New Drug Looks Good for Rare Genetic Severe Obesity

Marlene Busko

November 24, 2020

At the recent ObesityWeek® Interactive 2020 meeting, researchers discussed the investigational agent setmelanotide and it's potential to treat two rare genetic diseases that cause insatiable hunger (hyperphagia). 

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is being developed by Rhythm Pharmaceuticals to treat patients with deficiencies in pro-opiomelanocortin (POMC) or leptin receptor (LEPR) who develop persistent severe obesity soon after they are born.

Speaking at the virtual meeting, Gregory Gordon, JD, MD, vice president, clinical at Rhythm Pharmaceuticals, reported data on a once-weekly formulation of setmelanotide in people with obesity that showed it was comparable to the once-daily formulation that has already been trialed in people with these very rare genetic forms of obesity.

But weight loss in individuals with obesity was smaller "relative to data we've reported separately in patients with rare genetic obesities associated with an impaired MC4R pathway," said Gordon.

Hence, the niche market for this drug is patients with the genetic disorders, for which the drug has been tested for more than 3 years, he stressed.

And these latest data suggest further investigation of the once-weekly formulation in individuals with rare genetic disorders of obesity is warranted, he said.

Meanwhile, Karine Clément, MD, PhD, of Pitie-Salpetriere Hospital, Paris, France, who is the lead author of the two pivotal phase 3 studies of setmelanotide in people with the very rare genetic forms of obesity, reported two further posters at the meeting showing data from the extensions of the original trials.  

"There were no new safety concerns" with the drug when use was extended beyond a year, "providing a rationale for long-term use of setmelanotide in this population."

The company is expecting a decision any day by the US Food and Drug Administration on approval of setmelanotide for obesity caused by these genetic disorders, which was given priority review back in May.

Largest Studies to Date; Genetic Testing for Patients Who May Benefit?

Topline results from the two pivotal phase 3 studies, first presented last year, were also recently published in The Lancet Diabetes & Endocrinology by Clément and colleagues.

These are the "largest studies to date in POMC and LEPR deficiency obesities," said coauthor Peter Kühnen, MD, Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Germany, in a statement issued by Rhythm.

"We may soon have a targeted treatment option available for the first time for obesity disorders caused by impairments of the MC4R pathway," he said.

In an accompanying editorial, Donna H. Ryan, MD, speculates that approval of an effective drug for patients with proven genetic defects in the leptin–melanocortin pathway "would then drive clinicians to increase genetic testing for patients with a history of severe early onset obesity."

In the United States, about 100 to 500 patients have POMC-deficiency obesity and 500 to 2000 patients have LEPR-deficiency obesity, Rhythm estimates.

"Although they occur only rarely, these conditions present enormous challenges for health care providers, parents, and patients," Ryan writes.

"Thus, the impact of setmelanotide in the obesity clinic is likely to mean a renewed appreciation for the biological underpinnings of obesity and an increase in genetic screening to identify a subset of patients that can benefit from the drug," said Ryan, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana.

"Most Promising" for POMC, "Worth Trying" for LEPR Deficiencies

The two single-arm, phase 3 trials published in The Lancet Diabetes & Endocrinology enrolled 10 participants with POMC deficiency and 11 patients with LEPR deficiency.

The participants were adults aged 18 years and older and children aged 6 years and older at 10 hospitals in Canada, the United States, Europe, and the UK, who received daily subcutaneous injections of setmelanotide.

Eight of the 10 participants in the POMC trial (80%) achieved at least 10% weight loss at approximately 1 year (the primary efficacy endpoint); the 10 patients lost a mean of 26% of their initial body weight.  

"This result is excellent and in the range of bariatric surgery outcomes," Ryan commented. "Moreover, it should be interpreted in the context that mean weight loss for currently available anti-obesity medications on the market is 5%-7%."

The response was more variable for the 11 participants with LEPR deficiency, she noted. Four failed to achieve the required 5% weight loss by week 12, and only five (45%) achieved the primary outcome of 10% or more weight loss at approximately 1 year.

"Still, all five participants achieved 15% or more weight loss and two achieved 20% or more weight loss."

For participants with these two genetic deficiencies, "tolerability and safety seem to be acceptable." The most common adverse events were injection site reactions, hyperpigmentation, nausea, and vomiting, Ryan noted.

"Taken together, setmelanotide seems most promising for patients with POMC deficiency," she writes.

"The results do not seem as encouraging for all patients with LEPR deficiency, but prescribing a trial of setmelanotide would still be a worthy approach in the face of no alternative treatments for this severe disease."

Ryan has reported receiving personal fees and nonfinancial support from Real Appeal, Boehringer Ingelheim, Epitommee, Novo Nordisk, Bausch Health, Janssen, Redesign Health, and Sanofi; personal fees from Alyvant and Pfizer; and equity in lieu of cash compensation for services from Gila Therapeutics, Xeno Biosciences, Scientific Intake, and Phenomix.

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