C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia

Background Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. Methods In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 mu g per kilogram of body weight (8 patients in cohort 1), 7.5 mu g per kilogram (8 patients in cohort 2), 15.0 mu g per kilogram (10 patients in cohort 3), or 30.0 mu g per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 mu g per kilogram and then to 15.0 mu g per kilogram, and in cohort 2, the dose was increased to 15.0 mu g per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. Results During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 mu g per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 mu g per kilogram for up to 42 months. Conclusions In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, , , and .) Vosoritide is a biologic analogue of C-type natriuretic peptide, a stimulator of endochondral ossification, which is disordered in achondroplasia. In this phase 2 dose-finding study and extension study involving children with achondroplasia, once-daily administration of vosoritide resulted in a sustained increase in the annualized growth velocity.