FDA Approves Setmelanotide for Adult and Pediatric Patients With Acquired Hypothalamic Obesity

Setmelanotide (Imcivree; Rhythm Pharmaceuticals) on Thursday became the first FDA-approved therapy to treat acquired hypothalamic obesity (HO), a rare disease caused by hypothalamic injury or function that leads to accelerated and sustained weight gain.¹ The indication covers adults and children 4 years and older.

The melanocortin 4 receptor (MC4R) agonist works on the pathway that controls the body’s functions of hunger, energy expenditure, and body weight regulation via the hypothalamus, a region in the forebrain that coordinates the autonomic nervous system and pituitary activity. Whereas genetic forms of HO tend to act on leptin-melanocortin pathways, acquired HO can arise when the hypothalamus is damaged by tumors (eg, craniopharyngioma) and their treatment via surgery or radiation, or other types of injury to the region.² Hyperphagia, or excessive hunger, stems from structural damage to the hypothalamic nuclei and causes individuals to not feel full or satisfied after meals.

According to Rhythm’s press release, approximately 10,000 individuals may currently live with acquired HO in the US.¹ Typical weight management strategies like lifestyle interventions have largely failed to help patients achieve meaningful and sustained weight loss, so research in recent years has focused on insulin modulators, stimulants, incretin-based therapies (eg, glucagon-like peptide-1 receptor agonists), and MC4R agonists, with researchers concluding, “Although challenging, [acquired] HO is no longer untreatable.”²

Approval was based on positive results from the phase 3 TRANSCEND trial of setmelanotide in patients with acquired HO (NCT05774756).¹ The global study, which is ongoing, had new results read out on March 1 for 142 patients over 52 weeks, including achievement of the primary end point with a –18.8% placebo-adjusted difference in body mass index (BMI) reduction for the setmelanotide group.³ Mean BMI change from baseline was –16.4% for the treatment group (n = 94) vs 2.4% for the placebo group (n = 48) (P < .0001).

In patients 12 years and older (n = 98), the setmelanotide group had a mean weekly reduction of 2.5 points in the weekly average most hunger score vs a reduction of 1.3 points in the placebo group (P = .0015). These extended data added to the topline results announced in April 2025 showing that TRANSCEND met its primary and key secondary end points in a prespecified 120-patient cohort.³

The most common adverse reactions to setmelanotide (incidence rates ≥20%) include skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.¹ Prescribers are advised to monitor patients for new or worsening depression or suicidality, as well as melanocytic nevi and signs of adrenal insufficiency.

Setmelanotide was already FDA approved to reduce excess body weight in adult and pediatric patients 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome or genetically confirmed pro-opiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. Rhythm reports the agent is in development for other rare disorders, and it also has 2 investigational MC4R agonists in its pipeline.

“Having a therapy for individuals and families affected by acquired hypothalamic obesity has the potential to be transformational,” Amy Wood, executive director and founder of the Raymond A. Wood Foundation, a nonprofit dedicated to advocacy for survivors of hypothalamic-pituitary brain tumors, said in Rhythm’s release. “We’ve seen firsthand the devastating impact acquired hypothalamic obesity has on patients’ and families’ lives, including relentless hunger and accelerated and sustained weight gain. [Setmelanotide] offers hope and a path forward for thousands of patients who have long been without options.”

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. 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/