An oral formulation of infigratinib, a selective FGFR1-3 tyrosine kinase inhibitor, has demonstrated safety and efficacy in children with achondroplasia, according to a phase II dose-finding study. The trial, involving 72 participants, showed that infigratinib at the highest studied dose led to a significant increase in annualized height velocity. This offers a potential new treatment option for this genetic condition characterized by disproportionately short stature.
Height Velocity Improvement
The study, published in the New England Journal of Medicine, revealed that children receiving infigratinib at 0.25 mg/kg experienced a mean change from baseline in annualized height velocity of 2.5 cm per year (95% CI 1.22-3.79, P = 0.001) at 18 months. This improvement suggests a clinically meaningful impact on growth for children with achondroplasia.
Impact on Body Proportion
Researchers also observed a mean change from baseline in height z score of 0.54 (95% CI 0.35-0.72) relative to an untreated achondroplasia reference population. Additionally, the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI -0.18 to -0.06), indicating a positive shift towards more typical body proportions.
Safety Profile
While all participants experienced at least one adverse event during the treatment period, the majority were mild (54%) or moderate (39%) in severity. Notably, no adverse events led to treatment discontinuation, highlighting the drug's tolerability in this pediatric population. Grade 3 adverse events occurred in five children, including hydrocephalus, adenoidal hypertrophy, tonsillar hypertrophy, sleep apnea syndrome, cholesteatoma and bacillus infection, across different dosage cohorts.
Current Treatment Landscape
Currently, vosoritide (Voxzogo) is the only approved medication for children with achondroplasia, requiring daily subcutaneous injections. Ravi Savarirayan, MBBS, MD, of Royal Children's Hospital, noted that infigratinib's oral administration could be particularly beneficial in regions where injections are less practical. He added, "This oral treatment appears safe and at least as effective as the injectable form."
Infigratinib's Regulatory History
Infigratinib was previously granted accelerated approval for bile duct cancer treatment but was later withdrawn. This new application in achondroplasia represents a potential resurgence for the drug.
Study Details
The phase II study enrolled children aged 3 to 11 years with a confirmed genetic diagnosis of achondroplasia across 19 sites in multiple countries. Participants received daily infigratinib for 6 months, followed by a 12-month extension period. The study included five sequential cohorts with escalating doses of infigratinib.
Ongoing Phase 3 Trial
Based on the promising results of this phase II trial, a pivotal phase 3, double-blind, placebo-controlled trial is currently underway. This trial aims to enroll 110 children with achondroplasia aged 3 to under 18 years to further evaluate the efficacy and safety of infigratinib.
