SAT-712 - Setmelanotide Treatment in Patients with Acquired Hypothalamic Obesity and Previous Weight Loss Surgery

Background: Acquired hypothalamic obesity (aHO) is characterized by accelerated and sustained weight gain following injury to the hypothalamus, which can lead to hyperphagia, energy imbalance, and obesity. Traditional obesity management strategies, including bariatric surgery, are a less viable option in most individuals with aHO. In the Phase 3 trial of the melanocortin-4 receptor (MC4R) agonist setmelanotide (SET) in aHO (NCT05774756), the primary endpoint of percent change in body mass index (BMI) at Week 52 was met. Herein, we report a case series of participants (pts) from this Phase 3 trial who had a pre-trial history of bariatric surgery.

Methods: Pts aged ≥4 years (y) with BMI ≥95th percentile (4- < 18 y) or ≥30 kg/m2 (≥18 y) with aHO following hypothalamic tumor, lesion, or injury were included. Pts with a history of bariatric surgery were eligible for the trial if the procedure had occurred >2 years prior to enrollment. Pts were excluded if they experienced weight loss >2% (≥18 y) or BMI reduction >2% (4 to < 18 y) within 3 months before screening. Pts were randomized 2:1 to SET or placebo (PBO) for up to 60 weeks. The primary endpoint was the percentage change in BMI after 52 weeks.

Results: In total, 120 pts were included in the trial. Six adult pts (age range 21-49 y; 5 female) had a history of bariatric surgery that had occurred at varying intervals prior to the trial (all ≥3 years prior per protocol). Procedure types included gastric sleeve (n=4), gastric bypass (n=3), gastrojejunostomy end-to-side (n=1), and gastric band with subsequent reversal (n=1); 3 pts had received 2 different procedures. Four pts were randomized to SET; 2 to PBO. One pt in the SET arm and 1 pt in the PBO arm discontinued treatment due to adverse events (SET, rhinorrhea, itching at injection site, and muscle spasms in legs; PBO, breathing difficulties; all unrelated to treatment). All 3 pts remaining in the SET arm had BMI reductions from baseline after 52 weeks: -37.9% from 50.0 kg/m2 baseline BMI; -32.1% from 46.8 kg/m2; and -9.6% from 29.8 kg/m2. By contrast, the pt that received PBO had a 4.8% increase from 38.2 kg/m2 baseline BMI. Treatment-related adverse events were reported in 1 patient that received SET (upper abdominal pain, constipation, nausea, headache) and in 1 patient that received PBO (blood uric acid increased, peripheral swelling, and photosensitivity). Treatment regimens of pituitary hormone replacement, as well as micronutrient supplements including vitamin D, iron, calcium, B12, and folic acid, remained generally consistent throughout the trial in these pts.

Conclusions: The persistence of obesity that conferred trial eligibility in pts with aHO and a history of bariatric surgery highlights the unmet treatment needs for this population. The response to SET observed in these pts underscores the importance of targeted therapy to correct the deficiency in MC4R signaling in pts with aHO.

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