Setmelanotide Weekly as Safe and Effective as Daily Use, Trial Data Suggest

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by Marta Figueiredo |

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A new weekly formulation of setmelanotide, Rhythm Pharmaceuticals’ lead treatment candidate for rare genetic obesity disorders, is as safe and effective in promoting weight loss as the daily formulation, interim data from a Phase 2 trial show.

The findings, collected from people with obesity but without these genetic disorders, suggest that the weekly formulation may have comparable effectiveness to the daily formulation.

“As a daily injection, setmelanotide has achieved statistically significant and clinically meaningful weight loss in patients with rare genetic disorders of obesity across multiple Phase 2 and Phase 3 clinical trials,” Murray Stewart, MD, Rhythm’s chief medical officer, said in a press release.

“These new data suggest that weekly setmelanotide may provide the same clinical benefit in a more convenient formulation, with the potential to reduce the burden on patients without compromising safety or efficacy. We look forward to evaluating these data further and continuing discussions with the U.S. Food and Drug Administration (FDA) about our path to registering weekly setmelanotide,” he added.

Setmelanotide, given as an under-the-skin injection, is an activator of the melanocortin-4 receptor (MC4R) pathway, which regulates hunger and satiety (feeling full).

As this pathway is impaired in people with rare genetic disorders of obesity — including POMC deficiency, LEPR deficiency, Alström syndrome, and Bardet-Biedl syndrome — the therapy is intended to lessen insatiable hunger and promote weight loss.

Phase 3 trials have shown that one year of treatment with setmelanotide’s daily formulation resulted in at least a 10% weight loss, and a reduction in hunger levels and body mass index (BMI) in POMC and LEPR deficiency patients.

The therapy was also generally safe, with no reports of serious adverse effects related to treatment.

Another Phase 3 trial (NCT03746522) is assessing setmelanotide’s safety and effectiveness in people with Bardet-Biedl and Alström syndromes, with top-line data expected by the first quarter of 2021.

The therapy’s daily formulation is currently under priority FDA review to treat people with POMC and LEPR deficiencies. A decision is expected by Nov. 27. Rhythm plans to submit a similar request, called a marketing authorization application, to the European Medicines Agency (EMA) by mid-year.

Setmelanotide’s new weekly formulation is based on Camurus’ extended-release FluidCrystal injection depot technology, which Rhythm licensed specifically for setmelanotide in 2016.

The Phase 2 clinical trial was designed to evaluate the safety, tolerability, pharmacokinetics — movement of drug into, through, and out of the body — and effectiveness of setmelanotide’s weekly formulation in healthy obese people (BMI of at least 40 kg, or 88.2 lbs, per m2).

This preliminary analysis included 75 people treated for 12 weeks, or about three months. A total of 42 people were treated with weekly setmelanotide (10, 20, or 30 mg weekly doses), 23 were given a placebo, and 10 received daily setmelanotide — 2 mg for one week, followed by 3 mg for 11 weeks.

Results showed similar weight loss in both weekly and daily setmelanotide groups. The mean difference in weight loss between the two formulations varied between 0.02 and 1.71 kg (0.04 and 3.77 lbs), which were not statistically significant.

Both weekly and daily setmelanotide were safe and well tolerated, with no serious adverse events, consistent with reports from previous clinical trials. Side effects such as injection site reactions, darkening of the skin, and nausea or vomiting were deemed mild by the researchers.

The pharmacokinetics of both formulations were also comparable through treatment duration, including mean trough therapy levels in the blood, which refer to the levels found immediately before the next dose is administered. People treated with the 30 mg weekly dose showed higher trough levels.

Rhythm plans to present these data, which are still being analyzed, at an upcoming medical meeting.

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