Setmelanotide successfully targeting extreme hunger, obesity in PWS trial
Daily use of injection therapy also helps ease anxiety, 6-month data show
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Treatment with setmelanotide helped reduce uncontrollable hunger, known as hyperphagia, and also eased anxiety in children and adults with obesity due to Prader-Willi syndrome (PWS).
The Rhythm Pharmaceuticals‘ experimental injection therapy was also shown to reduce body fat and preserve lean mass in individuals with PWS.
That’s according to six-month interim data from a one-year Phase 2 clinical trial (NCT06772597) that’s evaluating the therapy candidate, given daily via subcutaneous, or under-the-skin, injections, in 17 PWS patients. In a company press release detailing the new data, Rhythm stated that trial participants also “achieved clinically meaningful … reductions” in body mass index (BMI) scores, which use a ratio of weight and height to assess body fat.
Setmelanotide — designed to activate the appetite-regulating MC4R pathway, thought to be impaired in many genetic forms of obesity, including PWS — is already approved in the U.S. under the brand name Imcivree for treating certain types of genetically associated obesity.
“These results demonstrate the potential for MC4R [activators] to address the underlying biology of this severe disease and increased our confidence to advance into Phase 3 trials for PWS,” said David Meeker, MD, chairman and CEO of Rhythm.
The interim data were presented at the 2026 Endocrine Society Annual Meeting (ENDO), held June 13-16 in Chicago. The poster was titled “Setmelanotide, a Melanocortin-4 Receptor Agonist, in Prader-Willi Syndrome: Initial Phase 2 Results.”
A rare genetic disease, PWS is caused by a loss of function in specific genes on chromosome 15, affecting metabolism, cognitive function, and behavior. Hyperphagia is a hallmark symptom of PWS, marked by insatiable hunger that starts in early childhood and often leads to overeating and obesity.
Earlier trial found setmelanotide can ease hyperphagia symptoms
“Patients and families living with PWS face severe hyperphagia and obesity due to underlying MC4R pathway dysfunction and have limited effective treatment options,” said Jennifer Miller, MD, a pediatric endocrinologist at the University of Florida College of Medicine and the principal investigator of the Phase 2 trial.
In a previous Phase 2 study (NCT02311673) involving 40 adolescents and adults with PWS, setmelanotide was shown to curb hyperphagia and achieve clinically meaningful weight loss. However, benefits were only observed at the highest dose (2.5 mg) over longer treatment periods.
The ongoing one-year Phase 2 study is testing a higher setmelanotide dose (5mg) in individuals ranging in age from 6 to 23, all of whom were considered obese at the study’s start based on BMI scores.
The participants’ mean age is 17.1, and nine of them also received Vykat XR (diazoxide choline), a therapy approved to reduce PWS-related hyperphagia, during the study.
As of a May 7 data cut-off, the six-month analysis of data from the study’s 10 adults and seven children showed that treatment with setmelanotide was associated with improvements in multiple clinically relevant outcomes, the researchers noted.
New study shows therapy is effective for at least 6 months
Across all 17 participants, setmelanotide treatment resulted in a mean reduction in BMI of 3.06%. In adults, the mean BMI dropped by 3.11%, with six participants achieving reductions greater than 2.5% and four exceeding 4%.
Children showed a mean BMI reduction of 3% and a mean BMI z-score reduction of 0.35, a measure that compares a child’s BMI against peers of the same age and sex. Five of the children achieved a clinically meaningful reduction of at least 0.2 point in BMI z-score, the data showed.
Body composition was assessed in 16 participants — nine adults and all of the children — using DEXA scans, a type of imaging that measures fat and lean tissue (total body weight minus body fat weight).
These results showed a mean lean mass gain of 0.74% alongside a mean loss in fat mass of 4.19%. Six of the adults (67%) achieved greater than 5% reduction in fat mass, and five of the children (71%) gained at least 2.95% in lean mass.
Among the 10 participants who entered the trial with moderate to severe hyperphagia, eight — marking 80% overall — achieved a clinically meaningful reduction in hyperphagia, defined as a score drop of seven points or more in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT).
Anxiety and behavioral symptoms were assessed using the PWS Anxiousness and Distress Behaviors Questionnaire (PADQ), where a score drop of at least 11 points is considered clinically meaningful. Of the 15 participants with a pretreatment PADQ score above 11, 10 (67%) achieved a clinically meaningful improvement.
These results show that MC4R [activation with setmelanotide] has the potential to deliver sustained and durable improvements in outcomes across BMI, hyperphagia scores, body composition, and food-related behaviors and anxiety.
Safety results were consistent with setmelanotide’s established profile. This included injection site reactions, affecting 61%), and skin darkening, or hyperpigmentation, experienced by 56%. One-third of patients experienced fatigue. There were no serious adverse events, treatment discontinuation due to adverse events, or deaths, per the data.
Still, “due to the small sample size, the potential impact of [simultaneous Vykat XR treatment] requires further investigation,” the researchers wrote.
Overall, according to Miller, “these results show that MC4R [activation] has the potential to deliver sustained and durable improvements in outcomes across BMI, hyperphagia scores, body composition, and food-related behaviors and anxiety.”
Miller said these results are promising.
“Importantly, such reductions in HQ-CT score and anxiety, as well as weight reduction, have the potential to ease the burden not only on patients, but also on their caregivers who manage the daily challenges of this disease,” Miller said.
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