Abstract
Disclosure: S.A. Phillips: Rhythm Pharmaceuticals. H.M. van Santen: Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals. J.K. Hamilton: Rhythm Pharmaceuticals, Eli Lilly & Company, Novo Nordisk, Pfizer, Inc. A.H. Shoemaker: Rhythm Pharmaceuticals. S.E. McCormack: Rhythm Pharmaceuticals. M.J. Abuzzahab: Ascendis, Lexicon Pharmaceuticals, Inc., Mannkind Corporation, Medtronic, Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals, Soleno. M.J. Wabitsch: Rhythm Pharmaceuticals. M.T. Dattani: Besins, Novo Nordisk, Pfizer, Inc., Sandoz, Rhythm Pharmaceuticals. T. Tanaka: Boehringer Ingelheim, Eli Lilly & Company, FUJIFILM Toyama Chemical, Mitsubishi Tanabe Pharma, Novo Nordisk, Rhythm Pharmaceuticals. C. Scimia: Rhythm Pharmaceuticals. G. Yuan: Rhythm Pharmaceuticals. H.L. Muller: Ferring Pharmaceuticals, Ipsen, Eli Lilly & Company, Merck Serono, Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals, Sandoz/Hexal. C.L. Roth: Rhythm Pharmaceuticals. J.L. Miller: Rhythm Pharmaceuticals. Background: Hypothalamic melanocortin-4 receptor (MC4R) signaling plays a critical role in the regulation of hunger, satiety, and energy expenditure. Hypothalamic injury from a tumor or its treatment, or following traumatic brain injury, can lead to hyperphagia and acquired hypothalamic obesity (aHO), for which there are no approved treatments. We present results of an international Phase 3 trial of treatment with the MC4R agonist setmelanotide (SET) in aHO (NCT05774756). Methods: Patients (pts) aged ≥4 years (y) with body mass index (BMI) ≥95th percentile (4-<18 y) or ≥30 kg/m(2) (≥18 y) with aHO following hypothalamic tumor, lesion, or injury were included. Pts were randomized 2:1 to SET (0.5 mg subcutaneously once daily [QD], titrated up to 1.5-3.0 mg QD based on age, weight, and tolerability) or placebo (PBO) for up to 60 weeks. The primary endpoint was a modified intent-to-treat (mITT) analysis of the percentage change in BMI at 52 weeks. Secondary endpoints included the proportion of pts with a ≥5% BMI reduction and the change in the maximal daily hunger score (scored 0-10 in pts ≥12 y). Safety was also assessed. Results: Of 120 pts included, 81 and 39 received SET or PBO, respectively (female, 60.0%; mean [SD] age, 19.9 [13.8; range: 4-66] y; BMI in pts ≥18 y, 41.2 [9.7] kg/m(2); BMI Z score in pts <18 y, 3.61 [1.66]). Fourteen pts discontinued treatment before end of trial (due to adverse events [AEs], n=7 [SET, n=5; PBO, n=2]; withdrew, n=7 [SET, n=4; PBO, n=3]). The primary endpoint was met: mean (standard error) change in BMI at 52 weeks was -16.5% (1.4%) for SET vs +3.3% (2.0%) for PBO, with a significant PBO adjusted–difference of -19.8% (95% CI: -24.6%, -15.1%; P<0.0001). A significantly greater proportion of pts who received SET vs PBO achieved a BMI reduction of ≥5% (79.5% vs 10.4%), ≥10% (63.0% vs 5.2%), ≥15% (50.6% vs 2.6%), and ≥20% (43.2% vs 0%; all P<0.0001). The mean (standard error) change in the weekly average of the maximal daily hunger score (≥12 y) was -2.68 (0.28) for SET vs -1.24 (0.40) for PBO (P=0.0030). Overall, 81 (100%) vs 35 (89.7%) pts receiving SET vs PBO experienced AEs, the most common of which were skin hyperpigmentation (55.6% vs 7.7%), nausea (50.6% vs 30.8%), vomiting (39.5% vs 17.9%), and headache (38.3% vs 30.8%). In the SET arm, there was 1 serious treatment-related AE of hypernatremia due to vomiting and an inability to tolerate their desmopressin. After 2 days, SET was reinitiated upon discharge from the hospital. One death due to seizures in a pt with a history of seizure disorder was reported in the SET cohort and was considered unrelated to treatment. Conclusions: In the largest randomized, PBO-controlled trial in aHO to date, SET demonstrated significant effects over PBO in the primary and all key secondary efficacy endpoints at 52 weeks, with no new safety signals. SET may represent an important treatment option for pts with aHO aged ≥4 y, for which there are no currently approved treatments. Presentation: Saturday, July 12, 2025