Rhythm Therapeutics reported positive topline results from two pivotal Phase 3 clinical trials evaluating setmelanotide, the company’s melanocortin-4 receptor (MC4R) agonist, for the treatment of pro-opiomelanocortin (POMC) and leptin receptor (LEPR) deficiency obesities. Both studies met their primary endpoints and all key secondary endpoints, demonstrating a statistically significant and clinically meaningful effect on weight loss and reductions in insatiable hunger, or hyperphagia, in patients with POMC and LEPR deficiency obesities.
Both trials were multicenter, open-label, single-arm trials that evaluated the efficacy and safety of setmelanotide for approximately one year in participants with either POMC or LEPR deficiency obesity who were 6 years of age and older. Subsequent to screening and dose titration, patients received 12 weeks of therapeutic dose. This was followed by an eight-week blinded, drug withdrawal phase and then 32 weeks of therapeutic dose to complete approximately one year of treatment. The primary endpoint in both studies assessed the percentage of participants who reached at least 10 percent weight loss as compared to historical controls in this population using an exact binomial comparison.
Eight of 10 patients with POMC deficiency obesity achieved the primary endpoint of greater than 10 percent weight loss over approximately one year. The mean reduction from baseline in body weight for POMC deficiency obesity patients was -25.4 percent and the mean reduction from baseline in most hunger rating for POMC deficiency obesity patients was -27.8 percent. In addition, 50 percent of the POMC deficiency obesity patients in the trial met or exceeded a 25 percent improvement in self-reported hunger scores. Mean weight loss for these patients was 31.9 kg, or 70.2 pounds, over one year on therapy.
Five of 11 patients with LEPR deficiency obesity achieved the primary endpoint of greater than 10 percent weight loss over one year. The mean reduction from baseline in body weight for LEPR deficiency obesity patients was -12.5 percent and the mean reduction from baseline in most hunger rating for LEPR deficiency obesity patients was -41.9 percent. In addition, 72.7 percent of the LEPR deficiency obesity patients in the trial met or exceeded a 25 percent improvement in self-reported hunger scores. Mean weight loss for these patients was 16.7 kg, or 36.8 pounds, over one year on therapy.
Setmelanotide was generally well-tolerated in both trials. The most common adverse events were injection site reactions, nausea and vomiting, and increased hyperpigmentation.
Based on this data, Rhythm is on track to complete submission of a rolling New Drug Application (NDA) to the U.S. FDA that will cover both POMC and LEPR deficiency obesities late in the fourth quarter of 2019 or the first quarter of 2020. Rhythm intends to request priority review of the application.
The FDA has granted Breakthrough Therapy designation to setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway, which includes POMC deficiency obesity, LEPR deficiency obesity, Bardet-Biedl syndrome, and Alström syndrome. The European Medicines Agency has also granted PRIority MEdicines (PRIME) designation for setmelanotide for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4R pathway.
About Rare Genetic Disorders of Obesity
Rare genetic disorders of obesity are characterized by severe, early-onset obesity and insatiable hunger known as hyperphagia. The MC4R pathway is a key part of the biological process responsible for regulating hunger and body weight. Variants in many different genes within the MC4R pathway are associated with several rare genetic disorders of obesity. POMC deficiency obesity is a disorder caused by variants in the POMC or PCSK1 genes that can often lead to severe obesity beginning early in life, insatiable hunger, endocrine abnormalities, including adrenocorticotropic hormone deficiency and mild hypothyroidism, red hair and light skin pigmentation. LEPR deficiency obesity is a disorder caused by variants in the LEPR gene that can often lead to severe obesity beginning early in life, insatiable hunger, and endocrine abnormalities, including hypogonadotropic hypogonadism and hypothyroidism.
Setmelanotide is a potent MC4R agonist in development for the treatment of rare genetic disorders of obesity. Setmelanotide activates MC4R, part of the key biological pathway that independently regulates energy expenditure and appetite. Variants in genes within the MC4R pathway are associated with unrelenting hunger and severe, early-onset obesity. Rhythm is currently developing setmelanotide as a replacement therapy for patients with monogenic defects upstream of MC4R, for whom there are no effective or approved therapies.