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Oral Infigratinib Therapy in Children with Achondroplasia
Ravi Savarirayan1, Josep Maria De Bergua2, Paul Arundel3
1Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Insights
Infigratinib treatment in children with achondroplasia showed increased height velocity and improved body proportions without major safety concerns. This FGFR inhibitor offers a promising therapeutic option for this genetic skeletal condition.
Area of Science:
- Pediatric Endocrinology
- Skeletal Dysplasias
- Pharmacology
Background:
- Achondroplasia is a genetic disorder causing disproportionate short stature and lifelong medical issues.
- Infigratinib is an oral FGFR1-3 selective tyrosine kinase inhibitor being developed for achondroplasia treatment.
Purpose of the Study:
- To evaluate the safety and efficacy of oral infigratinib in children aged 3-11 with achondroplasia.
- To determine the optimal dose for treating achondroplasia in pediatric patients.
Main Methods:
- A phase 2 dose-finding study involving 72 children with achondroplasia.
- Sequential cohorts received daily infigratinib at doses ranging from 0.016 to 0.25 mg/kg for 6 months, followed by 12 months of extended treatment.
- Primary outcomes assessed were adverse events and change in annualized height velocity.
Main Results:
- All participants experienced mild to moderate adverse events, with no treatment discontinuations.
- Cohort 5 (highest dose) showed a significant increase in annualized height velocity (2.50 cm/year) persisting over 18 months.
- Improvements were noted in height z-score (0.54) and a decrease in upper-to-lower body segment ratio (-0.12).
Conclusions:
- Oral infigratinib demonstrated a favorable safety profile in children with achondroplasia.
- The treatment significantly increased annualized height velocity and improved body proportion metrics.
- Infigratinib shows potential as an effective therapy for achondroplasia in pediatric patients.
Background:
Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia.
Methods:
In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity.
Results:
During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06).
Conclusions:
The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.).
