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® © Rhythm® Pharmaceuticals, Inc. All rights reserved. September 24, 2025 Commercial Readiness for Acquired Hypothalamic Obesity
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2 This presentation contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and that involve risks and uncertainties, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress of our products and product candidates, including setmelanotide, and including the anticipated timing for our expectations surrounding regulatory submissions, approvals and timing thereof, our business strategy and plans, including regarding commercialization of setmelanotide and our other product candidates, the announcement of data from our clinical trials, including our global Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity, the ongoing enrollment of patients in our clinical trials, the potential benefits of any of the Company's products or product candidates for any specific disease indication or at any dosage, expectations surrounding the potential market opportunity for our product candidates, anticipated milestones, our future financial performance and the sufficiency of our cash, cash equivalents and short-term investments to fund our operations, and strategy, prospects and plans, including regarding the commercialization of setmelanotide, our anticipated financial performance for any period of time, our participation in investor events, including our Commercial Readiness in acquired Hypothalamic Obesity event and webcast, and the timing of any of the foregoing. Statements using words such as "expect", "anticipate", "believe", "may" 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 ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our liquidity and expenses, the impact of global events on our business and 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. Forward-looking Statements Dr. Shoemaker and Dr. Blevins have been compensated for their time to prepare for and participate in today's investor presentation. Karmelo Bragg and his mother Miracle Bragg were compensated for their time to participate in the making of the video about Karmelo's experience with acquired HO. Speaker Disclosures
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David Meeker, MD Chairman, President, and CEO Ashley Shoemaker, MD, MSCI Associate Professor of Pediatrics, Vanderbilt University Medical Center Lewis Blevins, MD Medical Director, UCSF Medical Center Jennifer Lee Executive Vice President, Head of North America Today’s Speakers
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4 Agenda Welcome & Introduction David Connolly, Head of Investor Relations and Corporate Communications Setmelanotide Overview David Meeker, MD, Chairman, President, and CEO Physician Panel Ashley Shoemaker, MD, MSCI, Associate Professor of Pediatrics, Vanderbilt University Medical Center Lewis Blevins, MD, Medical Director, UCSF Medical Center Moderator: David Meeker, MD, Chairman, President, and CEO Break U.S. Commercial Strategy Jennifer Lee, Executive Vice President, Head of North America Q&A Closing David Meeker, MD, Chairman, President, and CEO
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David Meeker, MD Chairman, CEO and President Setmelanotide Overview ®
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6 Rhythm is Ready for a Successful U.S. Launch Significant unmet need Setmelanotide’s proven efficacy Transformative opportunity ® 6
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7 MC4R Pathway Biology is Clear Adipose tissue Leptin Blood-brain barrier MC4R neuron POMC neuron AgRP neuron AgRP LEPR Upstream Downstream Hypothalamus PCSK1 POMC LEPR MC4R Downstream MC4R activity Low Normal α-MSH β-MSH α-MSH β-MSH AgRP, agouti-related peptide; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte-stimulating hormone; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin. 1. Abuzzahab et al. Horm Res Paediatr. 2019;91:128-136. 2. Erfurth. Neuroendocrinology. 2020;110:767-779. 3. Rose et al. Obesity (Silver Spring). 2018;26:1727-1732. 4. Roth. Front Endocrinol (Lausanne). 2011;2:49. Hyperphagia Energy Expenditure Obesity
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8 IMCIVREE (setmelanotide) has Secured Multiple FDA Approvals, EU Authorizations for Label Expansion U.S. FDA approval for POMC, LEPR Deficiencies European Marketing Authorization for POMC, LEPR Deficiencies U.S. and European approvals for Bardet-Biedl syndrome U.S. and European approvals for patients as young as 2 years old 2020 2021 2022 2023 2024 2025
