FDA Approves IMCIVREE as First Therapy for Acquired Hypothalamic Obesity

The U.S. Food and Drug Administration (FDA) has approved an expanded indication for IMCIVREE® (setmelanotide) from Rhythm Pharmaceuticals for the treatment of acquired hypothalamic obesity (HO) in adults and pediatric patients aged 4 years and older. The approval marks the first FDA-approved therapy for acquired HO, a rare neuroendocrine disorder characterized by rapid and persistent weight gain due to hypothalamic injury or dysfunction.

David Meeker, M.D., Chairman, CEO and President of Rhythm Pharmaceuticals said the approval marks a major milestone, making IMCIVREE the first FDA-approved therapy for acquired hypothalamic obesity and addressing a significant unmet need with a treatment that targets the disease’s underlying biology.

Acquired hypothalamic obesity commonly develops following hypothalamic tumors such as craniopharyngioma or astrocytoma and their treatment, but may also occur after traumatic brain injury, stroke, or inflammatory damage to the hypothalamus. The condition disrupts signaling in the melanocortin-4 receptor (MC4R) pathway.

Setmelanotide works by activating the melanocortin-4 receptor (MC4R) pathway, a central regulator of appetite, energy expenditure, and body weight. Damage to the hypothalamus can disrupt this signaling pathway by reducing production of alpha-melanocyte-stimulating hormone (α-MSH), leading to uncontrolled hunger and accelerated weight gain. By restoring MC4R signaling, IMCIVREE addresses the underlying biological mechanism of the disease rather than simply managing symptoms.

The approval is supported by results from the Phase 3 TRANSCEND trial (NCT05774756), which evaluated setmelanotide in 142 patients with acquired HO. The study met its primary endpoint, demonstrating a placebo-adjusted 18.4% reduction in body mass index (BMI) at 52 weeks. Patients receiving setmelanotide achieved a mean BMI reduction of 15.8%, compared with a 2.6% increase among patients receiving placebo (p<0.0001). The therapy was generally well tolerated, with the most common adverse events including skin hyperpigmentation, nausea, vomiting, and headache.

According to Rhythm, approximately 10,000 people in the United States are living with acquired hypothalamic obesity, a condition that can emerge within months after hypothalamic injury and is often associated with severe hyperphagia and persistent weight gain. The company stated that IMCIVREE will be available immediately in the U.S., supported through its Rhythm InTune program that provides patient education and treatment access assistance.

Ashley Shoemaker, M.D., MSCI, Pediatric Endocrinologist at Vanderbilt Health noted that setmelanotide produced meaningful reductions in BMI and hunger in both children and adults, highlighting its clinical benefit in a severe condition that requires early and proactive management.

IMCIVREE is already approved in the U.S. and Europe for certain rare genetic obesity disorders, including Bardet-Biedl syndrome and obesity caused by POMC, PCSK1, or LEPR deficiency. The new indication further expands the therapy’s role in treating MC4R pathway-related diseases.

Rhythm Pharmaceuticals recently reported that its Phase 3 EMANATE trial of setmelanotide in rare genetically driven obesity linked to MC4R pathway disruptions failed to meet the primary endpoint of placebo-adjusted BMI reduction at Week 52.

Reference

Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE® (setmelanotide) for Patients with Acquired Hypothalamic Obesity, 19 March 2026, Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE® (setmelanotide) for Patients with Acquired Hypothalamic Obesity – Rhythm Pharmaceuticals, Inc.

A Trial of Setmelanotide in Acquired Hypothalamic Obesity, ClinicalTrials.gov ID NCT05774756, https://clinicaltrials.gov/study/NCT05774756\