Phase 3 setmelanotide results published for two rare genetic forms of obesity

Two phase 3 trials published Oct. 30, 2020, in The Lancet Diabetes & Endocrinology found that setmelanotide, an MC4R agonist given as an injection, produced at least 10 percent weight loss in some people with severe obesity caused by two rare genetic conditions: POMC deficiency and LEPR deficiency ^[1].

Both studies were single-arm, open-label and multicenter, run at 10 hospitals in Canada, the United States, Belgium, France, Germany, the Netherlands and the UK ^[1]. Participants were 6 years or older with severe obesity caused by biallelic variants in genes that affect the MC4R pathway ^[1]. Ten people were enrolled in the POMC trial and 11 in the LEPR trial, between Feb. 14, 2017, and Sept. 7, 2018 ^[1].

Everyone received open-label setmelanotide for 12 weeks. Those who lost at least 5 kg, or at least 5 percent if they weighed under 100 kg at the start, entered an 8-week placebo-controlled withdrawal sequence — four weeks of blinded setmelanotide and four weeks of placebo — followed by 32 more weeks of open-label treatment ^[1].

At about one year, eight of 10 participants in the POMC trial (80 percent) and five of 11 in the LEPR trial (45 percent) had lost at least 10 percent of their starting body weight. That was the primary endpoint ^[1]. Hunger scores fell as well. The mean change in the most hunger score on an 11-point Likert-type scale was -27.1 percent in the POMC trial (n=7; 90 percent CI -40.6 to -15.0; p=0.0005) and -43.7 percent in the LEPR trial (n=7; -54.8 to -29.1; p<0.0001) ^[1].

On safety, injection site reactions and hyperpigmentation were reported in all 10 POMC participants; nausea was reported in five and vomiting in three ^[1]. In the LEPR trial, injection site reactions were reported in all 11 participants, skin disorders in five and nausea in four ^[1]. No serious treatment-related adverse events occurred in either trial ^[1].

The authors wrote that the results support setmelanotide for obesity and hyperphagia caused by POMC or LEPR deficiency ^[1]. The trials were funded by Rhythm Pharmaceuticals and registered as NCT02896192 and NCT03287960 ^[1].

Why it matters for patients

The findings apply to a narrow group. POMC and LEPR deficiency are rare genetic causes of severe, early-onset obesity, not the common obesity that GLP-1 medicines are prescribed for ^[1]. Setmelanotide is an MC4R agonist — a different drug class, given by injection — and it does not act through GLP-1 receptors ^[1]. Someone taking or considering a GLP-1 would need genetic testing and a diagnosis of one of these conditions to fall into the group studied here.

The evidence base is also small and mostly uncontrolled: 21 people in total, and the main analysis was single-arm, meaning participants knew they were receiving the drug ^[1]. Hunger was assessed in only seven participants in each trial ^[1]. Long-term weight loss and safety beyond about one year are not reported.

The publication does not address regulatory approval, price, insurance coverage or U.S. availability.

What happens next

The paper appears in the December 2020 issue of the journal, alongside a commentary titled Setmelanotide: what does it mean for clinical care of patients with obesity? ^[1]. The report does not describe further trials, regulatory timelines or how soon the drug might reach patients.