FDA Approves Setmelanotide (Imcivree) for Acquired Hypothalmic Obesity

The US Food and Drug Administration (FDA) has approved an expanded indication for setmelanotide (Imcivreee) to treat acquired hypothalamic obesity (HO) in adults and pediatric patients aged 4 years and older, the company announced on March 19, 2026.

According to Rhythm Pharmaceuticals, the approval makes setmelanotide the first and only FDA-approved therapy for this rare condition, which is characterized by accelerated and sustained weight gain following injury to or dysfunction of the hypothalamus.¹

“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 both 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

Phase 3 TRANSCEND Trial

The approval was based on data from the global, randomized, double-blind, placebo-controlled phase 3 TRANSCEND trial enrolling 142 patients with acquired HO aged 4 years and older. According to the company, participants were randomized 2:1 to receive once-daily subcutaneous setmelanotide, titrated up to 1.5 to 3.0 mg depending on age, weight, and tolerability, or placebo for 52 weeks.¹

The trial met its primary endpoint. Patients on setmelanotide (n=94) achieved a mean BMI reduction of 15.8% from baseline at 52 weeks, compared with a 2.6% increase in the placebo arm (n=48), yielding a placebo-adjusted BMI reduction of 18.4% (P <.0001).¹ The result built on earlier phase 2 findings published in Lancet Diabetes and Endocrinology, in which 89% of 18 patients with hypothalamic obesity met the primary endpoint of at least a 5% BMI reduction after 16 weeks of setmelanotide treatment, with a mean BMI reduction of 15% across the study population.²

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

According to prescribing information, patients with acquired HO and secondary adrenal insufficiency experienced serious adverse reactions related to acute adrenal insufficiency in 5% of setmelanotide-treated patients, and sodium imbalances, including both hyponatremia and hypernatremia, were observed in patients with concomitant central diabetes insipidus. Depression and suicidal ideation have also been reported with setmelanotide across indications and warrant monitoring.¹

A Rare Disease With No Prior Approved Options

Acquired HO most frequently follows the growth or treatment of craniopharyngioma, astrocytoma, or other hypothalamic-pituitary tumors, though traumatic brain injury, stroke, and inflammatory causes are also recognized. Hypothalamic injury disrupts MC4R pathway signaling, resulting in impaired regulation of hunger and energy expenditure, driving rapid and often severe weight gain that proves resistant to conventional anti-obesity approaches. Rhythm estimates there are approximately 10,000 people in the US living with the condition, though the company acknowledged that figure is based on analysis of published literature, tumor registries, and claims data.¹

Setmelanotide is an MC4R agonist that Rhythm describes as designed to restore impaired MC4R pathway signaling. It was first approved by the FDA in 2020 for adults and pediatric patients aged 6 years and older with obesity due to POMC, PCSK1, or LEPR deficiency, and subsequently for Bardet-Biedl syndrome, establishing a prior regulatory track record in MC4R pathway-driven rare obesity.³ The acquired HO approval represents the first indication extending setmelanotide to an obesity phenotype driven by structural rather than genetic disruption of that pathway.

References

1. Rhythm Pharmaceuticals, Inc. Rhythm Pharmaceuticals announces FDA approval of IMCIVREE (setmelanotide) for patients with acquired hypothalamic obesity. Press release. Published 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

3. Walter K. FDA approves setmelanotide for obesity caused by genetic deficiencies. HCPLive. Published November 27, 2020. Accessed March 19, 2026. https://www.hcplive.com/view/fda-setmelanotide-obesity-genetic-deficiencies