Setmelanotide 10mg/1ml solution for injection vials

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/m2 (≥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/m2; 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

Abstract licence: CC BY-NC-ND

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. Consulting Fee; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J.L. 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. S. McCormack: None. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Rhythm Pharmaceuticals, Inc., Consynance. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc., Ascendis, NovoNordisk, Levo Pharmaceuticals, Lumos, Saniona, and Soleno. Background: Damage to the hypothalamus via physical trauma, tumors, surgical resection, and/or radiotherapy can impair the melanocortin signaling pathway and reduce energy expenditure, potentially leading to hypothalamic obesity, a severe form of obesity with no current specific therapeutic option. Recently, the selective melanocortin-4 receptor agonist setmelanotide demonstrated reduction in weight and hunger for patients with hypothalamic obesity who were treated in a Phase 2 trial. We describe the study design of a planned double-blind, randomized, placebo-controlled, Phase 3 trial of setmelanotide in patients with hypothalamic obesity. Methods: Approximately 120 patients will be enrolled across ≤35 sites globally. Eligibility criteria include age ≥4 years with documented evidence of acquired hypothalamic obesity with associated weight gain before and/or with tumor treatment and body mass index (BMI) ≥30 kg/m2 (≥18 years) or BMI ≥95th percentile (≥4 to <18 years). Key exclusion criteria include diagnosis of syndromic obesity, weight or BMI loss >2% based on age in the prior 3 months, bariatric surgery within the past 2 years, glycated hemoglobin >11.0%, and glomerular filtration rate <30 mL/min/1.73 m2. Patients will be randomized 2:1 and stratified by age to receive setmelanotide or placebo. Setmelanotide will be titrated over 2-8 weeks to a maximum daily subcutaneous dose of 1.5-3.0 mg based on age and weight. Double-blind treatment will continue for up to 60 weeks, with visits (in-clinic, at-home, or telehealth) at Weeks 20, 28, 36, 44, and 52 and at an end-of-treatment clinic visit at Week 60. The primary endpoint is the mean percent change in BMI after 52 weeks of treatment for setmelanotide versus placebo. Key secondary endpoints after 52 weeks are the proportion of patients aged ≥18 years with ≥5% reduction in BMI, proportion of patients aged <18 years with ≥0.2-point reduction in BMI Z score, and mean change in weekly average of the daily “most hunger” score in patients aged ≥12 years. Additional secondary endpoints include proportion of patients achieving ≥2-point reduction in weekly average of the daily maximal hunger score, Symptoms of Hyperphagia total score, additional weight-related parameters, and quality of life outcomes. Exploratory endpoints include change after 52 weeks in physical activity (measured by acDetigraphy), fatigue (via Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue©/Peds FACIT-F© scale), Impacts of Hyperphagia score, caregiver health status (via EuroQol-5-Dimension scale), cardiometabolic parameters, and waist circumference. Safety will be assessed by the frequency and severity of adverse events. Conclusions: This Phase 3 trial designed to assess the efficacy and safety of setmelanotide for weight loss and hunger reduction in patients ≥4 years of age with acquired hypothalamic obesity is planned to initiate in early 2023. Presentation: Friday, June 16, 2023

Abstract licence: CC BY-NC-ND 4.0

Abstract Aim To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet‐Biedl syndrome (BBS). Materials and methods Individuals aged 12 years and older with BBS received once‐daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52‐week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. Results From February 2017 and February 2018, 10 individuals were screened; eight completed the 3‐month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was −5.5% (90% CI, −9.3% to −1.6%; n = 8); change from baseline was −11.3% (90% CI, −15.5% to −7.0%; n = 8) at 6 months and −16.3% (90% CI, −19.9% to −12.8%; n = 7) at 12 months. All participants reported at least one treatment‐emergent adverse event (AE), most commonly injection‐site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. Conclusions Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS‐associated obesity and hyperphagia .

Abstract licence: CC BY-NC-ND 4.0