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Advancing Setmelanotide to Treat Obesity Due to Genetic Variants Within the MC4R Pathway

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Advancing Setmelanotide to Treat Obesity Due to Genetic Variants Within the MC4R Pathway Advancing Setmelanotide to Treat Obesity due to Genetic Variants within the MC4R Pathway Research & Development Event January 26, 2021 © Rhythm Pharmaceuticals, Inc. All rights reserved. Today’s Agenda Introductions Hunter Smith, Chief Financial Officer Welcome and Overview David Meeker, M.D., Chair, Chief Executive Officer and President Clinical Data Update on Setmelanotide Murray Stewart, M.D., Chief Medical Officer Translational Research and the MC4R Pathway Alastair Garfield, Ph.D., Head of Translational Research and Development Closing Remarks and Q&A 2 Forward-looking Statements This presentation contains certain statements that are forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and that involve risks and uncertainties, including without limitations statements regarding our expectations regarding prevalence for our target indications, which are based on our internal calculations and estimates, the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, anticipated timing for enrollment and release of our clinical trial results, the timing for filing of NDA, MAA or other similar filings, our goal of changing the paradigm for the treatment of rare genetic disorders of obesity, the application of genetic testing and related growth potential, expectations surrounding the potential market opportunity for our product candidates, and strategy, prospects and plans, including regarding the commercialization of setmelanotide. Statements using words such as "expect", "anticipate", "believe", "may", "will" and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including but not limited to, our ability to enroll patients in clinical trials, the outcome of clinical trials, the impact of competition, the impact of management departures and transitions, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our expenses, the impact of the COVID-19 pandemic on our business operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this presentation or to update them to reflect events or circumstances occurring after the date of this presentation, whether as a result of new information, future developments or otherwise. 3 Welcome David Meeker, M.D. Chair, Chief Executive Officer and President 4 Key Takeaways for Today Multiple genetic defects lead to MC4R pathway deficiencies Obesity is complex and not all patients with a pathway defect will respond to setmelanotide Growing confidence in our ability to identify genes that will respond Evolving paradigm to identify potential setmelanotide responders Individually each genetically defined population is rare – in the aggregate, these diseases are not so rare (Rare Disease Paradox) Strategy: Expanded sequencing efforts coupled with expansion of basket trial approach 5 Living with Early-onset, Severe Obesity and Hyperphagia Hallmark Symptoms of Rare Genetic Diseases of Obesity “They are constantly, all day “It causes extreme long saying they are hungry unrelenting hunger and and asking what’s for the excessive eating. As a next meal and what are we child…the fridge and food eating the next day. We keep was controlled massively…but a menu planned and if we nobody could understand deviate from that menu it’s a that I was desperately hungry disaster.” and just wanted to stop that feeling.” “We have had to put locks on our cupboards and fridge and - Katy, diagnosed with POMC freezer to protect them from heterozygous deficiency obesity themselves!” Katy, at 23 years old, 450 pounds Adalissa and Solomon with their – Olivia, Mother of siblings (unaffected) Adalissa and Solomon, siblings diagnosed with BBS 6 CONFIDENTIAL Our mission: Change the Paradigm for the Treatment of Rare Genetic Diseases of Obesity 7 Classic Rare Disease Challenges Apply to Genetic Obesities Lost in the Little Little No tools or No system knowledge awareness testing treatment Worst case: An irritation. It’s your fault. Eat less, exercise more. 8 The Rare Genetic Disease of Obesity Paradox <200,000 Definition population of * a rare disease ~5,000 • Obesity due to POMC, PCSK1 or LEPR Deficiency (FDA approved) Rare diseases ~7,000 • Bardet-Biedl syndrome (Ph3) • Alström syndrome (Ph3) Initial indications are ultra-rare. Total patients affected with But with additional genes, in the >30M rare diseases in the U.S. aggregate, not so rare. * Estimated prevalence