(RTTNews) - Rhythm Pharmaceuticals, Inc. (RYTM) has announced topline results from its global Phase 3 EMANATE trial of Setmelanotide, an MC4R agonist designed to address rare, genetically driven forms of obesity.
While the four sub studies did not meet their pre-specified primary endpoints, post hoc analyses revealed statistically significant and clinically meaningful reductions in body mass index (BMI) among patients with heterozygous variants of the POMC/PCSK1 and SRC1 (NCOA1) genes at 52 weeks.
Obesity linked to rare genetic variants in the MC4R pathway, with no approved therapies that directly target the underlying biology. Patients often struggle with severe weight gain and hyperphagia, conditions that can severely impact quality of life.
The EMANATE trial was randomized, double-blind, placebo-controlled study spanning four genetic subgroups: POMC/PCSK1, LEPR, SRC1 (NCOA1), and SH2B1. Across 52 weeks, patients received either Setmelanotide or placebo. The primary endpoint measured the difference in mean percent change in BMI from baseline to Week 52.
Topline findings included:
-POMC/PCSK1 heterozygous patients (n=78): -4.3% placebo-adjusted BMI reduction. -LEPR heterozygous patients (n=23): -3.6% placebo-adjusted BMI reduction.
-SRC1 (NCOA1) patients (n=73): -4.0% placebo-adjusted BMI reduction. -SH2B1 patients (n-121): -1.7% placebo adjusted BMI reduction However, post hoc analyses showed stronger signals:
-POMC/PCSK1 subgroup: -9.7% placebo-adjusted BMI reductions in patients completing 52 weeks
-SRC1 subgroup: -8.0% placebo-adjusted BMI reduction in completers.
No new safety concerns emerged, with the most common side effects being skin reactions, nausea, vomiting, and headache.
David Meeker, MD, Chair, President and CEO of Rhythm, emphasized that while the primary endpoints were not met, the results sharpen the company's ability to identify true loss-of-function variants and inform the development of next-generation MC4R agonists, including Bivamelagon and RM-718.
Upcoming milestones:
-Continued analysis of EMANATE data to guide development paths for SRC1 and POMC subgroups.
-Exploration of MC4R agonism in additional genetic families identified in the Phase 2 DAYBREAK trial.
-Advancement of next-generation MC4R agonist Bivamelagon and RM-718.
Rhythm's lead therapy IMCIVREE (Setmelanotide), is already FDA-approved for syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS), POMC/PCSK1 deficiency, or LEPR deficiency, and authorized in Europe and the UK for similar indications.
In 2025, IMCIVREE delivered net product revenue of $57.3 million in the fourth quarter, up from $41.8 million in the prior quarter. For the full year, revenue reached $194.8 million, compared with $130.1 million in 2024.
RYTM has traded between $97.72 and $170.46 over the past year. The stock closed Monday's trading session at $90.51, up 3.58%. During overnight trading, the stock fell to $83.48, down 7.77%.
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