Once-Daily Infigratinib Improves Growth in Children with Achondroplasia: Study
A phase III PROPEL 3 study has demonstrated that treatment with infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor taken once daily, significantly increased growth in children with achondroplasia, the most common form of dwarfism caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The oral capsule offers a promising alternative to currently available injectable therapies, providing a more convenient treatment option for children with achondroplasia.
Achondroplasia is the most common genetic skeletal dysplasia and is characterized by impaired bone growth due to overactivation of the FGFR3 signaling pathway. Although treatment options have expanded in recent years, most disease-modifying therapies require regular injections, creating an additional burden for children and their families. Researchers therefore evaluated whether an oral therapy could safely improve growth outcomes in affected children.
The findings, published in The New England Journal of Medicine, come from a phase III, multicenter, double-blind, placebo-controlled trial led by Ravi Savarirayan, M.B., B.S., M.D., of the Murdoch Children’s Research Institute, Melbourne, Victoria, Australia, and colleagues.
The PROPEL 3 trial enrolled 114 children aged 3 to 17 years with achondroplasia. Participants were randomly assigned in a 2:1 ratio to receive either once-daily oral infigratinib at 0.25 mg/kg or placebo for 52 weeks. The primary endpoint was the change in annualized height velocity from baseline at one year. Researchers also assessed changes in height z-score and body proportionality, measured by the upper-to-lower body segment ratio.
The trial revealed the following findings:
- After 52 weeks, children treated with once-daily oral infigratinib had significantly greater growth than those receiving placebo.
- Infigratinib increased annualized height velocity by 1.74 cm per year compared with placebo.
- Treatment significantly improved height z scores, indicating movement toward expected height for age.
- No significant improvement was observed in the upper-to-lower body segment ratio, suggesting body proportions remained largely unchanged despite faster growth.
- The overall safety profile was comparable to placebo.
- Adverse events occurred in 96% of children receiving infigratinib and 95% of those receiving placebo.
- Serious adverse events were infrequent, occurring in 5% of the infigratinib group and 3% of the placebo group.
- No serious adverse events or treatment discontinuations were considered related to infigratinib by the investigators.
These findings suggest that oral infigratinib can effectively increase growth velocity while maintaining an acceptable safety profile in children with achondroplasia. The availability of an oral therapy may also improve convenience and treatment adherence compared with injectable alternatives.
The researchers concluded that once-daily oral infigratinib significantly increased annualized height velocity over 52 weeks in children with achondroplasia compared with placebo. They noted that longer-term follow-up will be important to determine whether these improvements are sustained and to further evaluate the long-term safety and clinical benefits of treatment.
Reference:
DOI: 10.1056/NEJMoa2604565
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