ESPE Abstracts (2021) 94 P1-125

1Murdoch Children’s Research Institute, Melbourne, Australia; 2Sheffield Children’s NHS Foundation Trust, Sheffield, United Kingdom; 3Hospital Vithas San José, Vitoria-Gasteiz, Spain; 4NHS Greater Glasgow and Clyde, Glasgow, United Kingdom; 5Hôpital Necker-Enfants Malades, Paris, France; 6Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom; 7Manchester University NHS Foundation Trust, Manchester, United Kingdom; 8Hospital Universitario La Paz, Madrid, Spain; 9Hôpital des Enfants - Toulouse, Toulouse, France; 10Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; 11University of Alberta - Stollery Children’s Hospital, Edmonton, Canada; 12Nemours/Alfred I. duPont Hospital for Children, Wilmington, USA; 13Vanderbilt University Medical Center, Nashville, USA; 14Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; 15Benioff Children’s Hospital Oakland, Oakland, USA; 16University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom; 17QED Therapeutics, San Francisco, USA; 18Guy’s and Saint Thomas’ NHS Foundation Trust, London, United Kingdom

Background: ACH, the most common short-limbed skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating complications. Infigratinib is an orally bioavailable and selective FGFR1–3 tyrosine kinase inhibitor in development for FGFR-related conditions. In vitro data with infigratinib showed inhibition of FGFR1–3 activity with reversal of established growth arrest in chondrocytes. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice following treatment with infigratinib.

Methods: PROPEL2 is a prospective, phase 2, open-label dose-finding study of infigratinib that aims to provide preliminary evidence of safety and efficacy in children with ACH. Eligible subjects 3–11 years of age who completed at least 6 months of observation in PROPEL (a prospective clinical assessment study in children with ACH) will participate in PROPEL2. It consists of dose escalation with an extended treatment phase (ESC-ET), followed by a dose-expansion phase (EXP) to confirm the selected dose. A pharmacokinetic (PK) sub-study will evaluate the PK profile of infigratinib and major metabolites. The primary endpoints of ESC-ET are treatment-emergent adverse events and change from baseline in annualized growth velocity (AGV). Subjects (n = 40) are enrolled in ascending dose cohorts of approximately 10 subjects/cohort (4 cohorts planned) and treated for 6 months at their assigned dose, continuing for an additional 12 months with dose modifications as required. The primary endpoint of EXP is change from baseline in AGV at the dose identified from ESC. Up to 20 new subjects will be enrolled in this phase and receive infigratinib (mini-tablets, administered orally once daily) for 12 months. Main secondary objectives include safety/tolerability of infigratinib and changes from baseline in anthropometric parameters, including body proportions. Exploratory objectives are evaluation of changes in ACH disease burden and quality of life.

Current status: PROPEL2 is currently enrolling; the planned total enrollment is 78 children with ACH (40 ESC-ET, 20 EXP, 18 PK sub-study). Following completion of PROPEL2, subjects have the opportunity to enroll in an open-label long-term extension study to assess the safety and efficacy of long-term administration of infigratinib in children with ACH.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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