Rare Daily Staff

Rhythm Pharmaceuticals reported positive topline results from two pivotal, phase 3 clinical trials evaluating setmelanotide, the company’s melanocortin-4 receptor agonist in development for the treatment of pro-opiomelanocortin (POMC) and leptin receptor (LEPR) deficiency obesities.

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 activates MC4R, part of the key biological pathway that independently regulates hunger and body weight. Variants in genes within the MC4R pathway are associated with unrelenting hunger and severe, early-onset obesity.

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.

“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 Keith Gottesdiener, CEO of Rhythm.

Rhythm’s phase 3 pivotal 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. Following screening and dose titration, participants received 12 weeks of therapeutic dose. There was also an eight-week blinded, drug withdrawal phase incorporated to further illustrate the effect of the drug. Participants received 32 weeks of therapeutic dose to complete approximately one year of treatment, before becoming eligible for the extension portion of the trial.

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. Based on natural history data, it would be expected that no participant would be a responder over the course of a year. To be conservative, a comparator of 5 percent of patients who could have lost 10 percent weight or more without treatment was used.

The results showed that eight of 10 patients with POMC deficiency obesity achieved the primary endpoint of greater than 10 percent weight loss over approximately one year. 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 also achieved the primary endpoint of greater than 10 percent weight loss over one year. 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. 

The study design also 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 5 kg, or more than 11 pounds, and this weight gain was accompanied by a worsening in hunger scores. These trends reversed again when patients went back on drug.

Setmelanotide was generally well-tolerated in both trials. Treatment-emergent related adverse events included injection site reactions, nausea and vomiting, and increased hyperpigmentation. One LEPR study patient withdrew before the end of titration due to mild hypereosinophilia, a rise in the number of type of white blood cell that plays a key role in the immune system. One LEPR study patient died from injuries from a car accident, unrelated to the study drug. No serious adverse events were 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, chief medical officer of Rhythm. “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 on track to complete submission of a rolling New Drug Application to the U.S. Food and Drug Administration 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. Rhythm also expects to submit a Marketing Authorization Application with the European Medicines Agency for the same indications.

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

Photo: Murray Stewart, chief medical officer of Rhythm

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