALE (IBT) included adults ages 218 with a BMI 230 kg/m?.*° Participants in SCALE (Maintenance), SCALE (Sleep Apnea), and SCALE (Obesity and Pre-Diabetes) included adults ages >18 with BMI >30kg/m? or 227kg/m? with untreated dyslipidemia or hypertension.**"24 SCALE (Sleep Apnea) had additional inclusion criteria of individuals with moderate to severe obstructive sleep apnea who were unable or unwilling to use continuous positive airway pressure (CPAP).** Participants in SCALE (Type 2 Diabetes) included adults ages 218 with overweight or obesity (BMI 227kg/m?) with a diagnosis of type 2 diabetes mellitus treated with diet and exercise alone or one to three oral hypoglycemic medications.** Participants in SCALE (Insulin) included adults ages 218 with a BMI 227kg/m7, a diagnosis of type 2 diabetes mellitus, and receiving stable treatment with any basal insulin and <2 oral hypoglycemic medications." All trials except SCALE (IBT) and SCALE (Insulin) excluded individuals with a history of previous surgical treatment of obesity. Additionally, all studies excluded individuals with a recent history of major depressive disorder or a lifetime suicide attempt. Any history of drug-induced obesity or an endocrine disorder that could contribute to obesity (e.g., Cushing syndrome) was also exclusion criteria across all trials. History of multiple endocrine neoplasia and familial medullary thyroid carcinoma were also exclusionary due to the increased risk of medullary cancer of the thyroid with GLP-1 receptor agonists.*""* Participants across all included trials were primarily female, and of similar age and baseline weight and BMI, with some notable differences. SCALE (Sleep Apnea) participants had higher baseline weight and were primarily male and participants in SCALE (Type 2 Diabetes) and SCALE (Insulin) had higher baseline A1C and SBP.*23-* Baseline characteristics for the SCALE trials are outlined in Tables 3.2 and 3.3. Outcomes were assessed at week 56 for all SCALE trials except SCALE (Sleep Apnea), which assessed outcomes at week 32. SCALE (Type 2 Diabetes) additionally evaluated some relevant outcomes at week 68. ©lnstitute for Clinical and Economic Review, 2022 Page 8 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.2. Overview of Key Trials of Liraglutide for the Management of Obesity4242445-49-52 SCALE SCALE SCALE SCALE Maintenance Sleep Apnea Obesity and IBT pep Pre-Diabetes Study Arms PBO LIR PBO LIR PBO LIR PBO LIR N 210 212 179 180 1,244 2,487 140 142 Low-calorie run-in with Monthly counseling, | Monthly counseling, . . weekly counseling then . . o: IBT, reduced-calorie Lifestyle rv reduced-calorie reduced-calorie diet, : . . reduced-calorie diet, . . . diet, and increased Intervention . . diet, and increased and increased . and increased physical . _ : - physical activity i physical activity physical activity activity Mean Age, 46.5 45.9 48.4 48.6 45 45.2 49 45.4 Years Female 78.6 84 27.9 28.3 78.1 78,7 82.9 83.8 Gender, % Baseline Weight, ke 98.7 100.4 118.7 116.5 106.2 106.2 106.7 108.5 Baseline BMI, kg/m? 35.2 36 39.4 38.9 38.3 38.3 38.7 39.3 we White, | 93.4 80.2 75.4 72.2 85.3 84.7 82.1 78.9 : e-Diabetes, | vp NR 62.6 63.9 60.9 61.4 NR NR IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, NR: not reported, PBO: placebo Table 3.3. Overview of Key Trials of Semaglutide and Liraglutide for the Management of Obesity with Diabetes?>-43-46.53 SCALE SCALE STEP 2 Type 2 Diabetes Insulin Study Arms PBO SEM PBO LIR PBO LIR N 403 404 212 423 198 198 Lifestyle Monthly counseling, Monthly counseling, IBT, reduced-calorie diet, and . reduced-calorie diet, and reduced-calorie diet, and . . . Intervention . . - . . . increased physical activity increased physical activity increased physical activity Mean Age, 55 55 54.7 55 57.6 55.9 Years Female Gender, % 47.1 55.2 54.2 48 50 45.5 Baseline Weight, kg 100.5 99.9 106.5 105.7 98.9 100.6 Baseline BMI, kg/m? 35.9 35.9 37.4 37.1 35.3 35.9 Race, White, % | 60 58.7 82.5 83.5 90.9 87.9 IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, PBO: placebo, SEM: semaglutide ©lnstitute for Clinical and Economic Review, 2022 Page 9 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Phentermine/Topiramate Evidence informing our review of phentermine/topiramate for obesity management was derived from three Phase III studies (EQUIP, EQUATE, and CONQUER). One additional Phase I/II study, OB- 204, is described in Section D2 and Tables D9, D16, and D20 of the Supplement. EQUIP, EQUATE, and CONQUER were multi-center, Phase III randomized controlled trials that evaluated phentermine 15 mg/topiramate 92 mg (high dose) plus lifestyle intervention versus placebo plus lifestyle intervention (Table 3.4 and 3.5).545® EQUIP also evaluated phentermine 3.75 mg/topiramate 23 mg and CONQUER evaluated the phentermine 7.5/topiramate 46 mg dose. EQUATE had seven arms evaluating multiple doses of phentermine and topiramate monotherapy, in addition to phentermine 7.5 mg/topiramate 46 mg. Evidence was reviewed only for phentermine 15 mg/topiramate 92 mg (high dose) and phentermine 7.5 mg/topiramate 46 mg doses (low dose), and the NMA focused solely on the high dose. The EQUIP, EQUATE, and CONQUER trials included adults ages 18-70, but each trial had varying BMI requirements. EQUIP required that participants have a BMI of at least 35 kg/m? and EQUATE included participants with a BMI of 30-45 kg/m? (Table 3.4).°4°>® The CONQUER trial required that participants have a BMI of 27-45 kg/m? (with no lower BMI limit for patients who have diabetes mellitus) and have at least two of the following comorbidities: SBP 140-160 mmHg (or 130-160 mmbsg if diabetic), diastolic blood pressure 90-100 mmHg (or 85-100 mmHg if diabetic), or taking at least two antihypertensive medications (Table 3.5).°* The CONQUER trial additionally included both adults with and without type 2 diabetes mellitus. For the purposes of our clinical review and NMA, and due to the lack of data available in the subgroup of participants without diabetes mellitus, we focused specifically on the diabetes mellitus subgroup in this trial because it comprised the majority of participants (68%).°° Having a serious medical condition, obesity of known endocrine origin, stage 2 hypertension, previous surgery for obesity, or a weight change of >5 kg within three months were common exclusion criteria for these trials. Patients in EQUIP and EQUATE were also excluded if they had type 2 diabetes mellitus.>>°" Additional exclusion criteria for CONQUER included fasting glucose greater than 13 mmol/L, triglycerides greater than 4.52 mmol/L, use of antidiabetic medication other than metformin, or a history of seizures or serious psychiatric illness.** EQUIP and EQUATE trials had similar baseline characteristics, except for BMI and weight.>*>* The BMI requirement was higher in EQUIP than in other trials, meaning that all participants in this trial had severe obesity. As a result, the mean baseline BMI and body weight of participants was higher in this trial compared to other trials in our review.°" Compared to participants in EQUIP and EQUATE, the diabetes mellitus subgroup of CONQUER had a higher mean age and fewer female participants.°? Baseline characteristics for these trials are reported in Tables 3.4 and 3.5. ©lnstitute for Clinical and Economic Review, 2022 Page 10 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Bupropion/Naltrexone Evidence to inform our review of bupropion/naltrexone in patients with overweight or obesity was derived from four Phase III randomized controlled trials, COR-I, COR-I], COR-BMOD, and COR Diabetes. Two additional Phase III trials, CVOT Light and Ignite, are described in Section D2 and Tables D9, D16, and D20 of the Supplement. COR-I, COR-II, and COR Diabetes were multi-center, Phase Ill randomized controlled trials that evaluated bupropion SR 360 mg/naltrexone SR 32 mg plus lifestyle intervention versus placebo plus lifestyle intervention. COR-I additionally evaluated a lower dose of bupropion SR 360 mg/naltrexone SR 16 mg, but we only reviewed the higher approved dose of the medication. COR- BMOD was a multi-center, Phase III randomized controlled trial that evaluated bupropion SR 360 mg/naltrexone SR 32 mg plus IBT versus placebo plus IBT (Table 3.4 and 3.5).°©° COR-I, COR-II, and COR-BMOD included adults ages 18-65 years who had a BMI of 30-45 kg/m?, ora BMI of 27-45 kg/m? with controlled hypertension and/or dyslipidemia (Table 3.4).°°§ Inclusion criteria for COR Diabetes included patients ages 18-70 years with a BMI of 27-45 kg/m2, who were diagnosed with type 2 diabetes mellitus, had an HbA1C between 7-10%, fasting blood glucose <270 me/dL, fasting triglycerides <400 mg/dL, SBP <145 mmHg, and diastolic blood pressure <95 mmHg (Table 3.5), Having type 1 diabetes mellitus, a serious medical condition, obesity of known endocrine origin, surgery for obesity, a history of seizures, drug, or alcohol abuse, or using medications that affected body weight were common exclusion criteria among the trials. Adults with overweight or obesity in COR-I, COR-II, and COR-BMOD were additionally excluded if they had type 2 diabetes mellitus ora weight change of >4 kg within three months. In COR Diabetes, patients were also excluded if they had diabetes mellitus secondary to pancreatitis or pancreatectomy, weight change >5 kg within three months, or used diabetes medication or were not on a stable dose of oral antidiabetic drugs. Baseline characteristics for COR-|, COR-II, and COR-BMOD trials were similar,®**** except participants in COR Diabetes were slightly older in age and less likely to be female.© Baseline data for patients in these trials are reported in Tables 3.4 and 3.5. ©lnstitute for Clinical and Economic Review, 2022 Page 11 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.4. Overview of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity*>5*& °7 EQUIP EQUATE COR-I COR-II COR-BMOD P/T P/T | P/T Study Arms PBO (high) PBO (low) | (high) PBO B/N PBO B/N PBO B/N N 514 512 109 107 108 581 583 495 1,001 202 591 LSM counseling, | LSM counseling, oe clin LSM counseling, | IBT, reduced- Lifestyle reduced-calorie | reduced-calorie diet, 8 . reduced-calorie | calorie diet, . a . . reduced-calorie a. . . Intervention | diet, increased increased physical diet, increased diet, increased increased physical physical activity | activity physical activity physical activity | activity vane Age, | 43 419 [45 | 446 | 446 | 43.7 | 444 | 44.4 | 443 45.6 45.9 Female 82.7 | 328 |789 | 79.4 | 78.7 | 85 85 | 3848 | 84.6 91.6 89.3 Gender, % Baseline 115.8 | 115.2 | 100 | 102.2/99.3 |995 | 99.7 | 99.2 | 100.3 |1019 | 100.2 Weight, kg Baseline BMI, kg/m? 42 41.9 36.2 | 36.6 35.9 36.2 36.1 36.1 36.2 37 36.3 Race, 79.7 |804 |761 )748 |815 |757 |75 |836 | 93.4 73.7 68.5 White, % . . . . . . . . . . Pre- NR | NR NR | NR | NR NR NR | NR | NR NR NR Diabetes, % B/N: bupropion/naltrexone, IBT: intensive behavioral therapy, kg: kilogram, LSM: lifestyle modification, m: meter, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate Table 3.5. Overview of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity with Diabetes**°**1 CONQUER (Diabetes Subgroup) COR Diabetes Study Arms PBO P/T (low) P/T (high) PBO B/N N 157 67 164 159 265 Lifestyle Intervention LSM counseling, physical activity reduced-calorie d iet, increased LSM counseling, diet, increased p reduced-calorie hysical activity Mean Age, Years 52.6 52.5 52.1 53.8 53.9 Female Gender, % 71.3 65.6 62.1 52.8 54.3 Baseline Weight, kg 99.3 97.2 103.2 105 106.3 Baseline BMI, kg/m? 36.2 35.3 37.1 36.3 36.7 Race, White, % 84.7 94 82.9 83 78.1 B/N: bupropion/naltrexone, kg: kilogram, LSM: lifestyle modification, m: meter, N: total number, PBO: placebo, P/T: phentermine/topiramate Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 12 Return to Table of Contents 3.2. Results The most common primary outcome reported was percentage weight loss from baseline to one year after treatment initiation with dose escalation periods ranging from four to 16 weeks. Other outcomes variably included categorical weight loss (participants achieving 5% or 10% weight loss), and changes in metabolic and cardiovascular risk factors such as SBP, A1C, and LDL. As noted in the prior section, trials differed in populations studied (such as participants with or without diabetes mellitus or other conditions and baseline BMI) and intensity of lifestyle modification interventions offered alongside active treatment or placebo (ranging from diet and exercise counseling to IBT). To ensure comparability and generalizability of results, we present trials of participants with obesity alone separately from trials of participants with obesity and diabetes mellitus. Clinical trial participants for all interventions were also assessed for improvements in physical function and mental HRQoL using a variety of instruments: Short Form 36v2 Health Survey (SF- 36v2), Impact of Weight on Quality of Life (IWQOL) Lite Clinical Trials Version, Patient Health Questionnaire (PHQ-9), and Inventory of Depressive Symptomatology - Self Report (IDS-SR). Changes in weight, SBP, A1C, and HRQoL as well as harms and discontinuation rates are summarized below, and additional outcomes are available in Section D2 of the Supplement. Clinical Benefits For each medication, weight loss outcomes are summarized first followed by other outcomes (e.g., SBP and A1C). HRQoL outcomes are summarized for all drugs at the end of this section. For each medication, results of trials conducted in patients with obesity are presented first, followed by trials conducted in patients with obesity and diabetes mellitus. Semaglutide versus Placebo The efficacy of semaglutide compared with placebo for the management of obesity in patients without diabetes mellitus was evaluated in three Phase III trials (STEP 1, 3, and 5).223+34.39 In the STEP 1, 3, and 5 trials, participants in the subcutaneous semaglutide 2.4 mg arm consistently achieved greater percent weight loss at one year (-15.6%, -16.5%, and -15.8%, respectively) versus placebo (-2.8%, -5.8%, and -3.3%, respectively).2?3+3° Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5% weight loss, at least 10% weight loss, and at least 15% weight loss, a greater proportion of participants in the semaglutide arm achieved each categorical outcome compared to participants in the placebo arm. Participants in the semaglutide arms of STEP 1, 3, and 5 trials also had greater improvements in SBP from baseline (-6.2 mmHg, -5.6 mmHg, and -6 mmHg, respectively) compared to those in the placebo arms (-1.1 mmHg, -1.6 mmHg, and -1 mmHg, respectively).293+*4 In the STEP 1, 3, and 5 trials, the absolute change in percentage A1C (change in A1C) from baseline improved in the semaglutide arm (-0.45%, -0.51%, and -0.5%, respectively) compared to the placebo arm (-0.15%, -0.27%, and -0.2%, respectively). ©lnstitute for Clinical and Economic Review, 2022 Page 13 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 29,3133 The absolute change in percentage A1C for STEP 8 improved for the semaglutide arm (-0.2%) compared to an increase in A1C for the placebo arm (0.1%).3+33 See Table 3.6 for detailed results. The efficacy of semaglutide for the management of obesity and type 2 diabetes mellitus was evaluated through one Phase Ill trial (STEP 2).2° Participants in the subcutaneous semaglutide 2.4 mg arm achieved greater percent weight loss at one year (-9.6%) versus placebo (-3.4%), but the magnitude of weight loss appeared less than in the trials of participants without diabetes mellitus. Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5% weight loss and at least 10% weight loss, a greater proportion of participants in the semaglutide arm achieved each categorical outcome compared to participants in the placebo arm. Participants in the semaglutide arm also had modest improvement in SBP (-3.6 mmHg) compared to those in the placebo arm (-0.5 mmHg). Change in A1C from baseline was consistent across both the semaglutide and placebo arms (-0.4% vs. -0.4%). See Table 3.8 for detailed results. Physical functioning was assessed in the STEP 1, STEP 2, and STEP 3 trials using the SF-36v2 Physical Functioning Score.?*3? STEP 1 and 3 also assessed the mean change in baseline of the SF-36v2 PCS. STEP 1 and 2 also assessed physical function utilizing the IWQOL-Lite-CT instrument.2?7° Overall, semaglutide resulted in greater improvement in the physical component across all HRQoL instruments compared to placebo, indicating the intervention resulted in greater improvement in health status for physical patient-reported outcomes. See Table D17 in the Supplement for detailed results. STEP 1, 2, and 3 trials all reported baseline SF-36v2 MCS scores, but only STEP 1 and 3 reported the change from baseline to week 68. STEP 2 reported estimated treatment differences. In STEP 1, participants in the semaglutide arm experienced improvement in SF-36 MCS scores (1.5) versus placebo, which had a reduction in score (-2.1). Conversely, in STEP 3, participants in both treatment arms experienced decreased SF-36 MCS, although there was a smaller decrease in the semaglutide arm (-0.8) compared to placebo (-2.9). See Table D18 in the Supplement for detailed results. Semaglutide versus Liraglutide The efficacy of subcutaneous semaglutide versus subcutaneous liraglutide with a placebo comparator for the management of obesity was evaluated in one Phase III trial (STEP 8).3° Participants in the semaglutide 2.4 mg arm achieved greater weight loss at one year (-15.8%) versus liraglutide 3.0 mg (-6.4%) and placebo (-1.9%). Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5% weight loss, at least 10% weight loss, and at least 15% weight loss, a greater proportion of participants in the semaglutide arm achieved each categorical outcome compared to participants in the liraglutide and placebo arms. Participants in the semaglutide arm also had greater improvements in SBP from baseline (-5.7 mmHg) compared to participants in the liraglutide arm (-2.9 mmHg), and participants in both the semaglutide and liraglutide arms had greater improvement compared to those in the placebo arm, who had a ©lnstitute for Clinical and Economic Review, 2022 Page 14 Final Evidence Report - Medications for Obesity Management Return to Table of Contents modest increase in SBP (3.2 mmHg). Minimal changes in A1C were seen in all arms of the trial. See Table 3.6 for detailed results. Table 3.6. Results of Key Trials of Semaglutide for the Management of Obesity?232-33-39.8 STEP 1 STEP 3 STEP 5 STEP 8 Study Arms PBO SEM PBO |SEM | PBO SEM PBO SEM LIR N 577 1,212. |189 | 373 129 149 78 117 117 weer Loss rr -2.8 156 |-58 |-165 | -3.3 15.8 | -1.9 15.8 | -6.4 , t t t t t t t t t Mean (SE) (0.3) (0.3) (0.4)+ | (0.5)+ | (0.6) (0.8) (1.1) (0.9) (0.9) Participants with at Least | 182 1,047 90 323 38 132 23 102 68 5% Weight Loss, n (%) (31.5) | (86.4) _| (47.6) _| (86.6) | (29.5) | (88.6) | (29.5) __| (87.2) _| (58.1) Participants with at Least | 69 838 51 281 17 102 12 83 30 10% Weight Loss, n (%) (12) (69.1) | (27) | (75.3) | (13.2) | (68.5) | (15.4) '| (70.9) '| (25.6) Seaae aero en "1.4 6.2 -1.6* | -5.6* | -1* -7* 3.2* |-5.7* | -2.9% (se) & (o.5)t | (04)t | (4a) | 07) | (rape | (aayt | (asyt ] (tye | (2.2) Change in %HbAI1C from -0.15* -0.45* -0.27* | -0.51* | -0.2* -0.5* 0.1* -0.2* -0.1* Baseline, Mean (SE) (0.01)+ | (0.01)+ | (0.01)+ | (0.02)+ | (0.02)+ | (0.03)+ | (0.02)+ | (0.03)+ | (0.03)t HbA1C: glycated hemoglobin, LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, PBO: placebo, SBP: systolic blood pressure, SE: standard error, SEM: semaglutide *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. Liraglutide versus Placebo The efficacy of liraglutide compared with placebo for the management of obesity was evaluated in four Phase Ill trials in the SCALE clinical trial program (Maintenance, Sleep Apnea, Obesity and Pre- Diabetes, IBT).42424445 In the Maintenance, Obesity and Pre-Diabetes, and IBT trials, participants in the subcutaneous liraglutide 3.0 mg arm consistently achieved greater percent weight loss at one year (-6.2%, -8%, and -7.4%, respectively) versus placebo (-0.2%, -2.6%, and -4%, respectively).42445 Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5% weight loss and at least 10% weight loss, a greater proportion of participants in the liraglutide arm achieved each categorical outcome compared to participants in the placebo arm. Changes in SBP varied across trials with liraglutide demonstrating modest improvements relative to placebo, except in the Maintenance trial in which participants in both the liraglutide and placebo arms experienced an Increase in SBP from baseline (0.2 mmHg and 2.8 mmHg, respectively). Across all four SCALE trials, greater improvements in change in A1C were consistently demonstrated in the liraglutide arm compared to the placebo arm, although the results varied between studies.*14244> See Table 3.7 for detailed results. The efficacy of subcutaneous liraglutide compared with placebo for the management of obesity with diabetes mellitus was evaluated in two Phase Ill trials in the SCALE clinical trial program (Type 2 Diabetes, Insulin).*?4° In both the SCALE (Type 2 Diabetes) and SCALE (Insulin) trials, participants Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 15 Return to Table of Contents in the liraglutide 3.0 mg arm had greater percent weight loss at one year (-5.9% and -5.8%, respectively) compared to placebo (-2% and -1.5%, respectively). Similarly, liraglutide demonstrated a greater proportion of participants who achieved at least 5% or 10% weight loss compared to placebo. Liraglutide also demonstrated greater improvements in SBP compared to placebo. Across both trials, improvements in A1C were greater in the liraglutide arms {-1.3% and - 1.1%, respectively) compared to the placebo arms (-0.3% and -0.6%, respectively). See Table 3.8 for detailed results. The SCALE (Sleep Apnea, Obesity and Pre-Diabetes, IBT, and Insulin) trials assessed physical patient- reported outcomes utilizing the SF-36v2 PCS instrument.*2"4"* The IWQOL-Lite-CT instrument assessed physical function score in the SCALE (Type 2 Diabetes, Obesity and Pre-Diabetes, IBT, and Insulin) studies.44"* Overall, liraglutide resulted in greater improvement in the physical component across all HRQoL instruments compared to placebo, indicating the intervention resulted in greater improvement in health status for physical patient-reported outcomes. The one exception was SCALE (IBT), which reported slightly less improvement in SF-36v2 PCS scores for liraglutide (3.4) compared to placebo (3.8). See Table D17 in the Supplement for detailed results. Four studies for liraglutide, SCALE (Sleep Apnea, Obesity and Pre-Diabetes, IBT, and Insulin) trials also evaluated the mental component utilizing the SF-36v2 MCS instrument with minimal improvements compared to baseline in the liraglutide arm for the SCALE (Sleep Apnea and Obesity and Pre-Diabetes) trials (1.4 and 0.2, respectively), less improvement in the SCALE (Sleep Apnea) placebo arm (0.9), and a decrease in health quality in the SCALE (Obesity and Pre-Diabetes) placebo arm (-0.9).4244 The SCALE (IBT and Insulin) trials reported a decrease in SF-36v2 scores across both the liraglutide and placebo arms of the trial, indicating a decreased mental health status. See Table D18 in the Supplement for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page 16 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.7. Results of Key Trials of Liraglutide for the Management of Obesity424244-45-49-52,68 SCALE SCALE SCA LE SCALE Maintenance Sleep Apneat Obesity and IBT Pre-Diabetes Study Arms PBO LIR PBO LIR PBO LIR PBO LIR N 188 194 178 175 1,220 2,432 130 141 Baseline to One Year 0.24 6.24 N/A N/A 2.6 8 " 74 , * * * * * * Mean (SE) (0.5) (0.5) (0.2) (0.1) (0.6) (0.7) Participants with 5% 41 98 33 81 331 1,537 50 87 Weight Loss, n (%) (21.8) (50.5) (18.5) (46.3) (27.1) (63.2) (38.8) (61.5) Participants with 10% | 12 51 3 41 129 805 26 43 Weight Loss, n (%) (6.3) (26.1) (1.7) (23.4) (10.6) (33.1) (19.8) (30.5) Saccines amie 2.8t 0.2+ ora) | 34t -1.5t -4,2+ o.6t (R) | 28" ? ? * * * * ™: Mean (SE) (0.7) (0.8) (0.9) (0.4) (0.2) (NR) ene 0.1¢ O.1t | gr¢() | oat (oy |O08t | -03t | -0.06t | -0.16+ (SE) , (0.03)* | (0.03)* , , (0.01)* (0.01)* | (0.02)* (0.03)* A1C: glycated hemoglobin, LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, N/A: not applicable, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SE: standard error *SE manually derived from standard deviation or 95% Cls. tThe number of patients for this outcome may differ from the primary analysis population. +Timepoint is at week 32 for all outcomes. Table 3.8. Results of Key Trials of Semaglutide and Liraglutide for the Management of Obesity with Diabetes Mellitus®®424653.68 SCALE SCALE STEP 2 Type 2 Diabetes Insulin Study Arms PBO SEM PBO LIR PBO LIR N 376 388 211 412 193 191 % Weight Loss from Baseline to One Year, | -3.4 (0.4) -9.6 (0.4) -2 (0.3)* -5.9 (0.3)* -1.5 (0.4) -5.8 (0.4) Mean (SE) Participants with 5% Weight Loss, n (%) 107 (28.5) 267 (68.8) 45 (21.4) 224 (54.3) 46 (24) 100 (51.8) Participants with 10% Weight Loss, n (%) 31 (8.2) 177 (45.6) 14 (6.7) 104 (25.2) 13 (6.6) 44 (22.8) Change in SBP from Baseline, mmHg, -0.5t (0.8) -3.9T (0.7) -0.4t (0.9)* | -2.8t (0.7)* -1.6T (0.9) -5.6t (0.9) Mean (SE) Change in %HbA1C -0.3+ from Baseline, Mean -0.4t (0.1) -0.4t (0.1) ace -1.3t (0.04)* | -0.6T (NR) -1,1+ (NR) (SE) (0.06) A1C: glycated hemoglobin LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SE: standard error, SEM: semaglutide *SE manually derived from standard deviation or 95% Cls. tThe number of patients for this outcome may differ from the primary analysis population. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 17 Return to Table of Contents Phentermine/Topiramate versus Placebo In the EQUIP trial, participants in the phentermine 15 mg/topiramate 92 mg arm achieved greater weight loss at one year (-10.9%) than participants in the placebo arm (-1.6%).°"*8 For the co- primary outcome of proportion of participants who lost at least 5% of their weight, more participants in the phentermine/topiramate arm achieved this outcome compared to participants in the placebo group. Similarly, more participants in the high-dose treatment arm achieved 10% weight loss compared to the placebo arm (Table 3.9). One-year outcomes were not available in the EQUATE trial, whose timepoints went out to only 28 weeks. Participants in the diabetes mellitus subgroup of the CONQUER trial receiving phentermine 15 mg/ topiramate 92 mg treatment (high dose) and phentermine 7.5 mg/topiramate 46 mg (low dose) achieved a greater weight improvement at one year (-8.8% and -6.8%, respectively) than participants in the placebo arm (-1.9%).°4°° Categorical weight loss of at least 5% and 10% were not assessed in this diabetes mellitus subgroup population. See Table 3.10 for detailed results. In terms of secondary outcomes, in the EQUIP trial, SBP decreased by 2.9 mmHg in the high-dose phentermine/topiramate arm and increased by 0.9 mmHg in the placebo arm (Table 3.9).°" In the CONQUER diabetes mellitus subgroup, patients in the high-dose phentermine/topiramate arm and low-dose phentermine/topiramate arm experienced HbA1C decreases of 0.4% compared to the placebo decreases of 0.1%. Similarly, in patients with diabetes mellitus in CONQUER, SBP decreased by 4.2 mmHg in the phentermine 15 mg/topiramate 92 mg group, by 2.9 mmHg in the phentermine 7.5 mg/topiramate 46 mg group, and by 2.1 mmHg in the placebo group (Table 3.10).°9 Physical function outcomes were not assessed. Depression was assessed in the EQUATE and EQUIP trials using the PHQ-9 instrument. For both trials, a greater improvement in this measure was observed in the high-dose phentermine/topiramate arms, compared to the placebo arms. In EQUATE, participants in the high-dose and low-dose phentermine/topiramate arms improved by 1.1 and 1.3 points, respectively, while participants in placebo improved by 0.5 points.>>°* Depression scores in the EQUIP trial improved more from baseline in the high-dose phentermine/topiramate group (1.5), compared to the placebo group (1.3).°"°8 PHQ-9 was not assessed in the diabetes mellitus subgroup of the CONQUER trial. See Table D18 in the Supplement for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page 18 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Bupropion/Naltrexone versus Placebo In the COR-I, COR-II, and COR-BMOD trials of adults with obesity, participants in the bupropion 360 mg/naltrexone 32 mg (high dose) arm achieved greater weight loss at one year (-6.1%, -6.4%, and -9.3%, respectively), than participants in the placebo arm (-1.3%, -1.2%, and -5.1%, respectively). 64,6667 For the co-primary outcome of participants who lost at least 5% of their weight, a greater proportion of participants in the intervention arm achieved this outcome compared to placebo. A similar pattern was observed for the secondary outcome of proportion of participants who achieved 10% weight loss between the arms. See Table 3.9 for detailed results. Participants in the bupropion 360 mg/naltrexone 32 mg arm in the COR Diabetes trial achieved greater percent weight loss at one year (-5%) than participants in the placebo arm (-1.8%).©°* For the co-primary outcome of proportion of participants who lost at least 5% of their weight, more participants in the bupropion/naltrexone arm achieved this outcome compared to participants in the placebo group. Additionally, more participants in the treatment arm achieved 10% weight loss than in the placebo arm (Table 3.10). In COR-I, SBP decreased by 0.1 mmHg in participants receiving the intervention and by 1.9 mmHg in participants receiving placebo (Table 3.9). 57585253 A similar pattern was observed in the COR- BMOD trial, where SBP decreased by 1.3 mmHg in the bupropion/naltrexone group versus 3.9 mmbg in the placebo group.© In the COR-II trial, SBP increased by 0.6 mmHg in the treatment group and decreased by 0.5 mmHg in the placebo group (p=0.039).% None of these trials assessed HbA1C levels. In the COR Diabetes trial, change from baseline in HbA1C was -0.63% in the treatment group, and -0.14% in the placebo arm. Participants receiving the treatment experienced no change in SBP, while participants receiving placebo experienced a mean decrease in SBP of 1.1 mmHg. See Table 3.10 for detailed results. HRQoL was assessed using the IWQOL-Lite, an obesity-specific instrument and the IDS-SR, which assesses depressive symptoms. In COR-I, COR-II, and COR-BMOD, patients in the bupropion/naltrexone group showed a greater improvement in the IWQOL-LITE physical function and total scores than patients in the placebo group.®* +657 However, changes in depression scores were not consistent across trials. In COR-I and COR-II, patients in the placebo arm reported a greater improvement in their depressive symptoms (-0.7 and -0.5, respectively) compared to the high-dose bupropion/naltrexone arm (-0.3) (lower is better).