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POMC and LEPR deficiency obesities

Positive results from setmelanotide in deficiency obesities

Rhythm to complete NDA submissions to the FDA for both POMC and LEPR deficiency obesities in next 12 months

Rhythm Pharmaceuticals, a biopharmaceutical company focused on the development of therapeutics for the treatment of rare genetic disorders of obesity, has announced positive 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.

“For people living with genetically-driven, severe obesity and insatiable hunger, these pivotal data illustrate the potential of an effective therapy,” said Dr Peter Kühnen, Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Germany, lead investigator in the POMC deficiency obesity trial. “Recognising the signs of rare genetic disorders of obesity early may soon open new possibilities with treatment options on the horizon.”

Eight of ten patients with POMC deficiency obesity achieved the primary endpoint of greater than 10 percent weight loss over approximately one year (p<0.0001). The mean reduction from baseline in body weight for POMC deficiency obesity patients was -25.4 percent (p<0.0001) and the mean reduction from baseline in most hunger rating for POMC deficiency obesity patients was -27.8 percent (p=0.0005). 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 (p=0.0004). Mean weight loss for these patients was 31.9kg, or 70.2lbs, 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 (p=0.0001). The mean reduction from baseline in body weight for LEPR deficiency obesity patients was -12.5 percent (p<0.0001), and the mean reduction from baseline in most hunger rating for LEPR deficiency obesity patients was -41.9 percent (p<0.0001). 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 (p<0.0001). Mean weight loss for these patients was 16.7kg, or 36.8lbs, over one year on therapy. 

“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,” said Dr Keith Gottesdiener, CEO of Rhythm. “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. 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.”

In addition, the study design included a four-week placebo withdrawal period to further illustrate the effect of treatment with setmelanotide. Upon entry into the placebo period, participants almost immediately gained weight and experienced an increase in hunger, reversing their downward trends in weight loss and hunger scores observed during the first 12 weeks of the treatment period. In both trials, the mean weight increase during the four-week placebo period was approximately 5kg (>11lbs) and this weight gain was accompanied by a worsening in hunger scores. These trends reversed again when patients went back on drug.

Consistent with prior clinical experience, setmelanotide was generally well-tolerated in both trials and treatment-emergent related adverse events (AEs) included injection site reactions, nausea and vomiting, and increased hyperpigmentation (darkening of the skin); these were consistent with prior clinical trials of setmelanotide. In addition:

  • There were no reports of cardiovascular AEs related to setmelanotide.
  • One LEPR study patient withdrew before the end of titration due to AE of mild hypereosinophilia.
  • There were no serious adverse events (SAEs) related to treatment with setmelanotide.
  • One LEPR study patient died from injuries unrelated to the study drug (car accident)

“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 Dr Murray Stewart, Chief Medical Officer of Rhythm Pharmaceuticals. “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.”

Rhythm is planning to complete submission of a rolling New Drug Application (NDA) 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. Rhythm intends to request priority review of the application, which, if granted, could result in a six-month review process. Additionally, Rhythm also expects to submit a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA), which will cover both POMC and LEPR deficiency obesities. 

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