of U.S. patients based on company estimates; 9 MC4R Pathway Biology is Clear and Strong Setmelanotide can redress MC4R pathway impairment contributing to early onset, severe obesity POMC NEURON MC4R-EXPRESSING NEURON Leptin ALMS1 BBSx LEPR RAI1 SH2B1 MC4R Appetite SRC1 Satiety Signals ACTIVATION Weight (e.g. Leptin) MSH Energy expenditure POMC PCSK1 UPSTREAM DOWNSTREAM Setmelanotide 10 Setmelanotide Journey began with Phase 2 Data Published in New England Journal of Medicine1 and Nature Medicine2 * POMC Patient #1* LEPR Patient #1 1.5 1.5 1.5 1.5 23 yr old male 0.5 1.0 20 yr old 1.0 mg mg mg mg Starting Weight 0 10 female 0 10 = 130.6 kg Starting Weight Starting BMI = 9 = 155.0 kg 9 -10 39.9 kg/m2 -5 Starting BMI = 8 49.8 kg/m2 8 -20 7 7 -10 -30 6 6 -40 5 -15 5 4 4 -50 -20 3 3 -60 2 -29.0 kg* 2 -25 -70 -22.2% 1 1 -66.5 kg* -80 -42.9% 0 -30 0 0 10 20 30 40 50 60 70 80 90 100 110 120 0 5 10 15 20 25 30 35 40 45 50 Weight Change (kg) Hunger Score (0-10 points) (1) Kühnen, et. al, Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. July 2016. (2)Biebermann, et al. MC4R Agonism Promotes Durable Weight Loss in Patients with Leptin Receptor Deficiency. Nat Med. 2018 May 7; * Figures represent longer-term data as presented in January 2019 with cumulative weight lost in kgs | Not all patients had similar responses; Yellow vertical bars represent intervals with dose withdrawal or modifications; 11 Approval of IMCIVREE Based on Phase 3 Data from Largest Studies Conducted in Obesity due to POMC, PCSK1 or LEPR Deficiency POMC/PCSK1 LEPR of participants achieved ≥10% of participants achieved ≥10% weight loss weight loss (95% CI, 16.75% to 76.62%); 0% 45.5% P<0.0002; n=11 (95% CI, 44.39% to 97.48%); P=0.0002; n=10 0% 80% PRIMARY ENDPOINT PRIMARY ENDPOINT –5% –2% –10% –4% 5.0 kg mean increase in 5.5 kg mean increase in –6% –15% weight during double-blind Weight weight during double-blind Weight withdrawal period* –8% withdrawal period* –20% –10% Mean % Change in Body in Body Change % Mean Mean % Change in Bodyin ChangeMean% –25% –12% BL V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 FV BL V2 V3 V4 V5 V6 V7 V8 V9 V1 V1 FV Visit 0 2 Long-term • 12 of 15 eligible POMC • 12 of 15 eligible LEPR extension study: patients enrolled * patients enrolled * BL, baseline; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin; FV, final visit; V, visit. †N=9 POMC participants and N=7 LEPR participants who achieved weight loss threshold (5 kg or 5% if <100 kg) after the first open-label active treatment phase. Reference: IMCIVREE Prescribing Information; * Data as of Nov. 16, 2020 cutoff as presented Dec. 22, 2020, corporate conference call. 12 Phase 3 Bardet-Biedl and Alström Syndromes Trial Met Primary and All Key Secondary Endpoints Setmelanotide achieved statistical significance and delivered clinically meaningful weight loss and hunger reduction Phase 3 Topline Data (n=31a) 34.5%b -6.2% -30.8% 60.2% p=0.0024 p<0.0001 p<0.0001 p<0.0001 ≥10% mean mean ≥25% weight loss weight hunger reduction in reduction score worst hunger reduction All primary endpoint responders were BBS patients. As presented on Dec. 22, 2020, reflecting data cut-off of Dec 2. 2020. aStudy participants older than 12 counted in full analysis set for primary and key secondary endpoints; Five participants were younger than 12, and two participants older than 12 discontinued during placebo-controlled period prior active therapy. bResponse rate estimated based on imputation methodology discussed with FDA. 13 A Closer Look at Patients with Bardet-Biedl Syndrome a 28 BBS 11 BBS (38.1%) 53% of adult BBS patients patients included in patients achieved ≥10% (8/15) achieved ≥10% weight primary analysis set weight loss: loss • Mean actual weight loss: • Mean actual weight loss: -8.7 kg -17.2 kg • Mean percentage weight loss: • Mean percentage weight loss: 73% of adult BBS patients - 7.5% - 14.7% (11/15) had ≥5% weight loss • 15 of 28 were adults • 8 of 11 were adults As presented on Dec. 22, 2020, corporate conference call, reflecting data cut-off of Dec 2. 2020. aResponse rate estimated based on imputation methodology discussed with FDA. 14 Consistent Safety Profile Across All Programs in 590 Patients Patient experience with setmelanotide* Setmelanotide has been generally well- Duration on therapy # of patients tolerated < 1 year 515 Most treatment-related AEs were mild: > 1 year 75 • Mild injection site reactions > 2 years 29 > 3 years 10 • Skin hyperpigmentation > 4 years 2 • Nausea/vomiting: mild and early in > 5 years 1 treatment *
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