BridgeBio Pharma's infigratinib, an investigational oral small molecule designed to inhibit FGFR3 signaling, has shown positive results in a Phase 2 trial (PROPEL 2) for children with achondroplasia. The study, published in the New England Journal of Medicine, demonstrated statistically significant and sustained increases in annualized height velocity (AHV) in children treated with a daily oral dose of 0.25mg/kg.
The PROPEL 2 trial's Cohort 5, evaluating the aforementioned dosage, reported a mean change from baseline in AHV of +2.50 cm/year (P=0.001) at Month 18. These findings were also presented at the 62nd Annual European Society for Paediatric Endocrinology (ESPE) Meeting in Liverpool.
Key Findings from PROPEL 2
In addition to the significant increase in AHV, the study revealed a mean change from baseline in height Z-score of +0.54 (P<0.001) relative to an untreated achondroplasia population at Month 18. Furthermore, a statistically significant improvement in body proportionality, indicated by a mean upper to lower body segment ratio, was observed at -0.12 (P=0.001) at Month 18.
According to Ravi Savarirayan, M.D., Ph.D., of Murdoch Children’s Research Institute in Melbourne, Australia, and the global lead investigator for PROPEL 2, the NEJM publication and the FDA Breakthrough Therapy Designation highlight the potential of infigratinib to not only increase height but also enhance functionality for children with achondroplasia.
Safety and Tolerability
Infigratinib was well-tolerated in the PROPEL 2 trial. There were no serious adverse events (SAEs) or treatment-emergent adverse events (TEAEs) leading to treatment discontinuation. Notably, the study found no accelerated progression of bone age, negative changes in bone mineral density, or other bone-related adverse events.
Melita Irving, M.D., a clinical geneticist at Guy’s and St Thomas’ NHS Foundation Trust, London, UK, emphasized the encouraging safety profile, stating, "We are encouraged to see no safety signals and no adverse changes in bone age or bone mineral density." She added that these results suggest the potential of infigratinib for children with skeletal dysplasia.
Regulatory Status and Ongoing Trials
Infigratinib has received Breakthrough Therapy Designation from the FDA, along with Orphan Drug Designation, Fast Track Designation, and Rare Pediatric Disease Designation for achondroplasia. The Breakthrough Therapy Designation was granted based on the PROPEL 2 results, which demonstrated a substantial improvement in efficacy over available therapies on clinically significant endpoints.
The global Phase 3 registrational study of infigratinib in achondroplasia, PROPEL 3 (NCT06164951), is currently enrolling patients, with enrollment completion anticipated by the end of 2024. BridgeBio is also exploring the potential of infigratinib in the Phase 2 portion of the ACCEL program in children with hypochondroplasia.
About Achondroplasia
Achondroplasia, the most common cause of disproportionate short stature, affects approximately 55,000 individuals in the U.S. and EU, including up to 10,000 children and adolescents with open growth plates. The condition, uniformly caused by an activating variant in FGFR3, can lead to medical complications such as obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis.
