PWS patients see weight loss, less hunger with setmelanotide in trial
In early data, injectable therapy shows promise for curbing hyperphagia
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The injectable therapy setmelanotide, being developed by Rhythm Pharmaceuticals for Prader-Willi syndrome (PWS), curbs hyperphagia, or uncontrollable hunger, and reduces body weight in children and adults with obesity due to PWS.
Those are the early findings of an exploratory Phase 2 clinical trial, ongoing at a single U.S. site, that’s testing the treatment candidate in adults and adolescents with the genetic disease.
“We are encouraged by these preliminary results, which give us confidence to advance setmelanotide into a registrational Phase 3 trial for PWS,” David Meeker, MD, chairman and CEO of Rhythm, said in a company press release detailing the findings.
A registrational trial is designed to generate sufficient data to support an application for a therapy’s approval. Setmelanotide is already approved in the U.S. as Imcivree to treat certain types of genetic obesity. The new trial would, if successful, back the approval of setmelanotide for PWS.
Administered via subcutaneous, or under-the-skin, injections, setmelanotide is an activator, or agonist, of the melanocortin-4 receptor (MC4R) pathway, which regulates appetite and the feeling of fullness, known as satiety. This pathway is believed to be dysfunctional in many genetic forms of obesity, including PWS.
‘Very few treatments’ now available for hyperphagia in PWS
“Hyperphagia and severe obesity associated with PWS present serious challenges for patients and often lead to significant health complications over time,” said Jennifer Miller, MD, a pediatric endocrinologist at the University of Florida College of Medicine, and the principal investigator of the ongoing Phase 2 trial (NCT06772597), noting “a profound unmet need” for medications that can help.
According to Meeker, additional data from the trial are expected in the first half of 2026.
“We look forward to [that] … and remain committed to exploring the potential of MC4R agonism for this patient population, for whom there are very few treatment options available,” Meeker said.
Rhythm also announced that a Phase 1 clinical trial (NCT06239116) testing its next-generation MC4R agonist RM-718 will now include a group of as many as 20 PWS patients. The six-month, U.S.-based study is evaluating the therapy in individuals with obesity and those with obesity related to damage to a brain region called the hypothalamus.
Given once weekly, RM-718 is designed to reduce body weight and hyperphagia without causing skin hyperpigmentation.
“We look forward to evaluating our weekly MC4R agonist RM-718 in PWS, and we expect the first patient with PWS to enter screening for this study in December,” Meeker said.
A now-completed U.S.-based Phase 2 study (NCT02311673) tested several doses of setmelanotide against a placebo in 40 adults and adolescents with PWS. Those data showed that only the treatment’s highest dose (2.5 mg) — when given for longer periods — was associated with reduced hyperphagia and clinically meaningful weight loss.
Lead investigator calls setmelanotide effects ‘remarkable’
The exploratory Phase 2 study, underway in Florida, is testing an even higher setmelanotide dose: 5 mg/day. A total of 18 children and adults with PWS have been enrolled. The participants range in age from 6 to 65, and all are classified as obese based on body mass index (BMI), a ratio of weight and height.
At the study’s start, the participants’ mean age was 17.1 years, with three younger than age 12, four between ages 12 and 17, and 11 aged 18 years and older.
The daily dose of setmelanotide given these patients is increased to 5 mg as tolerated, and administered for one year (52 weeks). The study’s main goal is to assess the therapy’s safety and tolerability, while secondary goals include changes in BMI, hyperphagia, and body composition. The therapy’s pharmacological properties are also being investigated.
As of a Nov. 14 cutoff date, three-month data were available for eight participants, and six-month data for five participants.
These preliminary results showed that setmelanotide treatment reduced BMI in 75% of patients treated for three months and 60% of those treated for six months. In two of the three participants showing BMI reductions at six months, continued weight loss was observed between three and six months.
Additionally, body composition assessments showed decreases in fat mass in three of four evaluable patients at six months.
[Trial participants on setmelanotide are] moving better, their body composition looks better, the parents feel that they are eating somewhat less, that they’re less obsessed by food, and that they’re able to exercise more easily, and that they’re choosing to exercise on a regular basis.
Hyperphagia was reduced in six participants given setmelanotide for three months, as assessed by the caregiver-reported Hyperphagia Questionnaire for Clinical Trials; a seventh patient had no signs of hyperphagia at the study’s start.
So far, all but one trial participant remains on setmelanotide, according the researchers.
Safety and tolerability were consistent with the established clinical profile of setmelanotide. The most common adverse events were skin hyperpigmentation, or dark skin patches (27.8%), and injection site reactions (22.2%). There were no deaths, serious adverse events, or adverse events leading to treatment withdrawal.
“I’ve been very excited about the changes that we’re seeing in BMI reduction and body composition in the great majority of the patients,” Miller said in a Rhythm webcast. “They’re moving better, their body composition looks better, the parents feel that they are eating somewhat less, that they’re less obsessed by food, and that they’re able to exercise more easily, and that they’re choosing to exercise on a regular basis, which is remarkable to me.”
