The U.S. Food and Drug Administration (FDA) has accepted and given priority review to Rhythm Pharmaceuticals’ request that setmelanotide be approved to treat people with POMC deficiency and LEPR deficiency, two rare genetic obesity disorders.
This priority status is expected to shorten setmelanotide’s regulatory review to six months from the standard 10 months.
Currently, the agency is not planning to hold an advisory committee meeting as part of setmelanotide’s review.
“The FDA’s acceptance of our NDA for Priority Review signifies a critical milestone toward our mission of addressing the insatiable hunger and early onset, severe obesity that affects individuals living with rare genetic disorders of obesity,” Murray Stewart, MD, Rhythm’s chief medical officer, said in a press release.
“We are grateful to the Agency for its agility and dedication during these challenging times [the COVID-19 pandemic] … We look forward to working closely together throughout the review process to bring setmelanotide, if approved, to patients,” Stewart added.
Rhythm plans to also submit a similar marketing authorization application to the European Medicines Agency (EMA) by mid-year.
Rare genetic disorders of obesity, including POMC and LEPR deficiencies, as well as Bardet-Biedl syndrome and Alström syndrome, are caused by mutations that compromise the activity of the melanocortin-4 receptor (MC4R) pathway, which is involved in appetite regulation, and controls hunger and satiety (feeling full).
As an activator of the MC4R pathway, setmelanotide has the potential to lessen 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 MC4R-associated genetic obesity disorders. Both agencies also granted setmelanotide orphan drug designation for the same indication.
These designations are meant to accelerate the therapy’s development by providing support and financial benefits. They also ensure marketing exclusivity for a period of time (seven years in the U.S. and 10 years in Europe) if granted regulatory approval.
The NDA submission was based on positive data from two multi-center Phase 3 clinical trials — NCT02896192 for POMC deficiency and NCT03287960 for LEPR deficiency. Their top-line data were announced in August 2019, while additional findings were presented in November at ObesityWeek 2019.
Each trial evaluated setmelanotide’s safety and effectiveness in 10 people, who received the therapy for an initial period of 12 weeks, after which they were switched to a placebo. This withdrawal period was then followed by an additional 32 weeks of setmelanotide treatment, totaling about one year of treatment.
Those who finished the entire treatment course were given the option of joining the extension studies of both trials.
The trials’ primary goal was to assess the proportion of participants achieving at least 10% weight loss after one year. Key secondary objectives included mean percentage reduction in hunger and body weight.
Results showed that both trials met their main goal, with 80% of POMC deficiency patients and 45.5% of those with LEPR deficiency achieving at least 10% weight loss.
In addition, 50% of POMC deficiency patients and 72.7% of LEPR deficiency patients reported at least a 25% reduction in hunger. Participants 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).
Setmelanotide’s use also resulted in a significant drop in the body mass index of patients with POMC deficiency (by 22.3%–49.2%) and with LEPR deficiency (by 10.6%).
Notably, in both trials, participants’ weight and hunger levels increased during the withdrawal period, and lowered again once they restarted setmelanotide treatment.
Setmelanotide was generally safe and well-tolerated, with no reports of treatment-related serious adverse effects or deaths in any of the trials. The therapy did not affect patients’ cardiovascular health.
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