Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study

Abstract

Purpose: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.

Methods: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.

Results: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.

Conclusion: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Fig. 1. Line plot of mean annualized growth velocity shown in 6-month intervals starting in the baseline observation study and continuing through the randomized placebo-controlled study for 52 weeks and then into the extension study for a total of 104 weeks, displayed by treatment arm derived from observed data.

Numbers at each time point reflect mean annualized growth velocity in cm/year and the standard deviation. Orange and dotted blue lines represent annualized growth velocity for participants randomized to the placebo study treatment arm and the solid blue lines represent annualized growth velocity for participants in the vosoritide study treatment arm. After 52 weeks and completion of the phase 3 study, 119 children were enrolled into the extension study, where all participants received vosoritide at a dose of 15 μg/kg/day. Fifty-eight participants originally randomized to vosoritide continued vosoritide in the extension study. By week 104, n = 44 participants had standing height assessments available to determine six-month interval annualized growth velocity at the two-year analysis time point. Sixty-one participants crossed over from placebo to vosoritide in the extension study and n = 47 had standing height assessments available to determine the six-month interval annualized growth velocity at the 2-year analysis time point. The cause of the missing data is disruptions to study visits due to the COVID-19 pandemic, where many site visits were replaced by virtual visits.

Fig. 2. Line plot showing analysis of covariance (ANCOVA) LSmean change from baseline with 95% confidence intervals (CI) for upper-to-lower body segment ratio in 6-month intervals for a total of 24 months and displayed by treatment arm.

Separate ANCOVA models provide the LSmean change from baseline at each time point for the participants who had completed the 2-year follow up. Orange lines represent change from baseline in upper-to-lower body segment ratio for participants randomized to the baseline observation study and the placebo study treatment arm and the solid blue lines represent change from baseline in upper-to-lower body segment ratio for participants in the vosoritide study treatment arm. Comparative analyses were conducted for all participants randomized to the active arm after two years on active treatment with an assessment at month 24 (n = 45) versus the participants in the placebo arm with two years of untreated follow up considering the one year placebo period and an additional year from the observational study prior to start of the randomized controlled study (n = 38). By directly comparing the treated group to the untreated group, comparative analyses at two years were performed using the same ANCOVA model, which adjusted for covariates, as prespecified for the primary and key secondary analyses of the randomized placebo-controlled study, the LSmean change from baseline in upper-to-lower body segment ratio (95% CI) was −0.05 (−0.09, −0.01) at week 104 representing a greater decrease in the body ratio in the vosoritide treated versus the untreated participants.