Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM
Rhythm Pharmaceuticals — 32nd European Congress on Obesity 2025
15 slides from Rhythm Pharmaceuticals's conference presentation, May 2025
Slide 1: DAYBREAK Trial: Setmelanotide vs placebo in patients with melanocortin-4 receptor pathway variants
DAYBREAK Trial: Setmelanotide vs placebo in patients with melanocortin-4 receptor pathway variants Gloria Ortiz, MD1; Svetlana Ten, MD2; Whitney Herring, MD3; Orit Pinhas-Hamiel, MD4; Elif A. Oral, MD5; Nina Rosano, MD6; Dorit Koren, MD, MTR7; Hak-myung Lee, PhD7; Jill C. Garrison, PhD7; Olga Ohayon
Slide 2: ECO 2025 - Conflict Of Interest
ECO 2025 - Conflict Of Interest Name: Erica van den Akker I have the following potential conflicts of interest to report: X Research Contracts X Consulting Employment in the Industry Stockholder of a healthcare company Owner of a healthcare company Other(s) I declare that I have no poten
Slide 3: The central hypothalamus is a key regulator of energy balance, appetite, and bodyweight
The central hypothalamus is a key regulator of energy balance, appetite, and bodyweight • The hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance and food intake1,2 AgRP, agouti-related peptide; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyt
Slide 4: Impaired MC4R signalling due to rare genetic variants may result in hyperphagia and obesity
Impaired MC4R signalling due to rare genetic variants may result in hyperphagia and obesity from the first years of life1–4 • The MC4R agonist setmelanotide is approved by the FDA and EMA for the treatment of certain MC4R pathway diseases, controlling hyperphagia* and treating obesity5,6 • DAYBREAK
Slide 5: Objectives of this study
Objectives of this study • To determine the efficacy of setmelanotide in achieving weight loss in children and adults with obesity related to gene variants selected by Rhythm’s ClinGen-based framework based on their strong association with the MC4R pathway1 • To identify which populations may have t
Slide 6: Inclusion criteria and primary endpoint
Inclusion criteria and primary endpoint Stage 1 eligibility criteria Primary endpoint Stage 2 eligibility criteria • Genetic confirmation in patients • Proportion of patients by • Reduction at end of Stage 1, 6–65 years genotype who achieved a BMI from baseline • Patients with obesity reduction of ≥
Slide 7: Study design
Study design • Efficacy outcome assessed at end of Stage 2 was change from baseline in BMI (kg/m2) Stage 1: Open-label run-in Stage 2: Double-blind, placebo-controlled Open-label dose titration Open-label run-in Randomised, double-blind ≥12 years: Setmelanotide 3 mg starting dose 2 mg Screening Comp
Slide 8: Patient disposition
Patient disposition Randomised into Discontinued Moved to early bridging Completed Stage 2 DAYBREAK Stage 2 from Stage 2 due to weight regain N=49 n=4 n=6 n=39 3 placebo, 1 4 placebo, 2 3 were rescued under protocol setmelanotide setmelanotide version 1 (placebo to setmelanotide) 32nd European Congr
Slide 9: Patient and demographics
Patient and demographics • After Stage 1, 49 patients with PHIP, PLXNA(1-4), SEMA3(A-G), SIM1, MAGEL2, TBX3, or RPGRIP1L variants were randomised 2:1 to receive setmelanotide or placebo Stage 2 cohort demographics All <18 y ≥18 y Male, n (%) 22 (44.9) 10 (45.5) 12 (54.5) Female, n (%) 27 (55.1) 14 (
Slide 10: Results
Results A higher proportion of patients in the setmelanotide Mean (SD; range) percent BMI change in the arm achieved or maintained 5% BMI reduction from continuous setmelanotide arm from baseline to study baseline to the end of Stage 2 the end of Stage 2 100 P=0.001 84.4 Number of patients, % 80 n=2
Slide 11: Results in patients with PHIP variants
Results in patients with PHIP variants • Individuals with PHIP variants, which can lead to obesity by disrupting POMC transcription, maintained a consistent weight loss response PHIP Adult, n=5 Paediatric, n=4 Rescue with 5 setmelanotide 5 from baseline, % 0 0 BMI change Early bridging to setmelanot
Slide 12: Results in patients with SEMA3E variants
Results in patients with SEMA3E variants • SEMA3E had excellent response, but was limited by the sample size (n=3) • SEMA3 (A D, F, G) had a more variable degree of weight loss SEMA3 (A–G) Adult, n=7* Paediatric, n=8* 5 5 Early Bridging 0 0 Discontinued X from baseline, % X X -5 -5 BMI change -10 -1
Slide 13: Results in patients with PLXNA and SIM1 variants
Results in patients with PLXNA and SIM1 variants • PLXNA (1-4) and SIM1 had a more variable degree of weight loss, some of substantially greater magnitude than PHIP PLXNA (1-4) Adult, n=8 Paediatric, n=5 5 5 0 0 from baseline, % X -5 -5 BMI change X X -10 -10 -15 -15 -20 Rescue with setmelanotide -2
Slide 14: Safety
Safety • Setmelanotide was well tolerated with no new safety concerns across the entire study Most common adverse events (incidence >20%) • Skin hyperpigmentation • Melanocytic naevus • Injection site reactions • Headache • Nausea • Vomiting 32nd European Congress on Obesity ● May 11–14, 2025 ● Mala
Slide 15: Conclusion
Conclusion • Clinical response to setmelanotide treatment, a highly selective MC4R agonist, suggests that the MC4R pathway may be a key biologic driver of obesity in patients with variants of interest • The design of the exploratory DAYBREAK trial enabled the identification of multiple genes of inte
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