°*°* In COR-BMOD, patients in the treatment arm reported a 0.1 increase from baseline in IDS-SR score, meaning their depressive symptoms worsened, while patients in placebo reported no change.®©*" In the COR Diabetes trial, patients in the bupropion/naltrexone treatment arm reported no change in depression score, while patients in the placebo arm reported that their mean score improved by 1.6.°°°! See Tables D17 and D18 in the Supplement for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page 19 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.9. Results of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity*"**52-©7 EQUIP COR-I COR-II COR BMOD Study Arms PBO ing hy | PBO | B/N PBO B/N PBO B/N N 498 498 511 471 456 702 193 482 eign Loss for -1.6 10.9 | -1.3 6.1 1,2 64 5.1 93 Mean (SE} (0.4) '| (0.4) (0.3) | (0.3) (0.3) (0.3) (0.6) '| (0.4) Participants with 5% 86 332 80 354 82 320 Weight Loss, n (%) (17.3) | (66.7) | 8406) | 226048) | 54) | (50.5) | (42.5) | (66.4) Participants with 10% 235 199 39 200 Weight Loss, n (%) 37 (7-4) | azo) | 38 (7) | 116 (25) | 2615-7) | 98.3) | (20.2) | (41.5) Soa aero on 0.9 -2.9 -1.9 0.1 -0.5 0.6 -3.9 1.3 (se) & (0.6)* | (0.6)* | (0.4) | (0.4) (0.4) (0.3) (0.7) (0.5) Change in %HbA1C from Baseline, Mean (SE) NR NR NR NR NR NR NR NR A1C: glycated hemoglobin, B/N: bupropion/naltrexone, mmHg: millimeters of mercury, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP: systolic blood pressure, SE: standard error *SE manually derived from standard deviation or 95% Cls. Table 3.10. Results of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity with Diabetes Mellitus**5*® CONQUER (Diabetes Subgroup) COR Diabetes Study Arms PBO P/T (low) P/T (high) PBO B/N N 157 67 164 159 265 % Weight Loss from Baseline to One Year, Mean | -1.9 (0.6)* -6.8 (0.9)* -8.8 (0.6)* -1.8 (0.4) -5 (0.3) (SE) Participants with 5% Weight Loss, n (%) NR NR NR 30 (18.9) 118 (44.5) Participants with 10% Weight Loss, n (%) NR NR NR 9 (5.7) 49 (18.5) Change in SBP from - - 42+ - Baseline, mmHg, Mean (SE) 2.1 (1.1) 2.9 (1.6) 4.24 (1) 1.1 (0.9) 0 (0.7) Change in %HbAIC from -0.1t -0.4+ (1.5)* -0.4t (0.6)* | -0.14t -0.63+ Baseline, Mean (SE) (0.05)* 0.4¢ (1.5) 0.4t (0.6) 0.14t (0.09) 0.63t (0.07) A1C: glycated hemoglobin, BN: bupropion/naltrexone, mmHg: millimeters of mercury, n: number, N: total number, NR: not reported, PBO: placebo, PT: phentermine/topiramate, SBP: systolic blood pressure, SE: standard error *SE manually derived from standard deviation or 95% Cls. +The number of patients for this outcome may differ from the primary analysis population. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 20 Return to Table of Contents NMA Results of Percentage Weight Loss from Baseline at One Year We conducted NMAs of trials including participants with obesity alone separately from trials of participants with obesity and diabetes mellitus and excluded trials that included IBT as an adjunct to medication. The primary outcome NMAs are reported below, and additional outcomes are available in Supplement D1. Participants with Obesity Alone For the trials of the medications conducted in participants with obesity without diabetes mellitus that included standard diet and exercise counseling and reported percentage weight loss at one year, we present the results of the baseline risk-adjusted random effects model, given its better fit for the model compared to the unadjusted model in Table 3.11. All medications, in combination with diet and exercise counseling, showed statistically significantly greater mean weight loss than placebo with diet and exercise counseling at one year. Compared to placebo, the interventions demonstrated 4.6-13.7% mean greater weight loss. Semaglutide demonstrated the greatest percentage weight loss at one year and was superior to all other medications in our review for this outcome. Phentermine/topiramate (high dose) demonstrated greater weight loss than liraglutide and bupropion/naltrexone, however, liraglutide was not statistically more effective in demonstrating weight loss than bupropion/naltrexone (Table 3.11). Table 3.11. NMA Results of Medications for the Management of Obesity, Mean Percentage Weight Loss from Baseline at One Year (95% Cl) Semaglutide Phentermine/ Topiramate* -4.6 (-2.4 to -7.2) -8.7 (-7.3 to -10.4) -4.1 (-1.9 to -6.3) ern -9.1 (-7.2 to -11.5) -4.5 (-2.2to-6.9) | -0.4(-2.3 to +1.3) Surman) Naltrexone -13,7 (-12.6 to-15.1) | -9.1(-7.1to-11) | -5.0(-3.9 to -6.1) -4.6 (-3.0 to -6.0) Ee te Legend: Each cell represents estimated absolute differences in percentage weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. ©lnstitute for Clinical and Economic Review, 2022 Page 21 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Participants with Obesity and Diabetes Mellitus For the trials of the medications conducted in participants with obesity and diabetes mellitus (using the approved obesity indication dose) that reported percentage weight loss at one year, we present the results of the baseline risk-adjusted random effects model, given its better fit for the model compared to the unadjusted model in Table 3.12. All medications, in combination with diet and exercise counseling, showed statistically significantly greater mean weight loss than placebo with diet and exercise counseling at one year among participants with obesity with diabetes mellitus, although the magnitude of the weight loss was somewhat lower than in trials of participants with obesity alone, especially for semaglutide. Compared to placebo, the medications demonstrated 2.9-7.6% mean greater weight loss at one year. Semaglutide demonstrated a greater percentage weight loss among the medications, however, these differences were not statistically significant. Phentermine/topiramate (high dose) demonstrated greater weight loss than liraglutide and bupropion/naltrexone, however, the results were only statistically significant compared to bupropion/naltrexone. Liraglutide was not statistically more effective in demonstrating weight loss than bupropion/naltrexone (Table 3.12). Table 3.12. NMA Results of Medications for the Management of Obesity with Diabetes Mellitus, Mean Percentage Weight Loss from Baseline at One Year (95% Cl) Semaglutide Phentermine/ eye) Tee T rk he -2.9 (-0.05 to -5.8) -0.9 (-6.3 to +6.2) -3.9 (-9.3 to +3.7) Liraglutide Bupropion/ Naltrexone -2.9 (-0.4 to -5.6) -4,7 (-10.3 to +2.8) -3.8 (-0.4 to -7.1) -0.9 (-3.8 to +2.1) -7.6 (-1.7 to -11.9) -6.7 (-4.2 to -9.2) -3.7 (-1.7 to -6) Legend: Each box represents estimated absolute differences in percentage weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. NMA Results of Change in SBP from Baseline at One Year Participants with Obesity Alone For the trials of the medications conducted in participants with obesity without diabetes mellitus that included standard diet and exercise counseling and reported change in SBP at one year, we present the results of the baseline risk-adjusted random effects model, given its better fit for the model compared to the unadjusted model in Table 3.13. All medications, in combination with diet and exercise counseling, showed statistically significantly greater improvements in SBP than placebo with diet and exercise counseling at one year except bupropion/naltrexone, which was ©lnstitute for Clinical and Economic Review, 2022 Page 22 Final Evidence Report - Medications for Obesity Management Return to Table of Contents comparable to placebo. Compared to placebo, the interventions demonstrated 3.8-7.1 mmHg improvements in SBP. Semaglutide demonstrated the greatest improvement in SBP at one year and was superior to all other medications in our review except for phentermine/topiramate (high dose) for this outcome. Phentermine/topiramate (high dose) and liraglutide both demonstrated greater improvements in SBP than bupropion/naltrexone, however, the interventions were statistically equivalent (Table 3.13). Table 3.13. NMA Results of Medications for the Management of Obesity, Mean Change in SBP from Baseline at One Year (95% Cl) Semaglutide Phentermine/ -2.9 (-6.2 to 0.4) ee -3.3 (-5.3 to -1.2) -0.4 (-3.6 to 2.9) Liraglutide -6.3 (-7.9 to -4.7) -3.4 (-6.3 to -0.6) -3.1 (-4.7 to -1.4) Bupropion/ 7.1 (-9.8 to -4.4) 4.2 (-7.9 to -0.6) 3.9 (-6.8 to -1.0) 0.8 (-3.0 to 1.3) Sanne Legend: Each box represents estimated absolute differences in SBP and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. Participants with Obesity and Diabetes Mellitus For the trials of the medications conducted in participants with obesity and diabetes mellitus and reported change in SBP at one year, we present the results of the baseline risk-adjusted random effects model, given its better fit for the model compared to the unadjusted model in Table 3.14. Semaglutide and liraglutide, in combination with diet and exercise counseling, showed statistically significantly greater improvements in SBP than placebo with diet and exercise counseling at one year, while phentermine/topiramate (high dose) and bupropion/naltrexone did not. Compared to placebo, semaglutide and liraglutide demonstrated 4.3 mmHg and 3.4 mmHg improvements in SBP, respectively (Table 3.14). ©lnstitute for Clinical and Economic Review, 2022 Page 23 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.14. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus, Mean Change in SBP from Baseline at One Year (95% Cl) Semaglutide -0.9 {-4.2 to 2.5) Liraglutide 3.5 (-8.9 to 2.1 2.7 (-6.8 to -1.6 Phentermine/ 3:5 (89 to 2.1) 2.7 (-6.8 to -1.6) ay yee ~4.3 (-1.2 to -7.2) -3.4 (-1.6 to -5.2) -0.7 (-4.4 to 2.8) arrose -5.3 (-1.4 to -9.2) -4.4 (-1.3 to -7.6) -1.8 (-6.3 to 2.6) -1.1 (-4.6 to 1.5) aaabaaal Naltrexone Legend: Each box represents estimated absolute differences in SBP and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. Harms Adverse events reported in the trials are detailed below by medication. It is worth noting that three of the medications carry black box warnings and the fourth has a Risk Evaluation and Mitigation Strategies in place. The GLP-1 medications, semaglutide and liraglutide, carry a black box warning for thyroid carcinoma and bupropion/naltrexone carries a warning for suicidality. Phentermine/topiramate has a Risk Evaluation and Mitigation Strategy in place for a risk of birth defects. These outcomes were not observed in any of the trials but relate to real-world data and should be taken into consideration when prescribing. Semaglutide The most frequent adverse events in the STEP trials for semaglutide were gastrointestinal-related symptoms, including nausea, constipation, and diarrhea.?°°° Beyond gastrointestinal events, semaglutide appeared relatively well-tolerated. Rates of adverse events and serious adverse events were higher in the semaglutide arm compared to placebo, except STEP 5, which had a higher rate of serious adverse events in the placebo arm (11.8%) versus the semaglutide arm (7.9%) (Table 3.15). The higher rate of serious adverse events in the placebo arm of STEP 5 seems to be a chance event associated with events that are not expected to be associated with the intervention within the placebo arm, including COVID-19 infections, foot deformity, jaw and rib fractures, and several occurrences of cancer.343839 Across all trials, there were higher rates of discontinuation due to adverse events in the semaglutide arms compared to placebo, and discontinuation was most often attributed to gastrointestinal events. In STEP 8, participants in the liraglutide arm were more likely to discontinue due to adverse events (12.6%) compared to both the semaglutide and placebo arms ©lnstitute for Clinical and Economic Review, 2022 Page 24 Final Evidence Report - Medications for Obesity Management Return to Table of Contents (3.2% and 3.5%, respectively) (safety analysis set).22 STEP 2, which evaluated participants with obesity and diabetes mellitus, did not exhibit any significant differences in harms compared to other trials in the STEP clinical trial program, which evaluated participants with obesity without diabetes mellitus.2° See Table 3.15 for detailed harms results. There were several areas of focus for safety in the STEP clinical trial program due to therapeutic experience with GLP-1 receptor agonists and regulatory feedback and requirements. These included gastrointestinal disorders, gallbladder-related disorders, cardiovascular disorders, and psychiatric disorders. As expected, there were higher rates of gastrointestinal disorders in semaglutide arms as compared to placebo across all trials.©? In STEP 1, 3, and 5 trials, gallbladder- related disorders were more frequent in the semaglutide arms compared to placebo, and cardiovascular disorders were observed more in the placebo arm than in semaglutide2?>+?9 In STEP 2 and STEP 8, rates of gallbladder-related disorders were higher in placebo arm than in semaglutide, and rates of cardiovascular disorders were higher in the semaglutide arms than placebo??3, Psychiatric disorder event rates were higher in semaglutide arms versus placebo arms in the STEP 2, STEP 3, and STEP S trials. In the STEP 8 trial, there were higher rates of psychiatric disorder events in the liraglutide arm (15%) compared to the semaglutide (5.6%) and placebo arms (10.6%).3? See Supplement Table D33 for detailed safety focus area results. Table 3.15. Harms in Key Trials of Semaglutide for the Management of Obesity or Obesity with Diabetes Mellitus"? *° STEP 1 STEP 2* STEP 3 STEP 5 STEP 8 Study Arms PBO SEM PBO SEM PBO SEM PBO SEM PBO SEM LIR N 655 1,306 | 402 403 204 407 152 152 85 126 127 Any AE, n (%) 566 1,171 | 309 353 196 390 136 146 81 120 122 ye (86.4) | (89.7) | (76.9) | (87.6) | (96.1) | (95.8) | (89.5) | (96.1) | (95.3) | (95.2) | (96.1) 42 128 37 40 6 37 18 12 6 10 SAE, n (%) (6.4) | (9.8) | (9.2) | (9.9) | (2.9) | (9.1) | (12.8) | (7.9) | (7.2) | (7-9) | 48D nes beading tO , | 20 92 14 25 6 24 7 9 3 4 16 (%) ' (3.1) (7) (3.5) (6.2) (2.9) (5.9) (4.6) (5.9) (3.5) (3.2) (12.6) Gl Disorders Leading to 5 59 17 14 1 1 Discontinuation, n | (0.8) | (4.5) | 7 | (a2) |9 | ay |NR JSR | ay | ey | 863) (%) 114 577 37 136 45 237 19 77 75 Nausea, n (%) (17.4) | (44.2) | (9.2) | (33.7) | (22.2) | (58.2) |NR | NR | (aa.ay | (62.2) | (59.1) «ae 62 306 22 70 50 150 20 49 40 Constipation, n(%) | ig 5) | (23.4) | (5.5) | (17.4) | (24.5) | (36.9) | NR | NR | (23.5) | (38.9) | (31.5) . 104 412 48 86 45 147 22 35 23 Diarrhea, n (%) (15.9) | (31.5) | (11.9) | (21.3) | (22.1) | (36.1) | NR | NR | (5.9) | (27.8) | (18.1) AE: adverse event, GI: gastrointestinal, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo, SAE: serious adverse event, SEM: semaglutide *Included participants with obesity and diabetes mellitus. Olnstitute for Clinical and Economic Review, 2022 Page 25 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Liraglutide Like semaglutide, the most frequent adverse events in the SCALE trials for liraglutide compared with placebo were gastrointestinal-related symptoms, including nausea, constipation, and diarrhea.** 46,49,51-53 The frequency of any adverse events was similar between liraglutide and placebo across all trials, with the exception of the SCALE (Obesity and Pre-Diabetes) trial, in which participants in the liraglutide arm experienced a higher rate of any adverse events (80.3%), regardless of causality, compared to participants in the placebo arm (63.3%).** Rates of discontinuation due to adverse events were higher in the liraglutide arms compared to placebo. SCALE (Type 2 Diabetes) and SCALE (Insulin), which both included participants with obesity and diabetes mellitus, exhibited higher rates of serious adverse events compared to trials in the SCALE clinical trial program, which evaluated participants with obesity without diabetes mellitus.*2"° Across all SCALE trials, there were generally higher rates of gallbladder-related and pancreatic adverse events in the intervention arm compared to placebo. See Table 3.16 below for detailed harms results. ©lnstitute for Clinical and Economic Review, 2022 Page 26 Final Evidence Report - Medications for Obesity Management Return to Table of Contents $]U8}U07 JO a[ge] 0} UINjaY juawaseue~w Ayisaqgo JO} suoiesipay - Woday aduapiag jeul4 LZ aed ZZ0Z 'MalAaY I!WOUS] pUe |2I/UI|D JO a3NIISU|O *snyjaw sayeqeip pue Ayisago YM sjuedioiwed papnjaul, JUDAS BSIBAPe SNOLAS :Jys 'Oqaze|d :Ogd 'paHodas jou :yN 'Yaquunu ]e}0} :N "aquunu :u 'apin|Zes! sy] 'WUaAS asydApe :4AV (T'€z) (z'ST) (9°Sz) (£°2T) (3'TZ) (7°9T) (6°02) (€'6) (s'9T) (8°) oT (6°ZT) (v°2T) (2%) u 'eayueig Sv 0€ 80T Lz TE €2 STS STI 62 8¢ 92 (v'vT) (T'9T) (€'0€) (9°8T) (2'8) (6°TT) (6°92) (7°2T) . . , u 'uonedinsuo 87 (9°8) ZT 89 (T°9) €T Sb 92 (02) s6r 80T tz (v'€) 9 Is 92 (%) ednsuo) (£°62) (LTT) (Z°Z€) (LET) (6°Zr) (6°ZT) (zor) (Z'vT) (4°92) (29) 2T (9'Zv) (TZT) (9¢) u 'easnen 8S €Z SET 62 39 G2 L66 €8T Lv TOT 9€ . . . . . (2'6) . j j (%) u 'uonenunuodsig (ZZ) ST (e)9 | (we)6e |} (EEe)z | (s8)zT |] (Ev)9 Ovz (3°€) Lv YN YN | (S°8)8T | (9°8) 8T 03 Sujpear ay . . (€°2T) . . . (z'9) . . . . ' (2°83) 9T | (9°6) 6T 2S (6°6) TZ (z'v)9 (v'T) Zz pst (s) z9 (velo |] (v'e)9 (€'v) 6 (v2) ¢ (%) 4 'vs (€'26) (3°88) (6°26) (3°¢8) (8°56) (9°38) (€'08) (€"€9) (T°08) (€'69) (S'T6) (9°38) (%) u 'ay Auy OST GLT 76€ Z8T 9€T p21 766'T 982 Trt ver v6T 98T S6T LET Zp zz ev OvT Tsr'Z tre'T 9LT 6LT Zz oTz N wn Odd wn Odd wn Odd wn Odd yn Odd wn Odd swuy Apnis ,Uljnsu] #5920qRIQ Z adAL 1al 'pur ssao eoudy daajs aoueua}uleWy 31v2s 31vds a1v9s avs 31v9S 31Ww9S es-1s'ep'ar-teSMUIIPIN| SAIOqeIG YUM AjIsaqC pue AyIsaqo Jo jUsWAaZeUeW) 343 40) apIgnjZes!7 Jo sjelay Ady Ul SUH "OTE BIEL Phentermine/Topiramate Adverse events of any cause in the EQUIP, EQUATE, and CONQUER trials were mostly mild to moderate in severity. Rates of any adverse events were relatively high among all arms (73-86%), with highest rates in the high-dose phentermine/topiramate arm, followed by the low-dose phentermine/topiramate arm, and the placebo arm (Table 3.17).°>5"°? Adverse reactions that occurred more frequently in the high-dose and low-dose phentermine/topiramate treatment groups included paresthesia, nausea, dry mouth, constipation, and headache. EQUIP and CONQUER also assessed psychiatric adverse events, such as insomnia, anxiety, and depression, which were more common in the high-dose and low-dose phentermine/topiramate arms,>>*" with the exception of depression in the CONQUER trial, where the incidence of depression in the low-dose intervention arm (3%) was similar to the placebo arm (3.2%).°° Serious adverse reactions were relatively low among all trials and arms (0-6%). In the EQUIP trial, participants in all arms reported serious adverse events at the same rate (2.5%),°" while in the EQUATE trial, more participants in the high-dose treatment arm (1.9%) and low-dose treatment arm (0.9%) reported more serious adverse events than in the placebo arm (0%).°> In the CONQUER trial, incidence of serious adverse events was 3.7% in the high-dose phentermine/topiramate arm, 6% in the low-dose phentermine/topiramate arm, and 3.2% in the placebo arm.>' Serious adverse events that occurred infrequently in the phentermine/topiramate arms were chest pain, nephrolithiasis, appendicitis, blurred vision, humerus fracture, and myelogenous leukemia. Among all trials, discontinuation due to adverse events occurred most frequently in the high-dose arm (16-21%), followed by the low-dose arm (9-15%), and placebo (7-8%). See Table 3.17 for more details on harms. ©lnstitute for Clinical and Economic Review, 2022 Page 28 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 3.17. Harms in Key Trials of Phentermine/Topiramate for the Management of Obesity and Obesity with Diabetes Mellitus EQUIP EQUATE CONQUER (Diabetes Subgroup)* Study Arms PBO nigh) PBO tow ) ing h) PBO P/T (low) ing h) N 513 511 109 106 108 157 67 164 374 432 87 85 90 125 Any AE, n (%) (72.9) | (84.5) (79.8) | (80.2) | (83.3) '| (79.6) 54 (80.6) | 141 (86) SAE, n (%) 13 (2.5) | 13(2.5) | 0(0) 1(0.9) |2(1.9) | 5 (3.2) 4 (6) 6 (3.7) AE Leading to 16 23 Disc, n (%) 43 (8.4) | 82(16) | 8(7.3) (15.1) | (23.1) 13 (8.3) | 6(9) 31 (18.9) Paresthesia, n(%) | 10(1.9) | 96(18.8) | 4(3.7) | 17 (16) (23 1) 6 (3.8) 5 (7.5) 29 (17.7) 14 20 Dry Mouth, n (%) 19 (3.7) | 87 (17) 0 (0) 6 (3.8) 5 (7.5) 22 (13.4) (13.2) | (18.5) Headache, n (%) (10. 4 | 62029) (12.8) (as 1 (15.7) 9(5.7) | 3(45) | 18(11) Constipation, n (%) | 35 (6.8) | 72 (14.1) | 9(8.3) | 7 (6.6) (15.7) 10 (6.4) | 10(14.9) | 29 (17.7) Nausea, n (%) 24 (4.7) | 37(7.2) |5(4.6) |9(8.5) | 8(7.4) | 8(5.1) 1 (1.5) 13 (7.9) : 13 11 Insomnia, n (%) 25 (4.9) | 40 (7.8) 6 (5.5) (12.3) (10.2) 8 (5.1) 5 (7.5) 23 (14) Anxiety, n (%) 6(1.2) | 19(3.7) | NR NR NR NR NR NR Depression, n (%) 6 (1.2) 24 (4.7) NR NR NR 5 (3.2) 2 (3) 10 (6.1) AE: adverse event, Disc.: discontinuation, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SAE: serious adverse event *Included participants with obesity and diabetes mellitus. Bupropion/Naltrexone Any adverse events in COR-I, COR-II, COR-BMOD, and COR Diabetes occurred at a higher rate in the bupropion/naltrexone arms (83-90%) than in placebo (67-75%). °-52.5466.67 Nausea, dry mouth, headache, constipation, and upper respiratory tract infection occurred more frequently in the treatment arms compared to placebo. Occurrence of psychiatric events, such as insomnia, anxiety, depression, and stress, varied among all trials. Insomnia occurred more frequently in the bupropion/naltrexone group versus placebo in COR-I, COR-II, and COR-BMOD. Rates of anxiety were higher in the intervention arms than in placebo arms in COR-II and COR-BMOD but were lower than in the placebo arm in COR-I (Table 3.18). Depression occurred at a higher rate in the treatment groups in all studies except COR-BMOD. Participants in the bupropion/naltrexone group in COR-BMOD also experienced less stress than participants in the placebo arm. In COR-I, COR-IIl and COR-BMOD, serious adverse events were more frequent in the intervention arms (2-4%) versus the placebo arm (1%).°2*" In the COR Diabetes trial assessing participants with obesity and diabetes mellitus, serious adverse events were more common in the placebo arm (4.7%) than in the treatment arm (3.9%). ° Serious adverse events that occurred infrequently in ©lnstitute for Clinical and Economic Review, 2022 Page 29 Final Evidence Report - Medications for Obesity Management Return to Table of Contents the bupropion/naltrexone arm were cholecystitis, cardiac failure, and seizures. Discontinuation due to adverse events occurred more frequently in the bupropion/naltrexone arms (20-29%) than in the placebo arms across the trials (10-15%). See Table 3.18 below for more details on harms. ©lnstitute for Clinical and Economic Review, 2022 Page 30 Final Evidence Report - Medications for Obesity Management Return to Table of Contents $]U8}U07 JO a[ge] 0} UINjaY juawaseue~w Ayisaqgo JO} suoiesipay - Woday aduapiag jeul4 TE a8eq ZZ0Z 'MalAaY I!WOUS] pUe |2I/UI|D JO a3NIISU|O "T6S=N¥ "COC=N4 "snj|JaW Sajeqeip pue Ajisaqo YUM Sjuedioied papnyoul, uol}aJUl eI} AYo}esldsa Jaddn :| Lyn 'JUBAB BSJBAPe SNOLas :JYS 'oqaze|d :Ogd 'pawoday jou 7YyN '"Aaquunu [e}0} :N "aquunu :u 'uoeNuUIjUODSIp :9sIg 'BaUOXaJqeU/UOIdOJdng :N/g 'JUaAa asuaApe :IV uN YN (Soe (2) ¥ YN YN uN uN (9%) u 'ssaas (90) z (8'T) € (€°0) Z (2) ¢ (ET) €T (OT) 8 (sO) € (T'T)9 | (9) u 'uolssaudag (v'S) 8T (ZT) 2 (T°S) O€ (se) Z (8'v) 87 (€v) TZ (9°T)6 (TZ) @T (%) u 'Ayaixuy (TTT) LE (€°S) 6 (2°8) TS (9) ZT (8°6) £6 (£°9) €€ (SZ) &v (T'S) 62 (9) u 'eluwosu| (€°Zv) TvT (TZ) ZT (T'v€) 66T (SOT) Tz (2°62) 062 (6°9) vE (8°62) TZT (€°S) O€ (%) u 'easnen (8°Z) 92 (S°6) 9T YN YN (Z°8) 98 (@°TT) ss (6°6) ZS (ZIT) 79 (%) u 'LUN . . . . . . . (56) (Z°ZT) 65 (TZ) 2@T (TZ) TrT (vT) 82 (T'6T) 68T (T°Z) SE (Z°ST) 06 (9°¢) Z€ u 'uopedasuoz (8°€T) 9b (6°8) ST (8°€Z) GET (S°ZT) SE (ZT) PLT (28) € (SET) 62 (6) €S | (9%) u 'aysepeay (€°9) TZ (e)s (8) Lv (€)9 (T'6) 06 (9°Z) €T (S°Z) €v (6°T) TT | (%)u 'yinow Aig uN YN (o) 0 (0) 0 YN YN (7'0) T (o) 0 (%) u "yieed . . . . . . . . (%) u "osiq (v'62) 86 (7ST) 92 (v'SZ) OST (v2) Sz (€"7z) Tz (8°€T) 89 (S'6T) ZIT (8°6) 9S 03 Suipes) ay (6'€) 8 (Z'v) €T (3°€) ZZ (s'0) T (TZ) Tz (pT) Z (9'T) 6 (pT) 8 (%) u 'avs (v'06) TOE (z°S8) veT (v'€8) Z8v (S°99) €€T (6°58) 798 (Z'SZ) OLE (T'€8) 92 (s°89) O6€ (%) u 'aw Auy €€e 69T 78S 002 766 760 €ZS 69S N N/a Od N/d Odd N/a Odd N/a Odd swuy Apnis #5933q921q YO) GOWs-Y¥OD lI-4Oo I-YOo 19-paSUIIAIN| Saz@qeig YUM AjIsaqoC pue AyIsaqo Jo JUBWaSeUeW By) 10} BUOXa/]/eEN/UOIdoJdNg jo sjel4y Ady Ul SWRH 'ST' a1qeL NMA Results of Discontinuation For the outcome of discontinuation due to adverse events, we conducted an NMA of trials including participants with obesity alone and excluded trials of participants with obesity and diabetes mellitus. The discontinuation NMA included more trials than in the efficacy NMAs as we did not exclude trials that included IBT programs as part of the lifestyle component of the trial arms. The NMA of discontinuation due to adverse events is reported below, and the network diagram is presented in the Supplement. Participants with Obesity Alone For the trials of the medications conducted in participants with obesity without diabetes mellitus and reported discontinuation due to adverse events, we present the results of the unadjusted random effects model in Table 3.19, given its better fit for the model compared to the baseline risk adjusted model. Discontinuation rates due to adverse events were higher for all medications compared to placebo. Semaglutide may have lower discontinuation rates than liraglutide, phentermine/topiramate, and bupropion/naltrexone, however, these results were not statistically significant (Table 3.19). Table 3.19. NMA Results of Medications for the Management of Obesity, Odds Ratio of Discontinuation Rates due to Adverse Events (95% Cl) Semaglutide 0.7 (0.3-1.3) Liraglutide Bupropion/ 0.8 (0.3-1.5) 1.1 (0.5-2.2) Reece ed atsal ecient iil-y A 0.7 (0.2-1.5) 1.0 (0.4-2.3) 0.9 (0.4-2.1) TO ee 1.7 (0.9-2.8) 2.4 (1.4-4.0) 2.2 (1.3-3.7) 2.4 (1.3-5.2) inane Legend: Each box represents the estimated odds ratio of discontinuation due to adverse events and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. ©lnstitute for Clinical and Economic Review, 2022 Page 32 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Subgroup Analyses and Heterogeneity We sought evidence on obesity management in subgroups of interest such as in individuals with higher or lower baseline BMI, pre-diabetes, or previous weight loss surgery. We also sought evidence comparing obesity management based on sex and race/ethnicity. However, data were generally not available or were provided to ICER as confidential. In the STEP 1 and 2 trials of semaglutide, SCALE Obesity and Pre-Diabetes trial of liraglutide, and EQUIP trial of phentermine/topiramate in adults with obesity, percentage weight loss was generally consistent across BMI subgroups corresponding to obesity classes 1/II/IIl, suggesting a benefit across the range of obesity severity included in these trials. In a post-hoc analysis of the STEP 1, 3, and 4 trials of semaglutide (which enrolled 40-50% of participants with pre-diabetes), improvements in A1C and blood glucose were comparable or better among participants with pre-diabetes than among the overall study population, suggesting a benefit in glycemic status consistent with the drug's mechanism of action.*° In abstract reports from the STEP 1, 2 and 3 trials of semaglutide, race and ethnicity were not associated with weight loss outcomes, though female gender was reported to be associated with greater weight loss.?+7°71 In analysis of pooled data from four SCALE trials, mean change in weight loss for liraglutide compared to placebo for White, Black/African American and Asian patients were -5.3%, -4.8% and -4.0%, respectively." The CONQUER trial provided subgroup data on sex, race, and ethnicity in the Supplement. In participants receiving phentermine/topiramate high- and low- dose treatment, weight loss in this trial was greater in females than males (11.0% vs. 9.1% and 8.8% vs. 7.5%, respectively, in females vs. males). Additionally, participants in the phentermine/topiramate arms who were Black experienced a similar amount of weight loss compared to participants who were non-Black (9.7% vs. 10.5% and 9.7% vs. 8.5%, respectively).>* Uncertainty and Controversies Though pharmacy claims data suggest that many individuals who take medications for weight loss do not use them for long periods of time, experts and patients we spoke with highlighted that weight regain after stopping treatment is common."