Setmelanotide for rare genetic obesity: the POMC and LEPR trials

Why this study matters

A small number of people have severe obesity from early childhood because of changes in genes that control appetite. Two of these are POMC deficiency and LEPR deficiency. In these conditions, a signal in the brain that normally reduces hunger does not work properly. Setmelanotide is a medicine designed to act on that pathway, called the melanocortin 4 receptor or MC4R. These two trials were the main studies of the medicine for these conditions. They matter to Canadian readers because Canadian hospitals took part, and because they show what evidence exists for a medicine aimed at a rare cause of obesity, not at obesity in general.

Who was in the study

The trials enrolled people aged 6 years or older with severe obesity due to POMC deficiency (10 people) or LEPR deficiency (11 people). Participants were enrolled between February 14, 2017 and September 7, 2018 at ten hospitals across Canada, the United States, Belgium, France, Germany, the Netherlands and the United Kingdom. The summary we reviewed does not give the age range or say how many participants were children.

What the researchers did

These were single-arm, open-label, multicentre, phase 3 trials. Single-arm means everyone received the medicine and there was no separate comparison group. Open-label means participants and staff knew what was being given. Phase 3 means the trial was designed to support approval.

The design had several stages. Everyone first received setmelanotide openly for 12 weeks. Those who lost at least 5 kg (or at least 5% if they weighed under 100 kg at the start) entered an 8-week withdrawal sequence: 4 weeks of blinded setmelanotide and 4 weeks of blinded placebo, in an order not known to them. Placebo is an injection with no active medicine. After that, everyone received a further 32 weeks of open-label treatment.

The primary outcome was the proportion of people losing at least 10% of their starting weight at approximately one year. It was assessed in everyone who received at least one dose and had a baseline assessment. A key secondary outcome was the change in a hunger score, measured in a subset aged 12 or older who had responded in the first 12 weeks. The summary we reviewed does not report the therapeutic dose.

What they found

In the POMC trial, 8 of 10 participants (80%) reached at least 10% weight loss at about one year. In the LEPR trial, 5 of 11 participants (45%) did (R32-C87). There was no comparison group for this outcome, so there is no between-group difference to report.

Hunger fell in the subset measured. The mean percentage change in the "most hunger" score was -27.1% in the POMC trial (7 people; 90% confidence interval -40.6 to -15.0) and -43.7% in the LEPR trial (7 people; 90% confidence interval -54.8 to -29.1). A confidence interval is the range in which the true value most likely sits. Note that these are 90% intervals, not the more usual 95%.

Side effects and people who stopped

In the POMC trial, injection site reactions and hyperpigmentation (darkening of the skin) were reported in all 10 participants. Nausea occurred in 5 and vomiting in 3. In the LEPR trial, the most common treatment-related side effects were injection site reactions in all 11 participants, skin disorders in 5, and nausea in 4. No serious treatment-related side effects occurred in either trial.

The published summary we reviewed does not report how many people stopped treatment or withdrew from the trials.

What this study does not tell you

• These trials had 10 and 11 participants. Results from such small groups are uncertain and cannot show rare harms.
• There was no randomized comparison group for the main outcome. The short blinded withdrawal stage included only people who had already responded, so it was set up to favour the medicine.
• The trials were open-label, so knowing they were on the medicine may have affected how participants behaved and reported hunger.
• The participants had specific rare gene changes. Nothing here applies to people with common forms of obesity.
• The summary we reviewed does not report how long the weight loss lasted beyond about one year, or what happened after stopping.
• The trials were funded by the maker of setmelanotide.

What it means in Canada

Canadian hospitals took part in these trials, so some participants were Canadian. The page does not say whether setmelanotide is right for anyone, and it applies only to people with confirmed POMC or LEPR deficiency. For information on the medicine, see setmelanotide in Canada. For what provincial plans pay for, see public drug coverage by province.

Related reading

Other studies in this library that bear on the same question.

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