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9 Rapid Development in Acquired Hypothalamic Obesity 2020 2021 2022 2023 2024 2025 Achieved proof of concept in setmelanotide Ph2 trial Initiated 120-patient Ph3 trial; enrollment completed within one year Began patient enrollment in Ph3 Japanese cohort Achieved proof of concept in bivamelagon Ph2 trial 19.8% BMI reduction in setmelanotide Ph3 trial Setmelanotide PDUFA date: December 20
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Solid Global Foundation in Place >25 countries where IMCIVREE is available >350 employees in 15 different countries 7 country-level distribution partnerships
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11 Craniopharyngioma (CP) and other suprasellar brain tumors and treatment – tumor resection surgery and radiation – is most common cause MC4R pathway deficiency following injury to hypothalamic region causes reduced energy, hyperphagia and rapid-onset, severe obesity No approved treatments available Hypothalamic Obesity: A Rare, Acquired Form of Obesity Following Injury to the Hypothalamic Region van Iersel et al. Endo Rev. 2020 (PMID: 30247642)
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12 Severe, Life-long Burden for Patients with Acquired HO Frequent visits with multiple specialists, a complex regimen of medications, and hospitalization 89% were receiving ≥3 therapies for neuroendocrine dysfunction 22.1 average number of unique medications over 2 years 5.5 average active prescriptions per quarter 3.7 average hospitalizations during the two years following index; 23% included ICU admission in the first year 12 average number of general practitioner visits and 20 specialist visits, during the two years following index “Treatment of patients with tumor/treatment- related hypothalamic obesity in the first two years following surgical treatment or radiotherapy” Müller et al., 2025
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13 HO: Aggressive, Rapid Weight Gain follows Therapy for CP Setmelanotide therapyGLP1 therapy Patient Case Study: Setmelanotide therapy achieved rapid, significant weight loss Patient case of M. Jennifer Abuzzahab, MD, Pediatric Endocrinologist, at Children's Minnesota
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14 Setmelanotide Achieved Statistically Significant and Highly Clinically Meaningful Reduction in BMI in Phase 3 Acquired HO Trial Primary analysis cohort (N=120) -19.8% Placebo-adjusted difference in BMI reduction from baseline (P<0.0001) -16.5% BMI change from baseline in Setmelanotide arm (n=81) +3.3% BMI change from baseline in Placebo arm (n=39) NOTE: Shown are the least square (LS) means for setmelanotide and placebo groups and the LS mean difference in mean percentage change from baseline in BMI at Week 52, obtained from an analysis of covariance (ANCOVA) model. Rubin’s Rule was used to provide the overall estimates of differences in LS means and p-value.
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15 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 5% 10% 15% 20% Proportion of patients Consistent Response to Setmelanotide Therapy Observed across Majority of Patients in Phase 3 Trial in Acquired HO 5% 3% 51% 0% 43% Setmelanotide Placebo 10% 80% 63% P<0.0001 P<0.0001 P<0.0001 P<0.0001 Observed Reduction in BMI at 52 weeks
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16 -25.00% -20.00% -15.00% -10.00% -5.00% 0.00% 5.00% 10.00% Mean BMI Reduction Consistent Across Stratified Age Groups in Phase 3 Trial Evaluating Setmelanotide in Acquired HO < 12 Yrs -19.5% p <0.0001 (n=31: 20 setmelanotide, 11 placebo) 12 – < 18 Yrs -21.0% p <0.0001 (n=40: 28 setmelanotide, 12 placebo) ≥ 18 Yrs -19.2% p <0.0001 (n=49: 33 setmelanotide, 16 placebo) Pbo-Adj Set Pbo
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17 n= 57 24 *Weekly average of daily scores. participants ≥12 years of age who were able to self-report were administered the questionnaire. Participants were asked to rate their most hunger on an 11-point numerical rating scale from 0 to 10, where 0 = not hungry at all and 10 = hungriest possible via the question, “In the last 24 hours, how hungry did you feel when you were the most hungry?” CI, confidence interval; LSM, least squares mean. -2.23 -3.11 -3.22 -3.27 -3.00 -2.86 -2.96 -3.18 -1.07 -1.73 -1.60 -1.93 -1.43 -1.50 -1.48 -1.65 -4.0 -3.0 -2.0 -1.0 0.0 52-Week Most Hunger Score* Reduction -1.28 Reduction in Most Hunger Score* Over Time PBO-adjusted difference 0 4 12 24 32 40 48 56 EOT Weeks Setmelanotide, n 57 52 53 44 50 46 44 44 39 Placebo, n 24 18 19 23 22 19 18 17 15 Mean change in maximal daily hunger score (95% CI) Rapid and Statistically Significant Reduction in Most Hunger Score With Setmelanotide vs Placebo (Participants Aged ≥12 Years) †P=0.0086 vs placebo. ◼ Setmelanotide ◼ Placebo Change in maximal daily hunger score, LSM (95% CI) -2.73† -1.45 -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 As presented at ENDO 2025
