Novel therapy improves height for children with achondroplasia

via Healio/Endocrine Today

Children with a common form of skeletal dysplasia saw persistent and sustained improvements in annualized growth velocity with an investigational analogue of C-type natriuretic peptide, according to new data from an extension study.

Melita Irving

“Vosoritide is a safe and effective treatment for children with achondroplasia,” Melita Irving, MBBS, MD, a consultant and honorary reader in clinical genetics at Guy’s and St Thomas’ NHS Foundation Trust, told Healio. “The statistically significant increase in annualized growth velocity demonstrates that there is a physiological response of the bone to the drug, indicating further potential for additional beneficial effects. This could extend to amelioration of general health status, a reduction in the complications of the condition with lasting benefit into adulthood, and improvement in independence skills for affected children.”

Child estimating height
Source: Adobe Stock

Achondroplasia, caused by a dominant mutation in the FGFR3 gene, is the most common form of disproportionate short stature and has no approved pharmacologic therapy, apart from growth hormone in Japan, Ravi Savarirayan, MBBS, FRACP, a clinical geneticist and group leader of skeletal biology and disease at Murdoch Children’s Research Institute and head of clinical genetics services at the Victorian Clinical Genetic Services, both in Victoria, Australia, said during a virtual presentation at the ENDO annual meeting. Current treatment for complications related to achondroplasia is surgical intervention, including spine surgery and limb lengthening.

“A potential possibility for the precision treatment of this condition came about almost a decade ago, when it was discovered that C-type natriuretic peptide downregulates abhorrent FGFR3 signaling by inhibiting the MAPK-ERK pathway,” Savarirayan said. “Basically, it counteracts the underlying mutation — and the consequence of the underlying mutation — at its source.”

After completion of a 52-week phase 3 trial, researchers enrolled 119 children with achondroplasia into an extension study in which children received open-label vosoritide (BioMarin Pharmaceutical) 15 g/kg per day for an additional 52 weeks (58 continued treatment; 61 switched from placebo to vosoritide). Researchers assessed annualized growth velocity, height score and body proportion ratio to assess efficacy of vosoritide in children treated for up to 2 years. Two children receiving continuous vosoritide treatment discontinued before week 52; four children receiving continuous vosoritide treatment and seven children who switched from placebo to vosoritide missed the week-52 assessment due to COVID-19.

Among children who continued vosoritide, annualized growth velocity improved from a mean of 4.26 cm per year to a mean of 5.67 cm per year after the phase 3 trial, remaining stable at a mean of 5.57 cm per year during the extension phase. Mean change from baseline in height score improved by 0.24 at week 52 in the pivotal study and by 0.45 at week 52 during the extension study.

Mean upper-to-lower body segment ratio also improved, with a change from baseline of –0.03 at week 52 in the pivotal study and –0.09 at week 52 in the extension study.

For children who switched from placebo to vosoritide at 52 weeks, baseline annualized growth velocity fell from 4.06 cm per year to 3.94 cm per year after 52 weeks. After switching to vosoritide, mean annualized growth velocity rose to 5.65 cm per year; mean change in height score was 0.24, and the change in upper-to-lower body segment ratio was –0.03.

Most adverse events were mild and self-limiting injection site reactions, Savarirayan said.

“Compared with growth hormone therapy and invasive surgery for achondroplasia, the response to vosoritide is sustained with no evidence of tachyphylaxis, body disproportion does not worsen, and cumulatively, the increase in longitudinal bone growth is comparable to limb lengthening procedures,” Irving told Healio.

In a Q&A session after the presentation, Irving said a study of vosoritide in children aged 5 years or younger is ongoing.

“We are looking to see if there are differences in the response according to their growth rate that is normal for their age,” Irving said of the younger cohort.