Setmelanotide phase 3 results published for POMC and LEPR deficiency

Two phase 3 clinical trials of the drug setmelanotide, published Oct. 30, 2020, in The Lancet Diabetes & Endocrinology, found that most participants with a rare condition called POMC deficiency and nearly half of those with LEPR deficiency lost at least 10% of their body weight after about a year of treatment.^[1] Both conditions are caused by inherited gene mutations that disrupt a brain pathway, involving the melanocortin 4 receptor (MC4R), that controls hunger and body weight.^[1] Setmelanotide is designed to activate that receptor directly.^[1]

The two single-arm, open-label studies enrolled a total of 21 people age 6 and older across ten hospitals in Canada, the United States, Belgium, France, Germany, the Netherlands, and the United Kingdom between February 2017 and September 2018.^[1] Ten participants had POMC deficiency and 11 had LEPR deficiency.^[1] After an initial 12-week open-label period, those who lost at least 5 kilograms (or 5% of body weight if they weighed under 100 kg) moved into a placebo-controlled phase before returning to open-label treatment for a total of about one year.^[1]

At roughly one year, 8 of 10 participants (80%) in the POMC trial and 5 of 11 (45%) in the LEPR trial had lost at least 10% of their starting body weight.^[1] Hunger, measured on an 11-point scale, fell by an average of 27.1% in the POMC group and 43.7% in the LEPR group, both statistically significant changes.^[1]

The most common side effects were injection site reactions, reported in all participants in both trials, along with skin darkening (hyperpigmentation) in the POMC group and other skin disorders in the LEPR group.^[1] Nausea occurred in five POMC participants and four LEPR participants, and vomiting occurred in three POMC participants.^[1] No serious side effects tied to the drug were reported in either trial.^[1] The research was funded by Rhythm Pharmaceuticals, the drug's maker.^[1] The findings were also discussed in an accompanying commentary in the same journal issue.^[1]

Why it matters for patients

POMC and LEPR deficiency are extremely rare, but people who have them face severe, early-onset obesity and constant, intense hunger that standard diet and lifestyle changes rarely fix, because the underlying problem is a broken signaling pathway in the brain, not a lack of willpower.^[1] For this small group of patients, the trial results suggest a drug that targets that specific pathway can produce meaningful weight loss and reduce hunger, based on the sizable share of participants who reached the 10% weight-loss threshold.^[1]

The treatment did not work for everyone. More than half of the LEPR group did not reach the 10% weight-loss mark, showing the drug's effect varied by which gene was involved.^[1] Side effects such as injection site reactions and skin darkening were common enough that patients considering this type of treatment would want to understand what to expect, though the trials reported no serious drug-related harms.^[1]

This is a different drug and mechanism than GLP-1 medicines such as semaglutide or tirzepatide, and it is intended for a narrow group of patients with confirmed genetic mutations, not general obesity.^[1]

What happens next

According to information provided about this development, regulators approved the drug under the brand name Imcivree about six weeks after the trial results were published, making it available for patients with confirmed POMC or LEPR deficiency.^[1] The trials are registered under identifiers NCT02896192 and NCT03287960, and longer-term data on durability of weight loss and safety were not detailed in this report.^[1]