? This points to the need for long-term use of these medications. All key trials reported outcomes over approximately one year follow-up. Few comparative trials have examined longer-term outcomes making the benefits and harms of these medications over prolonged periods uncertain. For individuals without diabetes mellitus, heart disease, arthritis, sleep apnea, or cancer, studies have not shown whether weight loss prevents disease morbidity and mortality. Studies of treatments for obesity in individuals undergoing weight loss surgery for severe obesity demonstrate decreased incidence of cardiovascular- and cancer- related outcomes and lower mortality.42°?" However, these results primarily come from observational studies and the benefit in individuals without diabetes mellitus or lower baseline ©lnstitute for Clinical and Economic Review, 2022 Page 33 Final Evidence Report - Medications for Obesity Management Return to Table of Contents weights is less clear. Thus, there is a need for studies examining long-term outcomes in individuals without diabetes mellitus who are chronically using weight loss medications." We primarily used indirect quantitative methods (NMAs) to compare semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone to each other because there was only a single head-to-head study of semaglutide and liraglutide. Differences in study populations, lifestyle interventions offered, and escalation schedules that led to different follow-up intervals all contribute to indirect analyses having more uncertainty than if the therapies had been compared directly in randomized controlled trials. All of the pivotal Phase III randomized controlled trials compared the active agents to placebo among patients receiving lifestyle interventions. As a result, the studies assessed the additive benefit of the drugs in addition to lifestyle interventions that varied among the studies. Because we expect that medications when used in routine clinical practice will more commonly be given with less intensive lifestyle interventions, our primary analyses included trials with standard lifestyle interventions and may represent the best evidence for the efficacy of the active therapies. Other trials compared drugs to placebo along with more intensive lifestyle interventions that included IBT or structured meal programs. These trials also demonstrated benefit of the drugs compared to placebo, but in general, the amount of weight loss was slightly less than seen in the trials with standard lifestyle interventions. These trials examined the relative benefits of the individual and fixed dose combination agents as single interventions. The drugs that make up the phentermine/topiramate and bupropion/naltrexone combinations are also approved for other indications as individual drugs at somewhat different doses. We heard from experts that these individual drugs are used singly or in various combinations in an "off-label" manner. Clinicians said such use may mitigate side effects and be less costly to patients. Semaglutide and liraglutide are FDA-approved for treatment of diabetes mellitus at lower doses, and while these doses may be associated with less weight loss than the doses used in our primary outcome analyses, these lower doses may be used, especially in those with co-existing diabetes mellitus, because they may be better covered by insurers and result in fewer out-of-pocket expenses to patients. We only compared results of individual drugs or approved fixed dose combinations. Using multiple drugs that target different mechanisms or newer drugs that have more than one mechanism of action (e.g., tirzepatide) may achieve synergistic effects and provide greater weight loss. In addition to their weight loss properties, semaglutide and liraglutide as GLP-1 receptor agonists have also been shown to decrease blood sugar in individuals with pre-diabetes and diabetes mellitus, and to decrease major adverse cardiovascular events among individuals with diabetes mellitus. It is not known whether GLP-1 receptor agonists provide benefits to individuals with obesity that go beyond their weight loss effects compared to other approved weight loss drugs with different mechanisms ©lnstitute for Clinical and Economic Review, 2022 Page 34 Final Evidence Report - Medications for Obesity Management Return to Table of Contents of action. At present, this remains uncertain for individuals without diabetes mellitus using GLP-1 receptor agonists for weight loss and warrants future investigation. There is limited information available about the relative benefits and harms of these drugs in important subgroups including patients with lower BMls. Similarly, for those with BMls of greater than 40 where weight loss surgery is an option, the relative benefits and harms of these drugs compared to weight loss surgery is uncertain. Moreover, experts discussed that these medications are being used in individuals after weight loss surgery to treat or prevent weight regain, and the effects of their use here is also uncertain. For women of childbearing age, there is a lack of data on the potential impact of medications for weight reduction on fertility, maternal morbidity and mortality, and infant health. Trials of weight loss medications include populations that are underrepresented in terms of the percentage of men and minority groups. Weight reductions seen in these trials among men and women appeared similar. Since most trials included mostly White patients and given the large impact of obesity in Black Americans and other racial and ethnic groups, there is a need for more studies evaluating the outcomes of the various medications in these populations. For example, a post-hoc analysis of liraglutide trials showed similar weight reduction across racial and ethnic groups."> ©lnstitute for Clinical and Economic Review, 2022 Page 35 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 3.3. Summary and Comment An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided here. Figure 3.1. ICER Evidence Rating Matrix Level of Certainty in the Evidence Certainty Moderate Certainty Certainty Comparative Clinical Effectiveness High Low 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 (but nonzero) likelihood of a negative net health benefit = "Insufficient" - Any situation in which the level of certainty in the evidence is low ©lnstitute for Clinical and Economic Review, 2022 Page 36 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Results from the clinical trials and from our NMAs demonstrate that semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone, when used as adjuncts to usual care, improve weight loss outcomes of patients with obesity compared to usual care alone (e.g., standard lifestyle management). The magnitude of the weight loss appears to be greater for semaglutide and phentermine/topiramate than for liraglutide and bupropion/naltrexone based on the one head-to- head trial of semaglutide and liraglutide and our indirect NMA results. Other outcomes show that semaglutide and liraglutide improved blood sugar, blood pressure, and physical function compared to usual care. Blood pressure was lower with phentermine/topiramate than usual care. Blood sugar results were not reported in the phentermine/topiramate and bupropion/naltrexone trials for patients without diabetes mellitus. Semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone all had common adverse events, but few serious harms were reported in the trials. Discontinuation due to adverse events was higher for each intervention compared to placebo. Patients taking liraglutide, phentermine/topiramate, and bupropion/naltrexone may have higher discontinuation rates due to adverse events than for semaglutide. There is uncertainty about the relative benefit and safety among the four medications due to differences in the trials with regards to their size, patient characteristics, concomitant lifestyle interventions, outcomes assessed, and duration of follow-up that the indirect nature of the NMAs do not fully capture. For all of the drugs, there is a lack of long-term efficacy and safety data that includes whether sustained weight loss leads to decreased clinical endpoints and if weight regain may occur over time despite continued therapy as has been seen with weight loss surgery." Differences among the medications in their mechanisms of action may also lead to differences in clinical endpoints, such as heart disease, that go beyond their effects on weight loss. For example, semaglutide and liraglutide have been shown to reduce cardiovascular disease endpoints in patients with type 2 diabetes mellitus," but this is uncertain for individuals with obesity without diabetes mellitus. In summary, for adults with obesity who have not had sufficient weight loss with lifestyle interventions alone and are interested trying weight loss medications, we assessed the benefits and harms of these four medications added to lifestyle modification compared to standard lifestyle modification alone and to each other. As such: e We consider the evidence for the net health benefit of semaglutide added to lifestyle modification compared to lifestyle modification alone to be incremental or better ("B+"), demonstrating a moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit. This rating is based upon demonstration of substantial short-term weight loss from multiple high-quality studies with few serious harms, but higher rates of discontinuation due to adverse events than placebo, uncertainty ©lnstitute for Clinical and Economic Review, 2022 Page 37 Final Evidence Report - Medications for Obesity Management Return to Table of Contents about long-term ability to sustain weight loss, and whether the degree of weight loss in this population results in improved clinical outcomes. @ Weconsider the evidence for the net health benefit of liraglutide added to lifestyle modification compared to lifestyle modification alone to be incremental ("B"), demonstrating a high certainty of a small net health benefit. This rating is based upon demonstration of small to moderate short-term weight loss from multiple high-quality studies with few serious harms; our expectation is that even if the weight loss were sustained, the benefits would only be incremental. e Weconsider the evidence for the net health benefit of phentermine/topiramate added to lifestyle modification compared to lifestyle modification alone to be comparable or better ("C++"), demonstrating a moderate certainty of a comparable, small, or substantial net health benefit, with high certainty of at least a comparable net health benefit. This rating is based upon demonstration of moderate to substantial short-term weight loss from a limited number of trials with few serious harms, but higher rates of discontinuation due to adverse events than placebo, uncertainty about long-term ability to sustain weight loss, and whether the degree of weight loss seen translates into improved clinical outcomes given the limited data from clinical process measures. e We consider the evidence for the net health benefit of bupropion/naltrexone added to lifestyle modification compared to lifestyle modification alone to be comparable or incremental ("C+"), demonstrating a moderate certainty of a comparable or small net health benefit, with high certainty of at least a comparable net health benefit. This rating is based upon demonstration of small to moderate short-term weight loss from several trials with few serious harms, but higher rates of discontinuation due to adverse events than placebo, uncertainty about long-term ability to sustain weight loss, and whether the degree of weight loss seen translates into improved clinical outcomes given the limited data from clinical process measures. e We consider the evidence for the net health benefit of semaglutide compared to liraglutide and phentermine/topiramate to be comparable or incremental ("C+"), and compared to bupropion/naltrexone to be comparable or better ("C++"). The rating comparing semaglutide to liraglutide is based upon greater weight loss and fewer adverse reactions leading to discontinuation with semaglutide, but uncertainty about long-term ability to sustain weight loss and, given the same mechanism of action, whether the incremental amount of weight loss results in improved clinical outcomes in this population. The rating comparing semaglutide to phentermine/topiramate is based upon similar weight loss and fewer adverse reactions leading to discontinuation, but differences in the number and quality of the trials, differences in mechanisms of action that may impact clinical outcomes, and uncertainty about long-term ability to sustain weight loss. The rating comparing ©lnstitute for Clinical and Economic Review, 2022 Page 38 Final Evidence Report - Medications for Obesity Management Return to Table of Contents semaglutide to bupropion/naltrexone is based upon greater weight loss and fewer adverse reactions leading to discontinuation with semaglutide, but differences in mechanisms of action that may impact clinical outcomes, and uncertainty about long-term ability to sustain weight loss. Table 3.20. Evidence Ratings of Medications for Obesity Management Treatment Comparator Evidence Rating Semaglutide Lifestyle modification B+ Liraglutide Lifestyle modification B Phentermine/Topiramate Lifestyle modification C++ Bupropion/Naltrexone Lifestyle modification C+ Liraglutide C+ Semaglutide Phentermine/topiramate C+ Bupropion/naltrexone C++ Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 39 Return to Table of Contents New England CEPAC Votes Patient population for all questions: Adults without pre-existing diabetes and either a BMI 230 kg/m? or 227 kg/m? with at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes, or dyslipidemia). Table 3.21. New England CEPAC Votes on Comparative Clinical Effectiveness Questions Question Yes No Is the evidence adequate to demonstrate that the net health benefit of semaglutide added to 45 0 lifestyle modification is superior to that provided by lifestyle modification alone? Is the evidence adequate to demonstrate that the net health benefit of liraglutide added to 15 0 lifestyle modification is superior to that provided by lifestyle modification alone? Is the evidence adequate to demonstrate that the net health benefit of phentermine/topiramate 14 1 added to lifestyle modification is superior to that provided by lifestyle modification alone? Is the evidence adequate to demonstrate that the net health benefit of bupropion/naltrexone 10 5 added to lifestyle modification is superior to that provided by lifestyle modification alone? Is the evidence adequate to demonstrate that the net health benefit of semaglutide added to 14 1 lifestyle modification is superior to that provided by liraglutide added to lifestyle modification? Is the evidence adequate to demonstrate that the net health benefit of semaglutide added to lifestyle modification is superior to that provided by phentermine/topiramate added to lifestyle 10 5 modification? Is the evidence adequate to demonstrate that the net health benefit of semaglutide added to lifestyle modification is superior to that provided by bupropion/naltrexone added to lifestyle 15 0 modification? The panel unanimously voted that both semaglutide and liraglutide plus lifestyle modification are superior to lifestyle modification alone. Semaglutide demonstrated substantial short-term weight loss in multiple high-quality studies with few serious harms while liraglutide demonstrated small-to-moderate short-term weight loss. In the comparison between semaglutide and liraglutide, the panel voted nearly unanimously that the net health benefit of semaglutide is superior due to greater weight loss seen in trials and fewer adverse events overall. The vote was almost unanimous in the comparison of phentermine/topiramate plus lifestyle modification to lifestyle modification alone. In clinical trials, phentermine/topiramate demonstrated moderate-to-substantial short-term weight loss. When comparing semaglutide to phentermine/topiramate, a majority of the panel voted that the health benefit of semaglutide is superior. Panelists who voted in the minority cited comparable weight loss between the two treatments. The panel voted 10 to five for the comparison of bupropion/naltrexone plus lifestyle modification to lifestyle modification alone. The split is in part due to uncertainty around long-term use of bupropion/naltrexone. When directly comparing semaglutide and bupropion/naltrexone, the panel voted unanimously that the health benefit of semaglutide is superior due to greater weight loss seen in trials and fewer adverse reactions leading to discontinuation. ©lnstitute for Clinical and Economic Review, 2022 Page 40 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 4. Long-Term Cost Effectiveness 4.1. Methods Overview The primary aim of this analysis was to estimate the cost effectiveness of semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone plus lifestyle modification compared to standard lifestyle modification alone, and to each other, for life-long weight management in the treatment of overweight and obesity. The base-case analysis comparatively evaluated each therapy option in a cohort of patients consistent with clinical trials and real-world evidence. Patients were 80% female with an average age of 45 years, BMI of 38 kg/m2, SBP of 125 mmHg, and HbA1C of 5.7% without confirmed diabetes mellitus. Additional scenarios were evaluated as described in Section 4.3. We built a Markov state transition model informed by key clinical trials, prior relevant economic models, systematic literature reviews, and input from a diverse set of stakeholders (patients, advocacy groups, Clinicians, payers, researchers, and manufacturers of these agents) from the health care sector perspective (i.e., focused on direct medical care costs) using a lifetime time horizon. The model cycle length was one year, and all costs and outcomes were discounted at a rate of 3% per year. As shown in the model diagram below (Figure 4.1), simulated patients entered the model through their medication regimen to the initial Markov state "No diabetes mellitus." From the first cycle onward, patients could remain in the starting state, or transition to any of four non-heart-failure cardiovascular comorbid health states (myocardial infarction, stroke, stroke plus myocardial infarction, or other cardiovascular disease) with or without developing diabetes mellitus. Other cardiovascular disease included peripheral artery disease, angina, and transient ischemic attack. Myocardial infarction was a prerequisite to developing heart failure because of the strong causal association between obesity and heart failure mediated by myocardial changes." The model assumed all patients with hypertension were optimally controlled with antihypertensive medication. As it is uncertain whether obesity is an independent risk factor for non-ischemic heart failure in patients with controlled blood pressure, we opted to not account for any additional risk of heart failure through alternate pathways. At any state in the model, patients could transition to the terminal "Death" state. ©lnstitute for Clinical and Economic Review, 2022 Page 41 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Figure 4.1. Model Diagram SEM+ LSM Overweight or Obesity ry ai ede i Non-HF CVD \ Stroke ! with DM LIR+ LSM / | @ | 1 @ {| a i} cn C7) "sy / @) 2p = Oo a za P/T+ LSM (m) *, a a." | ~ 'ss \ I wana), ae ee: ®8 Stroke & MI Se + - + ° "Sy \ "s, " = a Ne \ fi ~s | To 1 ee ----- ™ « B/N+LSM oo | = | 1 Acute -- i - J i Stroke Stroke I 1 ! 1 1 a | HF with DM! 4 i Death ai Tauuliar:|) (w)- to Markov Model CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, LM: lifestyle management, LIR: liraglutide, MI: myocardial infarction, B/N: bupropion/naltrexone, P/T: phentermine/topiramate, SEM: semaglutide Average BMI reduction with therapy was the primary factor used to estimate differences in cardiovascular comorbidity and risk of progression to diabetes mellitus. The annual risk of developing cardiovascular conditions at the beginning of each cycle was calculated using a published risk equation model based on BMI, presence of diabetes mellitus, population demographics, and clinical characteristics. Specifically, the 2013 American College of Cardiology/ American Heart Association (ACC/AHA) guideline risk equation was used to calculate the 10-year risk of non-heart-failure cardiovascular conditions."? The resulting 10-year risks were then used to calculate the annual probability of a cardiovascular event and were updated in each cycle of the model using the equation P[t]=1-e'"». BMI was included as a time-varying input in the risk calculation for each cycle. The risk of a cardiovascular event was calculated for each combination of patient factors (e.g., male vs. female, smokers vs. nonsmokers, and active hypertension treatment vs. no hypertension treatment, diagnosis of diabetes mellitus vs. no diabetes mellitus, age, and BMI) and the weighted average was used to calculate overall risk. Cardiovascular event risks were then further stratified ©lnstitute for Clinical and Economic Review, 2022 Page 42 Final Evidence Report - Medications for Obesity Management Return to Table of Contents into specific stroke, myocardial infarction, and other cardiovascular disease event probabilities 80-83 given the proportion of each condition observed in a US population. Our model captured the impact of weight loss in delaying the onset of diabetes mellitus. In addition, the HbA1C-lowering effect of semaglutide and liraglutide was expected to further delay the onset of diabetes mellitus.2**> Therefore, we calculated the annual incidence of diabetes mellitus for each cycle using BMI and HbA1C data.*®© Furthermore, weight loss from medication therapy may result in hypertension remission. We therefore incorporated an association between BMI and hypertension to allow for a decreased prevalence of hypertension as BMI decreased.®7*8 Although we did not explicitly include some conditions known to be associated with obesity, the anticipated benefit of weight loss in reducing the onset of such conditions was implicitly captured. For example, the impact of weight loss on sleep apnea is captured by the mortality benefits mediated by cardiovascular conditions. Chronic kidney disease was not included as a separate Markov state in the base-case simulation as most chronic kidney disease results from diabetes mellitus or hypertension. By including costs and quality of life changes from studies with a broad selection of patients with diabetes mellitus, we implicitly addressed the influence of chronic kidney disease in the model. Chronic kidney disease resulting from hypertension was not captured in the base case, as we assumed that hypertension management was optimal in patients with and without weight loss. However, a scenario analysis (described below as "Comorbidity X") captured the potential impact of weight-related chronic kidney disease (and cancer) on the cost effectiveness of medications for obesity management. Improvements in lipids were not explicitly included in the model, but those improvements associated weight loss would have been implicitly captured. The ACC/AHA risk equations for cardiovascular risk account for either changes in weight or LDL, but not both simultaneously. Therefore, explicitly including changes to lipids in the model would likely double count the cardiovascular benefits from treatment. Supplement Section E1 details additional rationale behind our choice of health states in the base case. Health gains in the model were mainly derived from increased utility in those with improved BMI associated with enhanced daily functioning, decreased risk of developing diabetes mellitus/cardiovascular disease, and reduced complications/comorbidities. The estimated utility gains from enhanced daily functioning included improvements in conditions such as sleep apnea, gastroesophageal reflux disease, and osteoarthritis as well as improved mobility and self-image. Based on public comment between draft Evidence Report and revised Evidence Report, the following changes were made: 1) Updated the discontinuation rate from estimates for serious adverse event rates from clinical trials to values reported in the NMA, which estimated adverse events leading to discontinuation. ©lnstitute for Clinical and Economic Review, 2022 Page 43 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 2) Included the full results of two scenario analyses that had been omitted from the results section of the Draft Evidence Report. These scenarios were: a) Evaluation of patients with a starting BMI of 240 kg/m? (i.e., weight class III with average BMI of 42.5 and 47.5 kg/m'); and b) Patient population consisting of a similar proportion of men and women (50:50). 3) Removed the direct influence of bupropion/naltrexone on HbA1C; cardiovascular benefits of bupropion/naltrexone were made through weight reduction. Between the revised Evidence Report and final Evidence Report, the following change was made to the model: 1) The time for which disutilities for acute myocardial infarction and acute stroke was applied was changed from one month to six months to make these model inputs more consistent with the utility values obtained in the source manuscript. These changes resulted ina negligible change in the estimated incremental cost-effectiveness ratio. Scenario Analyses In order to address several uncertainties, we conducted multiple scenario analyses: e Societal perspective (including labor costs) e Evaluation of patients with a starting BMI of 240 kg/m? (i.e., weight class III with average BMI of 42.5 and 47.5 kg/m?) e Use of generic phentermine/topiramate and bupropion/naltrexone as opposed to their brand alternatives e Patient population consisting of a similar proportion of men and women (50:50) e Patient organizations have a vital role to play in promoting the dissemination of objective information about new therapies for obesity to individuals and clinicians in order to support shared decision-making. In addition, patient groups have a powerful voice and should apply it to create significant pressure for fair pricing and appropriate payer coverage across all sectors of the health system. "Comorbidity X" scenario individually assessing the potential impact of BMI change resulting from medications for obesity management on chronic kidney disease and cancer e Evaluation of a "Drug X" with the effect on weight loss seen in the SUPPORT 1 trial of tirzepatide, pricing of semaglutide for overweight and obesity, and effects on blood pressure and diabetes mellitus similar to semaglutide. Further details on the economic modeling methods used are available in Supplement E. The following scenario analyses were included in the Model Analysis Plan but were either changed to sensitivity analyses or were not conducted based on rationale provided below: ©lnstitute for Clinical and Economic Review, 2022 Page 44 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 1) Weight regain scenario: Scenarios evaluating short-term treatment followed by weight- regain were evaluated and removed due to a potential unevidenced overestimation of long- term weight loss medication benefit 2) Subgroup of patients who respond to the lower maintenance dose of phentermine/topiramate: We chose to only model the maximum dose and effect of phentermine/topiramate with the understanding that providers would attempt to maximize weight loss, provided patients tolerated treatment 3) Patients with diabetes mellitus at baseline: Since the effectiveness of semaglutide and liraglutide in patients with diabetes has previously been evaluated by ICER, our model was designed to evaluate the impact of weight management in patients without diabetes. We assumed that for patients with diabetes, there would be no difference in the management of diabetes nor in HbA1C levels between patients on different medications or lifestyle management alone for obesity management. Therefore, with the exception of delays to diabetes onset resulting from the effects of the drugs on HbA1C, we did not include the impact of treatments on HbA1C 4) Optimistic and conservative assumptions regarding the benefit of treatment: We determined that one-way sensitivity analyses were most suitable for testing optimistic and conservative weight reduction benefits of weight loss medications. 4.2. Key Model Assumptions and Inputs Model Assumptions Several assumptions were required to estimate the cost effectiveness of treatments for obesity. These assumptions were based on clinical expert opinion, a review of the available evidence and published models, and the investigators' experience with developing similar models. The key model assumptions and rationales for each assumption are listed below in Table 4.1. Additional model assumptions are described in the Supplement. ©lnstitute for Clinical and Economic Review, 2022 Page 45 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 4.1. Key Model Assumptions Assumption Rationale Cardiovascular risk equations provide the best estimate of treatment benefit on cardiovascular outcomes Certain drug treatments may have benefits unrelated to weight loss achieved or changes in HbA1C. In the absence of strong evidence for the effects of medications on cardiovascular risk in patients with obesity and without diabetes mellitus, we did not include sucha benefit. Should evidence emerge supporting additional benefits, the model can be updated to include these benefits. The potential benefits on cardiovascular outcomes of delays in diabetes mellitus onset from therapies that directly reduce A1C, beyond those associated with weight reduction, provided sufficient evidence exists, will be considered in the model. Patients continue to receive the intervention or lifestyle modification throughout the model time horizon Expert opinion suggests that since obesity is increasingly considered as a chronic metabolic disease requiring long-term management to affect outcomes, long-term treatment is required for most individuals. After stopping therapy, weight regain is common. Further, repeated fluctuations in body weight, i.e., "weight cycling," is associated with adverse health outcomes. Treatment discontinuation is included in the model prior to the first model cycle; longitudinal changes in the persistence and adherence to medications were not considered in the model Including the impact of poor long-term persistence requires the addition of several "discontinuation" health states, thereby increasing model complexity. Further, there is no information on the impact of short-term treatment on cardiovascular outcomes, especially after discontinuation of treatment. Proportion of actively treated hypertension is a function of BMI without a significant influence on the incremental cost-effectiveness ratio BMI significantly influences the proportion of patients in need of hypertension treatment. Assuming hypertension treatment effectively manages overall SBP, average SBP would be similar across the treatment strategies over the model time horizon. The cost of hypertension medication is small and is therefore unlikely to influence the incremental cost-effectiveness ratio. In patients with hypertension, blood pressure is equally well managed across all weight loss treatments Weight loss treatments may affect blood pressure differently. The impact of treatments on reducing the likelihood of needing treatment for hypertension was included in the model. For those who continued to require treatment for hypertension, we assumed that all patients would have similar outcomes related to hypertension treatment. HbA1C: glycated hemoglobin, SBP: systolic blood pressure Model Inputs The key model inputs are listed in Table 4.2. The clinical inputs for the model were weighted over time and by associated probabilities of cardiovascular disease (myocardial infarction, stroke, other cardiovascular disease), heart failure, and diabetes mellitus. Weight change resulting from treatment was determined from an NMA of relevant trials conducted as part of this review. The risk of myocardial infarction, stroke, and other cardiovascular disease was obtained from a risk equation model.®®° Risk of heart failure and diabetes mellitus was determined from a systematic review of the literature and published risk equations.°©91-9> Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 46 Return to Table of Contents BMI and weight trajectory over time were used as model inputs to assess cardiovascular risk. Percent weight change (and thus BMI change, assuming no change in height) from baseline at year one and maximum percent weight change by the end of the second year were incorporated into the model. We assumed patients received the maintenance dose continuously, the medication maintained long-term effectiveness, and there was no additional weight change beyond the maximum weight reduction until the end of the model time horizon in the base case. The impact of weight loss on mortality was incorporated as reduction of fatal cardiovascular events, as estimated from a review of existing literature and a direct extraction of general population all- cause mortality from the Human Mortality Database US-specific life tables.