Slide 1: Positive Topline Results from Phase 2 Trial Evaluating Oral MC4R Agonist Bivamelagon
Rhythm Pharmaceuticals Positive Topline Results from Phase 2 Trial Evaluating Oral MC4R Agonist Bivamelagon in Patients with Acquired Hypothalamic Obesity July 9, 2025 ® © 2025. Rhythm Pharmaceuticals, Inc. All rights reserved. Rhythm and its logo are trademarks of Rhythm Pharmaceuticals, Inc.
Slide 2: Forward-looking Statements
Forward-looking Statements This presentation and the accompanying oral presentation contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be
Slide 3: Bivamelagon Achieved Statistically Significant, Clinically Meaningful BMI Reductions at 14 Weeks
Bivamelagon Achieved Statistically Significant, Clinically Meaningful BMI Reductions in Patients with Acquired Hypothalamic Obesity at 14 Weeks Bivamelagon achieved BMI reductions comparable to 12- and 16-week reductions seen in similar patient populations in setmelanotide trials Safety and tolerabi
Slide 4: Impairments of MC4R Pathway Signaling Lead to Hyperphagia, Reduced Energy and Severe Obesity
Genetic, Traumatic and Inflammatory Impairments of MC4R Pathway Signaling Leads to Hyperphagia, Reduced Energy and Severe Obesity Hypothalamus Upstream Downstream Downstream AgRP neuron MC4R activity Low Normal LEPR AgRP Adipose Hyperphagia tissue PCSK1 MC4R Obesity MC4R neuron α-MSH POMC α-MSH Lept
Slide 5: MC4R Agonism Shown to Address Impaired Pathway Function
MC4R Agonism Shown to Address Impaired Pathway Function Causes of Impairment: Analogs of α-MSH Genetic • Setmelanotide Injury • Bivamelagon Consequence: Low levels • RM-718 Inflammation of α-MSH Similar to hormone replacement therapy Failure to develop ® 5
Slide 6: Significant Market Opportunity for MC4R Agonists
Significant Market Opportunity for MC4R Agonists U.S. patent protection for bivamelagon and RM-718 extends into 2040s Approved for IMCIVREE Acquired hypothalamic obesity Additional potential (setmelanotide) in U.S., EU,+ 5,000 – 10,000 ~29,000** 4,000 – 5,000* estimated U.S. prevalence1 EMANATE Bard
Slide 7: SIGNAL Trial: 14-week, Phase 2 Open-label Trial Evaluating Bivamelagon
SIGNAL Trial: 14-week, Phase 2 Open-label Trial Evaluating Bivamelagon in Patients with Hypothalamic Obesity RDZ 1:1:1:1 200 mg 200 mg 400 mg Long-term Screening 200 mg 400 mg 600 mg Extension (LTE) Trial 200 mg 400 mg 600 mg Placebo 2 weeks 12 weeks Open-label Week 0 Week 2 Week 14 Week 15 Week 16
Slide 8: Overall Baseline Demographics
Overall Baseline Demographics N=28 38.7 kg/m2 Mean BMI Overall bivamelagon 46.4% 82.1% population Female Patients with craniopharyngioma 25.4yo 7 years Mean Age Mean time from hypothalamic (13 of 28 <18yo) injury to trial enrollment ® 8
Slide 9: Baseline Demographics
Baseline Demographics BASELINE CHARACTERISTICS Biva 200 mg (N=6) Biva 400 mg (N=7) Biva 600 mg (N=8) Placebo (N=7) Age, years Mean (SD) 20.2 (9.2) 21.0 (7.9) 31.9 (23.0) 27.0 (20.2) Sex, n (%) Female 3 (50.0) 4 (57.1) 3 (37.5) 3 (42.9) Male 3 (50.0) 3 (42.9) 5 (62.5) 4 (57.1) Race, n (%) White 6 (10
Slide 10: Vast Majority of Patients Transitioned to Open-label Extension
Vast Majority of Patients Transitioned to Open-label Extension and Have Remained on Bivamelagon Therapy ENROLLED 26 of 27 eligible participants (n=28) transitioned to open-label extension (OLE) phase for up to 38 weeks DISCONTINUED 1 discontinuation OLE participants retitrated from due to SAE in Wee
Slide 11: Bivamelagon Achieved Statistically Significant BMI Reductions at All Doses
