Rhythm Pharmaceuticals EMANATE Trial Yields 6.2% BMI Drop in SRC1 Substudy
Rhythm Pharmaceuticals’ Phase 3 EMANATE trial substudies in heterozygous POMC/PCSK1, LEPR, SRC1 and SH2B1 variants failed to meet primary endpoints, with placebo-adjusted BMI reductions ranging from 1.7% to 4.3% (p>0.12). Post hoc analyses showed statistically significant 5.5% and 6.2% BMI decreases at 52 weeks in POMC/PCSK1 and SRC1 patients (p≤0.001).
1. Topline EMANATE Results
Rhythm’s global Phase 3 EMANATE trial evaluated setmelanotide across four genetic substudies in POMC/PCSK1, LEPR, SRC1 and SH2B1 heterozygous obesity patients, randomized 1:1 to drug or placebo for 52 weeks. None of the substudies achieved the prespecified primary endpoint of placebo-adjusted mean percent change in BMI (ranging –1.7% to –4.3%, all p>0.12).
2. Post Hoc Analyses Highlight Significant BMI Reductions
Exploratory analyses using last observation carried forward showed least-squares mean placebo-adjusted BMI reductions of 5.5% (p=0.0010) in POMC/PCSK1 heterozygotes (n=78) and 6.2% (p<0.0001) in SRC1 patients (n=73) at Week 52. Among patients who completed the trial, BMI dropped 9.7% (p=0.0002) and 8.0% (p=0.0158) respectively.
3. Safety Profile
No new safety signals emerged; adverse events aligned with prior data and commercial use of setmelanotide. The most common events were skin hyperpigmentation, injection site reactions, nausea, vomiting and headache.
4. Next Development Plans
Rhythm plans further analyses of the EMANATE dataset and to advance its next-generation MC4R agonists, bivamelagon and RM-718, targeting SRC1 and POMC genetic populations, while exploring additional genes identified in the Phase 2 DAYBREAK study such as SEMA3, PHIP, TBX3 and PLXNA families.