• Ravi Savarirayan, Josep Maria De Bergua, Paul Arundel, Jean Pierre Salles, Vrinda Saraff, Borja Delgado, Antonio Leiva-Gea, Helen McDevitt, Marc Nicolino, Massimiliano Rossi, Maria Salcedo, Valerie Cormier-Daire, Mars Skae, Peter Kannu, John Phillips, Howard Saal, Paul Harmatz, Toby Candler, Dawn Hill, Elena Muslimova, Richard Weng, Yun Bai, Supriya Raj, Julie Hoover-Fong, Melita Irving, and Daniela Rogoff.
• From Murdoch Children's Research Institute, Melbourne, VIC, Australia (R.S., S.R.); Hospital Vithas Vitoria, Vitoria-Gasteiz (J.M.D.B.), Hospital Universitario Virgen de la Victoria, Malaga (B.D., A.L.-G.), and Hospital Universitario La Paz, Madrid (M. Salcedo) - all in Spain; Sheffield Children's NHS Foundation Trust, Sheffield (P.A.), Birmingham Women's and Children's NHS Foundation Trust, Birmingham (V.S.), NHS Greater Glasgow and Clyde, Glasgow (H.M.), Manchester University NHS Foundation Trust, Manchester (M. Skae), University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (T.C.), and Guy's and St. Thomas' NHS Foundation Trust, London (M.I.) - all in the United Kingdom; Hôpital des Enfants-Toulouse, Toulouse (J.P.S.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon (M.N., M.R.), and Hôpital Necker-Enfants Malades, Paris (V.C.-D.) - all in France; the University of Alberta-Stollery Children's Hospital, Edmonton, Canada (P.K.); Vanderbilt University Medical Center, Nashville (J.P.); Cincinnati Children's Hospital Medical Center, Cincinnati (H.S.); Benioff Children's Hospital Oakland, Oakland (P.H.), and BridgeBio Pharma, San Francisco (D.H., E.M., R.W., Y.B., D.R.) - both in California; and Johns Hopkins University, Baltimore (J.H.-F.).
• N. Engl. J. Med. 2024 Nov 18.

BackgroundAchondroplasia 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.MethodsIn 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.ResultsDuring 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).ConclusionsThe 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.).Copyright © 2024 Massachusetts Medical Society.

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