Bivamelagon Achieved Statistically Significant BMI Reductions at All Doses Placebo 200 mg 400 mg 600 mg +2.18% -2.68% -7.69% -9.31% Mean BMI increase Mean BMI reduction Mean BMI reduction Mean BMI reduction from baseline from baseline from baseline from baseline (n=7) (n=6) (n=7) (n=8) p-value = 0.0
Slide 12: Individual Percentage Change in BMI from Baseline to Week 14
Individual Percentage Change in BMI from Baseline to Week 14 10 6.5 5.2 5 Percentage Change in BMI,% 2.1 1.5 1.8 1.0 1.3 0.4 0 -0.1 * -1.7 -1.4 -3.2 -3.0 -3.5 -5 -4.2 -4.2 -6.9 -8.0 -7.8 -10 -9.3 -8.9 -9.0 -9.0 -9.6 -13.7 * -15 -14.8 -14.5 -16.4 -20 Placebo BIVA 200mg BIVA 400mg BIVA 600mg (n=7) (n=
Slide 13: Patients Achieved BMI Reductions of at least 5%, 10% at Week 14
Patients Achieved BMI Reductions of at least 5%, 10% at Week 14 100 Percentage of patients achieving BMI% 90 2 80 71.4% 1 75.0% 70 reduction cut point, % 60 50 40 37.5% 30 20 16.7% 14.3% 10 0.0% 0.0% 0.0% 0 Placebo 200mg BIVA 400mg BIVA 600mg BIVA (N=7) (N=6) (N=7) (N=8) Achieved a >=5% Reduction Ac
Slide 14: Setmelanotide Results in Ph2, Ph3 Trials at 12 and 16 Weeks
Setmelanotide Results in Ph2, Ph3 Trials at 12 and 16 Weeks in Patients >12 Years Old Setmelanotide Phase 2 Phase 3 Phase 2+3 combined Placebo Placebo n=11 n=12† n=48 n=52 † n=20 n=22† n=59 n=64† Mean percent BMI reduction, % 4 1.8 2 0.6 0 -2 -4 -6 -8 -10 -9.5 -9.7 -9.7 -10.2 -10.1 -12 -11.7 -14 ◼ W
Slide 15: Bivamelagon BMI Reductions at Week 14
Bivamelagon BMI Reductions at Week 14 Bivamelagon All patients Removing 2 patients with documented non-compliance 400 600 placebo 5.0 400 600 mg mg n=7 mg mg Mean percent BMI reduction, % n=7 n=8 2.2 n=6* n=7* 0.0 -5.0 -7.7 -10.0 -9.3 -8.8 -10.1 -15.0 ◼ Week 14 *1 patient in 400 mg arm and 1 patient
Slide 16: Post-hoc Analysis: Bivamelagon BMI Reductions Consistent with Setmelanotide
Post-hoc analysis: Bivamelagon Achieved BMI Reductions Consistent with Setmelanotide Setmelanotide Bivamelagon Phase 2+3 combined All patients Removing 2 patients with documented non-compliance 400 600 400 600 5.0 mg mg mg mg Mean percent BMI reduction, % n=59 n=64 n=8 n=7* n=7 n=6* 0.0 -5.0 -10.0 -
Slide 17: Bivamelagon Achieved Meaningful Reductions in 'Most' Hunger Scores at Week 14
Bivamelagon Achieved Meaningful Reductions in ‘Most’ Hunger Scores at Week 14 Bivamelagon QD Placebo QD (n=7) Change in most hunger score 200mg (n=6) 400mg (n=6*) 600mg (n=8) 0.0 -1.0 -0.8 -2.0 -2.1 -3.0 -2.8 -2.8 Weekly average of daily scores on a 10-point scale with 10 being ‘most’ hungry. *One p
Slide 18: AEs consistent with MC4R Mechanism, Setmelanotide Trials in Acquired Hypothalamic Obesity
AEs consistent with MC4R Mechanism, Setmelanotide Trials in Acquired Hypothalamic Obesity BIVA 200mg BIVA 400mg BIVA 600mg Placebo n (%) (N=6) (N=7) (N=8) (N=7) Any AEs 6 (100) 7 (100) 8 (100) 6 (86) Serious AEs 0 (0) 1 (14) 0 1 (14) Treatment-Related AEs 6 (100) 7 (100) 8 (100) 3 (43) Treatment-Rel
Slide 19: Developing New, Smaller Bivamelagon Tablet Potentially to Improve Tolerability
Developing New, Smaller Bivamelagon Tablet Potentially to Improve Tolerability Current Phase 2 tablet New Formulation Tablet • 200 mg tablet • 600 mg Tablet 90% (26% drug load) (90% drug load) • Total weight 823 mg • Total weight 760 mg • 18 mm x 8.6 mm • 18 mm x 8.33 mm Size 1 Capsule 19.4 mm x 6.9
Slide 20: Next Anticipated Steps for Development of Bivamelagon
Next Anticipated Steps for Development of Bivamelagon Data presentations Regulatory feedback • ENDO 2025 • Request End-of-Phase 2 • Update on open-label meeting with U.S. FDA Initiate Phase 3 extension study • Seek scientific advice trial to evaluate from the Committee for Medicinal Products for biv
Slide 21: Questions?
Questions? Rhythm