Setmelanotide phase 3 results published for Bardet-Biedl syndrome

Results from a phase 3 trial of setmelanotide, a melanocortin-4 receptor (MC4R) agonist, were published in The Lancet Diabetes & Endocrinology, reporting that 32.3 percent of patients aged 12 and older with Bardet-Biedl syndrome reached at least a 10 percent reduction in body weight after 52 weeks of treatment ^[1]. The finding was statistically significant (95% CI 16.7 to 51.4; p=0.0006) ^[1]. Setmelanotide works differently from GLP-1 medicines like semaglutide (Ozempic, Wegovy, Rybelsus) or tirzepatide (Mounjaro, Zepbound); it targets a receptor pathway tied to hunger signaling in the brain rather than the gut hormone system those drugs mimic.

The trial enrolled 38 patients with Bardet-Biedl syndrome or Alström syndrome, two rare genetic conditions linked to early-onset severe obesity and constant hunger ^[1]. Participants were randomly assigned to receive daily injections of setmelanotide or placebo for 14 weeks, then all moved to open-label setmelanotide for 52 weeks ^[1]. Enrollment ran from December 10, 2018, to November 25, 2019, at 12 sites in the US, Canada, the UK, France, and Spain ^[1].

The study's authors say results in the Alström syndrome group were inconclusive, likely because only six patients in the trial had that condition, three in each treatment arm ^[1]. That is why the drug's US indication covers Bardet-Biedl syndrome only, not Alström syndrome ^[1]. The most common side effects across both conditions were skin hyperpigmentation, seen in 61 percent of the 38 patients, and injection site redness, seen in 48 percent ^[1]. Two patients experienced four serious adverse events, including blindness, an anaphylactic reaction, and suicidal ideation, but none were judged related to the drug ^[1]. The study was funded by Rhythm Pharmaceuticals, the drug's maker ^[1].

Why it matters for patients

Bardet-Biedl syndrome is a rare inherited condition that causes severe obesity along with other features such as vision loss, kidney problems, and extra fingers or toes ^[1]. People with this syndrome often experience intense, uncontrollable hunger that standard diet and exercise approaches do not fix, because the underlying problem lies in a brain signaling pathway rather than simple calorie intake ^[1].

For families affected by Bardet-Biedl syndrome, this trial provided the clinical evidence that supported approval of setmelanotide as what the study authors describe as the first treatment for obesity specifically tied to this syndrome ^[1]. About one in three older patients reached a meaningful weight loss threshold after a year, though roughly two in three did not reach that 10 percent mark within the trial period ^[1].

The skin pigmentation side effect, which affected more than half of participants, is a visible and potentially long-term change that patients and clinicians would need to weigh against the benefits of the drug ^[1]. Because the Alström syndrome results were inconclusive due to the small number of participants with that condition, people with Alström syndrome and their doctors do not yet have clear trial evidence supporting the same treatment approach ^[1].

What happens next

A correction to the study was published in Lancet Diabetes & Endocrinology in February 2023, though the specific nature of that erratum is not detailed in the available source material ^[1]. The sources reviewed do not describe any planned follow-up trials specifically addressing Alström syndrome, nor do they specify current real-world usage patterns of setmelanotide since its approval. Longer-term data beyond the 52-week open-label period covered in this publication is not yet available in the sources reviewed.