Rhythm Pharmaceuticals is seeking approval from the U.S. Food and Drug Administration (FDA) for its lead candidate setmelanotide to treat POMC deficiency and LEPR deficiency, two rare genetic obesity disorders.
Over the next two months, the FDA will determine whether Rhythm’s new drug application (NDA) is acceptable for filing and whether to grant it priority review, which would shorten setmenanotide’s regulatory review from 10 to 6 months.
“We look forward to further discussions with the FDA as we seek to obtain approval for setmelanotide, which we believe has the potential to address the insatiable hunger and early-onset, severe obesity that affects people living with POMC and LEPR deficiency obesities, who cannot be treated with lifestyle modifications alone and have no other treatment options,” Murray Stewart, MD, Rhythm’s chief medical officer, said in a press release.
Setmelanotide is an activator of the melanocortin-4 receptor (MC4R) pathway, which controls the sensations of hunger and satiety. This pathway is impaired in people with rare genetic disorders of obesity, including POMC and LEPR deficiencies, as well as Alström syndrome, and Bardet-Biedl syndrome. By restoring MC4R signaling, setmelanotide is thought to reduce hyperphagia, or insatiable hunger, and help patients lose weight.
Setmelanotide received the FDA’s breakthrough therapy and the EMA’s PRIority MEdicines (PRIME) designations for the treatment of genetic obesity disorders associated with the MC4R pathway. It also received orphan drug designation from both agencies for the same indication.
These designations are meant to provide support and financial benefits to accelerate the therapy’s development. Also, they ensure marketing exclusivity for a period of time upon regulatory approval (seven years in the U.S. and 10 years in Europe).
Rhythm’s application was based on positive data from two multi-center Phase 3 clinical trials (NCT02896192 for POMC deficiency and NCT03287960 for LEPR deficiency), which showed that setmelanotide treatment was safe and resulted in clinically meaningful reductions in patients’ weight and hunger levels.
Each trial evaluated the safety and effectiveness in 10 participants, who were initially treated with setmelanotide for 12 weeks, then switched to a placebo for eight weeks, and finally switched back to setmelanotide for an additional 32 weeks.
Participants completing the entire treatment course (one year) could join the extension studies of both trials.
The trials’ main goal was to assess the percentage of participants achieving at least a 10% weight loss after one year of treatment. Key secondary goals included mean percentage reduction in body weight and hunger.
Topline data showed that both trials met their primary goal, with 80% of POMC deficiency patients and 45.5% of those with LEPR deficiency achieving at least 10% weight loss.
In addition, more than half of the participants showed at least a 25% reduction in hunger. Patients with POMC deficiency lost a mean of 31.9 kilograms (70.2 pounds), while those with LEPR deficiency lost a mean of 16.7 kilograms (36.8 pounds).
Notably, in both trials, patients gained weight and reported higher hunger levels during the withdrawal period (when they received a placebo), and these effects were reversed once they restarted setmelanotide treatment.
Updated results also showed that one year of treatment with setmelanotide significantly reduced the body mass index of participants with POMC deficiency (by 22.3%–49.2%) and with LEPR deficiency (by 10.6%).
Setmelanotide was generally safe and well-tolerated, with no reports of serious adverse effects or deaths related to treatment in any of the studies. Also, the therapy did not affect cardiovascular health.
“The completion of our first NDA submission marks an integral first step in our journey to transform the care of people living with not only POMC and LEPR deficiency obesities, but also many other rare genetic disorders of obesity,” Stewart said.
In addition, by the first quarter of 2021, Rhythm expects to announce topline data from a Phase 3 trial (NCT03746522, and still recruiting participants) assessing setmelanotide’s safety and effectiveness in people with Bardet-Biedl syndrome and Alström syndrome.
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