Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia

BACKGROUND: pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

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Journal
New England Journal of Medicine
Published
2026-06-28
DOI
https://doi.org/10.1056/nejmoa2604565
Primary Topic
Connective tissue disorders research
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article
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article

Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia

Ravi Savarirayan, Valérie Cormier‐Daire, Daniela Rogoff, Janet M. Legare et al.
New England Journal of Medicine
Connective tissue disorders research
article

Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia

Ravi Savarirayan, Valérie Cormier‐Daire, Daniela Rogoff, Janet M. Legare, Helen McDevitt, Marie‐Eve Robinson, Massimiliano Rossi, Paul Arundel, Roberta Onesimo, David van Veenhuyzen, Josep Maria De Bergua, Philippe M. Campeau, Peter Kannu, Melita Irving, Antonio Leiva-Gea, Saumya Jamuar, Daniel Hoernschemeyer, Paul Harmatz, Mars Skae, John Phillips, Benjamin T. Cocanougher, Peter W. Butler, Klane K. White, Yun Bai, Jane Schmidt, Ted Lystig, Leanne M. Ward, Svein O. Fredwall, Henrik U. Irgens, Toby Candler, Thomas Edouard, Julie Hoover-Fong, Mariana del Pino, Ariana Salvatici
article en

Abstract

BACKGROUND: pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

New England Journal of Medicine
Università Cattolica del Sacro Cuore (IT), Oslo University Hospital (NO), Cincinnati Children's Hospital Medical Center (US), Hôpital Necker-Enfants Malades (FR), University of Wisconsin–Madison (US), Johns Hopkins University (US), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Guy's and St Thomas' NHS Foundation Trust (GB), Université Paris Cité (FR), Children's Hospital of Eastern Ontario (CA), Garrahan Hospital (AR), Sunnaas sykehus (NO), NHS Greater Glasgow and Clyde (GB), Haukeland University Hospital (NO), University Hospitals Bristol NHS Foundation Trust (GB), London Health Sciences Centre (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), Agostino Gemelli University Polyclinic (IT), Hôpital Femme Mère Enfant (FR), Institut Necker Enfants Malades (FR), Manchester University NHS Foundation Trust (GB), Children's Hospital Colorado (US), Hospices Civils de Lyon (FR), KK Women's and Children's Hospital (SG), Sheffield Children's NHS Foundation Trust (GB), Unidad de Cirugía Artroscópica (ES), UCSF Benioff Children's Hospital (US), Murdoch Children's Research Institute (AU), Stollery Children's Hospital (CA), Hospital Clínico Universitario Virgen de la Victoria (ES), Bridge Pharma (United States) (US), Vanderbilt Health (US), Instituto de Investigación Biomédica de Málaga (ES), University Hospitals Bristol and Weston NHS Foundation Trust (GB), University of Missouri (US), University of Colorado Denver (US)
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