BMN 111-301, Phase 3-Medikamenten-Zulassungsstudie bei Achondroplasie

Achondroplasia (ACH), the most common form of disproportionate short stature or dwarfism, is an autosomal dominant genetic skeletal disorder caused by a gain-of-function mutation in the fibroblast growth factor receptor-3 gene (FGFR3), a negative regulator of endochondral bone formation. Due to this FGFR3 mutation, there is exaggerated negative regulation on endochondral ossification, which results in ACH (Laederich and Horton, 2010, Curr Opin Pediatr).

The use of modified recombinant C-type natriuretic peptide (rhCNP) as a potential therapy for the treatment of ACH is based on the mechanism of action of C-type natriuretic peptide (CNP). CNP and its receptor, NPR-B, are key regulators of skeletal growth. CNP binding to its receptor, natriuretic peptide receptor-B (NPR-B), acts as a key regulator of longitudinal bone growth by down-regulating the mitogen-activated protein kinase (MAPK) pathway. CNP-mediated activation of NPR-B results in the rescue of the dwarfism phenotype of mice with a FGFR3 gain-of-function mutation (Yasoda, 2004; Yasoda 2009). The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a severe, Fgfr3Y367C/+ model (Lorget, 2012, Am.J Hum.Genet), and a mild [Ach] /+ model. Partial or complete reversion of the ACH phenotype was observed in these mouse models after BMN 111 administration. Additionally, in wild-type mice, and normal rats and monkeys, BMN 111 administration resulted in growth plate expansion and dose-dependent skeletal growth at hemodynamically-tolerated dose levels (Wendt, 2015, J Pharmacol Exp Ther). Therefore, administration of CNP has been proposed as a therapeutic approach for ACH.