ESPE Yearbook of Paediatric Endocrinology

Lancet Diabetes Endocrinol. 2020 Dec;8(12):960–970.https://pubmed.ncbi.nlm.nih.gov/33137293/

This article reports the results of two single-arm, open-label, multicentre, phase 3 trials of the MC4R agonist, setmelanotide, in patients with severe obesity due to pro-opiomelanocortin (POMC) deficiency or leptin receptor (LEPR) deficiency. Mean % change in bodyweight after ~1 year was −25·6% in patients with POMC deficiency and −12·5% in those with LEPR deficiency.

Melanocortin 4 receptor (MC4R) is a key component of the leptin-melanocortin pathway and plays an important role in the regulation of appetite and body weight. Severe early-onset obesity can be caused by biallelic variants in genes that affect MC4R signalling. These trials were conducted in 10 hospitals in North America (Canada and the USA) and Europe (Belgium, France, Germany, the Netherlands, and UK). The POMC trial (NCT02896192) included individuals aged 6+ years with obesity caused by POMC deficiency, defined as homozygous or compound heterozygous variants in POMC or PCSK1. The LEPR trial (NCT03287960) included individuals aged 6+ years with obesity caused by LEPR deficiency, defined as homozygous or compound heterozygous variants in LEPR. In both trials, setmelanotide produced significant weight loss and reduction in hunger scores in after ~1 year of treatment. Setmelanotide was well tolerated in all individuals, and no new safety concerns were observed. Patients in both groups reported injection site reactions.

Effectiveness was greater in POMC patients than in LEPR patients. The primary outcome, weight loss of 10+%, was observed in 80% of POMC and 45% of LEPR patients, and this was also reflected in mean % changes in bodyweight (−25·6% vs −12·5%, respectively). Furthermore, all POMC patients reported skin hyperpigmentation compared to 36% of LEPR patients.The authors comment on the potentially different aspects of POMC and LEPR deficiency. They posit that setmelanotide as an MC4R agonist is potentially able to completely restore signalling in POMC obesity (1). By contrast, in LEPR, setmelanotide might only partially restore signalling, given that apart from POMC neurons LEPR is also expressed on agouti-related peptide-positive neurons (2).

In the POMC trial, nausea was reported in 5 participants and vomiting in 3 participants. Five serious adverse events (depression, major depression, acute adrenocortical insufficiency, pneumonia, and pleurisy) were reported in 4 participants but none was considered to be related to setmelanotide. No treatment emergent adverse events led to study drug withdrawal or death. In addition, 1 participant reported suicidal ideation at baseline but not at ~1 year. Another participant developed suicidal ideation at ~1 year.

In the LEPR trial, nausea and vomiting were reported in 4 participants that both resolved without sequelae. Four serious adverse events (cholecystitis, suicidal ideation, gastric banding reversal, and road traffic accident leading to death) were reported in 3 participants; none was considered to be related to setmelanotide. One participant discontinued the trial because of grade 1 hypereosinophilia, which was considered to be possibly related to setmelanotide and resolved following discontinuation. In both studied groups, no treatment-related cardiovascular adverse events were reported, and there was no evidence that setmelanotide was associated with changes in blood pressure or heart rate. No cases of suicidal ideation and behaviour were reported at either baseline or at ~1 year.

Reference: 1. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016; 375(3): 240–6.2. Andermann ML, Lowell BB. Toward a Wiring Diagram Understanding of Appetite Control. Neuron. 2017; 95(4): 757–778.