Seventeen patients, one clinic: setmelanotide outside the trial setting

Almost every obesity drug story of the past three years has been about drugs given to very large numbers of people. Setmelanotide is the opposite case: a melanocortin-4 receptor agonist for obesity caused by specific rare genetic defects, approved on the strength of trials that enrolled 21 patients in total [s2].

A prospective cohort published in Obesity on September 2 reports what happened when the drug was used in routine care at a single French centre, in 17 adults [s1]. The numbers are small enough that the study's value lies in what it does not find as much as in what it does.

Who was studied

The cohort included 17 adults with obesity due to Bardet-Biedl syndrome (n = 11) or biallelic variants in the leptin receptor gene LEPR (n = 4) or in pro-opiomelanocortin, POMC (n = 2) [s1]. Participants either started setmelanotide in routine care between 2022 and 2024 under a pre-marketing early-access authorisation, or continued therapy after taking part in the RM-493-022 clinical trial [s1]. Average follow-up was 14.4 months [s1].

This is a monocentric, ongoing, single-arm cohort — no control group, no randomisation, no blinding [s1]. In a disease this rare, that is close to the only design available.

What was observed

Patients experienced a weight reduction of 20% from their highest pre-treatment weight within the first year, which the authors characterise as clinically significant [s1]. Those who had previously been treated in a clinical trial maintained their weight loss over time [s1].

Eating behaviour changed alongside weight. Hunger fell by 62% and food craving by 41%, and external eating, measured with the Dutch Eating Behaviour Questionnaire, also decreased significantly [s1].

The safety profile was consistent with the phase 3 data, with no new safety signals reported [s1].

How this compares with the registration trials

The 2020 phase 3 programme comprised two single-arm, open-label trials at ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK, enrolling ten participants with POMC deficiency obesity and 11 with LEPR deficiency obesity, all aged 6 or older [s2].

At approximately 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 bodyweight [s2]. Mean percentage change in the most-hunger score was −27.1% in the POMC trial and −43.7% in the LEPR trial [s2]. Injection site reactions were reported in every participant in both trials, and hyperpigmentation in all ten POMC participants [s2].

The real-world hunger reduction of 62% is larger than either trial figure, but the instruments are not the same — the trials used an 11-point Likert most-hunger score, the cohort used a different assessment [s1][s2] — and the cohort mixes Bardet-Biedl syndrome patients, who were not in those two phase 3 trials, with LEPR and POMC patients. Direct comparison of the numbers is not warranted.

The limits, which are severe and mostly unavoidable

Seventeen patients at one centre cannot establish an effect size. There is no comparator, so the 20% figure includes whatever the clinic's other care contributed. Some participants carried over from a trial, which selects for people who tolerated and responded to the drug — a form of survivorship that pushes real-world estimates upward.

Follow-up averaging 14.4 months is short for a treatment intended to be indefinite [s1]. The hyperpigmentation seen universally in the phase 3 POMC trial is a known effect of melanocortin receptor agonism [s2]; whether it accumulates over years of routine use is not something a 14-month cohort answers.

What the study does provide is a check that the drug behaves in ordinary clinical conditions roughly as it did under trial protocol, in a population where the alternative to trial evidence is no evidence at all. For ultra-rare disease, prospective registry-style cohorts like this one are often the only mechanism that will ever exist for detecting a divergence between trial and practice.

What to watch

Whether larger multi-centre registries accumulate enough Bardet-Biedl patients to characterise response in that group specifically; whether weight loss is maintained beyond two or three years; and whether the hyperpigmentation and injection-site effects seen in the registration trials prove to be tolerability-limiting in long-term routine use.

This article describes a small uncontrolled cohort study and earlier single-arm trials. It is informational only, is not medical advice, and does not recommend any drug. Setmelanotide is a prescription treatment for specific genetic diagnoses.

Sources

• [s1] Mifsud F, Chalopin S, Guillon E, Faucher P, Muller J, Le Bihan J, Clément K, Poitou C, Real-World Efficacy and Safety of Setmelanotide in Adults With Monogenic or Syndromic Obesity: A Prospective Cohort Study, Obesity (Silver Spring), 2025;33:1865-1872, published 2025-09-02.
• [s2] Clément K, van den Akker E, Argente J, et al., Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials, The Lancet Diabetes & Endocrinology, 2020;8:960-970, published online 2020-10-30.