Rhythm Pharmaceuticals announced that the Phase 3 EMANATE trial, a global, randomized, double‑blind study of setmelanotide in patients with rare, genetically‑driven obesity, failed to meet its primary endpoints across all four substudies.
The trial enrolled patients with heterozygous variants in POMC/PCSK1, LEPR, SRC1 (NCOA1), and SH2B1. In the intent‑to‑treat population, the mean percent change in BMI from baseline to week 52 was not statistically different from placebo. Post‑hoc analyses, however, revealed significant BMI reductions in the POMC/PCSK1 and SRC1 subgroups, suggesting potential signals that may guide future development.
Management attributed the miss to an exceptionally high dropout rate, ranging from 27.3% to 59.5% across placebo and treatment arms, and to the inclusion of patients without true loss‑of‑function variants, which diluted the treatment effect.
The result represents a setback for setmelanotide’s expansion into broader heterozygous MC4R pathway obesity indications. Rhythm will continue to analyze the data and focus on next‑generation MC4R agonists such as bivamelagon and RM‑718, while awaiting a March 20, 2026 FDA decision on a supplemental NDA for acquired hypothalamic obesity.
Rhythm’s Q4 2025 financial results, released on February 26, 2026, showed net product revenue of $57.3 million from IMCIVREE, up 12% sequentially and 37% YoY, and a net loss of $48.8 million. Cash and short‑term investments stood at $388.9 million, up from $320.6 million at year‑end 2024. For 2026, the company expects non‑GAAP operating expenses of $385 million to $415 million, reflecting continued investment in growth initiatives.
Analysts highlighted the high dropout rate and patient selection issues as key drivers of the trial miss, noting that these factors will shape Rhythm’s future development strategy and the commercial prospects of its MC4R‑targeted portfolio.
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