ECEESPE2025 Rapid Communications Rapid Communications 15: Metabolism, Nutrition and Obesity (6 abstracts)
Setmelanotide treatment in individuals with obesity and PHIP variants: results from the DAYBREAK trial
Peter Kühnen 1 , Vidhu Thaker 2 , Christopher Still 3 , Douglas Denham 4 , Heidi Shea 5 , Svetlana Ten 6 , Whitney Herring 7 , Dorit Koren 8 , Jill Garrison 8 , Fabian Zuiderwijk 8 , Patrick Sleiman 8 , Orit Pinhas-Hamiel 9,10 , Antje Koerner 11 & Erica van den Akker 12
1Charité - Universitätsmedizin Berlin, Berlin, Germany; 2Columbia University Irving Medical Center, New York, United States; 3Geisinger Clinic, Danville, United States; 4Clinical Trials of Texas, San Antonio, United States; 5Endocrine Associates of Dallas and Plano, Plano, United States; 6Ten’s Medical Center – Pediatric Endocrinology Clinic, Brooklyn, United States; 7Mississippi Center for Advanced Medicine, Madison, United States; 8Rhythm Pharmaceuticals, Inc., Boston, United States; 9Tel Aviv University, Tel Aviv, Israel; 10Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel; 11Universitaetsklinikum Leipzig, Leipzip, Germany; 12Erasmus University Medical Center, Rotterdam, Netherlands
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Introduction: The melanocortin-4 receptor (MC4R) pathway regulates energy balance, hunger, and satiety. DAYBREAK (NCT04963231) was a two-stage clinical trial evaluating setmelanotide in individuals carrying a variant in ≥1 of 31 genes involved in the MC4R pathway, including PHIP, which enhances POMC transcription. Heterozygous deleterious PHIP variants are associated with intellectual disability/developmental delay, behavioral disorders, obesity/overweight, and dysmorphic features. We report a post hoc analysis of individuals with PHIP variants and obesity.
Methods: Individuals from the DAYBREAK trial aged 6-65 years carrying a PHIP variant, classified as variant of unknown significance (VUS) or pathogenic/likely pathogenic (P/lP) according to American College of Medical Genetics criteria, and body mass index (BMI) ≥40 kg/m2 (≥18 years) or ≥97th percentile (6-17 years) and hyperphagia were included. Individuals meeting age-related weight loss criteria with setmelanotide after the 16-week open-label stage 1 (S1) could enter the 24-week, double-blind, randomized, placebo-controlled stage 2 (S2). Participants could reinitiate open-label setmelanotide if BMI increased ≥5% from S2 entry (switch to setmelanotide within S2 or transition early to bridging). Primary analyses were performed at S1. Hunger was assessed in individuals aged ≥12 years. The S2 analyses were exploratory/ad hoc.
Results: Sixteen individuals with PHIP variants were enrolled (age range, 7-58 years; 50% female; 81% White). At baseline, the mean (SD) BMI in adult participants (n=10) was 45.34 (7.01) kg/m2, and pediatric BMI Z score (n=6) was 2.46 (0.45). For S1 BMI data, 9 of 16 participants (56.3%) met age-related weight loss criteria. The mean (SD) BMI percent change in the 13 participants who completed S1 was −6.12% (3.62%). For S1 hunger data, 8 of 11 participants with baseline “most hunger” data had Week-16 follow-up for daily most hunger scores and exhibited a mean (SD) score reduction of −3.87 (1.41); 7 participants achieved a score reduction of ≥2. Nine participants entered S2 (5 adult and 4 pediatric). Participants receiving setmelanotide maintained consistent weight loss, whereas those receiving placebo did not. For post S2 data, 8 participants continued on treatment, with a mean (SD) bridging duration of 48.7 (14.1) weeks; 5 adult and 3 pediatric participants exhibited a final mean (SD) percent change in BMI of −14.18% (7.66%) and in BMI Z score of −0.71 (0.27), respectively.
Conclusions: Clinical response to setmelanotide, a highly selective MC4R agonist, suggests the MC4R pathway is a key biologic driver of obesity in individuals with PHIP variants of interest and merits further investigation.
Volume 110
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Endocrine Abstracts
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