Setmelanotide Lowers Weight, Hunger in Bardet-Biedl Syndrome, Phase 3 Trial Shows

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One year of treatment with setmelanotide was safe and resulted in a significant drop in body weight and hunger in Bardet-Biedl syndrome (BBS) patients, ages 12 years and older, with moderate to severe obesity, according to top-line data from a Phase 3 clinical trial.

“We are pleased with the robust response observed in BBS patients, which supports our goal of delivering a precision medicine to this well-characterized patient population who suffer from insatiable hunger and severe, early-onset obesity,” David Meeker, MD, the chair, president, and CEO of Rhythm Pharmaceuticals — the therapy’s developer — said in a press release.

Murray Stewart, MD, Rhythm’s chief medical officer, said these findings are particularly relevant given that “nearly half of the evaluable patients were growing adolescents, who we would normally expect to gain weight.”

Stewart added that the company is looking “forward to completing further analyses on the full data, which will include BMI [body mass index] and BMI-Z scores, two measures that more accurately assess weight gain in adolescents and may further demonstrate the impact from treatment with our precision therapy.”

Based on these positive findings, Rhythm plans to file applications with both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) seeking setmelanotide’s approval for BBS in the second half of 2021.

Notably, the trial’s available data showed only trends toward weight and hunger reductions in people with Alström syndrome, another rare genetic obesity disorder. Analyses of the full results, expected to be completed by March, will help finalize setmelanotide’s regulatory path for this patient group, Meeker said.

Rhythm plans to publish the trial’s full data and share them at an upcoming medical meeting.

Setmelanotide works by activating the melanocortin-4 receptor (MC4R) pathway, which regulates hunger and satiety (feeling full), and is impaired in people with rare genetic obesity disorders — including BBS and Alström syndrome, as well as POMC deficiency, PCSK1 deficiency, and LEPR deficiency.

As such, the therapy, given as an under-the-skin injection, is intended to lessen hunger and promote weight loss.

Setmelanotide was approved in the U.S. in November 2020, as the first treatment available for people, starting at age 6, with obesity due to POMC, PCSK1, or LEPR deficiency. It will be marketed as Imcivree.

Setmelanotide received the FDA’s breakthrough therapy and the EMA’s priority medicines designations for the treatment of MC4R-associated genetic obesity disorders. It was also granted orphan drug designation by both agencies and rare pediatric disease designation by the FDA for some of these conditions.

These designations are meant to expedite the therapy’s development by providing financial benefits, and a marketing exclusivity period of seven years in the U.S. and 10 years in Europe if granted regulatory approval.

Data from a global Phase 2/3 trial (NCT03013543, possibly still recruiting) showed that daily treatment with setmelanotide safely and significantly reduced body weight and hunger in both BBS and Alström syndrome patients.

This supported the launch of the confirmatory Phase 3 trial (NCT03746522), which recruited 38 people, 6 years and older, with moderate to severe obesity due to BBS (32 patients) or Alström syndrome (six patients). Most patients, 28 with BBS and three with Alström syndrome, were age 12 or older.

Participants were randomly assigned to either setmelanotide or a placebo, once a day for 14 weeks (about 3.5 months), after which all were given setmelanotide for a total of 52 weeks (about one year).

The trial’s main goal was to assess the proportion of patients achieving at least a 10% drop in body weight after one year of treatment. Key secondary goals included assessing mean reduction in body weight and hunger, and the proportion of participants achieving at least a 25% reduction in most hunger scores.

Analysis of the main goal included data from the 31 patients at least 12 years of age. Most were given setmelanotide for at least one year; three participants initially on a placebo had not yet reached one year of treatment.

Results showed that 11 patients (34.5%) achieved a body weight reduction of at least 10%, which was statistically significant, meeting the trial’s main goal. All 11 responders had BBS, and none of those with Alström syndrome reached the target weight loss.

The study also met its key secondary goals, as patients showed a significant mean drop in body weight (6.2%) and hunger levels (30.8%), and 60.2% of them achieved at least a 25% reduction in most hunger scores.

The therapy was generally well-tolerated, with no setmelanotide-related serious side effects. Reported side effects included mild injection site reactions, and nausea with infrequent vomiting.

Eight participants discontinued treatment: five due to side effects (one receiving placebo at the time) and three for other reasons — one being on placebo at the time.

“Despite conducting this trial during the COVID-19 pandemic, which has been linked to weight gain across many populations, these data demonstrate that setmelanotide reduced weight and alleviated hunger in BBS patients,” Stewart said.

“Overall, these results reinforce the potential value of the MC4R pathway as a therapeutic target for some rare genetic diseases of obesity and underscore our belief that obesity is a complex, multifactorial disease,” he added.

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