IMPE2023 Free Communications Fat, Metabolism and Obesity (4 abstracts)
Evaluation of Clinical Benefit Following Setmelanotide Treatment in Patients With Bardet-Biedl Syndrome
Andrea M. Haqq 1 , Wendy K. Chung 2 , Hélène Dollfus 3 , Anoop Iqbal 4 , Gabriel Á. Martos-Moreno 5 , Christine Poitou 6,7 , Jack A. Yanovski 8 , Sonali Malhotra 9,10,11 , Paul Miller 9 , Guojun Yuan 9 , Elizabeth Forsythe 12 , Karine Clément 6,7 & Jesús Argente 5,13
1Division of Pediatric Endocrinology, University of Alberta, Edmonton, Canada. 2Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, USA. 3Hôpitaux Universitaires de Strasbourg, CARGO and Department of Medical Genetics, Institut de Génétique Médicale d’Alsace, Université de Strasbourg, Strasbourg, France. 4Marshfield Clinic Research Institute, Marshfield, USA. 5Department of Pediatrics and Pediatric Endocrinology, Universidad Autónoma de Madrid, University Hospital Niño Jesús, CIBER “Fisiopatología de la obesidad y nutrición” (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 6Nutrition Department, Assistance Publique Hôpitaux de Paris, Pitié-Sal Pêtrière Hospital, Paris, France. 7Sorbonne University, Inserm, Nutrition and Obesity; Systemic Approaches (NutriOmique) Research Group, Paris, France. 8Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA. 9Rhythm Pharmaceuticals Inc., Boston, USA. 10Massachusetts General Hospital, Boston, USA. 11Harvard Medical School, Boston, USA. 12Genetics and Genomic Medicine Programme, University College London Great Ormond Street Institute of Child Health, London, United Kingdom. 13IMDEA Food Institute, Madrid, Spain
Bardet-Biedl syndrome (BBS) is a rare disease associated with signaling defects in the melanocortin-4 receptor (MC4R) pathway that lead to hyperphagia, severe obesity, and, consequently, reduced quality of life (QOL). We investigated the impact of setmelanotide, an MC4R agonist, on weight, body composition, hunger, and QOL in a Phase 3 trial of patients with BBS to characterize clinically meaningful and patient-relevant benefit. Patients aged ≥6 years with BBS and obesity were enrolled into a Phase 3 trial (NCT03746522) and received 52 weeks of setmelanotide. Body composition was assessed via dual-energy x-ray absorptiometry or bioelectrical impedance analysis at the screening and end-of-study visits. Hunger was assessed with an 11-point numerical scale in patients aged ≥12 years without cognitive impairment. QOL was assessed in adults and pediatric patients using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Pediatric Quality of Life Inventory (PedsQL), respectively. Clinically meaningful improvements in weight-related parameters were defined as ≥5% reduction in body weight for adults and ≥0.2-point decrease in BMI Z score or ≥5-percentage point decrease in percent of the 95th BMI percentile for pediatric patients. Clinically meaningful improvement in hunger was defined as ≥1-point reduction in hunger score. For QOL, patient-relevant improvements in adults and pediatric patients were increases in IWQOL-Lite score of 7.7-12 and increases in PedsQL score of >4.4, respectively. Twenty-seven of 32 patients (84%) had clinically meaningful and/or patient-relevant improvements in ≥1 measure (ie, weight-related parameters, hunger, and/or QOL) at the last study visit. Three of 5 patients without improvement showed weight stabilization; thus, 30 of 32 patients (94%) experienced clinically meaningful and/or patient-relevant improvement or weight stabilization. The mean (standard deviation [SD]) percent decrease in total fat mass was −10.16% (26.06%; n=18) and mean (SD) percent change in total lean mass was 0.06% (7.72%; n=18). Tolerability of setmelanotide was consistent with previous studies in patients with rare MC4R pathway diseases. One patient discontinued placebo due to an adverse event. Most patients with BBS showed clinically meaningful and/or patient-relevant benefit following setmelanotide, as measured by decreases in age-appropriate weight-related parameters, reduction in hunger, and improvements in QOL. Similarly, total fat mass was decreased in this cohort, while total lean mass was relatively preserved during setmelanotide treatment. Given the presence of hyperphagia and multiorgan pathology associated with BBS, evaluating benefits from antiobesity medications beyond weight change alone is particularly important for patients with this rare MC4R pathway disease.
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