Treatment with the investigational drug setmelanotide led to statistically significant and clinically meaningful reductions in body weight and hunger in children with obesity due to pro-opiomelanocortin (POMC) deficiency or leptin receptor (LEPR) deficiency in two phase-3 studies. POMC deficiency and LEPR deficiency are rare genetic disorders of obesity. People with these disorders have severe hunger (hyperphagia) and early-onset severe obesity resulting from impaired signaling in the melanocortin-4 receptor (MC4R) pathway. Setmelanotide is an MC4R agonist being developed by Boston-based Rhythm Pharmaceuticals, which funded the research. The studies were similarly designed, with participants receiving setmelanotide by subcutaneous injection once daily for 52 weeks (including four weeks on placebo). Both were single-arm trials conducted in several countries. At roughly one year, eight of the 10 participants (80%) with POMC-deficiency obesity (mean age, 18.4 years) and five of the 11 (45%) with LEPR-deficiency obesity (mean age, 23.7 years) achieved at least 10% weight loss at approximately one year, researchers report in The Lancet Diabetes and Endocrinology. "These results are significant because, as we know from natural history data, individuals living with POMC or LEPR deficiency obesity consistently experience substantial weight gain each year beginning in early childhood, and we would not expect any of these patients to be able to achieve 10% weight loss over the course of a year without continued treatment," co-investigator Dr. Karine Clement, of Pitie-Salpetriere Hospital and Sorbonne University in Paris, said in a news release from Rhythm Pharmaceuticals. The achieved weight loss of 10% or more with setmelanotide 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%," Dr. Donna Ryan, with Louisiana State University in Baton Rouge, writes in a linked comment. The mean percentage change in "most hunger" score was -27.1% in POMC-deficiency obesity (P=0.0005) and -43.7% (P<0.0001) in LEPR-deficiency obesity. Consistent with the phase-2 clinical experience, setmelanotide was generally well-tolerated in both trials. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all 10 participants in the POMC trial. Five POMC participants had nausea and three had vomiting. In the LEPR trial, the most common treatment-related adverse events were injection site reaction, seen in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. "These data and the significant unmet need to address the obesity and hyperphagia caused by rare genetic disorders of obesity underscore the importance of testing for genetic variants that may impair MC4R activation and lead to severe obesity," Dr. Clement said in the release. Last spring, the U.S. Food and Drug Administration (FDA) accepted the company's new drug application (NDA) for setmelanotide for the treatment of POMC-deficiency obesity and LEPR-deficiency obesity. The drug was granted priority review and given an action date of November 27, 2020. Dr. Ryan says setmelanotide "seems most promising for patients with POMC deficiency. The results do not seem as encouraging for all patients with LEPR deficiency, but prescribing a trial of setmelanotide would still be a worthy approach in the face of no alternative treatments for this severe disease." "The obvious question is whether setmelanotide could have a broader indication for weight management," Dr. Ryan notes. However, regulatory approval will probably come only for patients with proven genetic defects in the leptin-melanocortin pathway. "Having a drug that is effective would then drive clinicians to increase genetic testing for patients with a history of severe early-onset obesity. Thus, the impact of setmelanotide in the obesity clinic is likely to mean a renewed appreciation for the biological underpinnings of obesity and an increase in genetic screening to identify a subset of patients that can benefit from the drug," Dr. Ryan says. Three of the authors are employees of Rhythm Pharmaceuticals. —Reuters Staff Source
