A Phase III trial of Rhythm Pharmaceuticals’ Imcivree (setmelanotide) failed to meet its primary endpoints in four rare, genetically driven obesities of the MC4R pathway.
In the EMANATE trial (NCT05093634), there were four genetic substudies conducted in patients with obesity due to a heterozygous (Hets) variant of the POMC/PCSK1 gene, the LEPR gene, the SRC1 (NCOA1) gene, or the SH2B1 gene. Patients were randomised to receive Imcivree or placebo for 52 weeks.
The primary endpoint was the difference in BMI pre- and post-treatment. In the POMC/PCSK1 Hets, there was a 4.3% placebo-adjusted reduction in BMI and in the LEPR Hets cohort, a 3.6% placebo-adjusted reduction in BMI was reported. In the SRC1 (NCOA1) population, there was a 4.0% placebo-adjusted reduction and in the SH2B1 population, there was a 1.7% placebo-adjusted reduction in BMI. None of these were statistically significant.
There had been a very high drop out rate in the trial, the company confirmed during an investor call. As a result, when using post hoc analysis using last observation carried forward for missing values, Imcrivee achieved statistically significant and clinically meaningful BMI reductions in the modified intent-to-treat patient populations in the POMC/PCSK1 Hets (5.5%) and SRC1 (6.2%). The company will not be presenting this data to regulators.
No new safety signals were observed with Imcrivee, and the safety profile was consistent with prior clinical studies and commercial experience. The most common treatment-emergent adverse events (TEAEs) included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache.
Dr David Meeker, CEO of Rhythm Pharmaceuticals, said: “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.”
As a result, Rhythm will continue the analysis of the EMANATE dataset and evaluate potential development paths forward with SRC1 (NCOA1) and POMC with its next-generation MC4R agonists bivamelagon and RM-718.
This trial failure comes shortly before the US Food and Drug Administration (FDA) is set to issue an approval decision on Imcivree in a non-genetic obesity indication – acquired hypothalamic obesity, following a delay to the decision in November 2025.
The drug was first approved in November 2020 for patients six years of age and older with POMC, PCSK1 or LEPR deficiencies. Another approval came in June 2022 for use in patients with Bardet-Biedl syndrome, a rare type of genetic disorder.
