Evaluating Setmelanotide Treatment for 12 Months in Pediatric Age Groups With Rare Melanocortin-4 Receptor Pathway–Related Obesity: Efficacy in Weight Reduction and Safety Outcomes

Peter Kühnen; T. van den Akker Erica L.; Shoemaker Ashley H.; Uzoma Okorie; Verge Charles F.; Ilene Fennoy; Kelsey Megan M.; Haqq Andrea M.; Roth Christian L.; Garrison Jill C.; Martin Wabitsch; Sadaf Farooqi; Jesús Argente

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ESPE Abstracts (2024) 98 P1-296

ESPE2024 Poster Category 1 Late Breaking 1 (10 abstracts)

Evaluating Setmelanotide Treatment for 12 Months in Pediatric Age Groups With Rare Melanocortin-4 Receptor Pathway–Related Obesity: Efficacy in Weight Reduction and Safety Outcomes

Peter Kühnen ¹ , Erica L. T. van den Akker ² , Ashley H. Shoemaker ³ , Uzoma Okorie ⁴ , Charles F. Verge ⁵ , Ilene Fennoy ⁶ , Megan M. Kelsey ⁷ , Andrea M. Haqq ⁸ , Christian L. Roth ^9,10 , Jill C. Garrison ¹¹ , Martin Wabitsch ¹² , Sadaf Farooqi ¹³ & Jesús Argente ^14,15

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¹Department of Pediatric Endocrinology and Diabetology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Berlin, Germany. ²Division of Pediatric Endocrinology, Department of Pediatrics, Sophia Children’s Hospital and Obesity Center CGG, Erasmus University Medical Center, Rotterdam, Netherlands. ³Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, USA. ⁴Marshfield Clinic Research Institute, Marshfield, USA. ⁵Sydney Children’s Hospital Randwick and Paediatrics, University of New South Wales, Sydney, Australia. ⁶Division of Pediatric Endocrinology, Diabetes, and Metabolism, Columbia University Irving Medical Center, New York, USA. ⁷Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, USA. ⁸Division of Pediatric Endocrinology, University of Alberta, Edmonton, Canada. ⁹Seattle Children’s Research Institute, Seattle, USA. ¹⁰Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, USA. ¹¹Rhythm Pharmaceuticals, Inc., Boston, USA. ¹²Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany. ¹³Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom. ¹⁴Department 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. ¹⁵IMDEA Food Institute, Madrid, Spain

Objectives: Hyperphagia and severe obesity may result from impaired melanocortin-4 receptor (MC4R) signaling due to rare biallelic variants in POMC or PCSK1 (proopiomelanocortin [POMC] deficiency) or LEPR (leptin receptor [LEPR] deficiency), Bardet-Biedl syndrome (BBS) or acquired hypothalamic obesity (HO). Previously, setmelanotide in patients aged 2-17 years was well tolerated and improved weight-related measures and hunger severity. Here, we report changes in weight-related and safety measures after 12 months of setmelanotide in pediatric patients by age groups (2-5, 6-11, and 12-17 years).

Methods: Patients aged 2-17 years from 5 index clinical trials and a long-term extension trial with on-treatment measurements at baseline and Month 12 were included. Changes in body mass index (BMI) Z score per World Health Organization methodology from index trial baseline after 12 months of setmelanotide were assessed. Safety was evaluated by adverse event (AE) frequency.

Results: A total of 50 pediatric patients were analyzed, including those with POMC (n = 9) or LEPR (n = 7) deficiencies, BBS (n = 21), or HO (n = 13); 45 patients had data at Month 12. Mean (standard deviation [SD]) BMI Z score was reduced across disease state and age groups (Table). The most frequent AEs (≥20%) were skin hyperpigmentation (36/50; 72%), injection site erythema (22/50; 44%), vomiting (22/50; 44%), nausea (20/50; 40%), and injection site pruritus (20/50; 40%). AE frequency and severity did not differ substantially by age group. There were no serious treatment-related AEs.

**Table.** Change at Month 12 in BMI Z Score by age subgroup
BMI Z score, mean (SD), n	POMC	LEPR:	BBS	HO
2-5 years	−5.55 (1.17), n = 3	−4.82 (2.03), n = 3	−1.33 (1.10), n = 5
– 6-11 years	−1.15 (0.58), n = 2	–	−0.81 (0.35), n = 4	−2.34 (0.87), n = 5
12-17 years	−1.86 (0.77), n = 4	−0.48 (0.32), n = 3	−0.77 (0.57), n = 10	−1.34 (0.9), n = 6
BMI, body mass index; SD, standard deviation.

Conclusion: Pediatric patients with obesity related to POMC or LEPR deficiencies, BBS, or HO had improvements in weight-related measures regardless of age group and obesity causes. The greater absolute reduction in BMI Z score among those ages 2-5 years across obesity causes may reflect overall higher baseline scores and may additionally highlight the importance of early intervention. More understanding is needed about response variation across obesity causes and analyzing the impact beyond changes in weight-related parameters alone (eg, hyperphagia and quality of life). These weight-related findings and the favorable tolerability across ages support setmelanotide use in developmental ages in approved indications of hypothalamic MC4R pathway disruptions.