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Adipose Tissue_Appetite_and Obesity

SUN-723 - Weight Category Improvement Following Setmelanotide in Patients with Acquired Hypothalamic Obesity

Sunday, June 14, 2026
9:00 AM - 4:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Ashley H. Shoemaker, MD, MSCI: .NovoNordisk: Clinical Trial Investigator (); Aardvark Therapeutics: Clinical Trial Investigator (); Eli Lilly & Company: Contracted Research (Principal Investigators must provide information, even if received by the institution) (); Rhythm Pharmaceuticals: Advisory Board (), Clinical Trial Investigator (), Consultant (), Employee (any industry) (); Soleno Therapeutics: Clinical Trial Investigator (), Consultant ()
Christian L. Roth, MD: Rhythm Pharmaceuticals: Advisory Board (), Clinical Trial Investigator (), Consultant (), Honorarium Recipient ()
Jennifer L. Miller, MD: Rhythm Therapeutics: Clinical Trial Investigator (); Soleno Therapeutics: Clinical Trial Investigator ()


Background: Acquired hypothalamic obesity (aHO) is characterized by accelerated and sustained weight gain following injury to the hypothalamus. In the Phase 3 trial of the melanocortin-4 receptor (MC4R) agonist setmelanotide in aHO (NCT05774756), the primary endpoint of percent change in body mass index (BMI) at Week 52 was met. Here, we present changes in weight category in participants after 1 year of setmelanotide treatment.

Methods: Participants aged ≥4 years with BMI ≥95th percentile (in those aged 4- < 18 years) or ≥30 kg/m2 (in those aged ≥18 years) with aHO following hypothalamic tumor, lesion, or injury were included and randomized 2:1 to setmelanotide or placebo for up to 60 weeks. For this analysis, participants with an observed primary endpoint value at 52 weeks on therapeutic regimen were included. Changes in body mass index (BMI; for adult participants ≥18 years) and percent of the 95th BMI percentile (%BMI95; for pediatric participants < 18 years) from baseline to 1 year of setmelanotide or placebo treatment were assessed and stratified by respective weight categories: healthy weight (BMI < 25 kg/m2 [adult]; BMI ≥5th to < 85th percentile [pediatric]), overweight (BMI ≥25 to < 30 kg/m2; ≥85th to < 95th percentile), class I obesity (BMI ≥30 to < 35 kg/m2; BMI ≥95% to %BMI95 < 120%), class II obesity (BMI ≥35 to < 40 kg/m2; %BMI95 ≥120% to < 140%), and class III obesity (BMI ≥40 kg/m2; %BMI95 ≥140%).

Results: Of the 120 total participants, 71 were < 18 years old and 49 were ≥18 years old; 110 participants had an observed primary endpoint value at 52 weeks on therapeutic regimen and were included in this analysis. At baseline, 40 of 67 pediatric participants (59.7%) and 29 of 43 adult participants (67.4%) had class II or III obesity. After 1 year, improvements of ≥1 weight category were observed in 32 of 45 pediatric participants (71.1%) and 20 of 28 adults (71.4%) treated with setmelanotide, and improvements of ≥2 weight categories were observed in 20 of 45 pediatric participants (44.4%) and 14 of 28 adults (50.0%). By contrast, after 1 year, for the placebo group, 3 of 22 pediatric participants (13.6%) and 1 of 15 adults (6.7%) improved ≥1 weight category, and none at any age improved ≥2 weight categories. After 1 year, 32 of 73 participants (43.8%) treated with setmelanotide had healthy weight (n=16) or overweight (n=16); for placebo, 5 of 37 participants (13.5%) had overweight and none had healthy weight. Common adverse events that were reported in >30% of the setmelanotide group were skin hyperpigmentation (setmelanotide, 55.6% vs placebo, 7.7%), nausea (50.6% vs 30.8%), vomiting (39.5% vs 17.9%), and headache (38.3% vs 30.8%).

Conclusions: Most pediatric and adult participants treated with setmelanotide for 1 year exhibited an improvement of obesity class, underscoring the importance of correcting the MC4R pathway disruption in aHO to help patients achieve a healthier weight.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*