BioMarin announced detailed data from a phase 3 trial of vosoritide, an investigational analog of C-type Natriuretic Peptide (CNP), in children aged 5 to 18 years with achondroplasia, have been published online in The Lancet. Achondroplasia is the most common form of disproportionate short stature in humans. The data demonstrated that daily subcutaneous administration of vosoritide to children with achondroplasia resulted in significantly increased growth velocity and height Z scores over baseline after one year of treatment as compared to those who received placebo with similar adverse effect profiles.
The global randomized, double-blind, placebo-controlled phase 3 study enrolled 121 children with achondroplasia aged 5 to 14 for 52 weeks. Vosoritide is being tested in children whose growth plates are still open. This is approximately 25% of people with achondroplasia. Children in this study completed a minimum six-month baseline study to determine their baseline growth velocity prior to entering the Phase 3 study. The primary endpoint was change from baseline in AGV at 52 weeks in participants administered daily subcutaneous injections of vosoritide, at a dose of 15.0 µg/kg/day, compared with placebo.
The findings demonstrated that the adjusted mean difference in AGV between children in the vosoritide group and placebo group was 1.57cm per year in favor of vosoritide, a substantial proportion of the approximately 2 cm/yr AGV deficit relative to average-stature children. The results of subgroup analyses for change from baseline in AGV were consistent with the overall mean difference between treatment groups in favor of vosoritide. A prespecified analysis of the secondary endpoint of change from baseline in height Z score, (which measures the height deficit in standard deviations relative to the mean forage- and gender-matched average stature children), was also performed. The findings demonstrated that the adjusted mean difference in height Z score change from baseline between children in the vosoritide group and placebo group was +0.28 in favor of vosoritide.
There were no adverse effects on, or significant improvements in upper to lower body segment proportionality in children receiving vosoritide during this 52-week study. No statistically significant changes in secondary endpoints related to wider health outcomes such as quality of life, activities of daily living, and frequency and type of medical and surgical interventions were found. An ongoing, open-label, phase 3, extension study is underway to evaluate the balance of benefits and harms of vosoritide until the children reported in this study reach final adult height.
The European Medicines Agency (EMA) has validated the Company’s Marketing Authorization Application. BioMarin has also submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). Vosoritide has received orphan drug designation from the FDA and EMA for the treatment of children with achondroplasia.
Vosoritide is derived from a natural human peptide that is a positive regulator of bone growth. Vosoritide binds to a specific receptor, which initiates intracellular signals that inhibit the overactive FGFR3 pathway.
Achondroplasia is the most common form of disproportionate short stature in humans. It is characterized by slowing of endochondral ossification, which results in disproportionate short stature and disordered architecture in the long bones, spine, face and base of the skull. This condition is caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), a negative regulator of bone growth. Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway of the lower back, spinal stenosis and recurrent ear infections. More than 80% of children with achondroplasia have parents of average stature and have the condition as the result of a spontaneous gene mutation. The worldwide incidence rate of achondroplasia is about one in 25,000 live births.