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Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies
Ravi Savarirayan1, Josep Maria De Bergua2, Paul Arundel3
1Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Insights
This study investigates infigratinib for achondroplasia, a genetic disorder affecting bone growth. PROPEL 2 aims to assess the safety and efficacy of this FGFR3-targeted therapy in children, informing future treatment strategies.
Area of Science:
- Genetics and Molecular Biology
- Pediatric Endocrinology
- Clinical Pharmacology
Background:
- Achondroplasia, the most common skeletal dysplasia, stems from activating variants in the fibroblast growth factor receptor 3 (FGFR3) gene.
- Current treatments for achondroplasia are primarily symptomatic, addressing associated medical complications.
- Infigratinib, a selective FGFR1-3 tyrosine kinase inhibitor, presents a potential targeted therapy for achondroplasia by inhibiting FGFR3 overactivity.
Purpose of the Study:
- To gather baseline data in children with achondroplasia for future interventional studies (PROPEL).
- To obtain preliminary safety and efficacy data for oral infigratinib in pediatric achondroplasia patients (PROPEL 2).
- To determine optimal infigratinib dosage and characterize its pharmacokinetic profile in children with achondroplasia.
Main Methods:
- PROPEL: A prospective, noninterventional study collecting natural history data over 6-24 months.
- PROPEL 2: A Phase II, open-label study involving dose-escalation, dose-finding, and dose-expansion phases.
- Eligibility for PROPEL 2 requires children aged 3-11 years with achondroplasia to have completed at least 6 months in PROPEL.
Main Results:
- The primary endpoints for PROPEL 2 include treatment-emergent adverse events and changes in annualized height velocity from baseline.
- Dose escalation will involve four cohorts receiving ascending doses of infigratinib.
- A pharmacokinetic substudy will characterize the drug's behavior and its metabolites in pediatric participants.
Conclusions:
- PROPEL and PROPEL 2 are designed to provide initial evidence on the safety and efficacy of infigratinib for achondroplasia.
- Findings will guide the design of future clinical trials involving FGFR-targeted therapies for achondroplasia.
- This research supports the development of precision medicine approaches for achondroplasia treatment.
Background:
Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1-3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia.
Objectives:
The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites.
Design:
PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6-24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy.
Methods And Analysis:
Children aged 3-11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase.
Ethics:
PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable.
Discussion:
PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia.
Registration:
ClinicalTrials.gov: NCT04035811; NCT04265651.
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