Oral Infigratinib Promising in Children with Achondroplasia, Increasing Growth with Mild Side Effects: NEJM

Phase 2 data showed that once-daily oral administration of the fibroblast growth factor receptor (FGFR) 1–3 selective tyrosine kinase inhibitor infigratinib results in a sustained increase in annualized height velocity in children with achondroplasia, with generally mild side effects.

"Infigratinib targets the root cause of achondroplasia by inhibiting FGFR phosphorylation, thereby reducing the activity of the two primary downstream signaling pathways involved in the condition. This mechanism offers a potential therapeutic approach to address FGFR3 hyperactivity," explains Ravi Savarirayan (University of Melbourne, Victoria, Australia) and co-authors.

Achondroplasia is a genetic skeletal disorder characterized by disproportionate short stature and associated medical complications throughout an individual’s life. Infigratinib, an orally available FGFR1–3 selective tyrosine kinase inhibitor, is currently being developed as a potential treatment for achondroplasia.

Against the above background, Dr. Savarirayan and colleagues initiated the PROPEL2 dose-finding study to assess the safety and efficacy of oral infigratinib in children aged 3 to 11 years with achondroplasia.

A total of 72 children were enrolled across five sequential cohorts to receive daily infigratinib at varying doses: 0.016 mg/kg (cohort 1), 0.032 mg/kg (cohort 2), 0.064 mg/kg (cohort 3), 0.128 mg/kg (cohort 4), and 0.25 mg/kg (cohort 5) for 6 months. Following this, participants continued with 12 months of extended treatment, with the option for dose escalation in cohorts 1 and 2 at months 6 and 12. The primary safety outcome focused on the rate of adverse events leading to dose reduction or study discontinuation, while the primary efficacy outcome measured changes in annualized height velocity from baseline.

Key Findings:

• All children experienced at least one adverse event during treatment, though most were mild or moderate in severity, and none led to treatment discontinuation.
• In cohort 5, an increased annualized height velocity was observed, which continued throughout the study, with a mean change from baseline at 18 months of 2.50 cm per year.
• The mean change from baseline in height z score at 18 months was 0.54 compared to an untreated achondroplasia reference population.
• The mean change from baseline in the upper-to-lower body segment ratio was −0.12.

The study showed that oral infigratinib administration showed no major safety concerns and led to an increased annualized height velocity and height z score, along with a reduced upper-to-lower body segment ratio at 18 months of treatment in cohort 5.

Based on the current findings, Savarirayan and his team have initiated a pivotal phase 3 trial to assess infigratinib at a dose of 0.25 mg/kg per day in 110 children aged 3 to 17 years with achondroplasia who are still in the growth phase. Additionally, children who participated in the PROPEL2 study are continuing to receive infigratinib through an open-label extension study, which is monitoring long-term safety and efficacy outcomes.

Reference: N Engl J Med 2024; doi:10.1056/NEJMoa2411790