Leveraging setmelanotide in acquired hypothalamic obesity, with Ashley Shoemaker, MD, MSci

The FDA has approved setmelanotide for acquired hypothalamic obesity (HO) in adults and pediatric patients 4 years and older, marking the first approved therapy for this rare and treatment-resistant condition.

The approval, announced March 19, 2026, was based on robust phase 3 data demonstrating meaningful reductions in body mass index (BMI) in a population with historically no targeted options.

“Setmelanotide has shown effectiveness in targeting the underlying biology of acquired HO,” said Ashley Shoemaker, MD, MSci, associate professor of pediatrics and pediatric endocrinology at Vanderbilt Health. “Patients treated with setmelanotide experienced meaningful reductions in BMI and hunger, demonstrating the therapy’s ability to deliver clinically significant outcomes in children and adult patients. Acquired HO is a severe disease that requires early and proactive management. With the availability of Imcivree, physicians can offer a targeted therapy.”¹

The approval was supported by the global, randomized, double-blind, placebo-controlled phase 3 TRANSCEND trial, which enrolled 142 patients 4 years and older with acquired HO. Participants were randomly assigned 2:1 to once-daily subcutaneous setmelanotide titrated to 1.5 to 3.0 mg based on age, weight, and tolerability, or placebo over 52 weeks.

The trial met its primary end point decisively. Setmelanotide-treated patients achieved a mean BMI reduction of 15.8% from baseline at 52 weeks compared with a 2.6% increase in the placebo group, which yielded a statistically significant placebo-adjusted difference of 18.4% (P <.0001). These results are consistent with earlier phase 2 findings published in Lancet Diabetes and Endocrinology, in which 89% of patients met the threshold for at least a 5% BMI reduction after 16 weeks, with a mean reduction of 15% across the study population.

Setmelanotide was generally well tolerated. Adverse events occurring in more than 20% of participants included skin hyperpigmentation, nausea, vomiting, and headache.

Clinicians should be aware of several important safety signals: Serious adverse reactions related to acute adrenal insufficiency were observed in 5% of setmelanotide-treated patients with concomitant secondary adrenal insufficiency. Sodium imbalances, including both hyponatremia and hypernatremia, were reported in patients with concomitant central diabetes insipidus. Depression and suicidal ideation have also been reported across setmelanotide indications and warrant ongoing monitoring.

Relevant disclosures for Shoemaker include Rhythm Pharmaceuticals and Chiesi USA.

References

1. Rhythm Pharmaceuticals announces FDA approval of Imcivree (setmelanotide) for patients with acquired hypothalamic obesity. News release. Rhythm Pharmaceuticals. March 19, 2026. Accessed March 19, 2026. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1

2. Roth CL, Schulten S, Meeker D, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. 2024;12(6):385-393. doi:10.1016/S2213-8587(24)00085-8