Two ongoing Phase 3 clinical trials assessing the effects of setmelanotide as an obesity treatment for patients with proopiomelanocortin (POMC) and leptin receptor (LEPR) deficiency have met their primary goals, Rhythm Pharmaceuticals announced.
A high proportion of patients in both studies achieved more than 10% weight loss in a year and, according to top-line data from both trials, key secondary goals also were met, with more than half the patients in each trial reporting significant reductions in insatiable hunger (hyperphagia) after one year of treatment.
“We believe these statistically significant data demonstrate setmelanotide’s ability to induce marked weight loss and substantially reduce hunger and we are excited about the potential difference we can make in the lives of people with rare genetic disorders of obesity,” Keith Gottesdiener, MD, chief executive officer of Rhythm, said in a press release.
“We believe these pivotal data are the first step towards making a positive impact for people affected by rare genetic disorders of obesity who have grown up with insatiable hunger and early-onset, rapid weight gain that often leads to debilitating comorbidities,” Gottesdiener said. “We believe this milestone moves us closer to delivering a treatment for numerous MC4R pathway-driven disorders of obesity. We are working to advance setmelanotide to its first regulatory submission in POMC and LEPR deficiency obesities.”
Rare genetic disorders of obesity, including POMC and LEPR deficiency, are caused by genetic defects that compromise the normal activity of the melanocortin-4 receptor (MC4R) pathway, a signaling function that controls the sensations of hunger and satiety (feeling full).
Setmelanotide is a first-in-class activator of MC4R that has been specifically developed for patients carrying genetic mutations that hamper the activity of the MC4R pathway.
Both trials included an initial period of 12 weeks in which patients were treated with setmelanotide, followed by an eight-week withdrawal phase in which they were switched from setmelanotide to a placebo without their knowledge. After the withdrawal phase, they were switched back to setmelanotide for an additional 32 weeks. Participants completing the entire treatment course would become eligible to participate in the extension studies of both trials.
The trials’ primary goal was to assess the percentage of patients achieving at least a 10% weight loss after one year of treatment with setmelanotide. Key secondary goals in both studies included assessing the mean percentage reduction in body weight and hunger from baseline until the end of the study period.
Topline data from both trials, which are still recruiting patients, has shown that:
- 80% of the patients with POMC deficiency and 45.5% of those with LEPR deficiency lost more than 10% of their body weight after one year of treatment;
- On average, patients with POMC deficiency lost 25.4% of their body weight over the course of one year, which corresponded to a mean weight loss of 31.9 kg, or 70.2 pounds;
- On average, patients with LEPR deficiency lost 12.5% of their body weight over the course of one year, which corresponded to a mean weight loss of 16.7 kg, or 36.8 pounds;
- On average, patients with POMC deficiency had a reduction of 27.8% in hunger after one year of treatment, and 50% reported having felt at least a 25% reduction in their hunger levels;
- On average, patients with LEPR deficiency had a reduction of 41.9% in hunger after one year of treatment, and 72.7% reported having felt at least a 25% reduction in their hunger levels;
- In both trials, during the withdrawal phase, patients gained weight (approximately 5 kg or 11 pounds) and experienced an increase in their hunger levels; these effects were reversed once they restarted treatment with setmelanotide;
- Treatment with setmelanotide was generally safe and well-tolerated by study participants from both trials; no serious adverse side effects or deaths related to treatment have been reported.
“Setmelanotide demonstrated a clinically meaningful impact on severe hunger and obesity with 17 of 19 eligible patients choosing to participate in the extension study to continue setmelanotide treatment,” said Murray Stewart, MD, chief medical officer of Rhythm.
“Importantly, during withdrawal periods in both studies, patients experienced statistically significant, consistent increases in weight and hunger. Following re-initiation of therapy, the majority of patients resumed weight loss and hunger response. We believe these data speak to setmelanotide’s potential to help restore the function of the MC4R pathway in regulating weight and appetite control,” he said.
Rhythm is planning to publish complete findings from both trials in a medical journal, and present them at an upcoming meeting.
Meanwhile, the company is working on the submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval of setmelanotide for treating patients with POMC and LEPR deficiency, which should be completed by the end of 2019 or beginning of 2020, the company said.
Rhythm said it plans to request priority review for the NDA, which, if granted, may shorten the review process to a period of six months, instead of the 10 months under standard review.