Rhythm Pharmaceuticals (RYTM) Study result summary

Study overview and design

• EMANATE was a global, randomized, double-blind, placebo-controlled Phase 3 trial evaluating setmelanotide in four genetic obesity cohorts: POMC/PCSK1 HET, LEPR HET, SRC1 (NCOA1), and SH2B1, with BMI change at 52 weeks as the primary endpoint.

• Patient populations suffered from severe obesity (BMI >40), with diverse age and demographic profiles and similar demographics across cohorts.

• Patient numbers ranged from 23 (LEPR HETs) to 121 (SH2B1), with high dropout rates (27%-60%) due to adverse events, patient decision, non-compliance, and protocol violations.

• Variant classification and genetic confirmation were central to patient selection, especially for POMC, PCSK1, and LEPR HETs, but most SRC1 and SH2B1 variants were of unknown significance.

• The trial faced challenges in variant classification and high discontinuation rates, impacting analysis and future trial design.

Key efficacy and safety results

• None of the four substudies met their pre-specified primary endpoints for BMI reduction at 52 weeks versus placebo using the conservative multiple imputation method.

• Post hoc LOCF analyses showed statistically significant BMI reductions in POMC/PCSK1 HET and SRC1 cohorts, with LSM differences of -5.53% (p=0.0010) and -6.24% (p<0.0001) in mITT, and up to -9.7% and -8.0% in genetically confirmed completers.

• No significant BMI reduction was seen in SH2B1 or 16p11.2 subgroups at week 52, and the LEPR HET cohort was too small for meaningful analysis.

• Common adverse events included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache, with hyperpigmentation a leading cause of discontinuation.

• No new safety signals were observed; warnings include risk of hypersensitivity, depression, suicidal ideation, and skin pigmentation changes.

Learnings and future directions

• High dropout rates were attributed to trial burden, emergence of alternative therapies, and lack of dramatic response.

• Improved genetic testing and more precise identification of loss-of-function variants are priorities for future trials.

• Next-generation MC4R agonists will be prioritized for future studies, focusing on HO, Prader-Willi, BBS, and genetically confirmed patients.

• Regulatory filings will not proceed based on these results, but data will inform future trial design and regulatory discussions.

• Enhanced patient support and meaningful post-trial access to therapy are strategies to reduce placebo arm discontinuations.