The Phase 3 EMANATE study is a basket trial looking at the efficacy of Rhythm Pharmaceuticals’ injectable obesity drug across four types of obesities driven by specific genetic mutations.
Rhythm Pharmaceuticals’ injectable obesity drug Imcivree failed to significantly reduce weight versus placebo in a late-stage basket study across four key subpopulations of patients with rare forms of obesity linked to specific genetic mutations.
This outcome, stemming from the Phase 3 EMANATE trial, is “disappointing,” according to analysts at Stifel. “Candidly we had thought that at least one sub-population in the EMANATE basket study could’ve resulted in a fileable dataset,” the firm told investors in a note on Monday.
Stifel had previously modeled around $300 million in risk-adjusted Imcivree sales by 2034 across the four EMANATE indications. At $86 per share, Rhythm is down nearly 5% in premarket trading on Tuesday.
Imcivree was first approved in late 2020 to treat patients with obesity due to POMC, PCSK1 or LEPR deficiency. The drug picked up another indication in 2022 for weight management in patients with Bardet-Biedl Syndrome, a rare genetic disease that manifests as obesity in childhood. In 2025, Imcivree made $194.8 million in sales, up form its $130 million revenue the year prior.
EMANATE enrolled nearly 300 patients with obesity linked to variants in one of four variants genes linked to the melanocortin-4 receptor pathway: POMC/PCSK1, LEPR, SRC1 (NCOA1) or SH2B1. Each gene variant group was enrolled in its own EMANAGE sub-study, and patients were randomly assigned to receive Imcivree or placebo.
Across the four sub-studies, the trial’s primary objective was to assess the change in body mass index (BMI) at 52 weeks. Results presented on Monday pointed to a placebo-adjusted 4.3% BMI reduction in those with POMC/PCSK1 variants, and a 3.6% decrease in those with LEPR mutations.
Meanwhile, Imcivree treatment resulted in a 4% BMI drop in those the SRC1 (NCOA1) cohort and a 1.7% decline in patients with SH2B1 mutations. None of the sub-studies achieved statistical significance.
Despite missing its primary endpoint, Rhythm conducted posthoc analyses with a statistical maneuver to account for missing data. These analyses showed a “statistically significant and clinically meaningful” effect of Imcivree in the POMC/PSK1 and SRC1 (NCOA1) cohorts, in which BMI dropped 5.5% and 6.2% versus placebo, respectively.
Stifel looked at this posthoc evaluation optimistically. “There was an efficacy signal here,” the analysts wrote on Monday, adding that “there still is the opportunity for RYTM to try to leverage learning from EMANATE and address multiple of these sub-populations with one of their next-gen” drugs.
Rhythm appears to intend to do just that. The biotech said on Monday that it will continue to analyze EMANATE data to see if any of its other pipeline products—including the MC4R agonists bivamelagon and RM-718—could be developed for the SC1 (NCOA1) and POMC mutations.
Outside of EMANATE, Rhythm is awaiting the FDA’s decision on its application to expand Imcivree into hypothalamic obesity, an indication that according to Stifel is much more central to the biotech’s valuation, with peak global sales exceeding $2 billion. The regulator is set to release its verdict on or before March 20.