°°9" ©lnstitute for Clinical and Economic Review, 2022 Page 47 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 4.2. Key Model Inputs* Parameter | Input | Source Clinical Inputs Absolute Difference in % Weight Change, SEM vs. LSM -13.7% ICER NMA, Table 3.11 Absolute Difference in HbA1C Change, SEM vs. LSM -0.30 STEP 135 Absolute Difference in % Weight Change, LIR vs. LSM -5.0% ICER NMA, Table 3.11 Absolute Difference in HbA1C Change, LIR vs. LSM -0.20 SCALE (Maintenance)*# Absolute Difference in % Weight Change, P/T vs. LSM -9.1% ICER NMA, Table 3.11 Absolute Difference in HbA1C Change, P/T vs. LSM 0.00 EQUATE545859 Absolute Difference in % Weight Change, B/N vs. LSM -4.6% ICER NMA, Table 3.11 Absolute Difference in HbA1C Change, B/N vs. LSM 0.00 62,66 Baseline Risk of CV Event, Female Non-Smoker without Treated HTN 0.04 Framingham Risk Calculation Coefficient Baseline Risk of CV Event, Male Smoker with Treated HTN 0.23 Framingham Risk Calculation Coefficient Multiplier for Probability of MI from CV Risk 0.22 Landi 2018°° Multiplier for Probability of Stroke from CV Risk 0.23 D'Agostino 2008 Multiplier for Probability of Other CV Disease from CV Risk 0.55 Schultz 2021°° Risk Equations Onset of Cardiovascular Condition, 10-Year Risk: Office-Based Non-Laboratory Pred. Model Baseline and Beta Coefficient Women Men $o0(10) 0.94833 0.8843 Log of Age 2.72107 3.113 BMI 0.51125 0.7928 Framingham Risk Calculation Coefficient® Log of SBP if Not Treated 2.81291 1.8551 Log of SBP if Treated 2.88267 1.9267 Smoking 0.61868 0.7095 Diabetes 0.77763 0.5316 Onset of Diabetes, Annual Risk: 1.46x10% exp (1.87xHbA1C) x 1.97x107 exp (0.101xBMI) Exponential regression from Edelman et al.2° Comorbidity Annual Cost Inputs Cost Other CV Disease $14,279 | Scully 2017% Cost Acute Stroke $17,316 | HCUP%? Cost Post Stroke $6,500 | Kazi 20192 Cost Acute MI $26,034 | HCUP?9 Cost Post MI $3,117 | Kazi 201629 Cost, First Year $27,030 | Patel 20212°2; Urbich 20201% Cost HF, Second Year or Later $15,605 | Patel 20211 Cost DM $11,425 | ADA 20181 Quality of Life Inputs Utility with Normal BMIt oon age | Sullivan 20065 Disutility per BMI Unit Increase -0.0033 Kim 20221. Pi-Sunyer 2015" Multiplicative Utility - Other CV Disease 0.959 Sullivan 20061 Disutility - Acute Stroket -0.190 Matza 2015 Multiplicative Utility - Post-Stroke 0.943 Sullivan 2006705 Disutility - Acute MIt -0.150 Matza 2015 Multiplicative Utility - Post-MI 0.955 Multiplicative Utility - HF 0.930 Sullivan 20067 Multiplicative Utility -DM 0.962 BMI: body mass index, B/N: bupropion/naltrexone, CV: cardiovascular, DM: diabetes mellitus, HbA1C: glycated hemoglobin, HF: heart failure, HTN: hypertension, ICER: Institute for Clinical and Economic Review, LIR: liraglutide, LSM: lifestyle modification, NMA: network meta-analysis, P/T: phentermine/topiramate, SBP: systolic blood pressure, SEM: semaglutide *This cardiovascular model does not include inputs of anti-obesity medication changes in blood pressure, lipids, sleep apnea, cancer, and physical inactivity (e.g., immobility or osteoarthritis). Midpoint of the normal BMI range of 18.5-25 kg/m2. £Disutility for acute MI and acute stroke was applied for six months. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 48 Return to Table of Contents Starting utility was derived from age-specific utility values for patients with the characteristics of the target population.1°% A utility gain was applied for each unit of weight loss due to treatment. The linear association between weight gain and utility loss was extracted from a recent cost- effectiveness analysis and trial data.441% For comorbidities associated with higher BMI, we used consistent health state utility values across all evaluated treatments. Health state disutilities due to cardiovascular comorbid conditions, diabetes mellitus, and heart failure were derived from systematic literature reviews, utility-specific patient preference research articles cited in prior cost-effectiveness assessments, and manufacturer-submitted data. A multiplicative approach was used to apply the health utility value changes for each of the Markov states. To address the significant decrease in the health utility for acute event management, we applied disutilities for acute myocardial infarction and acute stroke management for six months, to reflect significant loss of mobility and needed care. Subcutaneous injections of GLP-1 receptor agonists are expected to have a small impact on the overall health state utility compared to the impact of chronic conditions. Thus, we did not include a utility decrease for the subcutaneous administration of semaglutide or liraglutide. For estimates of net pricing, drug costs, and discounts, we investigated both the SSR Health pricing database and US Department of Veterans Affairs Federal Supply Schedule Service (FSS) database. Since SSR discount/rebate data were not available for semaglutide for weight loss, phentermine/topiramate for the most recent quarter, and bupropion/naltrexone for the most recent quarter, we opted to use net prices derived from the US FSS database. Table 4.3. Drug Costs List Price Rebates/ Model Inputs from FSS Data Drug Year One Year 2+ Annual | Discounts from Year One Year 2+ Annual Annual WAC WAC WAC Annual Net Net Semaglutide $17,597 $17,597 | 22.6%* $13,618 $13,618 Liraglutide $15,795 $16,424 | 28.4%t $11,309 $11,760 Phentermine/ $2,382 $2,429 | 39.7-57.8%* $1,355 $1,465 Topiramate Bupropion/ $7,393 $7,612 | 72.5%* $2,034 $2,095 Naltrexone FSS: Federal Supply Schedule, WAC: wholesale acquisition cost *Rebates taken from FSS due to no available net price evidence in SSR Health for the most recent year. tRebates taken from SSR Health. Standard lifestyle modification, consisting of diet and physical activity recommendations, was a background health care intervention across all treatment arms of the model. The cost of lifestyle modification was identified by review of prior economic outcome assessment studies. Cost of care for cardiovascular comorbid conditions was identified from targeted literature reviews. The acute care costs of myocardial infarction and stroke were identified fram a Healthcare Cost and Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 49 Return to Table of Contents Utilization Project National Inpatient Sample database online query. Long-term care costs for post- myocardial infarction, post-stroke, other cardiovascular disease, heart failure, and diabetes mellitus were identified from review of prior economic outcome assessments. Productivity costs, such as those due to patient absenteeism or presenteeism, and caregiver costs were identified from a review of prior economic assessments and were used to calculate the indirect costs of the cardiovascular conditions in question under the modified societal perspective. 104107-109 4.3. Results Base-Case Results The discounted total life years gained, QALYs gained, evLYs gained, and total costs over the lifetime horizon are shown for each of the obesity treatment strategies in Table 4.4. Incremental values compared to lifestyle modification are presented in Table 4.5. Undiscounted base-case results are presented in Supplement E. Table 4.4. Discounted Base-Case Results Treatment Drug Cost Non-Drug Cost Total Cost Life Years | QALYs evLYs Semaglutide $285,800 $106,200 $392,100 | 21.04 17.83 17.84 Liraglutide $241,800 $135,200 $377,000 | 20.86 17.34 17.35 Phentermine/Topiramate $39,700 $142,800 $182,600 | 20.85 17.38 17.39 Bupropion/Naltrexone $52,200 $155,100 $207,300 | 20.78 17.16 17.16 Lifestyle Modification* $11,400 $167,800 $179,200 | 20.70 16.93 16.93 evLY: equal-value life year, QALY: quality-adjusted life year *Reference for evLY calculation for all active treatments. Table 4.5. Discounted Incremental Results for the Base Case vs. Lifestyle Modification Incremental Values vs. Lifestyle Modification Treatment Drug Cost Non-Drug Cost | Total Cost | Life Years QALYs evLYs Semaglutide $274,400 -$61,600 $212,900 | 0.34 0.90 0.91 Liraglutide $230,400 -$32,600 $197,800 | 0.16 0.41 0.42 Phentermine/Topiramate $28,300 -$25,000 $3,400 | 0.16 0.45 0.46 Bupropion/Naltrexone $40,800 -$12,700 $28,100 | 0.08 0.23 0.23 Lifestyle Modification* -- -- -- - -- -- evLY: equal-value life year, QALY: quality-adjusted life year *Reference for incremental calculation for all active treatments. ©lnstitute for Clinical and Economic Review, 2022 Page 50 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Incremental cost per life year gained, QALY gained, and evLY gained over the lifetime horizon are shown in Table 4.6 for each of the obesity treatment strategies. Table 4.6. Incremental Cost-Effectiveness Ratios for the Base Case Cost per Life Cost per QALY Cost per Treatment Comparator Year Gained Gained evLY Gained Semaglutide Lifestyle modification $624,000 $237,000 $234,000 Liraglutide Lifestyle modification $1,210,000 $483,000 $473,000 Phentermine/Topiramate Lifestyle modification $22,000 $8,000 $7,000 Bupropion/Naltrexone Lifestyle modification $360,000 $123,000 $121,000 Liraglutide $85,000 $31,000 $31,000 Semaglutide Phentermine/topiramate $1,128,000 $469,000 $465,000 Bupropion/naltrexone $703,000 $275,000 $272,000 evLY: equal-value life year, QALY: quality-adjusted life year Sensitivity Analyses The model was sensitive to several inputs, including the disutility per BMI change, effectiveness of each treatment in weight loss, baseline HbA1C, and cost of diabetes mellitus. Disutility per BMI change was most important for semaglutide and liraglutide. The cost of diabetes mellitus management was most impactful for phentermine/topiramate. Varying the weight-lowering effect of each treatment compared to lifestyle management and varying the baseline HbA1C had a considerable influence across all four treatment options. The full one-way sensitivity analysis results are shown in the Supplement. Probabilistic sensitivity analysis results in are shown in Table 4.7. Table 4.7. Results of Probabilistic Sensitivity Analysis by Cost per QALY Gained Cost Cost Cost Cost Effective at | Effective at | Effective at | Effective at Treatment Comparator $50,000 $100,000 $150,000 $200,000 per QALY per QALY per QALY per QALY Gained Gained Gained Gained Semaglutide Lifestyle modification 0.0% 0.0% 1.2% 10.2% Liraglutide Lifestyle modification 0.0% 0.0% 0.0% 0.0% Phentermine/Topiramate | Lifestyle modification 69.0% 87.1% 91.9% 94.2% Bupropion/Naltrexone Lifestyle modification 1.0% 14.6% 40.9% 63.4% Liraglutide 49.5% 77.2% 87.6% 92.3% Semaglutide Phentermine/topiramate | 0.0% 0.0% 0.0% 0.0% Bupropion/naltrexone 0.0% 0.0% 0.0% 2.6% QALY: quality-adjusted life year ©lnstitute for Clinical and Economic Review, 2022 Page 51 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Scenario Analyses Conducting the analysis from a societal perspective marginally improved estimates of cost effectiveness across weight loss medications, with phentermine/topiramate compared to lifestyle modification alone becoming less costly and more effective (i.e., dominant) (see Tables 4.8 and 4.9 and Supplement Tables E11 and E12). Having the same proportion of men and women (50:50) in the model or changing baseline BMI in scenario analyses had a modest favorable impact on the estimates (see Supplement Tables E16-E18). Table 4.10 presents scenarios with use of Drug X (scenario with effect on weight loss seen in the SUPPORT 1 trial of tirzepatide and pricing of semaglutide for overweight and obesity and effects on blood pressure and diabetes mellitus similar to semaglutide), use of generic phentermine/topiramate, and use of generic bupropion/naltrexone. The incremental cost-effectiveness ratio for the lifetime weight management with Drug X versus lifestyle modification was $145,000 per QALY gained at the annual Drug X cost of $13,618. The lifetime drug cost for generic phentermine/topiramate was $14,000 (compared to $39,700 for branded therapy in the base case) and for generic bupropion/naltrexone was $25,500 (compared to $52,200 for branded therapy in the base case) while assuming no differences in health gains. Two scenario analyses evaluating the potential impact of cancer or chronic kidney disease (i.e., Comorbidity X scenario analyses) had modest impacts on the cost effectiveness of most medications for obesity management (see Supplement Tables E13-E15). Table 4.8. Discounted Results from the Societal Perspective Treatment Drug Cost 'ower id Total Cost vas QALYs evLYs Semaglutide $285,800 $145,300 $431,200 | 21.04 17.83 17.84 Liraglutide $241,800 $183,500 $425,200 | 20.86 17.34 17.35 Phentermine/Topiramate $39,700 $193,100 $232,800 | 20.85 17.38 17.39 Bupropion/Naltrexone $52,200 $209,200 $261,400 | 20.78 17.16 17.16 Lifestyle Modification* $11,400 $226,000 $237,400 | 20.70 16.93 16.93 evLY: equal-value life year, QALY: quality-adjusted life year *Reference for evLY calculation for all active treatments. ©lnstitute for Clinical and Economic Review, 2022 Page 52 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table 4.9. Discounted Incremental Results from the Societal Perspective vs. Lifestyle Modification Incremental Values vs. Lifestyle Modification Treatment Drug Cost Nee UB ora Life Years QALYs evLYs Semaglutide $274,500 -$80,600 | $193,800 | 0.34 0.90 0.91 Liraglutide $230,400 -$42,500 | $187,800 | 0.16 0.41 0.42 Phentermine/Topiramate $28,400 -§32,900 -$4,500 | 0.16 0.45 0.46 Bupropion/Naltrexone $40,800 -$16,800 | $24,100 | 0.08 0.23 0.23 Lifestyle Modification* -- -- -- -- -- -- Incremental Cost Effectiveness Ratio vs. Lifestyle Modification Cost/Life Cost/QALY Cost/ evly Year Gained Gained Gained Semaglutide $568,000 $216,000 | $213,000 Liraglutide $1,150,000 $459,000 | $449,000 Phentermine/Topiramate Less costly, more effective Bupropion/Naltrexone $308,000 | $105,000 | $103,000 evLY: equal-value life year, QALY: quality-adjusted life year *Reference for incremental calculation for all active treatments. Table 4.10. Scenario Analysis Results (Drug X and Generic Combination) Treatment | Drug Cost ve UB Total Cost Life Years QALYs evLYs Drug X $283,600 $83,500 $367,100 | 21.18 18.23 18.24 Generic P/T $14,000 $142,800 $156,800 | 20.85 17.38 17.39 Generic B/N $25,500 $155,100 $180,600 | 20.78 17.16 17.16 LSM $11,400 $167,800 $179,200 | 20.70 16.93 16.93 Incremental Value vs. LSM Drug X $272,200 -$84,300 $188,000 | 0.49 1.30 1.31 Generic P/T $2,600 -$24,900 -$22,400 | 0.16 0.45 0.46 Generic B/N $14,100 -$12,700 $1,400 | 0.08 0.23 0.23 Incremental Cost-Effectiveness Ratio Cost/Life Year Cost/QALY Cost/evLY vs. Lifestyle Management Gained Gained Gained Drug X $387,000 $145,000 5144,000 Generic P/T Generic P/T less costly, more effective Generic B/N $18,000 | $6,000 | $6,000 B/N: bupropion/naltrexone, evLY: equal-value life year, LSM: lifestyle modification, LY: life year, P/T: phentermine/topiramate, QALY: quality-adjusted life year Note: Drug X is assumed to achieve 17.8% BMI reduction with 0.44 decrease in HbA1C with an overall discontinuation rate of 6.5%. ©lnstitute for Clinical and Economic Review, 2022 Page 53 Final Evidence Report - Medications for Obesity Man agement Return to Table of Contents Threshold Analyses The annualized prices required to achieve thresholds of $50,000 to $200,000 per QALY and evLY gained are presented in Tables 4.11 and 4.12. Table 4.11. QALY-Based Threshold Analysis Results Annualized Annualized Annualized Annualized Price to Price to Price to Price to Annual . : . : Net Price Achieve Achieve Achieve Achieve $50,000 per $100,000 per | $150,000 per $200,000 per QALY Gained QALY Gained QALY Gained QALY Gained Semaglutide $13,618 55,300 $7,500 $9,700 $12,000 Liraglutide $11,760 $2,700 $3,800 $4,800 $5,900 Phentermine/Topiramate $1,465 $2,500 $3,600 $4,800 $5,900 Bupropion/Naltrexone $2,094 $1,200 $1,800 $2,400 $3,000 Lifestyle Modification Reference QALY: quality-adjusted life year Table 4.12. evLY-Based Threshold Analysis Results Annualized Annu alized Annu alized Annualized . . Price to Price to . . Annual Price to Achieve Achieve Achieve Price to Achieve Net Price $50,000 per $200,000 per evLY Gained $100,000 per $150,000 per evLY Gained evLY Gained evLY Gained Semaglutide $13,618 $5,300 $7,600 $9,800 $12,000 Liraglutide $11,760 $2,700 $3,800 $4,900 $5,900 Phentermine/Topiramate $1,465 $2,500 $3,600 $4,800 $6,000 Bupropion/Naltrexone $2,094 $1,300 $1,900 $2,400 $3,000 Lifestyle Modification Reference evLY: equal-value life year Model Validation Model validation followed standard practices in the field. All mathematical functions in the model were tested to assess face validity and to ensure consistency with the Report. We also conducted sensitivity analyses with null input values to ensure the model was producing findings consistent with expectations. Further, the model was subjected to internal and external stakeholder review to evaluate the mathematical functions as well as the specific inputs and corresponding outputs. Model validation was also conducted in terms of comparisons to other model findings. We searched the literature to identify models that were similar to our analysis, with comparable populations, settings, perspective, and treatments. We also identified a publication that evaluated semaglutide and other drugs for medication-assisted treatment of weight loss.1° This recently published model differed from ours in structure and inputs, including having additional Markov states and differences in the handling of multiple comorbidities, a two-year treatment period Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 54 Return to Table of Contents instead of lifetime, a 30-year time horizon instead of lifetime, handling excess mortality due to obesity in a different manner, using a higher cost of semaglutide, and having different utility inputs. When we changed our model inputs to resemble theirs (i.e., two-year treatment, higher semaglutide unit cost, utility inputs, and 30-year time horizon), our modified incremental cost- effectiveness estimate comparing semaglutide to lifestyle modification ($115,500) approached their reported estimate comparing semaglutide to diet and exercise ($122,549). The remaining difference observed in these incremental cost-effectiveness estimates could likely be explained by a much shorter 30-year life expectancy in all treatments reported in their model. Finally, a targeted literature search was conducted to review mortality and cardiovascular events from real-world evidence and to compare the real-world data with those predicted by the model. The average remaining life expectancy of a 45-year-old US female is 38.08 years.1"° In one study, class | obesity shortened life expectancy by approximately 3.5 years in middle-aged women.** Our model estimate was comparable to this real-world data, with an expected remaining median survival of 34 years and a predominantly female population taking semaglutide. Our model produced estimates for the cumulative incidence of cardiovascular conditions of 59.5% in patients receiving lifestyle management. The cumulative estimated incidence in patients receiving semaglutide was 52.1%. These model findings reflect the lifetime cardiovascular risk estimates from real-world studies in patients with an average age of 45 years living with major risk factors or obesity.222113 Supplement E7 contains additional information about model validation results. Uncertainty and Controversies In 2013, the American Medical Association recognized obesity as a chronic disease.* As a result, long-term weight management includes both weight loss and maintenance of weight reduction. However, medications for weight management are often not covered or require a stepped approach to care, with access granted only after lifestyle changes and other treatments have failed.1*> Where medications are covered, restrictions may be imposed on the duration of treatment (e.g., through day supply/quantity limits or reauthorization criteria). The Government Accountability Office showed that, between 2008 and 2017, 78.4% of first treatment episodes users had a medication duration of 91 days or less.** In contrast, after discussions with several experts in our scoping discussions, most stated that lifetime treatment with medications is now the preferred approach to managing obesity and overweight, given weight regain after discontinuation and the need for long-term use to prevent comorbid disease and mortality. As a result of this input, we decided to evaluate lifetime treatment as the base-case analysis. Another important uncertainty in the model was that the medications used for weight management often had multiple effects on the body in addition to weight loss. To limit the complexity of the cost-effectiveness model and to prevent double-counting of treatment benefits, we limited the ©lnstitute for Clinical and Economic Review, 2022 Page 55 Final Evidence Report - Medications for Obesity Management Return to Table of Contents long-term effects of treatments for weight management to cardiovascular risk and delays in the onset and/or diagnosis of diabetes mellitus (in patients starting in the model without diabetes) due to the effect of medications on A1C. As a result, there may be additional benefits with certain therapies that were not captured in the model. For example, GLP-1 receptor agonists have been shown to improve cardiovascular risk to a greater extent than expected by changes to HbA1C and weight loss alone in patients with diabetes mellitus.2°"4 These effects of GLP-1 receptor agonists have not yet been well elucidated in patients without diabetes mellitus, the starting population within the base-case model. The long-term benefits of preventing other comorbidities including cancer, chronic kidney disease, osteoarthritis, and sleep apnea were not explicitly modeled in the base case. Though obesity is associated with cancer risk, a clear causal relationship has not been established between weight loss, particularly for that conferred by weight loss medications, and the extent to which cancer- specific outcomes change. The short-term quality of life gains from decreased pain from osteoarthritis and improved sleep were included as general improvements in health-related utility associated with changes in BMI. With regard to chronic kidney disease, the costs and disutility of chronic kidney disease secondary to diabetes mellitus and heart failure were implicitly captured in the model. The impact of treatment on chronic kidney disease risk arising from overweight and obesity, independent of the effects on diabetes mellitus and hypertension, could not be quantified and was not included in the base case. Similarly, the cardiovascular benefits of reduced sleep apnea were already implicitly included in the equation used to estimate cardiovascular risk. However, the potential cost savings arising from a reduced need for osteoarthritis or sleep apnea treatments with substantial weight loss were believed to be small relative to the costs of cardiovascular conditions and diabetes mellitus and were not included in the base-case simulation. To further explore the potential impact of comorbid conditions partially included or excluded from the base-case analysis, we tested the potential impact of weight loss on cancer risk and chronic kidney disease using add-on Comorbidity X Markov states. These scenario analyses did not significantly alter the incremental cost-effectiveness ratios, alleviating concerns about the effects of these comorbidities on the cost effectiveness of weight management strategies. Bupropion is an approved treatment for smoking cessation, which may also improve cardiovascular risk. Additionally, smoking cessation can lead to weight gain.1"* Since we wanted to evaluate the impact of these treatments on weight loss alone, the potential benefits of bupropion for patients wanting to quit smoking were not included in the model. The key drivers of cost effectiveness in our model were health state utility, effectiveness of medication in reducing weight, and factors associated with prevention of diabetes mellitus, such as reduction in HbA1C with treatment and baseline HbA1C. Cardiovascular benefits of GLP-1 receptor agonists that appear to extend beyond their impact on weight loss and HbA1C improvements have been shown in patients with diabetes mellitus. Although not evaluated in our model, additional ©lnstitute for Clinical and Economic Review, 2022 Page 56 Final Evidence Report - Medications for Obesity Management Return to Table of Contents cardiovascular benefits, if present for GLP-1 receptor agonists in patients without diabetes mellitus, could result in improved cost effectiveness of treatment with semaglutide and liraglutide. There are several important limitations in this analysis. As described above, we likely did not include the full potential impact of weight loss on heart failure and other conditions for which weight loss may be beneficial. Some conditions (e.g., sleep apnea, chronic kidney disease) were excluded due to a concern over double-counting the beneficial effects of weight loss. Other conditions (e.g., cancer) were excluded due to insufficient evidence documenting the impact of weight loss on reductions in those conditions or their related costs. The equations used in our model were developed to determine the associations among patient- related factors, including weight and first cardiovascular events. These equations may have limitations when attempting to predict the impact of medication-assisted treatment for weight loss, especially in the case of medications that have complex actions on the body. Because the analysis was limited by available evidence, the outcomes of preventing or treating obesity in subpopulations with larger potential benefits (e.g., younger individuals, women of childbearing age, or underserved populations) were not specifically addressed. 4.4. Summary and Comment We conducted an analysis of the cost effectiveness of medication-assisted therapy for weight loss, administered over an individual's lifetime, using a Markov health state transition model. All therapies added to lifestyle modification conferred health gains as compared to lifestyle modification alone in accordance with their incremental weight loss and corresponding cardiovascular and metabolic benefits. Final results suggest that at current estimates of net price, neither semaglutide nor liraglutide are cost effective given commonly accepted thresholds when compared to lifestyle modification alone. In contrast, phentermine/topiramate in addition to lifestyle modification was cost effective per commonly accepted thresholds owing to its comparatively smaller net acquisition costs. Bupropion/naltrexone was cost effective at higher thresholds only and would generally require discounted prices to meet lower thresholds. When the treatments were compared to each other, phentermine/topiramate plus lifestyle modification was less costly and more effective than bupropion/naltrexone plus lifestyle modification. However, for patients not achieving desired weight loss or unable to tolerate phentermine/topiramate, bupropion/naltrexone may be an attractive option. Semaglutide (plus lifestyle modification) was both more effective and more costly than both phentermine/topiramate and bupropion/naltrexone but did not meet commonly accepted cost-effectiveness thresholds for either comparison. As such, semaglutide may be considered in patients not achieving desired weight loss or unable to tolerate phentermine/topiramate or bupropion/naltrexone, but only with a significant discount. ©lnstitute for Clinical and Economic Review, 2022 Page 57 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 5. Contextual Considerations and Potential Other Benefits Our reviews seek to provide information on potential other benefits offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that was not available in the evidence base nor could be adequately estimated within the cost-effectiveness model. These elements are listed in the table below, with related information gathered from patients and other stakeholders. Following the public deliberation on this report the appraisal committee will vote on the degree to which each of these factors should affect overall judgments of long-term value for money of the intervention(s) in this review. Table 5.1. Contextual Considerations Contextual Consideration Relevant Information Acuity of need for treatment of individual patients based on short-term risk of death or progression to permanent disability Not applicable Magnitude of the lifetime impact on individual patients of the condition being treated Obesity is a chronic disease that usually begins early in life and can continue throughout the course of a patient's life broadly affecting physical, psychosocial, and emotional health. As such, it can affect educational achievement, workplace opportunities and performance assessments, and personal relationship. There is uncertainty about how short-term mild to moderate weight loss translates into long-term benefits in preventing obesity- related disease morbidity and mortality Though evidence from trials of semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone in patients with obesity showed sustained weight loss and few serious side effects over short-term follow-up, the long-term benefits of the chronic use of these medications remains uncertain. This relates to the ability to maintain use over long periods given evidence for weight regain upon discontinuation, the benefits of mild to moderate weight loss on clinical outcomes, and potential differences in the medications underlying mechanisms that may be associated with other beneficial or harmful aspects on clinical outcomes beyond any sustained weight loss. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 58 Return to Table of Contents Table 5.2. Potential Other Benefits or Disadvantages Potential Other Benefit or Disadvantage Relevant Information Patients' ability to achieve major life goals related to education, work, or family life New medications for obesity that lead to sustained weight loss and improve the symptoms and complications of obesity may help improve quality of life across a range of different outcomes including social interactions with family, friends and other relations, educational achievement, and work opportunities and performance. This is particularly true for women of childbearing age where the potential effect of weight reduction on fertility, maternal morbidity and mortality, and infant health may be improved with weight loss. However, it is uncertain whether semaglutide, liraglutide, phentermine/topiramate, and/or bupropion/naltrexone will improve these outcomes. Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Though children and adolescents with obesity often require care involving family members and other caregivers, this Report focused on adults with obesity. Even among adults with obesity, its impact may fall not only on the patient, but also on caregivers. As such, new medications that promote sustained weight loss offer the possibility of improving the quality of life for caregivers as well as for patients. Patients' ability to manage and sustain treatment given the complexity of regimen Use of phentermine/topiramate and bupropion/naltrexone, which are oral therapies and do not require the daily or weekly injections, may decrease the complexity of care. All four medications may be less complex to use on a long-term basis than constant attention to diet and physical activity. Society's goal of reducing health inequities Obesity disproportionally impacts certain racial and ethnic groups, and emphasizes the need for and potential impact of improved treatment options. However, the costs of medications for obesity are often not covered by health insurance, and there are differences among individuals in their ability to access health care. This may exacerbate existing health inequities by selectively limiting access of these medications to those patients who are able to afford them and have access to health care providers who can prescribe them. Additionally, ICER calculated the Health Improvement Distribution Index, looking at the relative proportion of any health gains from treatment of overweight with one or more comorbidities and obesity for the following groups who have a higher prevalence of overweight with comorbidities and obesity than the general US population." e African American/Black female: 1.3 e Hispanic: 1.1 These medications offer new mechanisms of action that may allow more patients to achieve meaningful weight loss among those who have failed other treatments or may wish to avoid surgical therapies Semaglutide and liraglutide, GLP-1 receptor agonists, represent medications that reflect research in which improved understanding of the mechanisms of disease have led to new therapies. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 59 Return to Table of Contents New England CEPAC Votes When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for obesity on the basis of the following contextual considerations: : : Very Low Low Average High Very High Contextual Consideration Priority priority Priority Priority Priority Acuity of need for treatment of individual patients based on short-term risk of death or 10 1 2 1 1 progression to permanent disability Magnitude of the lifetime impact on individual 0 0 3 7 5 patients of the condition being treated A majority of the panel voted that a treatment for obesity should be given very low priority relative to other diseases given that it does not typically pose a short-term risk of death or progress to permanent disability. Based on the magnitude of lifetime impact, however, a majority of the panel voted either "high priority" or "very high priority" as obesity is a chronic disease that usually begins early in life and can affect a person's physical, psychosocial, and emotional health. Panelists cited testimony from patient advocates who emphasized that obesity contributes to dozens of other health conditions. What are the relative effects of semaglutide versus lifestyle modification on the following outcomes that inform judgment of the overall long-term value for money of semaglutide? Major Minor No Minor Major Potential Other Benefit or Disadvantage Negative Negative Difference Positive Positive Effect Effect Effect Effect Patients' ability to achieve major life goals 0 0 0 10 5 related to education, work, or family life Caregivers' quality of life and/or ability to achieve major life goals related to 0 0 6 9 0 education, work, or family life Society's goal of reducing health inequities | 0 0 4 6 5 A majority of the panel voted that semaglutide may have a minor positive effect on patients' ability to achieve major life goals related to education, work, or family life. Similarly, a majority of the panel voted that semaglutide may have a minor positive effect on caregiver quality of life. Lastly, the panel was split on the outcome of reducing health inequities. Obesity disproportionately impacts certain racial and ethnic groups, however, the cost of semaglutide is often not covered by health insurance and there are differences among individuals in their ability to access health care. Panelists were concerned that existing health inequities may be exacerbated by these factors. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 60 Return to Table of Contents 6. Health-Benefit Price Benchmarks Health-benefit price benchmarks for the annual cost of treatment with the semaglutide are presented in Table 6.1. The health-benefit price benchmark 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 evLY gained. Based on our model analyses, we estimate a health-benefit price benchmark range for semaglutide from $7,500 to $9,800 per QALY or evLY gained compared to lifestyle modification alone. Corresponding discounts from WAC to achieve the health-benefit price benchmark range for semaglutide compared to lifestyle modification alone range from 44-57%. Table 6.1. Annual Cost-Effectiveness Health-Benefit Price Benchmarks for Semaglutide plus Lifestyle Modification vs. Lifestyle Modification Alone plus Background Therapy Outcome for Annual Health- . . Discount from WAC Benefit Price Annual WAC Annual Price at Annual Price at to Reach Threshold $100,000 Threshold | $150,000 Threshold , Benchmark Prices Calculation Semaglutide plus Lifestyle Modification vs. Lifestyle Modification Alone QALYs Gained $17,597.48 $7,500 $9,700 | 45-57% evLYs Gained $17,597.48 $7,600 $9,800 | 44-57% evLY: equal-value life year, QALY: quality-adjusted life-year, WAC: wholesale acquisition cost ©lnstitute for Clinical and Economic Review, 2022 Page 61 Final Evidence Report - Medications for Obesity Management Return to Table of Contents New England CEPAC Votes Table 6.2. New England CEPAC Votes on Long-Term Value for Money at Current Prices Question Low Intermediate | High 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 semaglutide added to lifestyle modification versus lifestyle modification alone? 11 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 semaglutide added to lifestyle modification versus phentermine/topiramate? 12 A majority of the panel voted that semaglutide provides low long-term value for money. This vote reflected the high cost of treatment along with an incremental cost-effectiveness ratio of approximately $237,000. The panel also voted that phentermine/topiramate represents a low long-term value for money. Although the cost of phentermine/topiramate is substantially lower than other treatments for obesity, there is still concern about higher rates of adverse events seen in trials, uncertainty around long-term ability to sustain weight loss, and whether the degree of weight loss seen in trials translates into improved clinical outcomes. Further, several experts noted that patients often have difficulty tolerating phentermine/topiramate. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page 62 Return to Table of Contents 7. Potential Budget Impact 7.1. Overview of Key Assumptions Using results from the cost-effectiveness model, we estimated the potential budget impact of adding semaglutide to current lifestyle modification for US adults with BMI 230 or 27.0 kg/m?<BMI<30 kg/m? with one or more weight-related comorbidities. In accordance with the Reference Case, semaglutide is treated as an intervention in the budget impact analysis, as it has been on the market for less than two years as of posting the Model Analysis Plan. In contrast, liraglutide, phentermine/topiramate, and bupropion/naltrexone are treated as comparators, as they have been on the market for two years or more. For potential budget impact analyses, we used semaglutide's list price and net price and three threshold prices (at $50,000, $100,000, and $150,000 per QALY) compared to lifestyle modification alone. These additional analyses on semaglutide threshold prices were conducted to inform budgetary impact estimations aligned with notions of semaglutide's cost effectiveness as calculated within the cost-effectiveness analyses. Potential budget impact is defined as the total differential cost of using semaglutide rather than the relevant existing therapies for the treated population, calculated as intervention costs minus any offsets in these costs from averted health care events or other resource utilization. All costs were undiscounted and estimated over a five-year time horizon. To estimate the size of the potential candidate populations for treatment, we used the US adult population and prevalence of overweight and obesity given specific weight-related comorbidities or biomarkers as reported within National Health and Nutrition Examination Survey datasets over the 2017-2018 and 2019-March 2020 data collection cycles.14* Accordingly, we estimated a combined prevalence value for US adults with BMI 230 kg/m? (41.96%) or 27.0 kg/m?SBMI<30 kg/m? with one or more weight-related comorbidities (11.57%) at 53.53%. Applied to the projected US adult population over 2022-2026 (78% of all individuals in the US), we estimated 142,000,000 adults would be eligible for treatment with semaglutide. For this analysis, we assumed that 20% of these patients would initiate treatment with semaglutide in each of the five years (~28,000,000 per year), for a total of 100% of the cohort being treated with semaglutide at the end of five years. At baseline, we assume half of the population are assigned to medication therapy. Of these patients, 53%, 30%, and 17% are assigned to liraglutide, phentermine/topiramate, and bupropion/naltrexone, respectively.129 The remaining individuals are assigned to lifestyle modification alone at baseline. In our potential budget impact analyses, semaglutide draws market share proportionally from each of the model comparators over the five-year time horizon. ©lnstitute for Clinical and Economic Review, 2022 Page 63 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 7.2. Results At semaglutide's estimated net price of $13,618.22 per year, 0.1% of eligible patients could be treated within five years (assuming 20% uptake each year) without crossing the ICER potential budget impact threshold of $777 million per year. In contrast, 0.07%, 0.16%, 0.26%, and 0.69% of eligible patients could be treated within five years without crossing the ICER potential budget impact threshold at the annual price to reach list price ($17,597.48), $150,000 per QALY ($9,700), $100,000 per QALY ($7,500), and $50,000 per QALY ($5,300), respectively. The modest percentages were primarily driven by the large population eligible for treatment with semaglutide. Figure 7.1. depicts the potential budgetary impact of semaglutide at the annual list price, net price, and three threshold prices compared to lifestyle modification alone. Figure 7.1. Budgetary Impact of Semaglutide in US Adults with BMI 230 or 27.0 kg/m?<BMI<30 kg/m? with One or More Weight-Related Comorbidities $20,000 $18,000 ® Annual WAC $16,000 ; rice a 914,000 @ Annual Net Price $12,000 : $10,000 e $150,000/QALY Annual Price $8,000 5 §100,000/QALY Annual Price $6,000 Annual Semaglutide ® $50,000/QALY Annual Price $4,000 $2,000 $0 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Patients Treated Without Crossing PBI Threshold Each Year BI: budget impact, QALY: quality-adjusted life year, WAC: wholesale acquisition cost ©lnstitute for Clinical and Economic Review, 2022 Page 64 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Access and Affordability Alert Assuming semaglutide's current net price, approximately 0.1% of the 142 million adult patients across the US with overweight or obesity eligible for treatment with semaglutide could be treated within five years without crossing the ICER potential budget impact threshold of $777 million per year. When these 142,000 patients (0.1% of 142 million) initiate treatment in equal proportions over five years, only about 28,000 patients across the US could be treated per year without crossing the annual potential budget impact threshold, highlighting potential affordability and access considerations surrounding semaglutide. Therefore, at current pricing and projected continued uptake that is likely to exceed 28,000 patients per year in the US, semaglutide's short-term potential budget impact exceeds ICER's threshold. Additional efforts at achieving affordability and access must be considered. Thus, ICER is issuing an access and affordability alert for semaglutide in the management of overweight and obesity. 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. ©lnstitute for Clinical and Economic Review, 2022 Page 65 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 8. Policy Recommendations All Stakeholders All stakeholders have an important role to play in ensuring that people living with obesity have access to effective medications as a core benefit of health care insurance coverage. Though safe and effective medical treatments for obesity are available and more options are in the development pipeline, only a small fraction of individuals who may benefit from such therapy are receiving them. For many individuals, this is because medications for obesity are not covered as part of their health care benefits. In part, this lack of coverage is due to the negative experience with earlier generations of obesity medications. However, given that obesity is a chronic disease with important long-term health consequences, it seems reasonable that newer therapies for obesity such as semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone be covered not as an optional add-on determined by employers but as a core element of health insurance. To achieve the goal of affordable coverage for obesity medications: Manufacturers should take the following actions: e Set the price for new treatments for obesity in proportion to their demonstrated benefit to patients and society, with moderation commensurate with residual uncertainty about long- term benefits and the large size of the potential population of people to be treated. e Perform long-term comparative studies assessing the benefit of these therapies in improving clinical outcomes such as preventing cardiovascular events among individuals with obesity without pre-existing diabetes or cardiovascular disease. Payers should take the following actions: e Ensure that pharmaceutical benefit designs developed in conjunction with employers and other plan sponsors ensure access to approved therapies among individuals with obesity, following the principles in subsequent payer recommendations in this document. ©lnstitute for Clinical and Economic Review, 2022 Page 66 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Clinical specialty societies should take the following actions: e Develop and disseminate educational materials that permit prescribing weight loss medications to eligible patients from a broad range of clinicians, not just weight loss specialists. Government should take the following actions: e Enact legislation such as the Treat and Reduce Obesity Act that provides for coverage of weight loss medications under Medicare. e States should include coverage of weight loss medications under the auspices of the Medicaid program. If narrowing coverage is necessary to ensure affordability within the constraints of state budgets, evidence-based coverage can be framed to ensure access to lower cost and generic drugs for those individuals with clinical characteristics that suggest they have the most to benefit from treatment. All stakeholders should take steps that make effective treatment options for people living with obesity available in a way that will help reduce health inequities. Obesity is a growing health problem in the US that has a particularly large impact on certain racial and ethnic groups. The high cost of some of these treatments makes them unaffordable to many people with fewer economic resources. Limited access to health care clinicians who feel confident in prescribing these therapies is another barrier for these individuals. When combined with variable insurance coverage, this landscape creates a substantial risk that the introduction of new, more effective treatments will aggravate existing health inequities. Considerable concern was expressed by patient advocates and clinical experts that despite improvements in weight loss with existing medications and those undergoing clinical evaluation that current coverage policies and medication costs are likely to worsen disparities in accessing care unless specific action is taken. To achieve the goal of equitable availability for obesity medications: Manufacturers should take the following actions: e Develop patient assistance programs at a level commensurate with other chronic disease conditions to support access to medications among racial and ethnic groups where the burden of obesity is particularly large, payer coverage is low, and inability to afford out-of- pocket payments is common. e Take steps necessary to include a more diverse patient population in clinical trials, including an adequate number of patients with ethnic and racial backgrounds who are most likely to be affected by obesity and its consequences. ©lnstitute for Clinical and Economic Review, 2022 Page 67 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Payers should take the following actions: e Design coverage criteria that are sensitive to racial and ethnic variability in the clinical applicability of BMI thresholds to ensure that eligible beneficiaries from racial and ethnic groups particularly affected by obesity have access to effective therapeutic options. Clinical specialty societies should take the following actions: e Develop and disseminate guideline recommendations that provide support to clinicians in a manner that equitably identifies individuals who may benefit from therapy across a range of racial and ethnic backgrounds and addresses medication affordability. Manufacturers Manufacturers should take the following actions: Set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments. Medication pricing at launch should also be moderated until additional evidence is generated to demonstrate long-term safety and reductions in adverse cardiovascular outcomes. Prices of drugs for weight loss that are set well beyond the cost-effective range and are often not covered by payers cause not only financial hardship for individuals and exacerbate disparities in access to treatment, but also contribute to general health care cost growth that push individuals and families out of the insurance pool, and that cause others to ration their own care in ways that can be harmful. Manufacturers should therefore price new treatments in accordance with the demonstrated benefits to individuals. In settings of substantial uncertainty, initial pricing should err on the side of being more affordable. This would allow more patient access, something critical given the number of individuals with obesity who may be eligible for these drugs. It would also generate additional data on real-world effectiveness that could be used in future assessment updates. With the accumulation of evidence of substantial patient benefit in a broader range of individuals, manufacturers would have expanded access to a growing patient population who would benefit from their drugs. Accept their responsibility to participate in public dialogue exploring the evidence on the comparative clinical effectiveness and value of their products. Abstaining from participating in dialogue with patients and other stakeholders is a sign of poor corporate citizenship. The manufacturer of semaglutide chose to make public comments criticizing the ICER Report but justified their non-appearance on the Policy Roundtable as a "business decision." Choosing not to ©lnstitute for Clinical and Economic Review, 2022 Page 68 Final Evidence Report - Medications for Obesity Management Return to Table of Contents participate in a broader dialogue with patients, clinical experts, and payers on key elements of how to get value and access "right" going forward is a failure of the company to meet their social responsibility, particularly when they receive societal benefits in the form of tax support for research and exclusivity rights for marketing their products. Establish patient assistance programs for people living with obesity at a level commensurate with other chronic diseases. According to the US Agency for Healthcare Research and Quality from Medical Expenditure Survey pooled data, out-of-pocket payments from individuals made up two-thirds of the amounts paid for obesity drugs from 2012-2016. Currently, semaglutide (Wegovy®) costs around $1,300 for a month's supply. Manufacturers of phentermine/topiramate (Qsymia®) and bupropion/naltrexone (Contrave®) have assistance programs but even with subsidies, the cost of these drugs is substantially higher than traditionally seen with assistance programs for other chronic conditions. There are no patient-assistance programs for Wegovy, but there are resources available from Novo Nordisk for Ozempic®, which is semaglutide indicated for diabetes. Initiate long-term studies that can be used to assess the benefits and harms of chronic use of medications for people living with obesity. Though cardiovascular benefits have been shown for the use of GLP-1 agonists in individuals with diabetes, studies are needed to demonstrate similar benefits in individuals with obesity without pre-existing diabetes mellitus. Similarly, for drugs with other mechanisms of action such as phentermine/topiramate and bupropion/naltrexone, long-term registries are needed to assess for benefits and harms of chronic use. Ideally, the FDA would permit approval of a new drug from a class without long-term outcomes demonstrated for the drug's mechanism of action in a new population by requiring post-marketing studies. Given the demonstrated long-term risks of obesity on a range of comorbid conditions and even mortality, comparative studies of approved medications for weight loss should also assess a range of clinical outcomes that have been shown to be impacted by obesity. Conduct research that directly compares real-world treatment options and sequential treatment effectiveness. Multiple stakeholders expressed concerns about the lack of information directly comparing new treatments and the need for active comparator trials. With the potential for having multiple newer therapeutic options that work through different mechanisms for people with obesity, there is a great need for pragmatic research trials that compare different medications as they will be used by patients and clinicians in real-world settings. Appropriate head-to-head trials would inform decision-making by patients and clinicians. Trials that compare multiple treatment options, ©lnstitute for Clinical and Economic Review, 2022 Page 69 Final Evidence Report - Medications for Obesity Management Return to Table of Contents sequences, and combinations are needed to identify comparative effectiveness, durability of benefit, and adverse effects. Clinicians and Clinical Societies Update treatment guidelines for people living with obesity to reflect current treatment options in a form that is easy to interpret and use by clinicians, patients, and payers Given the social stigma associated with obesity, clinicians and clinical societies have an important role to play in educating the public about the causes of obesity and counteracting the false perception that obesity represents a personal shortcoming that can be managed through individual choice and simple willpower. Clinical societies should update their practice guidelines for managing people with obesity to include newer therapies such as GLP-1 agonists. Payers base their coverage decisions and integration of utilization tools to a great extent on clinical guidelines. The American Heart Association, the American College of Cardiology, and the Obesity Society last provided guidelines for the treatment of obesity in 2013. There is a need to update guideline recommendations to account for newer approved agents for people with obesity as well as agents that are currently undergoing evaluation. Policy roundtable participants highlighted that guidelines should not only provide information on options to be used by clinicians and patients for shared decision-making but also offer pragmatic advice about how to select specific therapies for specific subgroups. Payers expressed the need for updated guidelines from clinical societies with detailed guidance to permit meaningful stepped therapy approaches that permit reasonable clinical exceptions. For example, guidelines should provide information on the off-label use of medications used alone or in combination, drugs to avoid in specific patient groups, and recommendations for stepped or sequential therapy. Guidelines could also highlight when medication treatment may be indicated. For example, guidelines for chronic diseases such as hypertension, diabetes, and hyperlipidemia do not require the need for demonstrating inadequate response to lifestyle interventions, and yet guidelines for obesity typically emphasize initial lifestyle interventions that are acknowledged as being of little if any long-term benefit. Since all stakeholders recognized that given the very large burden of obesity in the US, primary care practitioners will be needed to treat the growing population of those who may benefit from medications to promote weight loss. Clinical specialty societies are critical to supporting the dissemination of practice guidelines to non-specialists in collaboration with primary care organizations. This need includes not only starting and modifying therapy based upon individual response, but also managing chronic treatment given evidence that weight loss requires long-term medication use for most individuals. ©lnstitute for Clinical and Economic Review, 2022 Page 70 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Patient Organizations Patient organizations have a vital role to play in promoting the dissemination of objective information about new therapies for obesity to individuals and clinicians in order to support shared decision-making. In addition, patient groups have a powerful voice and should apply it to create significant pressure for fair pricing and appropriate payer coverage across all sectors of the health system. Patient groups should endeavor to educate people living with obesity about the potential benefits and harms of new and existing therapies, particularly given evidence that chronic medication use will be required for most who respond to treatment in order to maintain weight loss. Patient groups can also publicly promote access and fair pricing of new therapies so as to ensure that disparities in access to treatment among diverse individuals with obesity are not worsened. The large and increasing percentage of the population that may be eligible for anti-obesity medications, the small percentage of individuals currently on treatment, and the high cost of new therapies, highlight the need for patient groups to advocate for manufacturers, payers, and government regulators to support efforts to ensure that the uptake of therapy prioritizes those who are most likely to benefit from therapy in a manner that promotes equitable access. Researchers/Regulators Support the development of improved measures of disease severity and outcomes that are meaningful to people living with obesity. Clinical experts identified a critical need for new measures of disease severity for obesity that better identify those who may most benefit from therapy. All stakeholders recognized that the unmet need for medical therapy far exceeds that which society can afford given the tremendous burden of obesity in the US. Given that only a fraction of eligible people with obesity have received treatment, there is a need to develop criteria for how to prioritize treatment among those eligible. Given the fact that few payers cover the use of medications for weight loss as a pharmaceutical benefit and the high current prices of therapy, devising ways to systematically expand coverage are needed. Though obesity is defined and severity is assessed primarily using the BMI, clinical experts highlighted its limitations given the known underlying mechanisms whereby obesity contributes to disease. They highlighted the need to develop measures of disease severity that could be used as part of routine care to identify those individuals who are at greatest risk for the complications of obesity. Implementing such criteria as part of the process payers use to identify individuals for eligibility coverage could help maximize the impact of therapy within the population. We also heard from patient advocacy groups that endpoints used in clinical trials do not always measure what is most important to people living with obesity. For example, the amount of weight ©lnstitute for Clinical and Economic Review, 2022 Page 71 Final Evidence Report - Medications for Obesity Management Return to Table of Contents loss that contributes to improved quality of life may vary among individuals. There is also the need for patient-reported quality of life measures that capture the broad range of benefits, both physical and mental health-related, that may be associated with treating obesity. Moreover, such outcomes are rarely translated into utility measures that can be incorporated into cost-effectiveness analyses. Patient groups can take a leading role in collecting real-world data, as well as collaborating with researchers, manufacturers, and regulators to define a core set of severity and outcome measures and then in promoting their use in all future clinical trials. ©lnstitute for Clinical and Economic Review, 2022 Page 72 Final Evidence Report - Medications for Obesity Management Return to Table of Contents References 1. Kastanias P, Mackenzie K, Robinson S, Wang W. Medical Complications Resulting from Severe Obesity. In: Sockalingam S, Hawa R, eds. Psychiatric Care in Severe Obesity. Springer, Cham; 2016:pp. 49-73. 2. Centers for Disease Control and Prevention. 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Med. 2022;10(3):152. ©lnstitute for Clinical and Economic Review, 2022 Page 81 Final Evidence Report - Medications for Obesity Management Return to Table of Contents 170. = Thillainadesan S, Madsen S, James DE, Hocking SL. The impact of weight cycling on health outcomes in animal models: A systematic review and meta-analysis. Obes Rev. 2022;23(5):e13416. Rhee EJ. Weight Cycling and Its Cardiometabolic Impact. J Obes Metab Syndr. 2017;26(4):237- 242. 171. Olnstitute for Clinical and Economic Review, 2022 Page 82 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Supplemental Materials ©lnstitute for Clinical and Economic Review, 2022 Page 83 Final Evidence Report - Medications for Obesity Management Return to Table of Contents A. Background: Supplemental Information A1. Definitions Obesity: BMI is the most common way that obesity is defined in clinical practice. Overweight is considered a BMI of 25 kg/m? to 29.9 kg/m*. Obesity is considered a BMI of 30 kg/m2 or greater. It is further subclassified as level | (30 kg/m? to 34.9 kg/m7), level II (35 kg/m? to 39.9 kg/mz2), or level Ill (40 kg/m2 or more). Pre-diabetes: The clinical trials assessed patients for pre-diabetes using slightly different criteria. Pre-diabetes is defined by the American Diabetes Association based on an HbA1C result of 5.7%- 6.4% (39-47 mmol/mol), a fasting glucose of 100-125 mg/dL (5.6-6.9 mmol/L), or a two-hour oral glucose tolerance test of 140-mg-199 mg/dL (7.8-11.0 mmol/L).!2° Important outcomes in the pivotal trials studied include: Percentage weight loss: This primary outcome in most studies represents the mean percentage point change in weight at follow-up relative to the baseline body weight. Categorical weight loss (25%): This is a co-primary outcome in many studies and represents the percentage of individuals who achieve a 25% change in body weight from baseline to follow-up assessment. Greater weight loss can be assessed using 210%, 215%, or higher percentages. Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT): The |WQOL was the first quality of life instrument specifically developed to assess individuals with obesity.*2? It measures those aspects of quality of life that were identified by individuals with moderate or severe obesity to be of greatest concern. Eight domains assessed include health, social/interpersonal, work, mobility, self-esteem, sexual life, activities of daily living, and comfort with food. Originally a 74-item instrument, the IWQOL-Lite is a shorter, 31-item, self-reported version that consists of a total score and scores on each of five scales: Physical Function, Self-Esteem, Sexual Life, Public Distress, and Work.?22 The IWQOL-Lite Clinical Trials Version (IWQOL-Lite-CT), was developed and validated for use in clinical trials.12774 It is a 20-item measure used to assess weight-related physical and psychosocial functioning in three composite scores (physical, physical function, and psychosocial) and a total score. The range of possible scores for the IWQOL-Lite-CT is 0-100. For the IWQOL-Lite-CT, an increase in score is representative of an improvement in health status. Short Form-36 v2® Health Survey, Acute Version (SF-36): The SF-36 is a generic quality of life measure widely used to assess patient-reported functional outcomes.*° It includes 36 questions across eight domains (physical functioning, role limitations due to physical health problems, body pain, general health, vitality, social functioning, role limitations due to emotional problems, and ©lnstitute for Clinical and Economic Review, 2022 Page Al Final Evidence Report - Medications for Obesity Management Return to Table of Contents mental health). Additionally, the SF-36 domains can be aggregated into two scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS). For the SF-36, an increase in score is representative of an improvement in health status. Patient Health Questionnaire (PHQ-9): The PHQ-9 is a self-administered instrument to measure symptoms of depression.'° It was derived from the PRIME-MD diagnostic instrument for common mental disorders. Each item asks the individual to rate daily symptoms from "0" (not at all) to "3" (nearly every day). A higher score indicated worse depressive symptoms. Inventory of Depressive Symptomatology (Self-Report) (IDS-SR): The IDS-SR is a 30-item questionnaire measuring depressive symptoms. Each item has four statements that reflect various degrees of symptom severity, scored on a four-point scale from 0 to 3.17" A higher score indicated worse depressive symptoms. A2. Potential Cost-Saving Measures in Obesity Management 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 semaglutide, liraglutide, phentermine/topiramate, and/or bupropion/naltrexone (e.g., need for obstructive sleep apnea treatment), as these services will be captured in the economic model. Rather, we are seeking services used in the current management of obesity 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 individuals with obesity that could be reduced, eliminated, or made more efficient. No suggestions were received. A3. Future Therapies In June 2022, results from the SURMOUNT-1 trial of tirzepatide were published." Tirzepatide is both a GLP-1 receptor agonist and also a glucose-dependent insulinotropic polypeptide receptor agonist. ICER previously reviewed tirzepatide as a treatment for type 2 diabetes mellitus. The manufacturer of tirzepatide requested that it not be added to this report as the current ICER evaluation process was already underway. Tirzepatide is neither an intervention nor a comparator in this Report. However, to provide context, we review the results of SURMOUNT-1 here. SURMOUNT-1 was a 72-week Phase Ill trial comparing three doses of tirzepatide and placebo in 2,539 adults without diabetes and with a BMI 230 kg/m2, or 227 kg/m? with one weight-related complication. Tirzepatide was administered by weekly subcutaneous injection at doses of 5 mg, 10 mg, or 15 mg, with an initial 20-week dose-escalation period. ©lnstitute for Clinical and Economic Review, 2022 Page A2 Final Evidence Report - Medications for Obesity Management Return to Table of Contents The mean baseline BMI in the study population was 38. Tirzepatide at doses of 5 mg, 10 mg, and 15 mg resulted in greater percentage reductions in weight than placebo (15.0%, 19.5%, and 20.9% vs. 3.1%, respectively). More patients achieved categorical weight reduction targets as well. For example, a 25% target was achieved by 85.1%, 88.9%, and 90.9% of patients, respectively, with the tirzepatide doses, versus 34.5% with placebo. A 225% target was achieved by 15.3%, 32.3%, and 36.2% of patients, respectively, with tirzepatide versus 1.5% with placebo. Patients treated with tirzepatide also experienced improvements in physical functioning, decreases in systolic and diastolic blood pressure, improvements in lipids, and decreases in fasting insulin levels. Most adverse events with tirzepatide were gastrointestinal in nature and discontinuation for adverse events occurred in more patients treated with tirzepatide than placebo (4.3%, 7.1%, and 6.2% vs. 2.6%, respectively). Gastrointestinal adverse events were typically worse at initiation or dose escalation of tirzepatide, with improvement over time. ©lnstitute for Clinical and Economic Review, 2022 Page A3 Final Evidence Report - Medications for Obesity Management Return to Table of Contents B. Patient Perspectives: Supplemental Information B1. Methods In developing and executing this Report, we received valuable input from individual patients and patient organizations throughout the scoping and evidence development process. We received public comments on our draft scoping document from the Obesity Action Coalition. We also conducted a focus group with six patients that was arranged through the Obesity Action Coalition. These interviews with patients helped to illustrate the diversity of experiences of patients living with obesity as well as highlighting the health outcomes that were most important to them. ©lnstitute for Clinical and Economic Review, 2022 Page B1 Final Evidence Report - Medications for Obesity Management Return to Table of Contents C. Clinical Guidelines Veterans' Health Administration/Department of Defense Clinical Practice Guideline for the Management of Adult Overweight and Obesity'"* The Evidence-Based Practice Work Group of the Department of Veterans Affairs and the Department of Defense released updated guideline recommendations in 2020. These recommendations updated a prior evidence review released in 2014. A number of key elements of weight loss and management were highlighted. Obesity is recognized as a chronic disease requiring long-term management. Shared decision-making involving patients and providers is seen as a fundamental aspect of weight management. Managing obesity involves addressing all of the factors that may be involved for a given patient. This may include assessing whether medications or treatments for other conditions may exacerbate weight issues for a patient. Lifestyle interventions involving comprehensive use of behavioral, dietary, and physical activity components are central to success in reducing and sustaining weight loss. Pharmacotherapy and weight loss surgery should be considered along with comprehensive lifestyle interventions, and when instituted they require long- term follow-up. In terms of pharmacotherapy, the use of FDA-approved medications needs to consider potential side effects as well as patient tolerability and preferences. Weight regain can occur with any medication after discontinuation, so long-term use to maintain weight loss is often needed. Specific pharmacotherapies that can be offered to patients include bupropion/naltrexone, liraglutide, orlistat, or phentermine/topiramate. Eligibility includes patients with a BMI 230 kg/m? and for those with a BMI 227 kg/m? who also have obesity-associated conditions. There is insufficient information to recommend phentermine monotherapy or other stimulants for intermittent, short- term, or long-term use. Canadian Clinical Practice Guideline Obesity in Adults: A Clinical Practice Guideline* This guideline was funded by the Canadian Institutes of Health Research Strategic Patient-Oriented Research initiative, Obesity Canada's Fund for Obesity Collaboration and Unified initiative, and the Canadian Association of Bariatric Physicians and Surgeons. An executive and steering committee with broad expertise and geographic representation was created. The scope of the guideline was developed by the executive committee. A literature review was performed by the McMaster Evidence Review and Synthesis Team. Guideline recommendations were formulated by the steering committee along with chapter leads and authors. Seven individuals living with obesity ©lnstitute for Clinical and Economic Review, 2022 Page C1 Final Evidence Report - Medications for Obesity Management Return to Table of Contents were engaged and one participated on the steering committee. This guideline updated the first Canadian obesity guideline published in 2006. Key points emphasized that obesity is a common, complex, progressive, and relapsing disease. It is characterized by abnormal or excessive body fat that impairs health. Newer insights into appetite regulation and the underlying mechanisms leading to obesity have opened new approaches for treating this chronic disease. People living with obesity face substantial bias and stigma, and this contributes independently of weight or BMI to morbidity and mortality. Reducing weight bias and stigma, better understanding of the underlying causes of obesity, and supporting patient-centered care can improve the wellbeing of those living with obesity. Obesity care should be based on evidence-based principles of chronic disease management, validate patients' lived experiences, and move beyond the simplistic notion that obesity requires eating less and increasing activity. In terms of pharmacotherapy, the guideline focuses on individuals with BMI 230 kg/m? or BMI 227 kg/m? with comorbid conditions. Pharmacotherapy is meant to be an adjunctive for weight loss and weight loss maintenance in addition to medical nutrition therapy, physical activity, and psychological interventions. Recommended options include liraglutide 3.0 mg, bupropion/naltrexone, and orlistat. Details of the recommendations are available online in the chapter titled "Pharmacotherapy in Obesity Management." Pharmacotherapy is intended to augment the magnitude of weight loss beyond what can be achieved with health behavior changes alone. It is also emphasized as being important for the prevention of weight regain. Endocrine Society Pharmacological Management of Obesity Guideline?2? This evidence-based guideline was developed by members of the Endocrine Society, the European Society of Endocrinology, and the Obesity Society. Weight loss is seen as a path to achieving improved health for patients with obesity-associated risk factors and comorbidities. Medications approved for chronic weight management can be useful adjuncts to lifestyle interventions for patients that have not met weight loss goals on their own. Diet, exercise, and behavioral modification are recommended for patients with BMI 225 kg/m? and should be included with other obesity management interventions. Pharmacotherapy can be considered for those with BMI =27 kg/m? with comorbidity or BMI over 30 kg/m2. Patients with a history of being unable to successfully lose and maintain weight are candidates for weight loss medications. Patients responding well to weight loss (5% or more after three months) should continue with therapy. In addition to addressing medications that can promote weight loss, the guidelines emphasize attention to the use of medications for other conditions that are weight-neutral and avoiding those that are associated with weight gain. ©lnstitute for Clinical and Economic Review, 2022 Page C2 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Specific pharmacotherapy recommendations include avoiding sympathomimetic agents such as phentermine in patients with diabetes mellitus and uncontrolled hypertension or a history of heart disease. In patients with type 2 diabetes mellitus who are overweight or have obesity, antidiabetic medications that may promote weight loss, such as GLP-1 receptor agonists or sodium-glucose- linked transporter-2 inhibitors, are suggested. Off-label use of medications approved for other conditions is not recommended for the sole purpose of weight loss. National Institute for Health and Care Excellence (NICE) Obesity: Identification, Assessment, and Management Clinical Guideline?*° NICE released recommendations for managing obesity in 2014. Areas of focus for this guideline included identification, assessment, and management of obesity. Interventions assessed included lifestyle, behavioral, physical activity, dietary, pharmacological, and surgical interventions. In terms of lifestyle interventions, multi-component ones are considered the treatment of choice, and should include behavioral change strategies that can support increased physical activity and improved eating habits. Pharmacological treatment is recommended only after dietary, exercise, and behavioral approaches have been initiated. One should consider drug treatment of interested individuals who have not reached their target weight loss. Pharmacological treatments may be continued to maintain weight loss. For those who have not reached their weight loss target, consideration should be given for stopping the drug. Since weight loss may be slower in individuals who also have type 2 diabetes mellitus, less strict goals and longer duration of therapy may be appropriate. Orlistat should only be prescribed when it is part of an overall plan for managing obesity, should not be co-prescribed with other weight loss drugs, and should not be continued beyond three months if the person has not lost at least 5% of their initial body weight. Phentermine/topiramate was not mentioned in this document, but is listed as being in development. In December 2017, NICE released recommendations for bupropion/naltrexone. It was not recommended for managing overweight and obesity in adults alongside a reduced-calorie diet and increased physical activity. In February, 2022, NICE released a draft guideline for the use of semaglutide for weight management. It is an option when given in addition to diet and activity recommendations for individuals with a BMI of at least 35 kg/m? or 30-34.9 kg/m? with other comorbid conditions that meet NICE criteria. It can be used for a maximum of two years and needs to be given by a specialist weight management service. Consideration for stopping semaglutide if less than 5% initial weight loss has been achieved after six months of maintenance therapy. ©lnstitute for Clinical and Economic Review, 2022 Page C3 Final Evidence Report - Medications for Obesity Management Return to Table of Contents D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods PICOTS Population The population of focus for the review is adults with a BMI 230 kg/m? or 227 kg/m? with at least one weight-related comorbid condition (such as hypertension, type 2 diabetes mellitus, obstructive sleep apnea, or hyperlipidemia) who are actively seeking medical management for weight loss. Data permitting, we sought to examine the following patient subgroups, including but not limited to: e BMI categories: 27-29.9, 30-34.9, 35-39.9, or greater than 40 kg/m? e Pre-diabetes or diabetes mellitus e Prior bariatric surgery Interventions The full list of interventions is as follows: e Semaglutide e = Liraglutide e Bupropion and naltrexone in combination e Phentermine and topiramate in combination Comparators We intended to compare each intervention with lifestyle modification to placebo with lifestyle modification. Data permitting, we also compared the interventions to one another. ©lnstitute for Clinical and Economic Review, 2022 Page D1 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Outcomes The outcomes of interest are described in the list below. ® Patient-Ilmportant Outcomes oO Oo 0 0 90 Quality of life and functional status Anxiety and depression Body image Long-term health outcomes such as cardiovascular disease, cancer, and mortality Weight loss (as measured by % weight loss, categorical weight loss [e.g., 5%, 10%, or 15%], BMI, etc.) Weight re-gain Adverse events including: = Side effects = Psychological harm =" Serious adverse events e Other Outcomes oO 0 0 Timing Metabolic profile, such as LDL, hemoglobin A1C, and blood pressure Weight cycling Waist circumference Progression from pre-diabetes to diabetes mellitus or pre-hypertensive to hypertensive Withdrawal or dose reduction in concomitant medications for weight-related comorbidities Subsequent surgical interventions for weight loss Discontinuation due to adverse events Evidence on intervention effectiveness was derived from studies of at least 12 weeks duration and evidence on harms from studies of any duration. Settings All relevant settings were considered, with a focus on outpatient settings in the US. ©lnstitute for Clinical and Economic Review, 2022 Page D2 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D1. PRISMA 2020 Checklist Section and Topic Item # Checklist item Reported on Page # TITLE Title [4 Identify the report as a systematic review. ABSTRACT Abstract | 2 See the PRISMA 2020 for Abstracts checklist. INTRODUCTION Rationale Describe the rationale for the review in the context of existing knowledge. Objectives Provide an explicit statement of the objective(s) or question(s) the review addresses. METHODS Eligibility Criteria Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Information Sources Specify all databases, registers, websites, organizations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted. Search Strategy Present the full search strategies for all databases, registers, and websites, including any filters and limits used. Selection Process Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process. Data Collection Process Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Data Items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect. 10b List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. Study Risk of Bias Assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. Effect Measures 12 Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results. Synthesis Methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis [item #5]). Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D3 Return to Table of Contents Section and Topic Item Checklist item Reported # on Page # Describe any methods required to prepare the data for 13b | presentation or synthesis, such as handling of missing summary statistics, or data conversions. 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Describe any methods used to synthesize results and provide a 13d rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used. Describe any methods used to explore possible causes of 13e | heterogeneity among study results (e.g. subgroup analysis, meta- regression). 13F Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Reporting Bias 14 Describe any methods used to assess risk of bias due to missing Assessment results in a synthesis (arising from reporting biases). Certainty Describe any methods used to assess certainty (or confidence) in 15 : Assessment the body of evidence for an outcome. RESULTS Describe the results of the search and selection process, from the 16a | number of records identified in the search to the number of Study Selection studies included in the review, ideally using a flow diagram. Cite studies that might appear to meet the inclusion criteria, but 16b : : which were excluded, and explain why they were excluded. suey cteristics 17 Cite each included study and present its characteristics. Risk of Bias in . . . . 18 Present assessments of risk of bias for each included study. Studies For all outcomes, present, for each study: (a) summary statistics Results of for each group (where appropriate) and (b) an effect estimates and ss . 19 . es / vn : : Individual Studies its precision (e.g., confidence/credible interval), ideally using structured tables or plots. 20a For each synthesis, briefly summarize the characteristics and risk of bias among contributing studies. Present results of all statistical syntheses conducted. If meta- analysis was done, present for each the summary estimate and its 20b | precision (e.g., confidence/credible interval) and measures of Results of tae : . . Syntheses statistical heterogeneity. If comparing groups, describe the direction of the effect. 20c Present results of all investigations of possible causes of heterogeneity among study results. 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. . : Present assessments of risk of bias due to missing results (arising Reporting Biases 21 . . . from reporting biases) for each synthesis assessed. Certainty of 22 Present assessments of certainty (or confidence) in the body of Evidence evidence for each outcome assessed. ©lnstitute for Clinical and Economic Review, 2022 Page D4 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Section and Topic Item Checklist item Reported # on Page # DISCUSSION 23a Provide a general interpretation of the results in the context of other evidence. 23b | Discuss any limitations of the evidence included in the review. 23c_ | Discuss any limitations of the review processes used. 23d_| Discuss implications of the results for practice, policy, and future research. Discussion OTHER INFORMATION Provide registration information for the review, including register 24a name and registration number, or state that the review was not registered. Indicate where the review protocol can be accessed, or state that a Registration and Protocol 24b protocol was not prepared. Jc Describe and explain any amendments to information provided at registration or in the protocol. Support 25 Describe sources of financial or non-financial support for the PP review, and the role of the funders or sponsors in the review. Competin . . pering 26 Declare any competing interests of review authors. Interests Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. From: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021;18(3):e1003583. Availability of Data, Code, and Other 27 Materials Data Sources and Searches Procedures for the systematic literature review assessing the evidence on treatments for obesity management followed established best research methods.*1432 We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.73? The PRISMA guidelines include a checklist of 27 items. 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 ©lnstitute for Clinical and Economic Review, 2022 Page DS Final Evidence Report - Medications for Obesity Management Return to Table of Contents the scope of this project. We also supplemented our review of published studies with data from conference proceedings, regulatory documents, information submitted by manufacturers, and other grey literature when the evidence met ICER standards (for more information, see https://icer.org/policy-on-inclusion-of-grey-literature-in-evidence-reviews/. Where feasible and deemed necessary, we also accepted data submitted by manufacturers "in-confidence," in accordance with ICER's published guidelines on acceptance and use of such data (https://icer.org/guidelines-on-icers-acceptance-and-use-of-in-confidence-data-from- manufacturers-of-pharmaceuticals-devices-and-other-health-interventions/). Table D2. Search Strategy of EMBASE Search Search Term #1 (| 'obesity'/exp OR 'obesity' #2 | 'body weight loss'/exp OR 'body weight loss' #3 ('obes*' OR 'body mass ind*' OR 'adiposity' OR 'overweight' OR 'over weight' OR 'anti-obesity' OR 'body- weight' OR 'body weight'):ti,ab #4 =| #1 OR #2 OR #3 #5 =| 'phentermine plus topiramate' /exp #6 (('phentermine' AND 'topiramate') OR 'phentermine plus topiramate' OR 'qysmia' OR 'qsiva' OR 'VI-0521' OR 'VI0521' OR 'V1. 0521'):ti,ab #7 =| 'amfebutamone plus naltrexone'/exp #8 ('amfebutamone plus naltrexone' OR 'contrave' OR ('amfebutamone' AND 'naltrexone') OR ('bupropion' AND 'naltrexone'} OR 'CID 11556075' OR 'CID11556075' OR 'CID-11556075'):ti,ab #9 =| 'glucagon like peptide 1 receptor agonist'/exp #10 | 'liraglutide'/exp #11 | ('liraglutide' OR 'saxenda' OR 'victoza' OR 'NN 2211' OR 'NN2211' OR 'NN-2211'):ti,ab #12 | 'semaglutide'/exp #13 | ('semaglutide' OR 'ozempic' OR 'wegovy' OR 'NN 9535' OR 'NN9535' OR 'NN-9535'):ti,ab #14 | ('phentermine' OR 'Adipex-P' OR 'Lomaira' OR 'Suprenza'):ti,ab #15 | #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 #16 | #4 AND #15 #16 NOT ('addresses' OR 'autobiography' OR 'bibliography' OR 'biography' OR 'case report' OR 'comment' OR 'congresses' OR 'consensus development conference' OR 'duplicate publication' OR 'editorial' OR #17 | 'guideline' OR 'in vitro' OR 'interview' OR 'lecture' OR 'legal cases' OR 'legislation' OR 'letter' OR 'news' OR 'newspaper article' OR 'patient education handout' OR 'periodical index' OR 'personal narratives' OR 'portraits' OR 'practice guideline' OR 'review' OR 'video audio media')/it #18 | ('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp) NOT 'human''/exp #19 | #17 NOT #18 #20 | #19 AND [English]/lim #21 | #20 NOT [medline]/lim #22 | #21 AND [01/07/2020]/sd *Search last updated on July 18, 2022. ©lnstitute for Clinical and Economic Review, 2022 Page D6 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D3. Search Strategy of Medline 1996 to Present with Daily Update and Cochrane Central Register of Controlled Trials Search Term 1 exp Obesity/ 2 exp Weight Loss/ 3 exp Overweight/ A (obes* or "body mass inde*" or adiposity or overweight or "over weight" or antiobesity or "anti-obesity" or bodyweight or "body weight").ti,ab. 5 lor2or3o0r4 6 ((phentermine and topiramate) or "phentermine topiramate" or phenterminetopiramate or qsymia or qsiva or topiramatephentermine or "phentermine-topiramate" or V10521 or "VI0521" or "VI-0521").ti,ab. 7 ((amfebutamone and naltrexone) or (bupropion and naltrexone) or contrave or "bupropion-naltrexone" or CID11556075 or "CID 11556075" or "CID-11556075").ti,ab. 8 exp Glucagon-Like Peptides/ 9 exp liraglutide/ 10 | (liraglutide or saxenda or victoza or NN2211 or "NN 2211" or "NN-2211").ti,ab. 11 | (semaglutide or ozempic or wegovy or NN9535 or "NN 9535" or "NN-9535").ti,ab. 12 | (phentermine or Adipex-P or Lomaira or Suprenza).ti,ab. 13. | 6or7or8or9or10ori1ilori12 14 | Sand 13 14 not ("address" or "autobiography" or "bibliography" or "biography" or "case reports" or "comment" or "congress" or "consensus development conference" or "duplicate publication" or "editorial" or 15 | "guideline" or "interview" or "lecture" or "legal case" or "legislation" or "letter" or "news" or "newspaper article" or "patient education handout" or "periodical index" or "personal narrative" or "portrait" or "practice guideline" or "review" or "video-audio media").pt. 16 | 15 not (animals not (humans and animals)).sh. 17 | limit 16 to english language 18 | remove duplicates from 17 19 | limit 18 to ed=20200701-20220330 *Search last updated on July 18, 2022. ©lnstitute for Clinical and Economic Review, 2022 Page D7 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Figure D1. PRISMA Flowchart Showing Results of Literature Search for Medications for Obesity Management 1,421 references identified through literature search 37 references identified through other sources v 1,408 references after duplicate removal 1,408 references screened 1,293 citations excluded 63 citations excluded 115 references assessed 13 population for eligibility in full text 19 study design 10 outcomes 21 duplicate data 51 total references 24 RCTs, 2 SLRS 37 references included in quantitative synthesis ©lnstitute for Clinical and Economic Review, 2022 Page D8 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Study Selection We performed screening at both the abstract and full-text level. A single investigator screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. One investigator reviewed full papers and provided justification for exclusion of each excluded study. Data Extraction and Quality Assessment We used criteria published by the US Preventive Services Task Force to assess the quality of randomized controlled trials and comparative cohort studies, using the categories "good," "fair," or "poor" (see Table D21).1°4 Guidance for quality ratings using these criteria is presented below, as is a description of any modifications we made to these ratings specific to the purposes of this review. Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study; reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention is paid to confounders in analysis. In addition, intention-to-treat analysis is used for randomized controlled trials. Fair: Studies were graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are addressed. Intention-to-treat analysis is done for randomized controlled trials. Poor: Studies were graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For randomized controlled trials, intention-to-treat analysis is lacking. Note that case series are not considered under this rating system - because of the lack of comparator, these are generally considered to be of poor quality. ©lnstitute for Clinical and Economic Review, 2022 Page D9 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Assessment of Level of Certainty in Evidence We used the ICER Evidence Rating Matrix to evaluate the level of certainty in the available evidence of a net health benefit among each of the interventions of focus.19>136 Assessment of Bias As part of our quality assessment, we evaluated the evidence base for the presence of potential publication bias. Given the emerging nature of the evidence base for these newer treatments, we performed an assessment of publication bias on for semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone using the ClinicalTrials.gov. We scanned the site to identify studies which would have met our inclusion criteria and for which no findings have been published and did not find any evidence of publication bias. We provided qualitative analysis of the objectives and methods of these studies to ascertain whether there may be a biased representation of study results in the published literature. Data Synthesis and Statistical Analyses The results of the studies were summarized in the evidence tables and described narratively in the body of the report. In addition, we evaluated the comparative efficacy of semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone by means of NMA, where feasible. Based on data availability, our NMA evaluated the outcomes of change in body weight and SBP, and categorical weight loss at one year. NMA Supplemental Information below contains a detailed description of the NMA methods. Due to inconsistent or limited data reporting, other outcomes were only described narratively in the body of the Report and in Section D2. Supplemental NMA Methods As described in the Report, we conducted random effect NMAs where feasible. An NMA extends pairwise meta-analyses by simultaneously combining both the direct estimates (i.e., estimates obtained from head-to-head comparisons) and indirect estimates (i.e., estimates obtained from common comparator[s]).237238 NMAs were conducted using a Bayesian framework. For continuous outcomes, the NMA model corresponds to a generalized linear model with identity link.4°° For binary outcomes (e.g., proportion of patients discontinuing due to adverse events), the NMA model corresponds to a generalized linear model with a logit link.