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Positive top-line findings announced for congenital obesity drug
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Rhythm Pharmaceuticals announced positive results from two phase 3 clinical trials evaluating setmelanotide, a melanocortin-4 receptor agonist for the treatment of rare congenital forms of obesity, according to a company press release.
Setmelanotide (RM-493) is a first-in-class melanocortin-4 receptor (MC4R) agonist in development for the treatment of obesity caused by genetic deficiencies in the MC4 pathway, a key pathway in humans that regulates energy expenditure, homeostasis and appetite. Both studies met their primary endpoints and all key secondary endpoints, according to the company, demonstrating a statistically significant and clinically meaningful effect on weight loss and reductions in hyperphagia for patients with proopiomelanocortin (POMC) and leptin receptor (LEPR) deficiency obesities.
“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, CEO of Rhythm Pharmaceuticals, said in the release. “We believe these pivotal data are the first step toward 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. 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.”
The company reported that eight of 10 patients with POMC deficiency obesity achieved the primary endpoint of greater than 10% weight loss during approximately 1 year (P < .0001). The mean reduction from baseline in body weight for participants with POMC deficiency obesity was –25.4% (P < .0001). The mean reduction from baseline in most hunger ratings was –27.8% (P = .0005), with 50% of participants meeting or exceeding a 25% improvement in self-reported hunger scores (P = .0004). Mean weight loss for these patients was 31.9 kg during 1 year of treatment.
Among 11 participants with LEPR deficiency obesity, five achieved the primary endpoint of greater than 10% weight loss at 1 year (P = .0001). The mean reduction from baseline in body weight for LEPR deficiency obesity patients was –12.5% (P < .0001). The mean reduction from baseline in most hunger ratings was –41.9% (P < .0001), with 72.7% of participants meeting or exceeding a 25% improvement in self-reported hunger scores (P < .0001). Mean weight loss for these patients was 16.7 kg during 1 year of treatment.
The study design also included a 4-week placebo withdrawal period. Upon entry into the placebo period, participants almost immediately gained weight and experienced an increase in hunger, reversing downward trends in weight loss and hunger scores observed during the first 12 weeks of the treatment period, according to the release. In both trials, the mean weight increase during the 4-week placebo period was approximately 5 kg, accompanied by a worsening in hunger scores.
Setmelanotide was generally well tolerated in both trials. Treatment-related adverse events included injection site reactions, nausea and vomiting and increased hyperpigmentation. There were no serious adverse events.
“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,” Murray Stewart, MD, chief medical officer of Rhythm Pharmaceuticals, said in the release. “Importantly, during withdrawal periods in both studies, patients experienced statistically significant, consistent increases in weight and hunger. Following reinitiation 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.”
As Endocrine Today previously reported, a phase 2 study with two patients with congenital POMC deficiency completed in 2016 demonstrated that both participants experienced sustained weight loss and a reduction in hunger while treated with setmelanotide. The first patient (baseline weight, 155 kg) lost 51 kg after 42 weeks; the second patient (baseline weight, 152.8 kg) lost 20.5 kg after 12 weeks.
The company said it plans to submit a new drug application to the FDA that will cover both POMC and LEPR deficiency obesities late in the fourth quarter of 2019 or the first quarter of 2020, as well as a marketing authorization application to the European Medicines Agency. In January 2016, the FDA granted orphan drug designation to setmelanotide for the treatment of Prader-Willi syndrome.
Full data from the phase 3 clinical trials will be presented at an upcoming medical meeting. – by Regina Schaffer
Disclosures: Gottesdiener is CEO of Rhythm Pharmaceuticals. Stewart is chief medical officer of Rhythm Pharmaceuticals.