Rhythm Pharmaceuticals (NASDAQ:RYTM) reported Phase 3 top-line results from its EMANATE trial evaluating setmelanotide in four heterozygous genetic cohorts linked to MC4R pathway dysfunction, with company leadership describing the study as “statistically negative” on its prespecified primary endpoint but highlighting signals in select subgroups and lessons that could inform future development with next-generation assets.
Trial missed primary endpoint across all four cohorts
Chief Executive Officer David Meeker said the company “miss[ed] the primary endpoint in all four cohorts.” The primary endpoint was change in BMI at 52 weeks in a standard double-blind, placebo-controlled design with 1:1 randomization.
Variant classification and high discontinuation rate shaped outcomes
Management emphasized that patient selection and variant interpretation were central challenges in EMANATE. The company characterized enrollment as a heuristic process based on evolving scientific understanding of MC4R pathway dysfunction and noted that variant classification is dynamic across medical genetics.
Rhythm said it had stronger understanding of variants in its POMC, PCSK1, and LEPR heterozygous cohorts, while much less was known about SRC1 and SH2B1, where “almost all variants are classified as VUS” (variants of unknown significance). Meeker reminded investors that, on average, only about 20% of VUS are ultimately classified as pathogenic or likely pathogenic.
The company also pointed to an “exceptionally high dropout rate,” with discontinuation averaging 40% to 60% across cohorts. Rhythm said dropout rates were generally similar between treatment and placebo arms (except in the small LEPR heterozygous cohort). Aggregated across studies, patient decision was the most common reason for placebo discontinuations, while adverse events were the most common reason for discontinuations on setmelanotide.
POMC heterozygous and SRC1 showed signals in alternative analyses
While the prespecified primary endpoint analyses were negative, Rhythm highlighted post-hoc and subgroup analyses suggesting potential activity in POMC heterozygous and SRC1 populations.
- POMC heterozygous: Rhythm presented a post-hoc last observation carried forward (LOCF) analysis in the mITT population showing a 5.53% difference, described as highly statistically significant. In a genetically confirmed cohort (following a reconfirmation step that resulted in a net 11 patients being removed), the company showed a 6.8% difference using LOCF. In an additional post-hoc analysis limited to genetically confirmed patients who completed the study, Rhythm reported a 9.7% least squares mean difference.
- SRC1: Despite all enrolled variants being VUS, the mITT multiple imputation analysis showed a least squares mean value of -4% with a P-value of 0.12, which the company described as the strongest trend toward significance among cohorts. In a post-hoc LOCF analysis, Rhythm reported a highly statistically significant 6.24% difference. In a post-hoc analysis of genetically confirmed completers, Rhythm reported an 8% difference. The company also highlighted an exploratory analysis focusing on patients with variants in a critical SRC1 binding domain: among 12 completers (out of 19 identified), the placebo-adjusted difference was 12.7%.
Meeker said the company has learned more about the genes and believes patients with impaired MC4R-pathway signaling have difficulty losing weight with diet and exercise. He added that a stronger placebo response in some cohorts may reflect a higher proportion of benign variants and a pathophysiology closer to general obesity.
LEPR and SH2B1 outcomes; no plans to file based on EMANATE
Meeker described the SH2B1 16p11.2 cohort as “the most disappointing,” noting that the mITT analysis showed no effect on average. In a genetically confirmed completer analysis, the difference was about 3% and not statistically significant, and an analysis limited to known loss-of-function 16p11.2 deletion patients similarly showed only a modest, non-significant effect.
For the LEPR heterozygous cohort, Rhythm said recruitment was difficult due to rarity, and a small number of patients had a variant that was down-classified on reanalysis by the central lab. Meeker said the company does not anticipate further work in this population, though he added he still believes setmelanotide works in LEPR heterozygous patients and pointed to recruitment challenges.
In the Q&A, management said it will not pursue regulatory filings for any EMANATE cohorts based on the alternative analyses. Meeker also said Rhythm would not run another setmelanotide trial in these genetic indications; any additional work would be done with next-generation assets.
Next steps: next-generation programs, trial execution, and testing strategy
Meeker said future efforts would focus on next-generation therapies and prioritized programs including hypothalamic obesity (HO) studies, Prader-Willi syndrome studies, and Bardet-Biedl syndrome (BBS) work, as well as patients with confirmed loss-of-function variants. He also noted ongoing investigation of “Daybreak genes” from Phase 2 efforts to improve loss-of-function determination.
On discontinuations, Meeker cited several potential contributors, including trial burden, less dramatic average responses, the long study timeline (which began in 2022), and competition from emerging GLP-1 therapies. He also said Rhythm intends to improve future trials by better identifying true loss-of-function patients and by executing studies more effectively.
Regarding adverse events, the company said EMANATE’s profile was consistent with prior setmelanotide trials, with injection site reactions, gastrointestinal complaints, and hyperpigmentation most common. In response to a question, Meeker said that across Rhythm’s experience, about 5% of discontinuations are due to hyperpigmentation, and he expected EMANATE to be similar, though he noted he did not have the specific dataset detail on hand.
Meeker also discussed the company’s approach to genetic testing, saying Rhythm does not aim to be a testing company but often must provide testing in rare disease settings. He suggested broader recognition of GLP-1 “failures” could drive more genetic workups over time, potentially improving identification of patients more likely to carry pathogenic variants and supporting future enrollment.
Meeker closed by thanking patients, families, investigators, and study teams, calling EMANATE “not easy” and framing the outcome as a building block despite missing the primary endpoint.
About Rhythm Pharmaceuticals (NASDAQ:RYTM)
Rhythm Pharmaceuticals, Inc is a clinical‐stage biotechnology company dedicated to developing targeted therapies for rare genetic diseases of obesity and metabolic dysfunction. The company’s research focuses on the melanocortin‐4 receptor (MC4R) pathway, which plays a central role in regulating appetite, energy expenditure and body weight. Using proprietary peptide technology, Rhythm aims to provide precision treatments to patients with specific genetic variants that disrupt normal weight regulation.
The company’s lead investigational product, setmelanotide, is a selective MC4R agonist designed to restore signaling in patients with deficiencies in genes such as POMC, LEPR and PCSK1.
