Rhythm Pharmaceuticals’ Anti-Obesity Drug Setmelanotide Shows Promising Findings in Phase III Trial

Setmelanotide can be expected in the market soon based on its promising results in phase III trials. 

Rhythm Pharmaceuticals announced on Tuesday that its hunger and severe obesity drug, setmelanotide, significantly reduced weight and hunger scores in people with Bardet-Biedl syndrome (BBS) and Alström syndrome, according to topline results from a Phase III study.

Setmelanotide is a melanocortin-4 receptor (MC4R) agonist targeting the MC4 receptor, which is the component of the biological pathway that independently regulates hunger, caloric intake and energy expenditure. Genetic variants can impair the MC4R pathway’s function, increasing the risk of hyperphagia and early onset severe obesity. Setmelanotide was approved by the U.S. FDA in November for chronic weight treatment in adults and children 6 years of age and older with obesity caused by genetically confirmed proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency.

Rhythm’s final analysis of its pivotal Phase III trial included 28 patients with BBS and three patients with Alström syndrome, 12 years of age and older. A total of 5 participants in the study were younger than 12 at time of enrollment. Patients in the study were treated with either setmelanotide or placebo for the first 14 weeks. Participants initially randomized to setmelanotide continued the treatment for 52 weeks, while patients who received placebo received setmelanotide for 52 weeks after the first 14-week placebo treatment period.

Approximately 34.5% of patients in the open-label study experienced at least 10% reduction in body weight from baseline to 52 weeks (p=0.0024). In addition, a total of 11 out of 28 patients with BBS achieved a 10% reduction in body weight, while none of the patients with Alström syndrome achieved this endpoint.

There was a mean -6.2% reduction in body weight from baseline to the follow-up period (p<.0001). Additionally, participants in the trial experienced a mean -30.8% reduction in their most hunger rating (p<0.0001). Also, 60.2% of patients experienced a 25% reduction in most hunger scores by 52 weeks (p<0.0001).

Treatment with setmelanotide was associated with mild injection site reactions and nausea with infrequent vomiting. No serious adverse events (AEs) were reported. A total of eight patients discontinued treatment during the study, with five discontinuations due to AEs.

“These Phase 3 results add to our growing understanding of setmelanotide’s potential to treat people living with rare genetic diseases of obesity,” according to a statement made by David Meeker, M.D., Rhythm’s Chair, President and Chief Executive Officer. “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.”

Meeker added that while the company was “disappointed” to find none of the patients with Alström met the primary endpoint, they “are encouraged by trends in hunger and weight reduction in some patients and look forward to evaluating the full data as we finalize our path forward in this indication.”

Murray Stewart, M.D., Chief Medical officer of Rhythm, added, “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 suggests the results from the trial “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.

Stewart added that the company will work to complete additional “analyses on the full data, which will include BMI 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.”

Rhythm says it will complete regulatory submissions to the FDA as well as the European Medicines Association for BBS in 2021.