Although the window for Rhythm Pharmaceuticals’ Imcivree to break out of the genetic obesity realm is quickly approaching with an upcoming FDA decision, a few other potential areas of expansion for the treatment have now been closed off after a phase 3 study miss.
Rhythm had been evaluating melanocortin-4 receptor (MC4R) agonist Imcivree (setmelanotide) in four independent substudies across different genetically-driven obesities of the MC4R pathway. In the trial, called Emanate, patients with a heterozygous variant of the POMC/PCSK1 gene, the LEPR gene, the SRC1 gene, or the SH2B1 gene were randomized to receive placebo or treatment over 51 weeks. Investigators tracked changes in patients’ body mass index (BMI) from baseline, the company explained in a March 16 release.
The selected patient groups were handpicked from a vast array of genetic obesity variants under the belief that Imcivree would have the “highest likelihood for success” in these populations, Rhythm said when it optimized the trial design in 2022, noting that it was targeting an addressable U.S. patient population of about 53,000 people.
However, the trial suffered from an “exceptionally high dropout rate,” CEO David Meeker, M.D. said on a Monday afternoon call with investors, making meeting the primary endpoint based on the analyses performed “extremely challenging.”
Ultimately, the drug failed to meet its primary endpoint in any of the four substudies. After 54 weeks, the POMC / PCSK1 patient group saw a 4.3% placebo-adjusted reduction in BMI, while the LEPR cohort experienced a 3.6% decrease, the SRC1 group had a 4% reduction and those in the SH2B1 group had a 1.7% placebo-adjusted BMI reduction.
Each group had discontinuation rates ranging from 27.3% to 59.5% across both placebo and treatment arms, Rhythm pointed out in an investor presentation (PDF). The SRC1 cohort had the highest dropout rate, with 21 of the 36 patients on treatment and 22 of the 37 on placebo dropping out of the study.
Across all of the discontinuations in the Imcivree arms, 42% dropped out due to adverse events, with the most common being hyperpigmentation, nausea and vomiting, according to the company. No new safety signals were observed during the study, Rhythm noted.
Although the topline results were a bust, the drug fared better when the results were measured using different analyses, according to the company. For one, a post hoc analyses based on last observation carried forward (LOCF) for missing values showed that the modified intent-to-treat patient populations in the POMC/PCSK1 and SRC1 substudies achieved statistically significant and clinically meaningful BMI reductions at week 52.
The LOCF approach can sometimes be used when follow-up observations are missing, but the method has been criticized for its statistical validity.
Either way, Rhythm will not be bringing the dataset to the FDA to support a potential filing, Meeker confirmed on the call. The company will, however, continue its analyses of the Emanate data and instead evaluate “potential clinical development paths forward” for patients with SRC1 (NCOA1) and POMC variants through its pipeline of next-generation MC4R agonists, it said in its release.
Rhythm is encouraged by the “compelling signals” demonstrated through the additional analyses of those subgroups, Meeker added, which can inform further development efforts.
“These patients continue to face a profound unmet medical need, with no approved treatment options that target the underlying biology of their disease,” the CEO said. “These results provide important insights that support our commitment to advancing targeted therapies for patients with rare genetic obesities.”
The miss comes days before the FDA is set to issue an approval decision on what would be Imcivree’s first non-genetic obesity indication. After the agency in November pushed back its target decision date to March 20, the countdown is on for Imcivree’s potential introduction into acquired hypothalamic obesity, or obesity that stems from damage to the part of the brain that controls hunger and weight regulation.
Leerink analysts see the drug’s opportunity in this indication as its main value driver, with the latest miss a “small bump in the road,” according to a recent note to clients. Despite the setback, the analysts continue to view Rhythm as a “leader within the genetically-linked obesity space," the Leerink team wrote.
Since 2020, Imcivree has been serving patients with obesity due to genetic factors, with its first approval covering those with POMC, PCSK1 or LEPR deficiencies as confirmed through genetic testing.
Imcivree picked up another approval for those with obesity due to Bardet-Biedl syndrome in 2022 and garnered $194.8 million in 2025 sales.