Setmelanotide phase 3 trial reports weight loss in Bardet-Biedl syndrome

Results from a phase 3 trial of setmelanotide were published on Nov. 7, 2022, in The Lancet Diabetes & Endocrinology. Among patients aged 12 and older with Bardet-Biedl syndrome, 32.3% reached at least a 10% reduction in body weight after 52 weeks of treatment (95% CI 16.7 to 51.4; p=0.0006) ^[1].

Setmelanotide is not a GLP-1 medication. It is a melanocortin-4 receptor agonist, meaning it acts on a different appetite-signaling pathway than semaglutide (Ozempic, Wegovy, Rybelsus) or tirzepatide (Mounjaro, Zepbound) ^[1]. The trial tested it in two rare genetic conditions that cause early, severe obesity and hyperphagia: Bardet-Biedl syndrome and Alström syndrome ^[1].

How the trial was run

The study enrolled 38 patients between Dec. 10, 2018, and Nov. 25, 2019, at 12 hospitals, clinics and universities in the United States, Canada, the United Kingdom, France and Spain. Patients were 6 or older and had a clinical diagnosis of either syndrome plus obesity, defined as a BMI above the 97th percentile for age and sex for those aged 6 to 15, or 30 kg/m2 or higher for those 16 and older ^[1].

Participants were assigned at random, 1-to-1, to receive up to 3.0 milligrams of subcutaneous setmelanotide or placebo once daily during a 14-week double-blind period. Everyone then received open-label setmelanotide for 52 weeks. Each group included 16 patients with Bardet-Biedl syndrome and three with Alström syndrome ^[1].

The primary endpoint was the proportion of patients aged 12 and older who lost at least 10% of body weight from baseline after 52 weeks of setmelanotide. That endpoint was measured in patients with Bardet-Biedl syndrome, and 32.3% met it ^[1]. Because the 52-week measurement came after the placebo-controlled phase had ended, all patients were receiving active drug during that period, so the 52-week figure has no placebo comparison in the trial design ^[1].

In the Alström syndrome group, the paper states, results were inconclusive. The authors write that the Bardet-Biedl syndrome results supported use of the drug and provided the necessary evidence for approval of setmelanotide as the first treatment for obesity in patients with Bardet-Biedl syndrome ^[1].

The most commonly reported treatment-emergent adverse events were skin hyperpigmentation, reported in 23 of 38 patients (61%), and injection site erythema, reported in 18 of 38 (48%). Two patients had four serious adverse events — blindness, anaphylactic reaction and suicidal ideation — none of which were considered related to setmelanotide treatment ^[1]. The trial was funded by Rhythm Pharmaceuticals, the drug's maker, and several authors disclosed payments, consulting fees or stock ownership tied to the company ^[1]. A correction to the paper was published in February 2023 ^[1].

Why it matters for patients

Setmelanotide is aimed at a narrow group, not at obesity in general. The trial enrolled people with a confirmed clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome, and the positive result was reported in the Bardet-Biedl group ^[1]. Adults taking a GLP-1 drug for common obesity would not fall into that population based on what this paper describes.

The headline number also comes with wide statistical bounds. The 32.3% figure has a confidence interval running from 16.7% to 51.4%, which reflects how few patients were studied — 38 in total, split across two syndromes and two treatment groups ^[1]. That means the true share of Bardet-Biedl patients who might reach a 10% weight reduction is not pinned down precisely by this trial.

The safety picture in the paper is mostly local and cosmetic: skin darkening and injection site redness were the events reported most often, and the four serious events in two patients were judged unrelated to the drug ^[1]. Whether weight loss is maintained past 52 weeks was not reported in this paper, and no comparison between setmelanotide and any GLP-1 or other weight-loss medication has been reported in it ^[1].

A separate commentary on the trial appeared in the same journal issue ^[1].