Rhythm Pharmaceuticals announced on Mar. 17 that its injectable obesity drug Imcivree did not significantly reduce weight compared to placebo in a late-stage study involving patients with rare genetic forms of obesity.
The results are important because they affect the future of treatments for people with rare genetic mutations linked to obesity, as well as Rhythm's business outlook. The Phase 3 EMANATE trial tested Imcivree across four groups of patients, each with different gene variants related to the melanocortin-4 receptor pathway.
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 called the outcome “disappointing” in a note to investors. Stifel had previously estimated around $300 million in risk-adjusted sales for Imcivree by 2034 from these indications. Following the news, Rhythm shares fell nearly 5% in premarket trading.
Imcivree was first approved in late 2020 for patients with obesity due to POMC, PCSK1 or LEPR deficiency and gained another approval in 2022 for Bardet-Biedl Syndrome. In 2025, sales reached $194.8 million, up from $130 million the previous year.
The EMANATE trial enrolled about 300 patients and measured changes in body mass index (BMI) after one year. Results showed placebo-adjusted BMI reductions ranging from 1.7% to 4.3% across all groups, but none achieved statistical significance. Posthoc analyses using additional statistical methods indicated significant effects for some groups: BMI dropped by 5.5% and 6.2% versus placebo among those with POMC/PCSK1 and SRC1 (NCOA1) variants.
Stifel said there was an "efficacy signal" and suggested Rhythm could use these findings to develop next-generation drugs targeting these populations. Rhythm stated it will continue analyzing data from EMANATE and may explore other pipeline products such as bivamelagon and RM-718 for certain gene mutations.
Looking ahead, Rhythm is waiting for a decision from the Food and Drug Administration on expanding Imcivree’s use into hypothalamic obesity—a much larger market that could bring peak global sales above $2 billion—with a verdict expected on or before March 20.
