Journal Article

Oral Infigratinib Therapy in Children with Achondroplasia

Cormier-Daire, Valerie, Phillips, John, Candler, Toby, Savarirayan, Ravi, Rogoff, Daniela, Saraff, Vrinda, De Bergua, Josep Maria, Muslimova, Elena, Skae, Mars, Irving, Melita, Kannu, Peter, Nicolino, Marc, Raj, Supriya, McDevitt, Helen, Arundel, Paul, Rossi, Massimiliano, Hill, Dawn, Delgado, Borja, Harmatz, Paul, Leiva-Gea, Antonio, Bai, Yun, Hoover-Fong, Julie, Salles, Jean Pierre, Saal, Howard, Salcedo, Maria, Weng, Richard

2025

Overview

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. 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. 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). 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.).

• Publisher: Massachusetts Medical Society
• Subject: Achondroplasia / Achondroplasia - drug therapy / Achondroplasia - genetics / Achondroplasia - metabolism / Administration, Oral / Adverse events / Body Height / Body Height - drug effects / Body weight / Bone Disease / Child / Child, Preschool / Children / Clinical Medicine / Clinical Medicine General / Dose-Response Relationship, Drug / Drug dosages / Endocrinology / Endocrinology and metabolism / Endocrinology General / Female / Fibroblast growth factor receptor 1 / Gain of Function Mutation / Genetics / Genetics General / Growth and Development / Human health and pathology / Humans / Hypothesis testing / Kinases / Life Sciences / Male / Missing data / Oncology / Orthopedics / Orthopedics General / Osteoporosis / Pediatrics / Pediatrics General / Pharmacokinetics / Phenylurea Compounds / Phenylurea Compounds - administration & dosage / Phenylurea Compounds - adverse effects / Phosphorylation / Protein Kinase Inhibitors / Pyrimidines / Pyrimidines - administration & dosage / Pyrimidines - adverse effects / Pyrimidines - pharmacokinetics / Radiology / Radiology General / Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Rheumatology / Treatment Outcome / Tyrosine Kinase Inhibitors - administration & dosage / Tyrosine Kinase Inhibitors - adverse effects / Velocity