ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This phase 2, open-label, multicenter trial examined the efficacy of setmelanotide, a melanocortin-4 receptor agonist, in patients aged 6 to 40 years with obesity due to hypothalamic injury. Setmelanotide reduced body mass index (BMI) and hunger levels in most participants; 89% achieved a reduction in BMI of at least 5% after 16 weeks. These results indicate that setmelanotide is a promising treatment for hypothalamic obesity.

This phase 2 trial on setmelanotide for acquired hypothalamic obesity marks a pivotal advancement in addressing a historically intractable condition. Hypothalamic obesity often follows treatment for craniopharyngioma, and has been linked to severe metabolic dysregulation and an increased risk of premature mortality (1). Thus far, a variety of interventions, including dextro-amphetamine (2, 3), somatostatin analoges (4) and GLP- 1R agonists, were only partially successful or yielded inconsistent outcomes (5)?. Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has shown promise in treating monogenic obesity due to mutations in the leptin-melanocortin pathway? (6). The current trial found a significant reduction in BMI and hunger levels in patients with hypothalamic obesity. Therefore, setmelanotide could potentially address the disrupted melanocortin signaling due to hypothalamic damage.

However, the heterogeneity of hypothalamic obesity—rooted in varying degrees of hypothalamic injury—presents challenges in standardizing treatment outcomes. These encouraging trial results indicate that even in non-homogeneous patient populations, targeting the melanocortin pathway might yield substantial benefits. Still, the necessity for a double-blind, randomized phase 3 trial cannot be overstated to confirm these findings.

Moreover, the conceptualization of setmelanotide as a form of hypothalamic substitution therapy, rather than merely an anti-obesity drug, warrants further exploration. If proven effective in larger trials, setmelanotide could redefine the therapeutic landscape for hypothalamic obesity, offering a novel, precision-based approach to managing this complex condition.

References: 1. Müller HL, Tauber, M, Lawson, EA, Özyurt, J, Bison, B, Martinez-Barbera, JP et al. Nat Rev Dis Prim (2022) 8:24. doi:10.1038/s41572-022-00351-z.2. Denzer C, Denzer F, Lennerz BS, Vollbach H, Lustig RH, Wabitsch M. Treatment of hypothalamic obesity with dextroamphetamine: A case series. Obes Facts (2019) 12:91-102. doi:10.1159/000495851.3. van Schaik J, Welling MS, de Groot CJ, van Eck JP, Juriaans A, Burghard M, et al. Dextroamphetamine treatment in children with hypothalamic obesity. Front Endocrinol (2022) 13:845937. doi:https://doi.org/10.3389/fendo.2022.845937.4. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K, et al. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr (1999) 135:162-8. doi:10.1016/S0022-3476(99)70017-X.5. van Iersel L, Brokke KE, Adan RAH, Bulthuis LCM, van den Akker ELT, van Santen HM. Pathophysiology and individualized treatment of hypothalamic obesity following craniopharyngioma and other suprasellar tumors: A systematic review. Endocr. Rev (2018) 40:193-235. doi:10.1210/er.2018-00017.6. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol (2020) 8:960-70. doi:10.1016/S2213-8587(20)30364-8.