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18 Significant BMI Reductions Observed in Patients With Prior or Concomitant Use of GLP -1RA †P=0.0046 and *P<0.0001 vs placebo. BMI, body mass index; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist; LSM, least squares mean. Prior but no concomitant GLP-1 use Prior and concomitant GLP-1 use N= 10 6 9 6 * Percent change in BMI, LSM (95% CI) -19.3† -25.1* 5.4 2.0 -35 -25 -15 -5 5 15 25 * ◼ Setmelanotide ◼ Placebo
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19 Setmelanotide Was Generally Well Tolerated With No New AE Signals Setmelanotide (n=81) Placebo (n=39) Overall (n=120) ≥1 AE of any cause 81 (100.0) 35 (89.7) 116 (96.7) ≥1 Drug-related AE 71 (87.7) 26 (66.7) 97 (80.8) ≥1 Serious AE 23 (28.4) 3 (7.7) 26 (21.7) ≥1 Drug-related serious AE 1 (1.2)* 0 1 (0.8) ≥1 AE that resulted in death 1 (1.2) 0 1 (0.8) ≥1 AE leading to study drug withdrawal 6 (7.4) 3 (7.7) 9 (7.5) ≥1 AE leading to study discontinuation 4 (4.9) 0 4 (3.3) Most common (≥20% in setmelanotide arm) Skin hyperpigmentation 45 (55.6) 3 (7.7) 48 (40.0) Nausea 41 (50.6) 12 (30.8) 53 (44.2) Headache 31 (38.3) 12 (30.8) 43 (35.8) Vomiting 32 (39.5) 7 (17.9) 39 (32.5) Diarrhea 19 (23.5) 8 (20.5) 27 (22.5) Injection site reaction 19 (23.5) 9 (23.1) 28 (23.3) *In a participant with arginine vasopressin deficiency who was unable to ingest their oral desmopressin tablet because of drug-associated nausea and vomiting, which led to increased blood sodium concentrations and subsequent hospitalization. AE, adverse event. One serious AE was considered related to the study drug (setmelanotide): hypernatremia (sodium levels 150-158 mmol/L [normal upper limit 145 mmol/L]); resolved after 2 days with treatment Safety was generally consistent with previously reported AEs in other clinical trials One death due to seizures in a patient with a history of seizure disorder, which was not considered related to the study drug
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20 Significant Global Market Opportunity in aHO 1. U.S. estimates based on reported incidence of hypothalamic obesity following craniopharyngioma and long-term survival rates, (Zacharia, et al., Neuro-Oncology 14(8):1070–1078, 2012. doi:10.1093/neuonc/nos142; and Muller, et al., Neuro-Oncology 17(7), 1029– 1038, 2015 doi:10.1093/neuonc/nov044.); 2. European estimates limited to the EU4 (Germany, France, Spain, Italy), UK and the Netherlands and prevalence of 0.1-0.3 in 10,000 patients; 3. Rhythm estimates the prevalence of acquired hypothalamic obesity in Japan to be approximately 5,000 to 8,000 based on our review of tumor registries and claims data; Prevalence is 2-3 times higher than in the USA & Europe due to a higher reported frequency of craniopharyngioma. ~10,000 estimated U.S. prevalence1 ~10,000 estimated European prevalence2 5,000 – 8,000 estimated Japanese prevalence3 ~500 Estimated incidence in each U.S., Europe and Japan1, 2, 3
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21 Karmelo
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Ashley Shoemaker, MD, MSCI Lewis Blevins, MD Moderator: David Meeker, MD Physician Panel ®
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Break ®
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Jennifer Lee Executive Vice President, Head of North America U.S. Commercial Strategy ®
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25 Excitement Building for Launch in Acquired Hypothalamic Obesity RYTM is getting ready to launch Addressing a severe unmet need Transformative opportunity 25
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26 Focus for Today 26 Building on success in BBS Market research validates unmet need U.S. launch strategic priorities What we’ve done What we’ve learned What we’re focused on
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27 Leveraging Data and Persistent Patient Finding Drive BBS Growth 27 February 2022 Four months before BBS launch Steady growth over the last three years
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28 28 Education and Engagement with Health Care Providers Drives Awareness Differentiating MC4R disease and burden of hyperphagia Leptin Leptin receptor POMC neuron MC4TR neuron a-MSH MC4R Receptor Hypothalamus
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29 Experienced Rare Disease Team in Place to Support Ongoing Growth in BBS 29 Territory managers in the field Access team supporting reimbursement
