Rhythm’s EMANATE Trial For Setmelanotide Misses Primary Endpoints But Shows Promise In Select Genetic Obesity Subgroups

Rhythm Pharmaceuticals, Inc. announced topline results from its Phase III EMANATE trial evaluating setmelanotide in patients with rare, genetically driven obesities linked to the MC4R pathway. The study, which included four independent genetic substudies, did not meet its primary endpoints across all groups when analysed using the prespecified statistical approach.

The EMANATE trial was a global, randomised, double-blind, placebo-controlled study assessing patients with obesity associated with heterozygous variants in the POMC/PCSK1, LEPR, SRC1 (NCOA1), and SH2B1 genes. The primary endpoint measured the difference in percentage change in body mass index (BMI) at 52 weeks compared to placebo. Results showed modest placebo-adjusted BMI reductions across all substudies, but none reached statistical significance under the primary analysis.

“We are grateful to the patients with rare, genetically-driven MC4R pathway diseases and investigators who participated in this trial,” said David Meeker, MD, Chair, President and Chief Executive Officer of Rhythm Pharmaceuticals. “While we are disappointed the EMANATE substudies did not meet their primary endpoint, we are encouraged by compelling signals from additional analyses of the heterozygous POMC/PCSK1 and SRC1 substudies and learnings that sharpen our ability to identify true loss-of-function variants and inform the development of our next-generation MC4R agonists in rare genetically driven obesity indications.”

However, post hoc analyses provided more encouraging insights. Using alternative statistical methods, setmelanotide demonstrated statistically significant and clinically meaningful reductions in BMI in patients with POMC/PCSK1 and SRC1 variants. Among participants who completed the full 52-week treatment period, even greater reductions in BMI were observed, suggesting a potential benefit in specific patient subsets.

The safety profile of setmelanotide remained consistent with previous studies and real-world use, with no new safety concerns identified. The most commonly reported side effects included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache.

Dr. Meeker continued, “These patients continue to face a profound unmet medical need, with no approved treatment options that target the underlying biology of their disease. These results provide important insights that support our commitment to advancing targeted therapies for patients with rare genetic obesities.”

Despite missing the primary endpoints, Rhythm plans to continue analysing the EMANATE data and exploring future development strategies, with a particular focus on SRC1- and POMC-related obesity. The company is also advancing next-generation MC4R agonists, including bivamelagon and RM-718, and will further investigate additional genetic targets identified in earlier research.