Phase 3 trials of Rhythm Pharmaceuticals’ setmelanotide in patients with genetic obesity have met their primary endpoints. Rhythm plans to use the data to complete a rolling submission to the FDA around the end of the year, positioning it to bring the drug to market in 2020.
The two clinical trials investigated melanocortin-4 receptor (MC4R) agonist setmelanotide in patients with pro-opiomelanocortin (POMC) or leptin receptor (LEPR) deficiency obesity. The POMC and LEPR trials enrolled 10 and 11 patients, respectively, and assessed the effect of one year of once-daily subcutaneous setmelanotide injections of on their weight and hunger.
Eight of the 10 patients enrolled in the POMC trial experienced a reduction in body weight of 10% or more, resulting in the trial hitting its primary endpoint with a p value of less than 0.0001. Among the participants who hit a weight loss threshold after 12 weeks, the mean reduction in body weight over the course of the trial was 25.4%. Rhythm reported a 27.8% drop in hunger in those participants.
The LEPR trial recorded smaller but still statistically significant changes. Five of the 11 subjects in the LEPR trial experienced a 10% or more reduction in body weight. The average weight loss across the course of the trial was 12.5%.
As a single-arm, open-label trial, the study lacked a comparator to show how patients would have performed without setmelanotide. Rhythm offset that shortcoming by including a four-week placebo withdrawal period. During this period, subjects “almost immediately gained weight,” according to Rhythm, and had on average gained more than 11 pounds by the end of their time on placebo.
“Following re-initiation of therapy, the majority of patients resumed weight loss and hunger response,” Rhythm CMO Murray Stewart said in a statement, adding that 17 of 19 eligible patients enrolled in an extension study to continue treatment with setmelanotide.
On the safety front, Rhythm said setmelanotide was generally well tolerated, with treatment-related adverse events limited to outcomes such as injection site reactions, nausea and darkening of the skin.
No serious adverse events were linked to setmelanotide but one patient withdrew from the LEPR study due to mild hypereosinophilia, a condition defined by high levels of a white blood cell. The data add to evidence that setmelanotide is free from the cardiovascular events that have affected other MC4R agonists.
Rhythm thinks the data are good enough to land it regulatory approvals on both sides of the Atlantic. The plan is to complete a rolling FDA submission covering POMC and LEPR late this year or early in 2020 and seek a six-month priority review. A European filing covering both indications is also in the works.
If Rhythm executes that strategy, attention will turn to the question of the market opportunity for the drug. An NIH analysis of the medical literature found around 50 reported cases of POMC deficiency. The prevalence of LEPR deficiency is unknown, leaving scope to doubt whether setmelanotide will be a significant drug commercially even if it makes it to market.