Rhythm’s Bivamelagon achieved statistically significant and clinically meaningful reductions in BMI in patients with hypothalamic obesity

Rhythm Pharmaceuticals’ bivamelagon (formerly LB54640), an investigational oral melanocortin-4 receptor (MC4R) agonist, achieved statistically significant and clinically meaningful reductions in BMI at 14 weeks of treatment in patients with hypothalamic obesity.

In the 14-week, double-blind, four-arm, placebo-controlled portion of the trial, bivamelagon achieved:

• -9.3% BMI reduction from baseline in the 600mg cohort (n=8, p=0.0004)

• -7.7% BMI reduction from baseline in the 400mg cohort (n=7, p=0.0002)

• -2.7% BMI reduction from baseline in the 200mg cohort (n=6, p=0.0180); and

• BMI for patients in the placebo cohort (n=7) increased by 2.2% over 14 weeks.

In a post-hoc analysis comparing the randomized Phase 2 results to results from prior setmelanotide trials, bivamelagon demonstrated BMI reductions consistent with BMI reductions achieved with setmelanotide therapy, as observed in similar patient populations at comparable dosing durations.

In this post-hoc comparison of the subset of setmelanotide patients who demonstrated study compliance and were not on concomitant GLP1 therapy (no patients who enrolled in the Phase 2 bivamelagon trial were on concomitant GLP1 therapy), setmelanotide and bivamelagon achieved:

• -9.7% and -10.5% mean BMI reductions achieved in a pooled patient population (n=59; n=64) from Phase 2 and Phase 3 trials of setmelanotide therapy at 12 weeks and 16 weeks, respectively; as compared to:

• -8.8% and -10.1% mean BMI reductions achieved in patients (400mg n=6; 600mg n=7) at 14 weeks of bivamelagon therapy.

In addition, patients reported meaningful reductions in their ‘most’ hunger scores at 14 weeks on therapy compared to placebo, consistent with past setmelanotide trials and MC4R agonism.

Patients in the 600mg (n=8) and 400mg (n=6) cohorts achieved a mean reduction greater than 2.8 points in their ‘most’ hunger scores measured on a 10-point scale at 14 weeks of bivamelagon therapy. Six patients in the 200mg arm achieved a mean reduction of 2.1 points in their ‘most’ hunger score, while patients on placebo therapy reported a mean increase of 0.8 points in their mean ‘worst’ hunger score.

Bivamelagon demonstrated safety and tolerability results consistent with MC4R agonism and mechanism of action during the placebo-controlled portion of the trial. During the placebo-controlled portion of the trial, one patient discontinued therapy due to a serious adverse event (rectal bleeding).

The most common reported adverse events were episodes of diarrhoea and nausea, the vast majority of which were mild or grade 1. There were reports of mild, localized hyperpigmentation from four patients, including one patient on placebo. A total of 27 patients completed the 14-week, placebo-controlled portion of the trial, and 26 of them transitioned into the open-label extension of the trial and remained in that portion of the trial, as of 7 July 2025.

“We are excited by these results, which suggest bivamelagon has the potential to treat patients with acquired hypothalamic obesity, and has established an appropriate dose range for future clinical evaluation. Unlike in studies evaluating general obesity, once again we observed no placebo effect in this study,” said Dr David Meeker, Chair, Chief Executive Officer and President of Rhythm Pharmaceuticals. “We look forward to engaging with US and European regulatory authorities to seek alignment on a Phase 3 trial design as we continue advancing bivamelagon.”

With these results in hand, Rhythm plans to seek input from US and EU regulatory authorities on a Phase 3 trial design to advance bivamelagon in acquired hypothalamic obesity. The Company plans to request an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) and to seek scientific advice from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Rhythm also is refining the formulation of bivamelagon potentially to improve tolerability ahead of initiating a Phase 3 trial.