Rhythm Pharmaceuticals: Initiating Overweight – Next Generation Pipeline Could Strengthen Intellectual Property of MC4R Franchise

Research evidence excerpt

Rhythm Pharmaceuticals: Initiating Overweight – Next Generation Pipeline Could Strengthen Intellectual Property of MC4R Franchise

Priyanka Grover, Ph.D. AC North America Equity Research

(1-212) 622-5534 27 July 2026 J P M O R G A N

priyanka.grover@jpmchase.com

Table 3: Efficacy Results of the Phase 3 Trial for Patients Aged 2 to <6 Years with POMC, PCSK1,

and LEPR Deficiency after 52 Weeks of Setmelanotide Treatment

Source: Company reports.

Recently, a randomized, double-blind, and placebo-controlled phase 3

trial (NCT05093634) evaluated setmelanotide in broader monogenic obesity across four

cohorts: heterozygous POMC/PCSK1 Hets, heterozygous LEPR Hets, SRC1 (NCO1),

and SH2B1. Patients were randomized 1:1 to setmelanotide or placebo for 52 weeks,

followed by an open-label extension. None of the cohorts met the primary endpoint of

placebo-adjusted BMI reduction at week 52 under conservative multiple imputation

analysis. Results were affected by high discontinuation rates, with 40–60% of patients

discontinuing treatment. In addition, limited understanding of variant classification for

the SRC1 and SH2B1 cohorts, where most variants were VUS, also impacted the

efficacy. However, post hoc analyses in genetically confirmed patients suggested

potential benefits. See summary of the weight-reduction efficacy and discontinuation

rates in Table 4.

Table 4: Efficacy Results and Discontinuation Rates in the Phase 3 Trial in Patients with POMC/

PCSK1 Variants and SRC1 (NCOA1) Variants After 52 Weeks of Setmelanotide Treatment

Bardet-Biedl Syndrome

Setmelanotide demonstrated statistically significant and clinically meaningful

reductions in body weight and hunger in patients with BBS. In the Phase 3

trial (NCT03746522), completed in November 2019, patients aged ≥6 years with BBS