RARE Daily

Rhythm Obesity Drug Hits Endpoint in Bardet-Biedl Patients, but Misses in Alström Syndrome Patients

December 22, 2020

Rare Daily Staff

Rhythm Pharmaceuticals reported positive topline results from a pivotal phase 3 clinical trial evaluating setmelanotide for the treatment of insatiable hunger and severe obesity in individuals with Bardet-Biedl syndrome, but failed to meet its endpoint in three participants studied with Alström syndrome.

Setmelanotide is a melanocortin-4 receptor (MC4R) agonist that was recently approved for marketing in the United States for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to three rare diseases of obesity, POMC, PCSK1, and LEPR deficiency, confirmed by genetic testing. Rhythm hopes to expand its use to other rare indications.

Bardet-Biedl (BBS) and Alström syndrome are ultra-rare genetic diseases that affect multiple organ systems and with symptoms and presentation varying greatly among affected individuals. These conditions also trigger insatiable hunger, also known as hyperphagia, and can lead to severe obesity beginning early in life. In the United States, Rhythm estimates that BBS affects approximately 1,500 to 2,500 people and that Alström syndrome affects approximately 500 people. Currently, there are no approved therapies targeting the MC4 receptor pathway for reducing body weight and hunger in BBS or Alström syndrome.

The combined pivotal phase 3 trial is a multinational, open-label, single-arm study consisting of 52 weeks of treatment with setmelanotide. Participants were blinded and randomized for the first 14 weeks of the trial to receive either placebo or setmelanotide therapy. Those participants who began the trial on setmelanotide continued therapy for a total of 52 weeks, while those on placebo went on to receive 52 weeks of setmelanotide therapy after completion of the 14-week placebo period.

The phase 3 study met its primary endpoint of 10 percent weight reduction in 11 of 31 evaluable patients in the study, all of whom were patients with BBS. The three evaluable patients with Alström syndrome did not meet the primary endpoint. The study also met all key secondary endpoints that include -6.2 percent mean reduction from baseline in body weight, -30.8 percent mean reduction from baseline in most hunger rating, and 60.2 percent of participants achieving at least a 25 percent reduction in most hunger scores from baseline at approximately 52 weeks of therapy, when the primary analysis was conducted.

Treatment-emergent adverse events were mild and no serious adverse events related to treatment with setmelanotide were observed. Eight patients discontinued from study drug treatment during the trial, five due to adverse events (one on placebo at the time), and three for other reasons (one on placebo at the time).

“These phase 3 results add to our growing understanding of setmelanotide’s potential to treat people living with rare genetic diseases of obesity,” said David Meeker, chair, president and CEO of Rhythm. “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. Although we are disappointed that none of the three evaluable Alström patients met the primary endpoint, we 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.”

Rhythm expects to complete a subsequent analysis of the full data in the first quarter of 2021 and plans to share the full data in a forthcoming publication or in a presentation at an upcoming medical meeting.

Rhythm also plans to complete regulatory submissions to both the U.S. Food and Drug Administration and the European Medicines Agency for BBS in the second half of 2021. The company expects to finalize a path forward for Alström syndrome upon completing a full analysis of the final data from this trial.

“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. 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,” said Murray Stewart, chief medical officer of Rhythm.

Photo: David Meeker, chair, president and CEO of Rhythm

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