FDA Approves Expanded Indication for Setmelanotide in Treatment of Acquired HO

The FDA approved an expanded indication for setmelanotide (Imcivree; Rhythm Pharmaceuticals) to treat patients with acquired hypothalamic obesity (HO). With this label expansion, setmelanotide is indicated to reduce excess body weight and maintain reduction long term in adult and pediatric patients 4 years and older with acquired HO.¹

“[Setmelanotide] is now the first and only FDA-approved therapy for acquired HO, offering a targeted approach that addresses the underlying biology of this disease and meets a critical unmet need for patients who previously had no treatment options,” David Meeker, MD, chairman, CEO, and president of Rhythm, said in a news release. “This is a transformative milestone for Rhythm and reinforces our commitment to bringing meaningful therapies to patients living with rare MC4R pathway diseases.”¹

What Are Acquired HO and Setmelanotide?

The MC4R pathway is responsible for controlling certain physiological functions (eg, energy expenditure, hunger, and weight regulation), which are impaired in acquired HO. As a result, patients experience an accelerated and sustained weight gain that is often accompanied by hyperphagia and/or decreased energy expenditure. Acquired HO can occur as early as 6 months following hypothalamic injury.^1,2 According to Rhythm Pharmaceuticals, it is estimated that there are approximately 10,000 people in the US who are living with acquired HO.¹

In the US, setmelanotide is indicated to reduce excess body weight and maintain weight reduction long-term in adult and pediatric patients 4 years and older with acquired HO; and in adult and pediatric patients 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome or proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance.¹

Clinical Trials Findings Supporting the Expanded Indication

This expanded indication is supported by findings from the phase 3 TRANSCEND (NCT05774756)³ clinical trial, a double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of setmelanotide injections over a 52-week duration when treating patients with acquired HO. Positive data announced on March 1, 2026, included 12 patients from a Japanese cohort and 10 supplemental patients who were enrolled in addition to the primary 120-patient pivotal cohort.^3,4

According to these data, there was an observed –18.8% placebo-adjusted difference in the reduction in body mass index (BMI). Specifically, the trial met the primary end point, and a mean BMI reduction of approximately 16.4% from baseline for all patients receiving setmelanotide therapy (n = 94) compared with +2.4% in those receiving placebo (n = 48; P < .0001). Further, among those 12 years and older (n = 98), the setmelanotide group (n = 66) showed an average weekly reduction of about 2.5 points in the weekly average most hunger score, compared with a 1.3‑point reduction in the placebo group (n = 32; P = .0015).⁴

“Setmelanotide has shown effectiveness in targeting the underlying biology of acquired HO,” Ashley Shoemaker, MD, MSCI, associate professor of pediatrics, Pediatric Endocrinology at Vanderbilt Health, said in the news release. “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 [setmelanotide], physicians can offer a targeted therapy.”¹

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 20, 2026. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1

2. Roth CL, McCormack SE. Acquired hypothalamic obesity: a clinical overview and update. Diabetes Obes Metab. 2024;26(suppl 2):34-45. doi:10.1111/dom.15530

3. A trial of setmelanotide in acquired hypothalamic obesity. ClinicalTrials.gov. Updated July 2, 2025. Accessed March 20, 2026. https://clinicaltrials.gov/study/NCT05774756

4. Rhythm Pharmaceuticals announces additional positive data from phase 3 TRANSCEND trial of setmelanotide in patients with acquired hypothalamic obesity. News release. Rhythm Pharmaceuticals. March 1, 2026. Accessed March 20, 2026. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-additional-positive-data-phase/