Research Summary

Phase 3 Trial: Oral Infigratinib Improves Annualized Height Velocity in Children With Achondroplasia

Edited by:
Anthony Calabro, MA

Key Highlights

  • Once-daily oral infigratinib significantly improved annualized height velocity compared with placebo in children with achondroplasia at week 52.
  • The phase 3, multicenter, double-blind, placebo-controlled PROPEL 3 trial included 114 children aged 3 to 17 years with genetically confirmed achondroplasia.
  • Infigratinib also improved height z score vs placebo, although the between-group change in upper-to-lower body segment ratio was not statistically significant.
  • Adverse events occurred at similar rates in the infigratinib and placebo groups, and no treatment-related serious adverse events or treatment-related discontinuations were reported.

Once-daily oral infigratinib significantly increased annualized height velocity compared with placebo among children with achondroplasia, according to findings from a phase 3 trial published in The New England Journal of Medicine. The trial evaluated infigratinib, an oral fibroblast growth factor receptor 3 (FGFR1–3) selective tyrosine kinase inhibitor, in children aged 3 to 17 years with achondroplasia.

Achondroplasia is caused by pathogenic gain-of-function variants in FGFR3 that result in overactivity of downstream signaling pathways, including mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1), impairing endochondral skeletal ossification. Infigratinib directly inhibits FGFR3 phosphorylation and attenuates downstream signaling pathways implicated in achondroplasia pathogenesis.

Researchers conducted PROPEL 3, a phase 3, multicenter, double-blind, placebo-controlled trial at 27 sites in 10 countries. Eligible children had a confirmed genetic diagnosis of achondroplasia, were aged 3 to 17 years, had completed at least 26 weeks in the observational PROPEL study, and had defined growth potential. Participants were randomly assigned 2:1 to receive oral infigratinib at 0.25 mg/kg once daily for 52 weeks or placebo.

The primary endpoint was the change from baseline in annualized height velocity in the infigratinib group compared with placebo at week 52. Key secondary endpoints included change from baseline in height z-score and upper-to-lower body segment ratio at week 52. Efficacy was assessed in the full analysis population, and safety was assessed among all participants who received at least 1 dose of infigratinib or placebo.

Study Findings

Among 114 randomized children, 75 were assigned to infigratinib and 39 to placebo; 1 patient assigned to infigratinib withdrew before treatment. At week 52, the least-squares mean change from baseline in annualized height velocity was 1.58 cm per year in the infigratinib group and −0.16 cm per year in the placebo group. The between-group difference was 1.74 cm per year (95% CI, 1.31-2.17; P < .001).

Infigratinib also improved the achondroplasia-specific height z score, with a between-group least-squares mean difference of 0.32 at week 52 (96% CI, 0.23-0.41; P < .001). The between-group difference in least-squares mean change from baseline in upper-to-lower body segment ratio was −0.02 (96% CI, −0.06 to 0.01). In the subgroup of children aged 3 to younger than 8 years, the between-group difference in upper-to-lower body segment ratio was −0.05 (95% CI, −0.10 to −0.00).

Safety findings were broadly similar between groups. Adverse events occurred in 71 of 74 patients (96%) receiving infigratinib and 37 of 39 patients (95%) receiving placebo. Serious adverse events occurred in 4 patients (5%) in the infigratinib group and 1 patient (3%) in the placebo group; none were considered related to treatment. No deaths occurred, and no adverse events leading to treatment discontinuation were deemed related to infigratinib or placebo.

Clinical Implications

According to the study authors, the findings suggest that infigratinib may be a targeted oral therapy for children with achondroplasia. The authors noted that, unlike C-type natriuretic peptide, analogues that down-regulate FGFR3 signaling through the MAPK pathway, infigratinib directly binds FGFR3 and inhibits its phosphorylation and downstream signaling related to bone growth.

The study authors reported that the trial’s relatively short duration limited assessment of outcomes such as functionality, health-related quality of life, medical complications, and adult height. They stated that long-term efficacy and safety are being evaluated in the ongoing PROPEL OLE study.

Expert Commentary

“Treatment with once-daily oral infigratinib for 52 weeks led to larger increases in the annualized height velocity and height z score than placebo in children with achondroplasia between the ages of 3 and 17 years,” the researchers concluded.

Reference
Savarirayan R, Hoover-Fong J, Irving M, et al. Phase 3 trial of oral infigratinib in children with achondroplasia. N Engl J Med. Published June 28, 2026. doi:10.1056/NEJMoa2604565