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30 30 Diagnosis Access Market Insights: What we’ve Learned about the HO Opportunity Disease management
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31 Current Challenges with Diagnosing and Treating HO 31 Distinct and variable presentation Underdiagnosed and treated as general obesity Further education needed on signs and symptoms Immediately after the surgery, I was ravenously hungry. I gained 20 pounds in two weeks, and that was on just what the hospital was feeding me. I was hungry a lot, and I have struggled with fatigue ever since then.” - Brain Tumor Survivor
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32 Patient Care Highly Complex Following Hypothalamic Injury 32 Transient weight changes with corticosteroids or other therapies Multiple interventions for hormonal insufficiencies Shock of tumor diagnosis Primary concerns following hypothalamic injury Pituitary insufficiencies Hypothalamic obesity (Hyperphagia and fatigue) Diabetes insipidus Urgent need for new and effective treatment options for hypothalamic obesity
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33 Setmelanotide Product Profile Resonates with Endocrinologists In a hypothetical placebo-controlled trial, how compelling would you find 15% BMI reduction vs 0% for placebo? I love seeing that there is improvement in a patient-centered outcome – that being the change in hunger. For me, it’s not all weight-centric all the time – I think we get really focused on that” - Endocrinologist 33 94% 100% (N=50) extremely compelling or compelling would prescribe setmelanotide to patients with HO
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34 Anticipate Strong Commercial, Medicaid Coverage for Setmelanotide for HO *Adjusted to include only patients <18yo in states where approvals for reimbursement are limited to EPSDT Anticipate similar or better coverage than BBS Vast majority of commercial and Medicaid lives covered Prior authorizations aligned with label
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35 Strategic Priorities for IMCIVREE Launch in Hypothalamic Obesity Differentiating MC4R pathway diseases Expediting patient diagnosis Establishing IMCIVREE as the foundational treatment upon approval 35 Securing market access
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36 Data-driven Approach to Identifying Patients 36 Patients with tumor + treatment Evidence of hypothalamic dysfunction Evidence of obesity Endocrinologist visit within 18 months
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37 Specialty Opportunity Focused on Endocrinologists 37 ~2,400 Top targets Territory Manager Coverage ~5,000 Endocrinologists potentially caring for a patient with acquired HO
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38 ~2,000 Immediate Focus on Patients Diagnosed or Suspected of Having HO patients diagnosed or suspected to have acquired hypothalamic obesity
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39 The Right Teams are in Place Area development managers and medical science liaisons remain in the field 43 Scaled access and patient support teams for launch 16 Territory Managers for BBS Territory Managers for HO
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40 Hypothalamic Disease Education Programming Underway DifferentObesity.com
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41 41 DECEMBER PDUFA
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David Meeker, MD Chairman, CEO and President Closing ®
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43 Expanding the Opportunity for IMCIVREE ( setmelanotide) FDA approval in POMC, LEPR deficiencies 2020 FDA approval in Bardet-Biedl syndrome 2022 Label expansion down to 2 years old in BBS and POMC, LEPR 2024 PDUFA goal date for acquired hypothalamic obesity Dec. 20, 2025 43
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44 Bivamelagon, RM718 May Extend MC4R Franchise Well into 2040s Bivamelagon (LB54640) • Daily oral, highly selective MC4R agonist • Achieved positive Ph2 results as announced in July 2025 • Phase 3 trial anticipated to begin 2026 RM-718 • 7-amino acid peptide administered QW • In vivo results: supportive of no off-target cardiovascular effects, like setmelanotide; No hyperpigmentation observed • Ongoing Ph1 trial in healthy volunteers and patients with acquired hypothalamic obesity
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45 Key Takeaways 1 2 3 Clear unmet need for an effective treatment for acquired hypothalamic obesity Rhythm is getting ready to launch Acquired HO is a transformative global opportunity for Rhythm
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Q&A ®