The chance for Rhythm Pharmaceuticals’ Imshivly to break out of the genetic obesity realm is rapidly approaching with the upcoming FDA decision, but several other areas of potential expansion for this treatment are currently closed off due to failed Phase 3 trials.
Rhythm was evaluating the melanocortin 4 receptor (MC4R) agonist Imsivly (cetomelanotide) in four independent substudies targeting obesity due to various genetic factors in the melanocortin 4 receptor (MC4R) pathway. In the trial, called Emanate, patients with heterozygous variants in the POMC/PCSK1, LEPR, SRC1, or SH2B1 genes were randomly assigned to receive a placebo or treatment for 51 weeks. In a March 16 release, the company said researchers tracked changes in patients’ body mass index (BMI) from baseline.
The selected patient groups were hand-picked from a vast number of genetic obesity variants with the belief that Imsivly is “most likely to be successful” in these populations, Rhythm said when it optimized the trial design in 2022, noting that it targeted an addressable U.S. patient population of approximately 53,000 patients.
However, the trial has been plagued by an “unusually high dropout rate,” making it “extremely difficult” to meet the primary endpoint based on the analyzes conducted, CEO David Meeker, MD, said on a conference call with investors Monday afternoon.
Ultimately, the drug failed to meet its primary endpoint in any of the four substudies. After 54 weeks, the POMC/PCSK1 patient group had a 4.3% placebo-adjusted BMI reduction, while the LEPR cohort had a 3.6%, SRC1 group had a 4%, and SH2B1 group had a 1.7% placebo-adjusted BMI reduction.
Discontinuation rates in each group ranged from 27.3% to 59.5% for both the placebo and treatment groups, Rhythm noted in an investor presentation (PDF). The SRC1 cohort had the highest dropout rate, with 21 of 36 patients receiving treatment and 22 of 37 patients receiving placebo dropping out of the study.
The company said 42% of discontinuers in the Imcivree arm discontinued due to adverse events, the most common being hyperpigmentation, nausea and vomiting. Rhythm noted that no new safety signs were observed during the study.
The company said the top-line results were a failure, but when the results were measured using a different assay, the drug performed better. First, post-hoc analysis based on last observation carryforward of missing values (LOCF) showed that the modified intention-to-treat patient population in the POMC/PCSK1 and SRC1 substudies achieved statistically significant and clinically meaningful BMI reductions at week 52.
The LOCF approach is sometimes used when follow-up observations are missing, but this method has been criticized for its statistical validity.
In any case, Rhythm does not intend to bring the data set to the FDA to support a potential application, Meeker confirmed by phone. However, the company said in a statement that it will continue to analyze Emanate data and instead evaluate “potential for future clinical development” in patients with SRC1 (NCOA1) and POMC mutations through its pipeline of next-generation MC4R agonists.
Meeker added that “compelling signals” demonstrated through additional analysis of these subgroups could drive cadence and inform further development efforts.
“These patients continue to face significant unmet medical needs, and there are no approved treatment options that target the underlying biology of the disease,” the CEO said. “These results provide important insights that support our efforts to advance targeted therapies for patients with rare genetic obesity.”
The mistake came just days before the FDA was scheduled to issue an approval decision for Imshivly’s first non-genetic obesity indication. After the agency in November pushed back the target date to March 20, the countdown has begun on the potential introduction of Imusivly for acquired hypothalamic obesity, obesity caused by damage to the part of the brain that controls hunger and weight regulation.
Analysts at Leerink see the drug’s opportunity in this indication as the primary value driver, with recent failures representing “minor bumps in the road,” according to a recent note to clients. Despite the setback, analysts continue to view Rhythm as a “leader in the field of genetic-related obesity,” the Leerink team wrote.
Imcivree has been serving patients with genetically induced obesity since 2020, and its initial approval was for patients with POMC, PCSK1, or LEPR deficiencies confirmed by genetic testing.
Imcivree received new approval in 2022 for patients with obesity due to Bardet-Biedl syndrome and achieved sales of $194.8 million in 2025.
