ESPE2023 Rapid Free Communications Growth and syndromes (to include Turner syndrome) (6 abstracts)
Results from the PROPEL 2 dose-finding study: oral infigratinib leads to significant increases in height velocity with good tolerability in children with achondroplasia
Ravi Savarirayan 1 , Josep Maria De Bergua 2 , Paul Arundel 3 , Jean Pierre Salles 4 , Vrinda Saraff 5 , Borja Delgado 6 , Antonio Leiva-Gea 7 , Helen McDevitt 8 , Marc Nicolino 9 , Massimiliano Rossi 10 , Maria Salcedo 11 , Valerie Cormier-Daire 12 , Mars Skae 13 , Peter Kannu 14 , Michael B. Bober 15 , John Phillips III 16 , Howard Saal 17 , Paul Harmatz 18 , Christine Burren 19 , Toby Candler 19 , Terry Cho 20 , Elena Muslimova 20 , Richard Weng 20 , Supriya Raj 1 , Julie Hoover-Fong 21 , Melita Irving 22 & Daniela Rogoff 20
1Murdoch Children’s Research Institute, Melbourne, Australia. 2Hospital Vithas San José, Vitoria-Gasteiz, Spain. 3Sheffield Children’s NHS Foundation Trust, Sheffield, United Kingdom. 4Children Hospital, Toulouse University Hospital, Toulouse, France. 5Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom. 6Campus de Teatinos sin número, Hospital Universitario Virgen de la Victoria, Malaga, Spain. 7Instituto de Investigación Biomédica de Málaga – IBIMA, and Hospital Universitario Virgen de la Victoria, Malaga, Spain. 8NHS Greater Glasgow and Clyde, Glasgow, United Kingdom. 9Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France. 10Lyon University Hospital, Bron, Lyon, France. 11Hospital Universitario La Paz, Madrid, Spain. 12Imagine Institute, Hôpital Necker-Enfants Malades, University of Paris, Paris, France. 13Manchester University NHS Foundation Trust, University of Manchester, Manchester, United Kingdom. 14Department of Medical Genetics, University of Alberta, Edmonton, USA. 15Nemours Children’s Hospital, Wilmington, USA. 16Vanderbilt University Medical Center, Nashville, USA. 17Cincinnati Children’s Hospital Medical Center, Cincinnati, USA. 18UCSF Benioff Children’s Hospital Oakland, Oakland, USA. 19University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom. 20QED Therapeutics, San Francisco, USA. 21Johns Hopkins University, Baltimore, USA. 22and St Thomas’ NHS Trust, London, United Kingdom
Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by impaired endochondral ossification resulting from gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone growth. People with ACH are at risk for several significant co-morbidities, including brainstem compression due to foramen magnum stenosis, sleep-disordered breathing, chronic otitis media with conductive hearing loss, and symptomatic spinal stenosis. Infigratinib is an oral, selective FGFR1–3 tyrosine kinase inhibitor being investigated for treating children with ACH.
Methods: PROPEL 2 (NCT04265651) is a phase 2 dose-finding, open-label study of infigratinib in children 3−11 years with ACH who participated for ≥6 months in PROPEL (NCT04035811), a non-interventional clinical assessment study. The PROPEL 2 dose-escalation (DE) phase includes 5 ascending dose cohorts ranging from 0.016 mg/kg/day to 0.25 mg/kg/day. Primary endpoints: safety; change from baseline in annualized height velocity (AHV); infigratinib pharmacokinetics.
Results: Children enrolled in PROPEL 2 DE completed ≥6 months of treatment at the assigned dose. Cohorts 1–3 (n=37; 0.016, 0.032, 0.064 mg/kg/day) did not show a significant increase in AHV and these doses were assessed as non-efficacious. Treatment at the cohort 4 dose (0.128 mg/kg/day) resulted in an increase in AHV from baseline of 1.52 cm/year in children ≥5 years old (n=11; P=0.02). Infigratinib at the cohort 5 dose (0.25 mg/kg/day, n=10, month 6) resulted in a significant mean increase from baseline of 3.03 cm/year (P=0.0022). In cohort 5, collagen X marker, a biomarker of endochondrial ossification, showed a median increase of 28% from baseline at month 6 (n=6). Infigratinib was well tolerated with no serious AEs or AEs leading to study discontinuation, with most AEs mild/moderate in severity. At the cohort 5 dose, no grade 3 AEs or treatment-related AEs were reported.
Conclusion: Oral infigratinib in children with ACH, up to 0.25 mg/kg/day, was well tolerated and showed dose-dependent increases in AHV, with a significant mean change from baseline of +3.03 cm/year at the cohort 5 dose. The safety and efficacy of this oral, once-daily dose of infigratinib (0.25 mg/kg/day) will be further explored in a phase 3 randomized controlled study. If these phase 2 data are confirmed, infigratinib could potentially offer children with ACH the first safe and effective oral therapy to improve growth, enhance functionality and decrease medical complications.
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