ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: N Engl J Med. 2019 Jul 4;381(1):25–35.

In brief: Inhibition of endochondral ossification in Achondroplasia leads to disproportionate short stature. In this phase 2 study, daily subcutaneous injection of vosoritide, a biologic analogue of C-type natriuretic peptide and a potent stimulator of endochondral ossification, results in sustained increase in the annualized growth velocity for up to 42 months, with minimal side effects.

Commentary: Achondroplasia is characterised by rhizomelic short stature with macrocephaly. Associated complications include hydrocephalus, obstructive sleep apnea and foramen magnum stenosis and cervicomedullary compression, leading to an increased risk of sudden death in infancy. Mortality is increased from birth to 4 years of age and in the fourth and fifth decades of life.

The condition is caused by an autosomal dominant mutation in the fibroblast growth factor receptor 3 gene (FGFR3) that constitutively activates the mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase pathway in chondrocytes, and in turn inhibits endochondral ossification. C-type natriuretic peptide, encoded by NPPC, and its receptor, natriuretic peptide receptor 2 (NPR2), are potent stimulators of endochondral ossification at the level of the growth plate. Continuous intravenous infusion of exogenous C-type natriuretic peptide restores the impaired bone growth observed in mice with achondroplasia and increases long-bone growth in wild-type monkeys. It acts, at least in part, by inhibiting the FGFR3-mediated MAPK signaling pathway. Vosoritide is a recombinant C-type natriuretic peptide analogue with longer half-life.

In this phase 2 study, 35 children (5–14 years of age) with achondroplasia were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kg body weight (8 patients in cohort 1), 7.5 μg/kg (8 patients in cohort 2), 15.0 μg/kg (10 patients in cohort 3), or 30.0 μg/kg (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg/kg and then to 15.0 μg/kg, and in cohort 2, the dose was increased to 15.0 μg/kg; the patients in cohorts 3 and 4 continued on their initial doses.

During the study period, the most common treatment-related adverse events were mild, transient injection-site reactions. Therapy was discontinued in 6 patients (only in 1 because of an adverse event). The annualized growth velocity increased from baseline in all cohorts during each 12-month interval by 1.10–2.34 cm/year for up to 42 months. Among patients who received the 15.0 μg/kg dose, the mean annualized growth velocity was 5.51 cm/year, as calculated between 30 and 42 months. This change represents an annual increase of 1.46 cm (95% CI, −0.15 to 3.07) from baseline. Among patients who received the 30.0-μg-per-kilogram dose, the mean annualized growth velocity was 5.60 cm/year, as calculated between 18 and 30 months, representing an annual increase of 1.10 cm (95% CI, −0.27 to 2.48) from baseline. Whether earlier start and longer duration of this treatment would produce clinically meaningful improvements in growth and other features of the condition remains to be determined.

A phase 3, randomized, double-blind, placebo-controlled trial (NCT03197766) is currently evaluating the efficacy and safety of the 15.0 μg/kg dose of vosoritide in up to 110 children (age range, 5 to <18 years) with achondroplasia. An open-label phase 3 extension study (NCT03424018) will further evaluate the efficacy and safety of vosoritide until patients reach final adult height.