Rhythm’s EMANATE Misses Endpoint, Highlights Subgroup Benefit

Rhythm Pharmaceuticals has reported topline results from its global Phase 3 EMANATE trial evaluating setmelanotide in patients with rare, genetically driven obesity linked to disruptions in the melanocortin-4 receptor (MC4R) pathway. The trial’s four genetic substudies failed to meet their primary endpoint of placebo-adjusted reduction in body mass index (BMI) at Week 52.

EMANATE (NCT05093634) was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of setmelanotide in individuals with obesity associated with heterozygous variants in key MC4R pathway genes. The trial enrolled patients across four independent substudies involving heterozygous variants in the POMC/PCSK1, LEPR, SRC1 (NCOA1), and SH2B1 genes. Participants were randomized 1:1 to receive setmelanotide or placebo over a 52-week treatment period.

In the primary analysis, which evaluated mean percent change in BMI from baseline to Week 52 using a modified intent-to-treat population with prespecified multiple imputation for missing data, none of the substudies achieved statistical significance. The placebo-adjusted reductions in BMI were –4.3% in POMC/PCSK1 heterozygous patients (p=0.15), –3.6% in LEPR heterozygous patients (p=0.94), –4.0% in SRC1 (NCOA1) patients (p=0.12), and –1.7% in SH2B1 patients (p=0.43).

Despite missing the primary endpoints, additional analyses suggested meaningful weight-loss signals in certain genetic subgroups. Post hoc analyses using a last observation carried forward method showed statistically significant BMI reductions at Week 52 in the POMC/PCSK1 heterozygous and SRC1 substudies, with least-squares mean differences of –5.5% (p=0.0010) and –6.2% (p<0.0001), respectively. Further analyses of genetically confirmed patients who completed the 52-week treatment period showed larger placebo-adjusted BMI reductions of –9.7% in POMC/PCSK1 heterozygous patients (p=0.0002) and –8.0% in SRC1 patients (p=0.0158).

No new safety signals were identified in the EMANATE trial, and the safety profile of setmelanotide remained consistent with previous studies and commercial experience. The most frequently reported treatment-emergent adverse events included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache.

According to Rhythm Pharmaceuticals’ leadership, the results provide important insights for refining genetic patient selection and guiding future development of MC4R-targeted therapies. The company plans to continue analysing the EMANATE dataset and explore potential development strategies in the SRC1 and POMC genetic obesity populations using next-generation MC4R agonists bivamelagon and RM-718.

Rhythm will also continue evaluating MC4R agonism across additional genetic obesity targets identified in the exploratory Phase 2 DAYBREAK study, including variants within the SEMA3, PHIP, TBX3, and PLXNA gene families.

Setmelanotide is a first-in-class melanocortin-4 receptor (MC4R) agonist that targets the biological pathway regulating hunger and energy balance in certain rare genetic forms of obesity. It is approved for adults and children aged 2 years and older with obesity due to Bardet-Biedl syndrome (BBS) or genetically confirmed POMC, PCSK1, or LEPR deficiencies. The therapy is intended for patients with pathogenic or likely pathogenic variants affecting the MC4R pathway and is not indicated for general or polygenic obesity.

Reference

Rhythm Pharmaceuticals Announces Topline Results from Phase 3 EMANATE Trial, 16 March 2026, https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-topline-results-phase-3-emanate

EMANATE: A Study of Setmelanotide in Patients with Specific Gene Variants in the MC4R Pathway, ClinicalTrials.gov ID NCT05093634, https://clinicaltrials.gov/study/NCT05093634