ESPE Abstracts (2022) 95 RFC4.2

ESPE2022 Rapid Free Communications Fat, Metabolism and Obesity (6 abstracts)

Effect of Setmelanotide Treatment in Children and Adolescents With Proopiomelanocortin (POMC) Deficiency, Leptin Receptor (LEPR) Deficiency, and Bardet-Biedl Syndrome (BBS)

Jesús Argente 1,2 , Peter Kühnen 3 , Andrea M. Haqq 4 , Martin Wabitsch 5 , Wendy K. Chung 6 , Erica van den Akker 7 , Gabriel Á. Martos-Moreno 1 , Anoop Mohamed Iqbal 8 , Elizabeth Forsythe 9 , Béatrice Dubern 10,11 , Sonali Malhotra 12,13,14 , Goujun Yuan 12 , Nicolas Touchot 12 , Hélène Dollfus 15 , Sadaf Farooqi 16 & Karine Clément 11,17

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1Department 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; 2IMDEA Food Institute, Madrid, Spain; 3Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany; 4Division of Pediatric Endocrinology, University of Alberta, Edmonton, AB, Canada; 5Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany; 6Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, USA; 7Division of Pediatric Endocrinology, Department of Pediatrics, Sophia Children’s Hospital and Obesity Center CGG, Erasmus University Medical Center, Rotterdam, Netherlands; 8Marshfield Clinic Research Institute, Marshfield, USA; 9Genetics and Genomic Medicine Programme, University College London Great Ormond Street Institute of Child Health, London, United Kingdom; 10Assistance Publique Hôpitaux de Paris, Nutrition et Gastroentérologie Pédiatriques, Hopital Trousseau, Paris, France; 11Sorbonne Université, Inserm, NutriOmics Research Unit, Paris, France; 12Rhythm Pharmaceuticals, Inc., Boston, USA; 13Massachusetts General Hospital, Boston, USA; 14Harvard Medical School, Boston, USA; 15Hôpitaux Universitaires de Strasbourg, CARGO and Department of Medical Genetics, Institut de Génétique Médicale d’Alsace, Université de Strasbourg, Strasbourg, France; 16Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom; 17Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France


Background: The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance and satiety. Variants in genes upstream of MC4R encoding leptin receptor (LEPR), proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1(PCSK1) and those involved in Bardet-Biedl syndrome (BBS) can impair MC4R pathway signaling. Clinically, these variants are characterized by hyperphagia (Pathologic insatiable hunger) and early-onset, severe obesity. Early intervention, particularly in younger patients, is critical in reducing the development of long-term obesity-related morbidities and quality-of-life burden. Despite this unmet need with limited treatment options, there is no consensus on optimally assessing the effects of interventions targeting excess weight and hunger. We assessed the effects of setmelanotide, an MC4R agonist, in a cohort of pediatric patients in separate Phase 3 trials of patients with POMC deficiency (NCT02896192), LEPR deficiency (NCT03287960), and BBS (NCT03746522) using multiple age-appropriate weight-related measures, which are relevant to clinical practice and regulatory authorities, to understand the effectiveness of setmelanotide in this unique population.

Methods: Patients included were aged 6-17 years. Patients with POMC and LEPR deficiency received ~1 year of setmelanotide, inclusive of 4 weeks of placebo during a withdrawal period. Patients with BBS received 1 year of setmelanotide.

Results: Pediatric-relevant weight-related measures are reported in the Table.

Table. Weight-Related Measures in Pediatric Patients
  Proopiomelanocortin deficiency (n=9)a Leptin receptor deficiency (n=4) Bardet-Biedl syndrome (n=16)b
BMI, mean (SD), kg/m2      
Baseline 36.3 (8.1) 40.7 (3.3) 37.4 (9.4)
~1 year of setmelanotide 27.2 (5.5) 34.4 (1.3) 34.2 (10.1)
Percent change −26.5 (10.2) −14.9 (10.3) −9.5 (6.4)
BMI Z score, mean (SD)      
Baseline 3.5 (0.6) 3.5 (0.3) 3.7 (1.3)
~1 year of setmelanotide 1.9 (0.9) 3.0 (0.0) 3.0 (1.5)
Change −1.5 (0.8) −0.6 (0.3) −0.8 (0.5)
Proportion of patients with ≥ −0.2-point change, n/N (%) 9/9 (100) 3/4 (75) 14/15 (93)
Proportion of patients with ≥ −0.3-point change, n/N (%) 9/9 (100) 3/4 (75) 11/15 (73)
Percent of BMI 95th percentile, mean (SD)      
Baseline 142.1 (19.5) 155.5 (19.9) 144.5 (35.8)
~1 year of setmelanotide 100.1 (16.1) 126.3 (2.2) 126.8 (37.0)
Change −42.4 (15.3) −29.2 (18.4) −17.3 (7.7)
BMI, body mass index; SD, standard deviation; an=9 at baseline; n=8 at ~1 year; bn=16 at baseline; n=14 at ~1 year.

Conclusions: Early, targeted intervention with setmelanotide resulted in improvements across all weight-related measures in pediatric patients with POMC deficiency, LEPR deficiency, and BBS. These results highlight the variability observed across pediatric measures and the need to identify an optimal measure.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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