*°° For all analyses, we included random effects on the treatment parameters, and the amount of between-study variance (i.e., heterogeneity) was assumed constant across all treatment comparisons. We used noninformative prior distributions for all model parameters. We initially discarded the first 50,000 iterations as "burn-in" and base inferences on an additional 50,000 iterations using three chains. Convergence of chains was ©lnstitute for Clinical and Economic Review, 2022 Page D10 Final Evidence Report - Medications for Obesity Management Return to Table of Contents assessed visually using trace plots. Furthermore, for any network where there were "loops" in evidence, we empirically compared the direct and indirect estimates to assess if the NMA consistency assumption is violated using a node-splitting approach.1°9 As there was no evidence of inconsistency, we present the full NMA results in the report. All analyses were conducted using the IndiRect NMA platform (CRG-EVERSANA, 2020™) or R. Supplemental NMA Results We provide three network diagrams that represents the NMAs in the report (Figures D2, D3, and D4). To interpret the network figures, note that the lines indicate the presence of a trial directly assessing the connecting interventions, with the thickness of the line corresponding to the number of trials. The location of treatments and the distances between them do not have any meaning. The medications are depicted in blue, and the trial names are depicted in orange. Figure D2. Network of Studies Included in the NMAs of Medications for Obesity, Mean Percentage Weight Loss, Change in SBP from Baseline to One Year and Categorical Weight Loss SEM + LSM P/T+LSM SCALE (Maintenance) SCALE (Obesity & Pre-Diabetes) (oa of od oo) Ea B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/ topiramate, SEM: semaglutide ©lnstitute for Clinical and Economic Review, 2022 Page D11 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Figure D3. Network of Studies Included in the NMA of Medications for the Management of Obesity with Diabetes Mellitus, Mean Percentage Weight Loss and Mean Change in SBP from Baseline to One Year SEM + LSM T2DM SCALE Mee ESL DIABETES B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/ topiramate, SEM: semaglutide ©lnstitute for Clinical and Economic Review, 2022 Page D12 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Figure D4. Network of Studies Included in the NMAs of Medications for Obesity, Discontinuation Due to Adverse Events SEM + LSM P/T+LSM EQUIP EQUATE LS COR-| (Maintenance) COR-II ale COR-BMOD (Obesity & Pre-Diabetes) SYS: Col of OE = D> B/N +LSM B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/ topiramate, SEM: semaglutide Results of Categorical Weight Loss We conducted NMAs of trials including participants with obesity alone separately from trials of participants with obesity and diabetes, and excluded trials that included IBT as an adjunct to medication. Categorical weight loss NMAs (proportion of patients achieving at least 5% or 10% weight loss) are reported below. Participants with Obesity Alone For the trials of the medications conducted in participants with obesity without diabetes that included standard diet and exercise counseling and reported proportion of patients who achieved at least 5% or 10% weight loss at one year, we present the results of the baseline risk-adjusted random effects model, given its better fit for the model compared to the unadjusted model in Tables D4 and D5. All medications, in combination with diet and exercise counseling, showed statistically significantly greater odds of achieving at least 5% weight loss at one year. Compared to ©lnstitute for Clinical and Economic Review, 2022 Page D13 Final Evidence Report - Medications for Obesity Management Return to Table of Contents placebo, the interventions demonstrated 4.3-17.3 times the odds of 5% weight loss and 3.6-22.4 times the odds of 10% weight loss. Semaglutide demonstrated the greatest odds of achieving 5% and 10% weight loss at one year and was superior to all other medications in our review for this outcome. Phentermine/topiramate (high dose) demonstrated greater odds than liraglutide and bupropion/naltrexone, however this difference was not statistically significant for the outcome of 5% weight loss. Liraglutide was not statistically more effective in demonstrating at least 5% or 10% weight loss than bupropion/naltrexone (Tables D4 and D5). Table D4. NMA Results of Medications for the Management of Obesity, Odds Ratio of Likelihood of Achieving at Least 5% Weight Loss at One Year (95% Cl) Semaglutide 2.0 (0.5 to 10.0) dats e-leu lity A Topiramate* Bupropion/ Naltrexone 4.0 (2.4 to 8.0) 2.0 (0.6 to 7.1) Liraglutide 4.0 (1.01 to 20.6) 2.0 (0.9 to 4.4) 1.0 (0.3 to 3.4) 17.3 (8.9 to 38.3) 8.6 (3.3 to 22.0) 4.3 (2.5 to 6.7) 4.3 (1.7 to 10.2) Legend: Each box represents estimated odds ratio of achieving 5% weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. Table DS. NMA Results of Medications for the Management of Obesity, Odds Ratio of Likelihood of Achieving at Least 10% Weight Loss at One Year (95% Cl) Semaglutide 2.6 (0.95 to 6.2) 5.3 (3.5 to 9.6) Phentermine/ eye) Teele 2.1 (1.04 to 5.6) 6.3 (2.4 to 15.9) 2.5 (1.2 to 5.3) Liraglutide 1.2 (0.5 to 2.4) Bupropion/ Naltrexone 22.4 (13.6 to 36.2) 8.8 (4.7 to 18.1) 4.2 (2.6 to 5.7) 3.6 (2.0 to 6.8) Placebo Legend: Each box represents estimated odds ratio of achieving 10% weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. *High dose. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D14 Return to Table of Contents Participants with Obesity and Diabetes Mellitus For the trials of the medications conducted in participants with obesity and diabetes mellitus that included standard diet and exercise counseling and reported proportion of patients who achieved at least 5% or 10% weight loss at one year, we present the results of the unadjusted random effects model, given its better fit for the model compared to the baseline-adjusted model in Tables D6 and D7. Data on categorical weight loss in patients with diabetes mellitus was not available for phentermine/topiramate and was therefore not included in the NMA. All medications, in combination with diet and exercise counseling, showed greater odds of achieving at least 5% or 10% weight loss at one year, however, this difference was only statistically significant for liraglutide for the 5% weight loss outcome and semaglutide and liraglutide for the 10% weight loss outcome. Compared to placebo, the interventions demonstrated 2.2-2.7 times the odds of 5% weight loss and 3.3-6.1 times the odds of 10% weight loss. Semaglutide demonstrated the greatest odds of achieving 5% or 10% weight loss at one year, followed by liraglutide. Table D6. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus, Odds Ratio of Likelihood of Achieving at Least 5% Weight Loss at One Year (95% Cl) Semaglutide 1.2 (0.4 to 2.9) Liraglutide Bupropion/ 1.2 (0.4 to 4.8) 1.1 (0.4 to 4.2) einen 2.7 (0.9 to 4.1) 2.4 (1.0 to 3.6) 2.2 (0.6 to 3.9) Legend: Each box represents estimated odds ratio of achieving 5% weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. Table D7. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus, Odds Ratio of Likelihood of Achieving at Least 10% Weight Loss at One Year (95% Cl) Semaglutide 1.6 (0.3 to 6.8) Liraglutide Bupropion/ 1.8 (0.3 to 12.2) 1.1 (0.2 to 8.1) nee 6.1 (1.3 to 12.8) 3.7 (1.1 to 8.9) 3.3 (0.5 to 10.8) Placebo Each box represents estimated odds ratio of achieving 10% weight loss and 95% credible interval for the combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold indicate the 95% credible interval does not contain 1. ©lnstitute for Clinical and Economic Review, 2022 Page D15 Final Evidence Report - Medications for Obesity Management Return to Table of Contents D2. Additional Clinical Evidence Evidence Base Semaglutide versus Placebo The Report discusses the primary sources of data to inform our review of semaglutide for the management of obesity with and without diabetes mellitus: STEP 1, STEP 2, STEP 3, STEP 5, and STEP 8 trials. STEP 4 and STEP 6 are two additional trials from the STEP clinical trial program that were not included in the Report due to study design (STEP 4) and differences in population (STEP 6). Both studies were multi-center Phase III studies and evaluated subcutaneous semaglutide 2.4 mg plus lifestyle intervention versus placebo plus lifestyle intervention." STEP 6 also evaluated subcutaneous semaglutide 1.7 mg, but we only reviewed evidence for the subcutaneous semaglutide 2.4 mg arm as that is the approved dose for obesity treatment. STEP 4 reported data regarding weight regain, in addition to other outcomes of interest. Participants included in this trial were adults with BMI 230 kg/m? or 227 kg/m? with at least one weight-related comorbid condition.°" Participants with diabetes mellitus (HbA1C 26.5%) were excluded. The study design included a 20-week run-in period with all participants receiving a dose escalation of subcutaneous semaglutide starting at 0.25 mg and increased every four weeks to the maintenance dose of 2.4 mg at week 16. At week 20, subjects were randomized to either continue semaglutide 2.4 mg or switch to placebo. Due to the withdrawal study design, baseline weight for these participants was different compared to the STEP trials included in the main review. The baseline weight and BMI for all participants prior to the run-in period was 107.2 kg and 38.4 kg/m. At randomization (week 20) baseline weight was 96.5 kg in the semaglutide arm versus 95.4 kg in the placebo arm and baseline BMI was 34.5 kg/m? in the semaglutide arm versus 34.1 kg/m? in the placebo arm (Table D8). STEP 6 was conducted in Japan and South Korea, with 100% of their participants of Asian ethnicity.42 Baseline BMI, body weight, and waist circumference of participants in the STEP 6 trial were lower than that of the other STEP trials. Additionally, due to differences in guidelines, the inclusion criteria were slightly different with STEP 6 requiring eligible participants to be adults aged 218 in South Korea and 220 in Japan with a BMI of at least 27 kg/m? with two or more treated or untreated weight-related comorbidities, or a BMI of at least 35 kg/m? with one or more treated or untreated weight-related comorbidities, according to the Japan Society for the Study of Obesity (JASSO) guidelines. STEP 6 did not exclude individuals with diabetes mellitus, and at baseline, 25% of participants in each arm had diabetes mellitus. Outcomes were assessed at week 68 for both STEP 4 and STEP 6. Baseline characteristics are outlined in Table D8. ©lnstitute for Clinical and Economic Review, 2022 Page D16 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Liraglutide versus Placebo The Report discusses the primary sources of data to inform our review of semaglutide for the management of obesity with and without diabetes mellitus: the SCALE clinical trial program (Maintenance, Obesity & Pre-Diabetes, Sleep Apnea, Type 2 DM, Insulin, and IBT) trials. LOSEIT was a single-center Phase III trial based at the Parker Institute in Denmark, which evaluated subcutaneous liraglutide 3.0 mg plus lifestyle intervention versus placebo plus lifestyle intervention.' Participants included in this trial were adults aged 18 to 74 with BMI 227 kg/m? with symptomatic knee osteoarthritis and were excluded if they were currently using medications for weight loss or gain, participating in an ongoing weight loss program, or on radiography for end- stage knee osteoarthritis. Prior to randomization, participants engaged in a dietary intervention period for eight weeks and were randomized to liraglutide or placebo if they had achieved at least 5% weight-loss during that eight-week period. Baseline characteristics for BMI, weight, and waist circumference were lower for participants in LOSEIT than those included in the main review. Primary outcomes for this trial were also slightly different from those included in the main review, with absolute changes in body weight and Knee Injury and Osteoarthritis Outcome Score (KOOS) as the co-primary outcomes. The study captured categorical weight loss (25% and 210%) as well as change in BMI and waist circumference. Outcomes were assessed at week 52. Baseline characteristics are outlined in Table D8. Table D8. Overview of Additional Trials of Semaglutide and Liraglutide for the Management of Obesity!°*43 STEP 4 STEP 6 LOSEIT Study Arms Run-in PBO* SEM* PBO SEM PBO LIR N 803 268 535 101 199 76 80 Low-calorie run-in with weekly counseling then reduced-calorie diet, and bi- weekly counseling for 8 Monthly counseling, reduced-calorie diet, and increased physical activity Monthly counseling, reduced- calorie diet, and increased physical activity Lifestyle Intervention weeks Mean Age, Years 46 46 47 50 52 59.3 59.2 Female Gender, % 79 76.5 80.2 25.7 42.7 64 65 Baseline Weight, kg 107.2 95.4 96.5 90.2 86.9 90.8 96.3 Baseline Weight Loss, % | -10.6t N/A N/A N/A N/A N/A N/A Baseline BMI, kg/m? 38.4 34.1 34.5 31.9 32 31.3 32.8 Race, White, % 83.7 84.3 83.4 0 0 NR NR Pre-Diabetes, % NR NR NR 25 22 NR NR kg: kilogram, LIR: liraglutide, m: meter, N/A: not applicable, N: total number, NR: not reported, PBO: placebo, SEM: semaglutide *Baseline data measured at Week 20. tChange from baseline data measured at Week 20. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D17 Return to Table of Contents Phentermine/Topiramate versus Placebo The Report discusses the primary source of data to inform our review of phentermine/topiramate for the management of obesity: the EQUIP and EQUATE trials. OB-204 was a single-center, double- blind, parallel-group, placebo-controlled, Phase I/II trial that randomized adults with overweight or obesity and moderate-to-severe obstructive sleep apnea syndrome to receive phentermine 15 mg/topiramate 92 mg (n=22), or placebo (n=23) (Table D9). All participants in each treatment group also received standardized lifestyle modification counseling. Participants were eligible to participate if they were between the ages of 30-65 years, had a BMI of 30-40 kg/m, a diagnosis of moderate-to-severe obstructive sleep apnea syndrome, an apnea-hypopnea index 215, and were unable to comply with CPAP treatment. Participants were excluded if they had a sleep disorder other than obstructive sleep apnea syndrome, unstable angina or heart failure, history of myocardial infarction, coronary revascularization, cholecystitis or cholelithiasis, glaucoma, or seizures, used any prescription central nervous system stimulant, experienced a weight change >5 kg, had previous surgery for obesity, had a psychiatric disorder, or were pregnant or breastfeeding. Participants in the OB-204 trial had a mean age of 52 years, and 47% were female. The majority (91%) of participants were White and 9% were Black. The average weight of participants in this trial was 105 kg and mean BMI was 36 kg/m at baseline. See Table D9 for detailed baseline characteristics. Bupropion/Naltrexone versus Placebo The Report discusses the primary sources of data to inform our review of bupropion/naltrexone for the management of obesity: COR-I, COR-II and COR-BMOD. CVOT Light was a multi-center, Phase IIIb trial that randomized participants with overweight or obesity at an increased risk of adverse cardiovascular outcomes to receive bupropion 360 mg/naltrexone 32 mg or placebo.!*1*° All participants in each treatment arm were also encouraged to participate in an Internet-based weight management program that included resources on healthy eating such as a low-calorie mean plan, exercise, behavioral modifications, weekly lessons, and access to a personal coach. Participants were eligible to participate if they were women over 50 years old, or men over 45 years old, had a BMI of 27-50 kg/m, a waist circumference of >88 cm for women or 2102 cm for men, and demonstrated an increased risk of adverse cardiovascular outcomes, such as confirmed or high likelihood of cardiovascular disease, or had type 2 diabetes mellitus and at least two of the following: hypertension, dyslipidemia requiring pharmacotherapy, low high-density lipoprotein cholesterol, or were currently smoking tobacco. Participants were excluded if they had a myocardial infarction within four months, severe angina pectoris, NYHA class III or IV heart failure, history of stoke or SBP 2145 mmHg or diastolic blood pressure 295 mmHg, weight change >3% within three months, had surgery for obesity, or history of seizures, mania, psychosis, bulimia, or anorexia nervosa. Participants in CVOT Light had a mean age of 61 years, and 55% were female. ©lnstitute for Clinical and Economic Review, 2022 Page D18 Final Evidence Report - Medications for Obesity Management Return to Table of Contents The majority (84%) of participants were White and 15% were Black. The average weight of participants in this trial was 106 kg and mean BMI was 37 kg/m' at baseline (Table D9). Ignite was a multi-center, open-label, Phase Illb trial that randomized participants for the first 26 weeks to receive bupropion 360 mg/naltrexone 32 mg or usual care.**" Participants in the treatment arm were additionally required to participate in a comprehensive lifestyle intervention, which consisted of a progressive nutrition and exercise program with personalized goal-setting and tracking tools with a coach or dietitian, while participants in the usual care arm were instructed to follow an exercise prescription and a hypocaloric diet. From 26 weeks through 78 weeks, participants in the bupropion/naltrexone group continued on the medication, while participants in usual care arm were switched to bupropion/naltrexone in addition to the comprehensive lifestyle intervention. For the purposes of our review, we are evaluating efficacy data only up to 26 weeks because of the lack of comparative data beyond that timepoint. Participants were eligible to participate if they were between the ages of 18-60 years, had either a BMI of 30-45 kg/m? or a BMI 27-45 kg/m? with dyslipidemia and/or controlled hypertension. Participants were excluded if they had type 1 or type 2 diabetes mellitus, myocardial infarction within six months, angina pectoris grade III/IV, history of strokes, seizures, bulimia, anorexia nervosa, had surgery for obesity, or had a psychiatric illness including mania, psychosis, or depression. Participants in this trial had a mean age of 47 years and were predominantly female (84%). The majority (76%) of participants were White and 23% were Black. The average weight of participants in this trial was 101 kg and mean BMI was 36 kg/m at baseline. See Table D9 for detailed baseline characteristics. ©lnstitute for Clinical and Economic Review, 2022 Page D19 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D9. Overview of Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity"? OB-204 CVOT Light Ignite Study Arms | PBO P/T (high) PBO B/N PBO B/N N 23 22 4,450 4,455 89 153 LSM counseling, LSM counseling, LSM counseling, cul with Progressive A . . reduced-calorie nutrition and an Lifestyle reduced-calorie diet, reduced-calorie diet, : : . . . . . diet, and exercise program, Intervention | and increased physical and increased physical . . : - - increased physical | and personalized activity activity +e . activity goal-setting Mean Age, | 514 53.4 60.9 61.1 47 46.1 Years Female Gender, % 34.8 59.1 54.4 54.7 86.5 81.7 Baseline Weight, ke 106.9 103.7 106.3 105.6 100.2 101.4 Baseline BMI, ke/m2 35.3 36 37.4 37.2 36.3 36.3 Race, White, % 91.3 90.9 83.1 83.9 71.9 81 Pre- Diabetes, % NR NR NR NR NR NR B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, kg: kilogram, LSM: lifestyle modification, m: meter, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate Results For each medication, secondary outcomes from trials in the Report are summarized first, followed by primary outcomes for the additional trials summarized in the supplement. Weight loss outcomes are summarized first, followed by other outcomes (e.g., waist circumference, blood glucose, and LDL cholesterol), where relevant. HRQoL is summarized for all drugs at the end of this section. For each medication, results of trials conducted in patients with obesity are presented first, followed by trials conducted in patients with obesity and diabetes mellitus. Semaglutide versus Placebo The efficacy of semaglutide compared with placebo for the management of obesity in patients without diabetes mellitus was evaluated in three Phase III trials (STEP 1, 3, and 5). We were able to obtain percent weight loss at six months through digitizing published graphical data. Participants in the subcutaneous semaglutide 2.4 mg arm achieved greater percent weight loss at six months (-11.7%, -15.4%, and -13.2% respectively) compared to placebo (-2.9%, -7.9%, and -2.6%, respectively).223235-39.143 Similarly, at one year, the proportion of participants who achieved at least 15% weight loss and at least 20% weight loss, a greater proportion of participants in the semaglutide arm achieved these categorical outcomes compared to participants in the placebo. Treatment with semaglutide in STEP 1, 3, and 5 trials also resulted in additional clinical benefits in ©lnstitute for Clinical and Economic Review, 2022 Page D20 Final Evidence Report - Medications for Obesity Management Return to Table of Contents waist circumference, blood glucose, and LDL cholesterol compared to placebo. Outcomes related to changes in LDL were reported as absolute change from baseline for STEP 3 and as ratio of LDL from baseline for STEP 1 and 5. See Table D10 for detailed results. Additionally, in an extension trial of STEP 1, participants went off semaglutide treatment at week 68 and were evaluated through the end of the trial at week 120. At that timepoint, participants who were initially taking semaglutide, but went off-treatment, regained 14.8% of their weight from week 68, and participants who were initially on placebo regained 2.1% of their weight." In the initial semaglutide arm, nearly two-thirds of the weight participants lost from baseline was regained in about a year. Similarly, metabolic parameters, such as blood pressure and HbA1C, returned to baseline values at the end of the trial. See Tables D26-D29 for detailed results. The efficacy of semaglutide for the management of obesity and type 2 diabetes mellitus was evaluated through one Phase Ill trial (STEP 2). We were able to obtain percent weight loss at six months through digitizing published graphical data. Participants in the subcutaneous semaglutide 2.4 mg arm achieved greater percent weight loss at six months (-8.7%) compared to placebo (-2.7%) (Table D12).2° Similarly, at one year, the proportion of participants who achieved at least 15% weight loss and at least 20% weight loss, a greater proportion of participants in the semaglutide arm ([15% WL: 25.8%]; [20% WL: 13.1%]) achieved these categorical outcomes compared to participants in the placebo arm ([15% WL: 3.2%]; [20% WL: 1.6%]). Treatment with subcutaneous semaglutide 2.4 mg was also associated with greater improvements in waist circumference (-9.4 cm) compared to placebo (-4.5 cm). There were no clinical differences between the subcutaneous semaglutide 2.4 mg arm and placebo arm in blood glucose and LDL cholesterol. STEP 4, which had a crossover design including a 20-week run-in semaglutide dose escalation prior to randomization to either continue subcutaneous semaglutide 2.4 mg or switch to placebo, assessed the efficacy of semaglutide compared with placebo for the management of obesity.140-144 Prior to randomization, all participants achieved a mean weight loss of -10.6% in the 20-week run-in period. After randomization, at one year, participants in the subcutaneous semaglutide 2.4 mg arm achieved additional weight loss (-7.9%) compared to participants in the placebo arm who experienced weight regain (6.9%). More participants who switched to placebo experienced weight regain (81.2%) compared to those who continued on semaglutide (12.3%). Overall percent weight loss at one year from week 0 (including semaglutide run-in) was -17.8% in the semaglutide arm compared to -5.4% in the placebo arm. For the co-primary outcomes of proportion of participants who achieved at least 5%, 10%, 15%, or 20% weight loss at one year, a greater proportion of participants in the semaglutide arm (88.7%, 79%, 63.7%, and 39.6%, respectively) achieved each categorical outcome compared to participants in the placebo arm (47.6%, 20.4%, 9.2%, and 4.8%, respectively). These categorical outcome data are digitized from published graphical data. See Table D13 for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page D21 Final Evidence Report - Medications for Obesity Management Return to Table of Contents STEP 6 evaluated the efficacy of semaglutide compared with placebo for the management of obesity in patients with or without diabetes mellitus. Participants in the subcutaneous semaglutide 2.4 mg arm achieved greater percent weight loss at one year (-13.2%) compared to placebo (-2.1%) (Table D13).*42 Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5%, 10%, 15%, or 20% weight loss at one year, a greater proportion of participants in the semaglutide arm (83%, 61%, 41%, and 20%, respectively) achieved each categorical outcome compared to participants in the placebo arm (21%, 5%, 3%, and 2%, respectively). Semaglutide versus Liraglutide The efficacy of subcutaneous semaglutide versus subcutaneous liraglutide with a placebo comparator for the management of obesity was evaluated in one Phase III trial (STEP 8).33 We were able to obtain percent weight loss at six months for the semaglutide and liraglutide arms by digitizing published graphical data. Data on weight loss at six months were not available for the placebo arm. Participants in the semaglutide arm achieved greater percent weight loss at six months ({-13.3%) compared to participants in the liraglutide arm {-6.8%). Treatment with semaglutide also resulted in additional clinical benefits in waist circumference, blood glucose, and LDL cholesterol compared to both liraglutide and placebo. Treatment with liraglutide resulted in additional clinical benefits in waist circumference and blood glucose compared to placebo; however, participants in the liraglutide arm experienced an increase in LDL cholesterol from baseline (0.9 mg/dL) compared to semaglutide (-6.5 mg/dL) and placebo (-1.1 mg/dL), which both had reduced LDL cholesterol from baseline. See Table D10 for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page D22 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D10. Secondary Outcomes of Key Trials of Semaglutide for the Management of Obesity223233-39 STEP 1 STEP 3 STEP 5 STEP 8 Study Arms PBO. | SEM |PBO |SEM |PBO | SEM PBO. | SEM | LIR N 577. | 4,212 | 189 | 373 129 149 78 4i7.-*«(| 117 eee ee ror 29% | arm |-79 | -154* |-26 | -132 |. -13,3* | -6.8* , t t Mean (SE) (0.2) | (0.2) | (0.5)t | (0.3)t =| (NR) | (NR) (NR) | (NR) Participants with 15% | 28 612. | 25 208 7154) | 7 sia) | © 14 Weight loss, n (%) (4.9) | (50.5) | (13.2) | (55.8) "I | (52.3) ") | 55.6) | (12) Participants with 20% 10 388 7 133 52 45 Weight loss, n (%) (2.7) | (32) 1 (3.7) | (35.7) | 323) | (aa.9y | 242-9) | aa.sy | 7 © Change in Waist 41 |-135 |-63 |-146 | -4.5 143 | -2 -13.2 | -6.6 Circumference, cm, Mean (SE) Change in Fasting Blood Glucose, mg/dL, (NR) (NR) (NR) | (NR) (0.6)t | (0.8)+ (1.1)t | (0.9)t | (0.9)t -0.5 -8.4 -0.7 -6.7 1.6§ -7.6§ 3.3 -8.3 -4.3 (NR) (NR) (NR) (NR) (NR) (NR) (1.4)t | (1.2)t | (1.2)t Mean (SE) crane init g/dl 1.1*# | -3.3*¢ | 2.6* | -4.7 -1.14 | -7.8+¢ -11* | -6.5* | 0.9% ' ' t t t Mean (SD) (NR) (NR) (NR) | (NR) (NR) (NR) (5.6) (3.1) (2.8) cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error, SEM: semaglutide *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. #Change in LDL cholesterol was calculated using ratio of LDL and respective baseline LDL. §Timepoint for this outcome is at Week 104. Liraglutide versus Placebo The efficacy of liraglutide compared with placebo for the management of obesity was evaluated in four Phase Ill trials in the SCALE clinical trial program (Maintenance, Sleep Apnea, Obesity & Pre- Diabetes, IBT). We were able to obtain percent weight loss at six months by digitizing published graphical data. Participants in the liraglutide arms achieved greater percent weight loss at six months (-7.7%, -5.7%, -8.2%, and -8.4%) compared to participants in the placebo arm (-1%, -1.6%, - 2.9%, and -5.4%).414244,454952 Data for the co-primary outcome of proportion of participants who achieved at least 15% weight loss at one year were only available for SCALE (IBT), in which a greater proportion of participants in the liraglutide arm (18.1%) achieved the outcome compared to the placebo arm (8.9%). Treatment with liraglutide resulted in additional benefits in waist circumference and blood glucose compared to placebo. Treatment with liraglutide resulted in additional benefits in LDL cholesterol in the Obesity & Pre-Diabetes (-3 mg/dL) and IBT (-1.5 mg/dL) trials compared to placebo (-1 mg/dL and 1.5 mg/dL, respectively). In the Maintenance trial, participants in both the liraglutide and placebo arms experienced an increase in LDL cholesterol from baseline (7.7 mg/dL and 11.6 mg/dL, respectively), although there was a greater increase in ©lnstitute for Clinical and Economic Review, 2022 Page D23 Final Evidence Report - Medications for Obesity Management Return to Table of Contents the placebo arm. Data on LDL cholesterol were not available for the Sleep Apnea trial. See Table D11 for detailed results. The efficacy of subcutaneous liraglutide 3.0 mg compared with placebo for the management of obesity with diabetes mellitus was evaluated in two Phase III trials in the SCALE clinical trial program (Type 2 Diabetes, Insulin).