Setmelanotide demonstrates BMI reduction in patients with acquired hypothalamic obesity | Image Credit: © rangizzz - © rangizzz - stock.adobe.com.

Setmelanotide (IMCIVREE; Rhythm Pharmaceuticals), a melanocortin-4 receptor (MC4R) agonist for the treatment of acquired hypothalamic obesity, has demonstrated positive data in the phase 3 TRANSCEND trial, according to an announcement from Rhythm Pharmaceuticals.¹

In the trial, setmelanotide met the primary endpoint of mean body mass index (BMI) reduction of -16.5% from baseline for all patients on setmelanotide therapy (n = 81) compared with +3.3% BMI change for patients on placebo (n=39) at 52 weeks (P < 0.0001).

Among all participants, (n = 120) a –19.8% placebo-adjusted difference in BMI was observed.

Additionally, a –20.2% placebo-adjusted BMI reduction was achieved in patients younger than 18 years ( n = 71) at 52 weeks. For those aged 18 years and older (n = 49), a –19.2% placebo-adjusted BMI reduction was observed at 52 weeks.

With these data, Rhythm Pharmaceuticals plans to have regulatory submissions in the United States and European Union completed in the third quarter of 2025.

“Acquired hypothalamic obesity is a serious disease resulting from damage to the hypothalamus, often due to brain tumors or their treatment or certain other injuries resulting in accelerated weight gain, hyperphagia and reduction in energy expenditure," said Susan Phillips, MD, pediatric endocrinologist at Rady Children's Hospital-San Diego and professor of pediatrics at UC San Diego School of Medicine, in a statement.

"These data are highly clinically meaningful, offering hope that a new targeted therapy may become available for patients – both adults and children – living with acquired hypothalamic obesity.”

The TRANSCEND trial (NCT05774756), according to Rhythm, is a global, randomized, placebo-controlled, and double-blind study that featured 120 patients aged 4 years and older. individuals were randomized 2:1 to either a daily subcutaneous injection of setmelanotide (n = 80) or placebo (n = 40).^1,2

The trial is believed to be the largest and longest placebo-controlled trial to evaluate a therapy for those with acquired hypothalamic obesity.¹

Additional data

Multiple secondary outcome achievements were announced in addition to the primary endpoint, including¹:

• 83% percent of patients on setmelanotide therapy achieved 5% or greater reduction in BMI (n = 33 patients 18 or older) or BMI Z-score reduction of 0.2 or greater points (n = 48 patients younger than 18); and
• -1.4 placebo-adjusted mean change in weekly average of the daily maximal hunger score for patients 12 years old or older (n = 81) (P = 0.003).

Safety

There were no new safety signals observed with setmelanotide, which was generally well tolerated.

Nausea, diarrhea, vomiting, injection site reaction, skin hyperpigmentation and headache were the most common treatment-emergent adverse events, that affected >20% of the study population, stated Rhythm.

Additional comments

“This 12-month placebo-controlled trial required an incredible commitment from patients, their families and clinical staff for which we are extremely grateful," said David Meeker, MD, chiarman, president and CEO of Rhythm, in the announcement. "Given these compelling new efficacy data with setmelanotide in a broader patient population than in our Phase 2 trial, we are preparing to submit a supplemental New Drug Application to the FDA and a Type II variation request to the European Medicines Agency in the third quarter of 2025. These planned submissions could pave the way for setmelanotide to become the first-ever approved therapy for these patients."

"In addition, these strong results with an MC4R agonist increase our confidence in the development of our next-generation MC4R agonists, currently in ongoing Phase 1/2 clinical trials in acquired hypothalamic obesity," added Meeker.

References:

1. Rhythnm Pharmaceuticals announces pivotal phase 3 TRANSCEND trial meets primary endpoint with –19.8% placebo-adjusted BMI reduction in patients (n = 120) with acquired hypothalamic obesity. Rhythm Pharmaceuticals. Press release. April 7, 2025. Accessed April 7, 2025. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-pivotal-phase-3-transcend-trial

2. A trial of acquired hypothalamic obesity. ClinicalTrials.gov. Updated February 12, 2025. Accessed April 7, 2025. https://clinicaltrials.gov/study/NCT05774756