Slide 1: Positive Preliminary Results from Phase 2 Trial Evaluating Setmelanotide in Prader-Willi Syndrome
® © Rhythm® Pharmaceuticals, Inc. All rights reserved. December 11, 2025 Rhythm Pharmaceuticals Positive Preliminary Results from Phase 2 Trial Evaluating Setmelanotide in Patients with Prader-Willi Syndrome
Slide 2: Forward-Looking Statements
2 ® 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 considered forward-look
Slide 3: On Today's Call
3 ® On Today’s Call David Meeker, MD Chairman, President & Chief Executive Officer, Rhythm Pharmaceuticals Jennifer Miller, MD Professor of Pediatric Endocrinology, University of Florida
Slide 4: David Meeker, MD
4 ® David Meeker, MD Chairman, President & Chief Executive Officer
Slide 5: Promising Phase 2 Preliminary Results in Patients with Prader-Willi Syndrome
5 ® Potential therapeutic benefit with BMI, hyperphagia reductions observed in patients with Prader-Willi syndrome (PWS) treated with setmelanotide at Month 3 (n=8) and Month 6 (n=5) Promising preliminary results supportive of Phase 3, registrational trial of setmelanotide in PWS Initiated Part D in
Slide 6: Significant Unmet Need in Prader-Willi Syndrome
6 ® PWS is a complex, multi-system disorder Obesity and hyperphagia may begin in early childhood; if not managed by stringent food restrictions and environmental controls, often results in life-threatening obesity Currently limited therapeutic options that effectively reduce the extreme hyperphagia
Slide 7: PWS: Complex Pathophysiology; MC4R Pathway Plays a Central Role
7 ® PWS: Complex Pathophysiology; MC4R Pathway Plays a Central Role
Slide 8: Historical Context: Beloranib Trial Results in PWS
8 ® Historical Context: Beloranib Trial Results in PWS with Mean % Change in Body Weight from Baseline to Week 26 Diabetes Obes Metab. 2017;19:1751–1761.
Slide 9: Prior Setmelanotide Trial in PWS in 2016
9 ® Individual patients demonstrated promising weight loss after 8 weeks Prior Setmelanotide Trial in PWS in 2016 had Maximum Dose of 2.5 mg for 8 Weeks in 4 Patients -8 -6 -4 -2 0 2 4 6 PBO run-in 2 wks 2.5 mg 4 wks 2.5 mg 2 wks 2.5 mg 2 wks 04005 03007 04004 04001
Slide 10: Exploratory Phase 2, Open-label Trial of Setmelanotide in PWS
10 ® 18 patients with PWS and obesity aged 6 to 65 years old enrolled Daily dose of setmelanotide escalated up to 5 mg/day as tolerated for 52 weeks Primary endpoints: safety and tolerability Key secondaries: assessments on BMI, hyperphagia, body composition and pharmacokinetics Exploratory Phase 2,
Slide 11: Baseline Demographics
11 ® Baseline Demographics N=18 Patients enrolled Parameter Statistic Overall (N=18) Age, years Mean (SD) (range) <12 years old, n (%) >12 years and <18, n (%) ≥18 years old, n (%) 17.1 (5.6) (6 – 23) 3 (16.7) 4 (22.2) 11 (61.1) Sex, n (%) Female / Male 8/10 (44.4/55.6) Race, n (%) White Multiple As
Slide 12: Setmelanotide Achieved BMI Reductions in 6 of 8 Patients at Month 3
12 ® Setmelanotide Achieved BMI Reductions from Baseline in 6 of 8 Patients with PWS at Month 3 -4.8 -3.8 -3.7 -2.8 -2.7 -1.3 2 2.4 -6 -4 -2 0 2 4 6 Pt 8 Pt 7 Pt 3 Pt 2 Pt 6 Pt 5 Pt 4 Pt 1 Age/Sex/BMI 12/F/32.6 23/M/37.4 23/F/42.2 18/F/44.6 23/M/45.4 14/M/38.8 21/M/41.5 20/F/67.0 V V % Change from B
Slide 13: HQ-CT Scores Showed Meaningful Hyperphagia Reductions at Month 3
13 ® HQ-CT1 Scores Showed Meaningful Hyperphagia Reductions from Baseline Observed in 6 of 7 Evaluable Patients at Month 3 14 6 10 0 7 18 24 20 1 4 0 0 4 22 10 11 0 5 10 15 20 25 30 Pt 8 Pt 7 Pt 3 Pt 2 Pt 6 Pt 5 Pt 4 Pt 1 Baseline Month 3 HQ-CT Score 1. The Hyperphagia Questionnaire for Clinical Tri
Slide 14: BMI Reductions After 3 and 6 Months of Treatment
14 ® -4.8 -3.8 -3.7 -2.8 -2.7 -1.3 2 2.4 -5.9 -5.6 -2.6 0.5 4.2 -8 -6 -4 -2 0 2 4 6 Pt 8 Pt 7 Pt 3 Pt 2 Pt 6 Pt 5 Pt 4 Pt 1 Mo3 Mo 6 Setmelanotide Achieved BMI Reductions from Baseline in Patients with PWS After 3 and 6 Months of Treatment Age/Sex/BMI 12/F/32.6 23/M/37.4 23/F/42.2 18/F/44.6 23/M/45.
Slide 15: Positive Body Composition Changes from Baseline to Month 6
15 ® Positive Body Composition Changes from Baseline to Month 6 Note: There are no DEXA data for Patient 1 (exceeded table’s weight limits) -7.9 -7.2 -10.1 3.2 -6.3 -0.1 -1 -0.2 -12 -10 -8 -6 -4 -2 0 2 4 Pt 3 Pt 2 Pt 6 Pt 5 Fat Mass Lean Mass % Change from Baseline
Slide 16: BMI Reductions After 3 and 6 Months of Treatment
16 ® -4.8 -3.8 -3.7 -2.8 -2.7 -1.3 2 2.4 -5.9 -5.6 -2.6 0.5 4.2 -8 -6 -4 -2 0 2 4 6 Pt 8 Pt 7 Pt 3 Pt 2 Pt 6 Pt 5 Pt 4 Pt 1 Mo3 Mo 6 Setmelanotide Achieved BMI Reductions from Baseline in Patients with PWS After 3 and 6 Months of Treatment Age/Sex/BMI 12/F/32.6 23/M/37.4 23/F/42.2 18/F/44.6 23/M/45.
Slide 17: Adverse Events for All Patients (N=18)
17 ® Adverse Events Overall n (%) (n=18) Skin hyperpigmentation 5 (27.8) Injection site reaction 4 (22.2) Fatigue 1 (5.6) Injection site irritation 1 (5.6) Peripheral swelling 1 (5.6) Nausea 1 (5.6) Vomiting 1 (5.6) Localized infection 1 (5.6) Diabetes mellitus inadequate control 1 (5.6) Lymphedema
Slide 18: Discussion with Dr. Jennifer Miller
18 ® Discussion with Dr. Jennifer Miller
Slide 19: Next Steps
19 ® Next Steps
Slide 20: Next Steps
20 ® Next Steps Setmelanotide PWS Updates • Complete six-month data readout in H1 2026 • Submit for presentation at a medical conference in 2026 • Begin planning for Phase 3 registrational trial Phase 1, Part D initiated to evaluate RM-718 in PWS • Up to 20 patients; 28-day screening period followed
Slide 21: Questions?
21 ® Questions?