Achondroplasia is the most common form of skeletal dysplasia, yet no effective therapies exist
It leads to a disproportionately short stature and is characterised by a slowing of endochondral ossification, giving a disordered architecture in the long bones, spine, face and base of the skull.
It is caused by problems with the fibroblast growth factor receptor 3 gene (FGFR3), a negative regulator of bone growth.
Those with the condition will often experience significant health difficulties, including sleep apnoea, foramen magnum compression, bowed legs, mid-face hypoplasia, spinal problems and recurrent ear infections. Invasive surgery may be required to correct some of these.
The majority of children with the condition have parents of average stature, with the achondroplasia arising from a spontaneous gene mutation. A potential treatment, vosoritide, is being developed by Biomarin, which is being tested in children whose growth plates are still open.
It is an analogue of C-type natriuretic peptide, which is a potent stimulator of endochondral ossification.
Its safety and side-effect profile were evaluated in a Phase II dose finding study and extension.1 In all, 35 children aged 5–14 were enrolled in four sequential cohorts and given 2.5, 7.5, 15 or 30 µg/kg; after 6 months, the dose for the first cohort was increased to 7.5 and then 15 µg/kg, the second cohort to 15 µg/kg and the remaining cohorts stayed at their initial doses.
At data cut-off, the 24-month study was complete and 30 of the patients were enrolled in an ongoing long-term extension study. All 35 patients experienced adverse events and four had serious ones; six discontinued, one because of adverse events.
A dose-dependent increase in growth velocity was seen with vosoritide, up to the 15 µg dose, and a sustained increase was seen at the two highest doses for up to 42 months.
A randomised, double-blind, placebo-controlled Phase III trial has also been done in 121 children (aged 5–18) with achondroplasia who had already participated in a baseline growth study for 6 months.2
Patients were given 15 µg/kg of vorositide or a placebo as a daily subcutaneous injection for 52 weeks (administered at home by a trained caregiver). The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks.
The adjusted mean difference in annualised growth velocity between the treatment and placebo groups was 1.57 cm/year in favour of those given the drug.
Almost all had at least one adverse event, but none were considered to be treatment related and there were no deaths.
Although it remains unclear whether final adult height will be increased, or what the potential harm of long-term therapy could be, within the scope of the trial it proved to be an effective way of increasing growth in children with achondroplasia.