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 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram 
(8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 
30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in 
cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, 
and in cohort 2, the dose was increased to 15.0 μg 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 μg per kilogram, and a sustained increase in the 
annualized growth velocity was observed at doses of 15.0 and 30.0 μg 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, NCT01603095, NCT02055157, and 
NCT02724228.).