medwireNews: The melanocortin 4 receptor (MC4R) agonist setmelanotide has significantly reduced hunger and resulted in weight loss in a phase 3 trial involving patients, including children, with pro-opiomelanocortin (POMC) or leptin receptor (LEPR) deficiency obesity.
These ultra-rare conditions arise from mutations in the POMC, PCSK1 or LEPR genes, disrupting the melanocortin pathway and resulting in hyperphagia and early-onset severe obesity.
“Although they occur only rarely, these conditions present enormous challenges for health-care providers, parents, and patients”, writes Donna Ryan (Louisiana State University, Baton Rouge, USA) in a commentary accompanying the publication in The Lancet Diabetes & Endocrinology.
Study author Peter Kühnen (Charité Universitätsmedizin Berlin, Germany) and colleagues note that “multiarm, randomised controlled trial designs are the gold standard” for phase 3 intervention studies, but this was not possible for such rare conditions: just 10 patients with POMC deficiency (including six <18 years old) and 11 with LEPR deficiency (including three <18 years old) were recruited across 10 centres in North America and Europe.
The trial was therefore open label. “[H]owever, all participants entered a placebo-controlled withdrawal sequence”, note the researchers.
The setmelanotide doses used ranged from 1.5 to 3.0 mg given subcutaneously once daily and established during a run-in phase of up to 12 weeks during which the investigators titrated the dose to achieve weight loss of approximately 1–2 kg/week in children and 2–3 kg/week in adult patients.
There then followed a 10-week, open-label treatment phase, an 8-week double-blind placebo-controlled withdrawal sequence, and a final 32 weeks of open-label active treatment.
Over this entire period, eight (80%) of the participants with POMC deficiency achieved the primary endpoint of at least 10% weight loss relative to baseline. Of note, one of the two patients who did not achieve this target received approximately 20 weeks’ treatment with risperidone for major depressive disorder, coincident with the return of hyperphagia and weight regain in the blinded placebo phase.
Of the patients who achieved the primary endpoint, all in fact achieved at least 20% weight loss, with seven achieving 25%, three 30% and one 35% weight loss.
In her commentary, Ryan says: “This result is excellent and in the range of bariatric surgery outcomes. Moreover, it should be interpreted in the context that mean weight loss for currently available anti-obesity medications on the market is 5–7%.”
The results were less clear-cut for patients with LEPR deficiency, with five (45%) of these participants achieving the primary endpoint, of whom all achieved 15% weight loss, and two achieved 20% weight loss.
Ryan suggests that for LEPR deficiency “prescribing a trial of setmelanotide would still be a worthy approach in the face of no alternative treatments for this severe disease.”
Participants’ mean most hunger scores were assessed using an 11-point Likert scale only in those aged 12 years or older, where 0 indicated no hunger and 10 the hungriest possible. Between baseline and 1 year these decreased from an average of 8.1 to 5.8 in the POMC deficiency group and from 7.0 to 4.1 in the LEPR deficiency group, and the scores were significantly different between the active and placebo phases of the double-blind period of the trial.
The safety profile of setmelanotide was similar to that established in the phase 2 studies, say the researchers, with no new safety concerns identified. All patients experienced injection site reactions, and skin hyperpigmentation affected all those in the POMC deficiency group and 36% of those in the LEPR deficiency group. Nausea was also common in both groups (50 and 36%, respectively).
“Overall, the efficacy and safety profile of setmelanotide supports its potential long-term use as a treatment for early-onset severe obesity and hyperphagia caused by POMC or LEPR deficiency”, conclude the investigators.
“Further evaluation of setmelanotide is warranted in other disorders resulting from variants in the central melanocortin pathway that cause impaired MC4R activation.”
By Eleanor McDermid
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