FGFR1-3 inhibitor for achondroplasia
Infigratinib (BGJ398) is an orally administered, ATP-competitive, FGFR1-3 tyrosine kinase inhibitor in development for the treatment of FGFR-driven conditions, including achondroplasia, a bone growth disorder in children. Overactivating FGFR3 mutations drive downstream MAPK and STAT1 signaling that aberrates growth plate development, thereby causing disproportionate short stature and serious health complications stemming from cranial and spinal defects. Low dose infigratinib has the potential to help these patients due to its direct inhibition of the mutant FGFR3 receptor. In mouse models of achondroplasia, infigratinib demonstrated robust bone growth and clear improvement in cranial and spinal defects. BridgeBio initiated PROPEL 3, a Phase 3 clinical trial studying the efficacy and safety of infigratinib in children with achondroplasia. Both the U.S. FDA and the EU EMA indicated the trial design for PROPEL 3 would be acceptable as a registrational study to support a marketing application for the treatment of children with achondroplasia.
Achondroplasia is the most frequent cause of disproportionate short stature.
Achondroplasia is an autosomal dominant condition caused by a gain-of-function point pathogenic variant in the FGFR3 gene. Approximately 97% of cases are due to G380R substitution and 80% of cases are the result of de novo mutations. FGFR3 is expressed in osteoblasts and chondrocytes where it plays a critical role in regulating bone growth through the STAT1 pathway, which drives chondrocyte proliferation and through the MAPK pathway, which drives hypertrophic differentiation.
While some people with achondroplasia have few medical complications, achondroplasia affects multiple body systems and people can experience a range of medical problems across their lifespan. Beyond the day-to-day implications of disproportionate short stature with anomalies in bone development, achondroplasia can cause foramen magnum stenosis, spinal stenosis, cardiovascular complications, sleep-disordered breathing, and obesity and many people with achondroplasia undergo multiple surgical interventions, including spine surgery and limb lengthening. Collectively, these represent a complex medical condition that affects the overall health, independent function and quality of life.
The foramen magnum is the opening at the base of the skull through which the spinal cord passes, and its narrowing can lead to neurologic emergencies in children that require emergency surgery or cause sudden infant death. Children with achondroplasia ages 1 and younger have an increased risk of sudden infant death more than 5-6x that of their peers without achondroplasia, in large part attributed to stenosis of the foramen magnum. Spinal stenosis, or narrowing of the spinal canal, can result in chronic back pain in children, adolescents, and adults, and may require surgery later in life.
BridgeBio is developing a small molecule named infigratinib as an oral FGFR1-3 inhibitor to treat achondroplasia at its source.
FGFR3 gain-of-function mutations are the driver behind the pathophysiology of achondroplasia. As an FGFR1-3 inhibitor, we believe that infigratinib has the potential to decrease pathologic signaling downstream of FGFR3, including blocking upregulated STAT1 and MAPK, which may allow for amelioration of key symptoms.
Infigratinib has been studied preclinically in a mouse model of achondroplasia that recapitulates anomalies of the growth plates, vertebrae, and intervertebral discs. Investigators observed that infigratinib rescued ex vivo bone growth of mutant mouse embryo femurs after six days of treatment. Further, 15 days of treatment with 2 mg/kg infigratinib showed in vivo bone growth and robust penetration of the growth plate. Effects on both appendicular and axial skeletal parameters were observed in this study, and an effect was seen on the size and shape of the foramen magnum.
In vivo bone growth was further demonstrated at even lower doses (0.2 mg/kg and 0.5 mg/kg) by the same laboratory. Together, preclinical studies at all of these very low doses have demonstrated meaningful increases in skeletal growth parameters between treated and untreated mutant mice with no other gross side effects being observed in these preclinical studies.
BridgeBio initiated PROPEL 3, a Phase 3 clinical trial studying the efficacy and safety of infigratinib in children with achondroplasia. Both the U.S. FDA and the EU EMA indicated the trial design for PROPEL 3 would be acceptable as a registrational study to support a marketing application for the treatment of children with achondroplasia.
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