Vosoritide

Overview

Achondroplasia is caused by a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) that overactivates the MAPK pathway in the growth plate, suppressing chondrocyte proliferation and differentiation and producing disproportionate short stature. C-type natriuretic peptide, acting through natriuretic peptide receptor B (NPR-B), naturally opposes this pathway, but native CNP is degraded too quickly to be therapeutic.

Vosoritide is a stabilized CNP analog resistant to neutral endopeptidase (NEP) cleavage, giving it a duration suitable for daily injection. In the pivotal phase 3 trial, once-daily subcutaneous vosoritide 15 mcg/kg significantly increased annualized growth velocity over 52 weeks compared with placebo in children with achondroplasia, with a comparable safety profile, leading to regulatory approval.

Because it activates natriuretic peptide signaling, the main dose-limiting effect is transient decreases in blood pressure; injection-site reactions are common. Dosing is weight-based and adjusted as children grow, and treatment is used while growth plates remain open.

Mechanism of Action

NPR-B activation by vosoritide increases intracellular cyclic GMP, which suppresses the RAF-MEK-ERK (MAPK) cascade downstream of FGFR3. In achondroplasia this cascade is constitutively overactive and inhibits growth-plate chondrocytes; by counterbalancing it, vosoritide re-enables the proliferation and hypertrophy of chondrocytes needed for longitudinal bone growth. NEP resistance is the key engineering feature that gives the analog a usable duration of action compared with native CNP.