ORF44-05 - Long-Term Efficacy with Setmelanotide in Patients with Acquired Hypothalamic Obesity

Background: Melanocortin-4 receptor (MC4R) pathway signaling in the hypothalamus plays a critical role in the regulation of energy balance. Hypothalamic injury due to brain tumors or resection of those tumors, or traumatic brain injury can lead to acquired hypothalamic obesity (aHO) through potential MC4R pathway signaling disruption, which may cause hyperphagia (insatiable hunger accompanied by abnormal food-seeking behaviors) and accelerated and sustained weight gain. Treatment with the MC4R agonist setmelanotide resulted in consistent, clinically meaningful reductions in body mass index (BMI) at Week 16 (−15%; primary time point) in a Phase 2, open-label aHO trial and at 1 year (−26%) after entering a long-term extension trial (LTE). Here, we assessed the continued efficacy and safety after 2.5 years of setmelanotide treatment.

Methods: Participants who completed the 16-week Phase 2 index trial (NCT04725240), experienced a ≥5% reduction in BMI or had an investigator-determined clinically meaningful benefit, and exhibited adequate safety after 16 weeks of treatment were eligible to enroll in an LTE (NCT03651765). The current analysis assessed changes from baseline in percent of the 95th BMI percentile (%BMI95) for pediatric participants < 18 years, BMI for adult participants ≥18 years, and adverse events (AEs) in all participants with aHO after 2.5 years of setmelanotide treatment.

Results: Of the 14 participants who entered the LTE, 12 were pediatric and 2 were adult. The 14 participants had a mean (SD) age of 13.6 (5.0) years, were predominantly male (71.4%), and all had obesity at index trial baseline (mean [SD] BMI, 37.0 [7.1] kg/m2; mean [SD] %BMI95 in participants < 18 years [n=12], 145.8 [21.9] percentage points). Eleven participants completed 2.5 years of setmelanotide treatment. After 2.5 years, the mean (SD) change from baseline in BMI across all participants was −18.9% (16.0). In participants aged < 18 years (n=10), the mean (SD) %BMI95 at 2.5 years was 109.9 (25.9) percentage points, a mean (SD) change of −34.2 (21.4) percentage points. The most commonly reported AEs were nausea (8/14; 57.1%), skin hyperpigmentation (7/14; 50.0%), upper respiratory tract infection (6/14; 42.9%), and vomiting (6/14; 42.9%).

Conclusion: Two and a half years of setmelanotide treatment was associated with robust and sustained reductions across age-related weight measures in patients with aHO. These long-term data underscore the importance of correcting the MC4R pathway signaling disruption with targeted therapy to reduce the accelerated and sustained weight gain typically observed in this patient population.