Treatment history and comorbidities reported by patients with hypothalamic obesity treated with setmelanotide in a Phase 2 trial

Abstract Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Consynance, Rhythm Pharmaceuticals, Inc., Endo Pharmaceuticals. Background: Hypothalamic obesity (HO) is an acquired form of severe obesity that can occur following surgical resection or radiotherapy of brain tumors. Multiple factors associated with the development of HO—including degree of hypothalamic damage from tumor treatment, comorbidities (eg, pituitary deficiencies), polypharmacy used to treat comorbidities, and unique pathophysiology—confer treatment challenges; HO is often unresponsive to lifestyle modifications and traditional obesity pharmacotherapies. In a Phase 2, 16-week trial of setmelanotide in patients with HO, 16 of 18 patients (88.9% [90% confidence interval, 69.0%-98.0%]; P<0.0001) achieved ≥5% body mass index (BMI) reduction from baseline, with a mean percent BMI change of −15.4% in patients adhering to treatment (n=17). We assessed patient histories (ie, tumor treatments, prior attempts to lose weight, and comorbidities) reported in the trial to further characterize this patient population. Methods: Patients aged ≥6 to ≤40 years with documented evidence of HO were enrolled in an open-label Phase 2 trial (NCT04725240) and received setmelanotide once daily for 16 weeks. The primary endpoint was the proportion of patients with ≥5% BMI reduction from baseline at Week 16. Tumor treatments, prior attempts to lose weight, and comorbidities are summarized narratively. Results: Eighteen patients with HO (age range, 6-24 years) were treated with setmelanotide. HO was diagnosed in patients following treatment of craniopharyngioma (n=14), hamartoma (n=3), or juvenile pilocytic astrocytoma (n=1). Six patients (33.3%) had tumor recurrence and/or multiple tumor treatments. Thirteen patients (72.2%) reported prior lifestyle modifications (ie, calorie restriction [n=4], low-carbohydrate diet [n=6], dietary tracking/modification [n=4], food access restriction [n=1], personal training [n=1]) and/or pharmacotherapy use (ie, exenatide [n=3], semaglutide [n=1], liraglutide [n=2], metformin [n=2], methylphenidate [n=2], dextroamphetamine [n=1], lisdexamfetamine [n=2], naltrexone [n=3], oxytocin [n=3], phentermine [n=1]) without substantial benefit. Comorbidities occurring in ≥25% of patients were diabetes insipidus (n=14), hypothyroidism (n=14), growth hormone deficiency (n=11), adrenal insufficiency (n=10), hypogonadism (n=8), pan/hypopituitarism (n=8), psychiatric disorders (n=8), vision problems (n=6), gastrointestinal symptoms (n=6), obstructive sleep apnea (n=5), and hypothalamic-pituitary disorder (n=3). All patients adhering to treatment (n=17, including those with pituitary deficiencies and common comorbidities)) experienced BMI reductions with setmelanotide. Conclusions: Despite complex medical histories, hypothalamic damage, and various prior failed interventions, setmelanotide reduced BMI in patients with HO in a Phase 2 trial. Presentation: Friday, June 16, 2023