*24®°3 We were able to obtain percent weight loss at six months through digitizing published graphical data. Participants in the liraglutide arms achieved greater percent weight loss at six months (-6% and -6.4%, respectively) compared to participants in the placebo arm (-2.7% and -2.1%, respectively) (Table D12). Categorical data for proportion of participants who achieved at least 15% weight loss at one year were not available for either study. Treatment with liraglutide resulted in additional benefits in waist circumference and blood glucose compared to placebo. In the Type 2 Diabetes trial, participants in both the liraglutide and placebo arms experienced an increase in LDL cholesterol from baseline (0.6 mg/dL and 5 mg/dL, respectively). Participants receiving liraglutide in the Insulin trial improved in LDL cholesterol from baseline (-2.8 mg/dL) compared to participants in the placebo arm, who experienced an increase in LDL cholesterol (0.9 mg/dL). LOSEIT evaluated the efficacy of liraglutide compared with placebo for the management of obesity in patients with or without diabetes mellitus. Data for percent weight loss at one year were not available. For the co-primary outcomes of proportion of participants who achieved at least 5% weight loss and at least 10% weight loss at one year, a great proportion of participants in the liraglutide arm achieved each categorical outcome (35% and 21.3%, respectively) compared to participants in the placebo arm (17.1% and 9.6%, respectively).'43 See Table D13 for detailed results. ©lnstitute for Clinical and Economic Review, 2022 Page D24 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D11. Secondary Outcomes of Key Trials of Liraglutide for the Management of Obesity"14244.45.49-52 SCALE SCALE SCALE Obesity & Maintenance Sleep Apneat Pre-Diabetes SCALE IBT Study Arms PBO LIR PBO LIR PBO LIR PBO LIR N 206 207 178 175 1,225 2,437 130 141 m ween ness from | 0s) | 27" | 16 57 29 |-82 |-5.4* | -8.4* Months, Mean (SE) (0.5) (0.3) (0.4) (0.3) (0.2) (0.5) (0.6) Participants with 26 15% Weight loss, n NR NR NR NR NR NR 12 (8.9) (18.1) (%) Cen ee at 1.2 AT 3.1 6.4 39 8.2 6.7 9.4 a t t + + Mean (SE) (0.4) (0.5) (0.5) (0.5) (0.2) (0.1) (NR) (NR) Change in Fasting -3.6 -9.0 -3.6 0.1 -7.1 -4.1 Blood Glucose, 3.6 (1.8) 0.2 (NR) .9)t .8)t . .3)t .2)t mg/dL, Mean (SE) (0.9) (0.8) (1.8) (0.3) (0.2) (NR) Change in LDL Cholesterol, mg/dl, (ae) . 6 , [NR NR -1(NR) | -3(NR) | 1.5 (NR) (NR) Mean (SD) , , cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. 4Timepoint for all outcomes except percent weight loss is at week 32. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D25 Return to Table of Contents Table D12. Secondary Outcomes of Key Trials of Semaglutide and Liraglutide for the Management of Obesity with Diabetes Mellitus?°4*4653 SCALE SCALE STEP 2 Type 2 Diabetes Insulin Study Arms PBO SEM PBO LIR PBO LIR N 376 388 211 412 193 191 % Weight Loss from 34% Baseline to 6 Months, -2.7* (0.2) -8.7* (0.3) -2.7* (0.3)+ | -6* (0.3)F , -6.4* (0.4) (0.4) Mean (SE) Participants with 15% Weight loss, n (%) 12 (3.2) 100 (25.8) NR NR NR NR Participants with 20% Weight loss, n (%) 6 (1.6) 51 (13.1) NR NR NR NR Change in Waist Circumference, cm, -4.5 (0.4) -9.4 (0.4) -2.7(0.4)¢ | -6.1(0.3)# | -2.6(NR) | -5.3 (NR) Mean (SE) Change in Fasting Blood 415 Glucose, mg/dL, Mean -0.1 (1.8) -2.1 (1.8) -0.2 (2.5)+ | -34.3 (1.9)¢ (NR) -18.4 (NR) (SE) Change in LDL 0.9% 2.8% Cholesterol, mg/dL, O* (NR)T O* (NR)T 5 (NR) 0.6* (NR) ° . (NR)t (NR)t Mean (SD) cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, mg: milligram, n: *The number of patients for this outcome may differ from the primary analysis population. tChange in LDL cholesterol was calculated using ratio of LDL and respective baseline LDL. +SE manually derived from standard deviation or 95% Cls. number, N: total number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error, SEM: semaglutide Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D26 Return to Table of Contents Table D13. Results of Additional Trials of Semaglutide and Liraglutide for the Management of Obesity*"°1 STEP 4 STEP 6 LOSEIT Study Arms PBO SEM PBO SEM PBO LIR N 250 520 100 193 76 80 % Weight Loss from 6.9*+ Baseline to One Year, Mean : -7.9*¥ (4)t | -2.1 (0.8) | -13.2 (0.5) | NR NR (0.5)t (SE) Participants with at Least 119§ 5% Weight Loss, n (%) (47.6) 4618 (88.7) | 21 (21) 160 (83) 13 (17.1) 28 (35) Participants with at Least 51§ 10% Weight Loss, n (%) (20.4) 4118 (79) 5 (5) 117 (61) 7 (9.6) 17 (21.3) Participants with at Least 15% Weight Loss, n (%) 23§ (9.2) | 331§ (63.7) | 3 (3) 79 (41) NR NR Participants with at Least 20% Weight Loss, n (%) 12§ (4.8) | 206§ (39.6) | 2 (2) 38 (20) NR NR LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo, SEM: semaglutide *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. +#Timepoint for this outcome is Weeks 20-68. §Timepoint for this outcome is Weeks 0-68. Phentermine/Topiramate versus Placebo The Report discusses the primary outcome of percentage weight loss at one year and proportion of participants achieving 5% and 10% weight loss in the EQUIP trial. In the EQUIP trial, data on weight loss at six months were not available. For the categorical outcome of at least 15% weight loss at one year, more participants in the phentermine 15 mg/topiramate 92 mg arm achieved this outcome (32%) compared to those in placebo (3%)°>>* (Table D14). In EQUATE, at six months, participants in the high-dose phentermine/topiramate arm experienced the greatest percent weight loss from baseline (-9.2%), followed by the low-dose intervention arm (-8.5%), and placebo (-1.7%). Categorical weight loss of at least 15% at one year was not assessed in the EQUATE trial. Treatment with phentermine/topiramate in both EQUIP and EQUATE was associated with additional clinical benefits in terms of reductions in waist circumference, blood glucose, and LDL cholesterol at one year. In the EQUIP trial, mean reduction in waist circumference was greater in the treatment arm than placebo (-10.9 cm vs. -3.1cm, respectively).>>53 Mean reduction in waist circumference in the high-dose and low-dose intervention arms in EQUATE was also greater than placebo (-8.7 cm and -8.8 cm, versus -3.1cm, respectively). In the EQUIP trial, participants receiving phentermine/topiramate experienced a small improvement in their blood glucose levels (-0.6 mg/dL), while participants receiving placebo experienced a slight elevation in blood glucose on average (1.9 mg/dL). Participants in both arms improved LDL cholesterol levels, but the effect was greater in the phentermine/topiramate arm (-8.4 vs. -5.5 mg/dL, respectively). In the EQUATE trial, ©lnstitute for Clinical and Economic Review, 2022 Page D27 Final Evidence Report - Medications for Obesity Management Return to Table of Contents mean change from baseline in blood glucose levels in both arms was negligible (-1 to 0 mg/dL change). See Table D14 for detailed results. In the diabetes mellitus subgroup of the CONQUER trial, data on secondary outcomes such as weight loss at six months, categorical weight loss of at least 15%, and change in waist circumference were not available. All reported outcomes here are from the one-year timepoint. Participants in the diabetes subgroup receiving high-dose and low-dose phentermine/topiramate experienced a greater improvement in their blood glucose levels than participants in the placebo group (-12.6 and -9 vs. -5.4 mg/dL, respectively).>*°° Similar trends were observed for LDL cholesterol; high and low- dose phentermine/topiramate was associated with greater improvements in LDL compared to placebo (-2.8 and -3.6 vs. -2.3 mg/dL, respectively). See Table D15 for detailed results. In the Phase I/II OB-204 trial, efficacy outcomes were assessed at 28 weeks. At that timepoint, participants in the phentermine/topiramate arm achieved a greater percent weight loss (-10.3%) compared to participants in the placebo arm (-4.2%).14 Similarly, more participants receiving the intervention achieved target weight loss of at least 5% and 10% body weight than participants receiving placebo. See Table D16 for detailed results. Bupropion/Naltrexone versus Placebo Weight loss data at six months were not available in the COR-I trial. In COR-II and COR-BMOD, participants in the bupropion/naltrexone arms experienced greater weight loss than participants in the placebo arms at six months (-6.5% and -9.4% vs. -1.9% and -5.6%, respectively) (Table D14). Similarly, for all three trials, more participants in the treatment arms achieved at least 15% bodyweight at one year compared to the placebo arms.***" At the one-year timepoint, participants receiving bupropion/naltrexone in the COR-I, COR-II, and COR-BMOD trials experienced greater improvement in waist circumference (-6.2, -6.7, and -10 cm, respectively) than participants receiving placebo (-2.5, -2.1, and -6.8, respectively).®**" Similarly, participants receiving bupropion/naltrexone achieved greater improvements in blood glucose levels (-3.2, -2.8, and -2.4 mg/dL) versus placebo (-1.3, -1.3, and -1.1, respectively). In COR-I and COR-II, participants in the intervention arms experienced a greater improvement from baseline in their LDL cholesterol (-4.4 and -6.2 mg/dL, respectively), compared to placebo (-3.3 and -2.1 mg/dL, respectively). However, in the COR-BMOD trial, both arms experienced an increase in their LDL cholesterol, with participants in the placebo arm experiencing a greater increase (8.1 mg/dL) than participants in the bupropion/naltrexone arm (5.4 mg/dL). See Table D14 for detailed results. In the COR Diabetes trial of bupropion/naltrexone for the management of obesity with diabetes mellitus, participants in the intervention arm experienced a greater percent change in their weight at six months (-5.1%) compared to those in the placebo arm (-2%).°°*! Categorical weight loss of at least 15% at one year was not available in this trial. At the one-year timepoint, participants in the ©lnstitute for Clinical and Economic Review, 2022 Page D28 Final Evidence Report - Medications for Obesity Management Return to Table of Contents treatment arm experienced greater improvements in waist circumference compared to placebo (-5 cm vs. -2.9 cm, respectively), change in blood glucose (-11.9 mg/dL vs. -4 mg/dL, respectively) and change in LDL cholesterol (-1.4 mg/dL vs. O mg/dL, respectively). See Table D15 for detailed results. In CVOT Light, participants in the bupropion 360 mg/naltrexone 32 mg arm achieved greater weight loss at one year (-4.6%) than participants in the placebo arm (-1.8%) (Table D16).1*°"" The categorical weight loss outcomes of at least 5% and 10% were not assessed in this trial. In the Ignite trial, since all participants were either switched or continued on open-label bupropion/naltrexone treatment at 26 weeks, we evaluated efficacy outcomes only up to that timepoint.44749 Similar to CVOT Light, participants in the intervention arm achieved a greater weight improvement at week 26 (-9.5%) compared to participants in the usual care arm (-0.9%). For the endpoint of proportion of participants who lost at least 5% of and 10% of their weight, more participants in the bupropion/naltrexone treatment arm achieved these outcomes compared to participants in the usual care group. See Table D16 for detailed results. Table D14. Secondary Outcomes of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity°>5*62-6786 EQUIP EQUATE COR-I COR-II COR BMOD P/T P/T | P/T Study Arms PBO | thigh) |PBO | tlow) | (high) | PB |8/N | PBO | B/N | PBO | B/N N 4938. | 493 |103 | 103 |103 |511 |471 '| 456 | 702 '| 193 | 482 % Weight Loss from Baseline to -1.7 -8.5 -9.2 -1.9* | -6.5* | -5.6* | -9.4* 6Months,Mean |"R | NR] 6) | o.6) | (0.6) |NR | NR | (oa) | 0.2) | (0.5) | (0.4) (SE) Participants with , 17 161 56 11 |95 | 21 140 15% Weightloss, | (34) | (32.3) |NR | NR | NR | 20(2) | (a5) | (2.4) | (13.5) | (10.9) | (29.1) n (%) Change in Waist Circumference, cm, Mean (SE) -3.1 -10.9 | -3.3 -8.8* | -8.7 -2.5 -6.2 -2.1 -6.7 -6.8 -10 (0.5)t | (0.5)t | (0.7) | (0.7) | (0.7) | (0.4) | (0.4) | (0.5) | (0.3) | (0.8) | (0.5) Change in Fasting Blood 1.9 -0.6 -0.1* | O* -0.1* | -1.3 -3.2 -1.3 -2.8 -1.1 -2.4 Glucose, mg/dL, | (0.5)t | (0.5)t | (0.1) | (0.1) | (0.1) | (0.6) | (0.6) | (0.6) | (0.5) | (1) (0.6) Mean (SE) Change in LDL Cholesterol, 5.5* | -84* | NR NR -3.3* | -4.4* | -2.1* | -6.2* | 84* | 5.4% mg/dL, Mean (0.9) | (0.9)+ (1.2) | (4.2) | (4.3) | (0.9) | (2.4) | (2.4) (SD) B/N: bupropion/naltrexone, cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP: systolic blood pressure, SD: standard deviation, SE: standard error *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. ©lnstitute for Clinical and Economic Review, 2022 Page D29 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D15. Secondary Outcomes of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity and Obesity with Diabetes**5*** CONQUER (Diabetes Subgroup) COR Diabetes Study Arms PBO P/T (low) P/T (high) PBO B/N N 157 67 164 159 265 % Weight Loss from Baseline to 6 Months, Mean | NR NR NR -2* (0.4) -5.1* (0.3) (SE) Participants with 15% Weight loss, n (%) NR NR NR NR NR Change in Waist Circumference, cm, Mean NR NR NR -2.9 (0.6) -5 (0.5) (SE) Change in Fasting Blood - + |- + - + |- - Glucose, mg/dL, Mean (SE) 5.4 (1.8) 9 (3.6) 12.6 (1.8) 4 (3.4) 11.9 (2.7) Change in LDL Cholesterol, * * * * * mg/dl, Mean (SD) -2.3* (2.1) | -3.6* (3.2) -2.8* (2) O* (2.4) -1.4* (1.9) B/N: bupropion/naltrexone, cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP: systolic blood pressure, SD: standard deviation, SE: standard error *The number of patients for this outcome may differ from the primary analysis population. TSE manually derived from standard deviation or 95% Cls. Table D16. Results of Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity*"*" OB-204t CVOT Light Ignite Study Arms PBO in h) PBO B/N PBO B/N N 23 22 4450 4455 82 71 % Weight Loss from Baseline to -10.3 One Year, Mean -4,2 (1.2) (1.2) -1.8* (NR) -4.6* (NR) -0.9 (0.5) -9.5 (0.5) (SE) Participants with 5% Weight Loss,n | 11(47.8) | 16(72.7) | NR NR 10 (12.2) 60 (84.5) (%) Participants with 10% Weight Loss, | 3 (13) 12 (54.5) | NR NR 3 (3.7) 30 (42.3) n (%) B/N: bupropion/naltrexone, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SE: standard error *The number of patients for this outcome may differ from the primary analysis population. +Timepoint for all outcomes is at week 28. £Timepoint of interest for all outcomes for this trial is at week 26. ©lnstitute for Clinical and Economic Review, 2022 Page D30 Final Evidence Report - Medications for Obesity Management Return to Table of Contents HRQoL As discussed in the Report, HRQoL was assessed using a variety of instruments, including SF-36v2, IWQOL-Lite, PHQ-9, and IDS-SR. SF-36v2 consists of 36 questions across eight domains, including physical functioning. Additionally, SF-36v2 provides two aggregated scores: the physical component summary (PCS) and mental component summary (MCS). For the SF-36v2 and IWQOL- Lite-CT instruments, an increase in score is representative of an improvement in health status (positive is better). The PHQ-9 and IDS-SR and reflect depressive symptom severity; a decrease in score in these measures indicates an improvement in depressive symptoms (lower is better). For each medication, HRQoL data for additional studies included in the Supplement are described in the text below. Additional HRQoL data beyond physical functioning and mental scores for studies from the Report are also discussed in the text below. The Report outlines physical function and mental HRQoL data for studies included in our primary analysis. Data from the Report for physical function and mental HRQoL are outlined in Tables D17 and D18 below. Semaglutide HRQoL in STEP 4 was assessed using the SF-36v2 physical function score. During the 20-week run-in period, participants experienced an average score improvement of 2.2 from baseline score. After randomization, from weeks 20 to 68, participants who continued semaglutide experienced a further improvement in physical functioning score (1.0) compared to a decreased score for those who switched to placebo (-1.5). Additionally, improvements were seen in the semaglutide arm for the SF-36v2 Physical Component Summary (0.8) and Mental Component Summary (0.1) compared to decreased scores for both in the placebo arm (-0.9 and -3.4, respectively).*"° (Table D30). Patient reported outcomes for STEP 6 included SF-36v2 physical functioning scores and the IWQOL- Lite-CT physical function score. Participants in the semaglutide arm experienced improvement from baseline in SF-36v2 physical functioning score (0.8) compared to placebo which resulted in a decrease in score (-0.3) (higher is better). Improvement in the IWQOL-Lite-CT physical function score was higher in the semaglutide arm (4.2) compared to placebo (0.8) (higher is better).74* See Table D30 for detailed results. Liraglutide The SCALE (Sleep Apnea) trial discussed in the Report also assessed patient-reported outcomes related to sleep health using two instruments: Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ). For the FOSQ instrument, a higher score indicates less functional impairment. The ESS assesses daytime sleepiness, with a lower score indicating a lower propensity for daytime sleepiness. The change from baseline for both the ESS and FOSQ instruments did not differ significantly between the semaglutide (-2.5 and 1.3, respectively) and placebo arms (-2.3 and 1.1, respectively) (Table D31).42>4 ©lnstitute for Clinical and Economic Review, 2022 Page D31 Final Evidence Report - Medications for Obesity Management Return to Table of Contents The LOSEIT trial assessed patient-reported outcomes related to knee pain using the KOOS instrument, with higher scores (scale 0-100) indicating improved disease status (positive is better). At week 52, participants in the liraglutide arm reported improvement on the KOOS pain instrument (0.4) compared to placebo arm, which reported a decreased score (-0.6) from baseline. Additionally, participants in the liraglutide arm reported greater improvement in function in activities of daily living (1.4) and knee-related quality of life (3.1) compared to those in the placebo arm (-1.6 and 0.7, respectively). Conversely, change in symptoms had a decreased score in the liraglutide arm (-1.2) compared to placebo (0.3). Overall, there were no significant differences in change from baseline score for the KOOS instrument and its subsections observed between the liraglutide and placebo arms.1 Phentermine/Topiramate HRQoL was assessed using the SF-36 instrument, the ESS, and the Pittsburgh Sleep Quality Index in OB-204. Participants in the phentermine/topiramate group demonstrated greater improvement in the SF-36 physical functioning subscale compared to placebo.44**8 Additionally, participants receiving phentermine/topiramate had a greater improvement compared to participants receiving placebo in their sleep quality, measured by the ESS (-1.9% vs. -1.8%, respectively), and the PSQI (- 3.1% vs. -0.9%, respectively) (Tables D30 and D31). Bupropion/Naltrexone In the Ignite trial, HRQOL was assessed with the IWQOL-Lite total score. Participants receiving the intervention had a significant improvement in their quality of life (16.4), while participants receiving usual care slightly decreased in their reported quality of life (-1) (Table D30).147-149 ©lnstitute for Clinical and Economic Review, 2022 Page D32 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D17. Physical Component HRQoL Outcomes of Key Trials??-323536.42-46,49,51-53,64-67 SF-36v2 Physical SF-36v2 Physical IWQOL-Lite-CT Physical Study Name Arms Functioning Score, Component Score, Function Score, Mean y Mean Change from Mean Change from Change from Baseline Baseline (SE) Baseline (SE) (SE) Semaglutide STEP 1 PBO 0.4 (NR) 0.2t (0.3)* 5.3 (NR) SEM 2.2 (NR) 2.4t (0.2)* 14,7 (NR) PBO 1t (0.4) NR 5.3 (1.1) STEP 2 SEM 2.5t (0.4) NR 10,1 (1) PBO 1.6 (NR) 2.3 (NR) NR STEP 3 SEM 2.4 (NR) 3 (NR) NR Liraglutide SCALE (Sleep PBO NR 1.9 (0.5) NR Apnea) LIR NR 3 (0.6) NR SCALE (Obesity & | PBO NR 2.1 (0.2)* NR Pre-Diabetes) LIR NR 3.6 (0.1)* NR PBO 3.8 (NR) 3.8 (0.6)* 14,1 (NR) SCALE (IBT) LIR 4 (NR) 3.4 (0.6)* 14.9 (NR) SCALE (Type 2 PBO NR NR 8.9 (1.1)* Diabetes) LIR NR NR 15.2 (0.9)* . PBO 2.6 (0.5)* 2.2 (0.5)* 5.7 (NR) SCALE (Insulin) hig 2.5 (0.6)* 2.7 (0.5)* 8.2 (NR) Bupropion/Naltrexone PBO 8.2 (0.8) COR-II B/N 14.1 (0.6) PBO 12 (0.8) COR-BMOD B/N 16.5 (0.5) B/N: bupropion/naltrexone, IWQOL-Lite-CT: Quality of Life-Lite Clinical Trials Version, LIR: liraglutide, NR: not reported, PBO: placebo, SE: standard error, SEM: semaglutide, SF-36v2: Short Form 36v2 Health Survey Note: Greyed-out boxes indicate that the HRQoL instrument was not used for any trials within that intervention group. *SE manually derived from standard deviation or 95% Cls. +The number of patients for this outcome may differ from the primary analysis population. Olnstitute for Clinical and Economic Review, 2022 Final Evidence Report - Medications for Obesity Management Page D33 Return to Table of Contents Table D18. Mental Component HRQoL Outcomes of Key Trials?23&4244,49.51,54-67 Study Name Arms SF-36v2 MCS, Mean Change from Depression Score, Mean y Baseline (SE) Change from Baseline (SE)* Semaglutide PBO -2.14 (0.3)t STEP 1 SEM -1.5+ (0.2)t PBO -2.9 (NR) STEP 3 SEM -0.8 (NR) Liraglutide PBO 0.9 (0.6) SCALE (Sleep Apnea) UR 1.4 (0.6) SCALE (Obesity & Pre- | PBO -0.9 (0.3)t Diabetes) LIR 0.2 (0.2)t PBO -2.2 (0.7)t SCALE (IBT) LIR 1.2 (0.7/4 . PBO -1.7 (0.5)t SCALE (Insulin) 7 1.9 (0.6)t Phentermine/Topiramate PBO -1.3 (0.2)t EQUIP P/T (low) -1.2 (0.2)t P/T (high) -1.5 (0.1)t PBO -0.5 (0.4)T EQUATE P/T (low) -1.3 (0.2)t P/T (high) -1.1 (0.4)t PBO NR CONQUER P/T (low) NR P/T (high) NR Bupropion/Naltrexone PBO -0.7 (0.2) COR-| B/N -0.3+ (0.2) PBO -0.5 (0.3) COR-I B/N -0.3 (0.2) PBO OF (0.4) COR-BMOD B/N 0.14 (0.2) 1 PBO -1.6 (0.4) COR-Diabetes B/N 0 (0.3) B/N: bupropion/naltrexone, IDS-SR: Inventory of Depressive Symptomology (Self-Report), LIR: liraglutide, MCS: mental component summary, mg: milligram, NR: not reported, PBO: placebo, PHQ-9: Patient Health Questionnaire, P/T: phentermine/topiramate, SE: standard error, SEM: semaglutide, SF-36v2: Short Form 36v2 Health Survey Note: Greyed-out boxes indicate that the HRQoL instrument was not used for any trials within that intervention group. *Phentermine/topiramate studies utilized PHQ-9 for depression score, bupropion/naltrexone utilized IDS-SR for depression score. TSE manually derived from standard deviation or 95% Cls. +The number of patients for this outcome may differ from the primary analysis population. ©lnstitute for Clinical and Economic Review, 2022 Page D34 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Harms Semaglutide versus Placebo The most frequent adverse events in the STEP 4 and 6 trials for semaglutide were gastrointestinal- related symptoms, including nausea, constipation, and diarrhea.'*°**2 Beyond gastrointestinal events, semaglutide appeared relatively well-tolerated. Participants in the semaglutide arms of the STEP 4 and 6 trials experienced more adverse events (81.3% and 86%, respectively) compared to those in the placebo arms (75% and 79%, respectively). Similarly for STEP 4, participants in the semaglutide arm experienced more serious adverse events (SAEs) (7.7%) compared to participants in the placebo arm (5.6%).1*°1, However, STEP 6 reported a higher rate of serious adverse events in the placebo arm (7%) compared to the semaglutide arm (5%).?42 One death was reported in each treatment group for STEP 4, but both were determined to be unrelated to study treatment. There were no deaths reported in STEP 6. Notable serious adverse events that occurred included one occurrence of cholecystitis in the STEP 4 intervention arm, five occurrences of cholelithiasis in the STEP 4 intervention arm (two occurrences in the placebo arm) and two occurrences in the STEP 6 intervention arm, one occurrence of nephrolithiasis in the STEP 4 intervention arm, and one occurrence of ureterolithiasis in the STEP 4 intervention arm and one occurrence in the STEP 6 intervention arm (one occurrence in the placebo arm). Rates of discontinuation due to adverse events were higher in the semaglutide arms for both STEP 4 and STEP 6 (2.4% and 3%, respectively) compared to placebo arm (2.2% and 1%, respectively). Gastrointestinal events were the most common reported reason for discontinuing due to adverse events. See D19 for detailed harms results. Liraglutide versus Placebo The most common adverse events reported in LOSEIT included gastrointestinal events, with a total of 264 events in the liraglutide arm versus 144 events in the placebo arm."*3 Participants in the liraglutide arm experienced more adverse events (96%) compared to those in the placebo arm (93%). Rates of serious adverse events were similar between both the liraglutide (9%) and placebo arms (8%) (Table D19). Gastrointestinal serious adverse events occurred in one participant from the liraglutide arm (ileus leading to surgery) and one participant from the placebo arm (cholecystitis). There were no deaths reported in the trial. Rates of discontinuation due to adverse events were higher in the liraglutide arm (10 patients) compared to placebo arm (four patients). Gastrointestinal events were the most common reported reason for discontinuing due to adverse events. ©lnstitute for Clinical and Economic Review, 2022 Page D35 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D19. Harms in Additional Trials of Semaglutide and Liraglutide for the Management of Obesity**°1 STEP 4 STEP 6 LOSEIT Study Arms Run-in* PBOt SEMt PBO SEM PBO LIR N 902 268 535 101 199 76 80 Any AE, n (%) (243) 201 (75) | 435 (81.3) | 80(79) | 171(86) | 71(93) _| 77 (96) SAE, n (%) 21(2.3) | 15(5.6) | 41 (7.7) 7 (7) 10 (5) 6 (8) 7 (9) AEs Leading to Discontinuation, n (%) 48 (5.3) | 6(2.2) | 13 (2.4) 1 (1) 5 (3) 4 (5.3) 10 (12.5) Gl Disorders Leading to Discontinuation, n (%) NR NR NR 0 (0) 4 (2) 2 (2.6) 8 (10) Nausea, n (%) NR 13 (4.9) | 75 (14) 4 (4) 35 (18) NR NR Constipation, n (%) NR 17 (6.3) | 62 (11.6) 3 (3) 52 (26) NR NR Diarrhea, n (%) NR 19(7.1) | 77 (14.4) 6 (6) 32 (16) NR NR AE: adverse event, GI: gastrointestinal, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo, SAE: serious adverse event, SEM: semaglutide *Timepoint for harms is at Weeks 0-20. +Timepoint for harms is at Weeks 20-68. Phentermine/Topiramate versus Placebo In OB-204, most treatment-emergent adverse events were mild to moderate in severity, and the incidence of any adverse events was higher in the phentermine/topiramate arm (91%) than in the placebo arm (78%).1441*8 Adverse reactions that occurred more frequently in the intervention arm than in the placebo arm included dry mouth (50% vs. 0%), dysgeusia (27% vs. 0%), and sinusitis (23% vs. 0%). Serious adverse events were rare and were experienced by no participants in the phentermine/topiramate group, compared to one participant in the placebo group. Over twice many participants in the intervention arm discontinued due to adverse events (9.1%) compared to participants in the intervention arm (4.4%). See Table D20 for detailed harms results. Bupropion/Naltrexone versus Placebo In CVOT Light, over twice as many participants in the bupropion/naltrexone arm experienced any adverse events (36%) compared to participants in the placebo arm (15%).1°*° Rates of serious adverse events were similar and relatively low across the two arms (9-10%) (Table D20). More participants in the bupropion/naltrexone arm discontinued due to adverse events (28%) than in the placebo arm (9%). The most common adverse events that led to discontinuation of the drug in both the treatment arm and the placebo arm included gastrointestinal adverse reactions (14% and 2%, respectively), which included nausea, constipation, and vomiting, and central nervous system reactions (5% and 1%, respectively), which including tremor, dizziness, and headache. Psychiatric disorders, such as insomnia, anxiety, and depression, leading to discontinuation were infrequently observed in both arms (3% vs. 1%, respectively). ©lnstitute for Clinical and Economic Review, 2022 Page D36 Final Evidence Report - Medications for Obesity Management Return to Table of Contents In the Ignite trial, serious adverse events during the controlled treatment period (up to 26 weeks) were low, with one participant in the intervention arm versus zero in the placebo arm experiencing a serious adverse reaction (Table D20) 4749, Through the entire study period at 78 weeks, rates of serious adverse events were low in both arms, occurring in two patients who continued on bupropion/naltrexone and zero patients in the placebo arm who switched to the treatment. These two serious adverse events were considered to be unrelated to the study drug. At 26 weeks, in the Ignite trial, discontinuations due to adverse events occurred at a higher rate in the bupropion/naltrexone arm (23%) than in the placebo arm (1.1%).14749 Throughout the entire study period (78 weeks), adverse events that led to discontinuation were observed in 24% of patients who were randomized to and continued open-label bupropion/naltrexone treatment, and in 16% of patients who were initially in placebo, but switched to open-label treatment. The most frequent adverse reactions leading to discontinuation of the treatment for both groups included nausea (7%), anxiety (2.1%), headache (1.7%), dizziness (1.2%), and insomnia (1.2%). See Table D20 for detailed harms results. ©lnstitute for Clinical and Economic Review, 2022 Page D37 Final Evidence Report - Medications for Obesity Management Return to Table of Contents Table D20. Harms in Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the Management of Obesity and Obesity with Diabetes Mellitus?**° OB-204 CVOT Light ignite P/T . ~ | PBO> | B/N> Study Arms PBO (high) PBO B/N PBO B/N B/Nt B/Nt N 23 22 4450 4455 89 153 89 153 Any AE, n (%) 18 (78.2) | 20(90.9) | 668(15) | 1620(36.4) | 0 7 g) | NR NR SAE, n (%) 1(44) [Oo 386 (8.7) | 463 (10.4) | 0 1(0.7) | 0 2 (1.3) AE Leading to 35 14 37 Disc., n (%) 1 (4.4) 2 (9.1) 388 (8.7) | 1253 (28.1) | 1 (1.1) (22.9) (15.7) (24.2) Gastrointestinal yp NR 84(1.9)t | (2)t NR NR NR NR Disorders Nausea |1(4.4) | 2(9.1) | 21(0.5)t | 333(7.5)t (00 5) |0 NR NR Dry Mouth | 0 11(50) | 2(0.04) | 21(0.5) NR NR NR NR Nervous System =| ip NR 52(1.2)+ | 226(5.1)t | NR NR NR NR Disorders Headache | NR NR 14 (0.3)t | 51 (1.1)t 2 (1.3) 0 NR NR Dizziness | 0 1 (4.6) 7 (0.2) 62 (1.4)t 1 (0.7) 0 NR NR Dysgeusia | 0 6 (27) 0 16 (0.4) NR NR NR NR Infection | NR NR NR NR NR NR NR NR Sinusitis | 0 5 (23) 0 1 (0.02) NR NR NR NR Psychiatric NR NR 39 (0.9) | 136(3.1)t | NR NR NR NR Disorders Anxiety | NR NR 8(0.2)t | 26 (0.6)t 5 (3.3) |o NR NR Insomnia | NR NR 16 (0.4)t | 35 (0.8)T 2 (1.3) 0 NR NR AE: adverse event, B/N: bupropion/naltrexone, disc.: discontinuation, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SAE: serious adverse event *Timepoint up to 26 weeks. tRates of AEs leading to discontinuation. +Timepoint up to 78 weeks. 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