SUN-730 TYRA-300 Promotes Bone Growth In Two Mouse Models Of FGFR3-related Skeletal Dysplasia

Abstract Disclosure: J.H. Starrett: None. C. Lemoine: None. M. Guillo: None. C. Fayad: None. N. Kaci: None. M. Neal: None. E. Pettitt: None. M. Pache: None. Q. Ye: None. M.S. Stalvey: None. R. Charlton: None. R.V. Swanson: None. L. Legeai-Mallet: None. Achondroplasia (ACH) and hypochondroplasia (HCH), the two most common types of dwarfism, are each caused by gain-of-function alterations in FGFR3. FGFR3 is expressed in growth plate chondrocytes where it negatively regulates endochondral bone growth. Mutations such as G380R, which causes approximately 99% of ACH, increase FGFR3 signaling, disrupting chondrogenesis and osteogenesis resulting in disproportionately shortened long bones. Beyond the functional challenges related to short stature, people with ACH can experience serious medical complications and require multiple surgeries throughout their lives. TYRA-300, a potent and selective FGFR3 inhibitor, was evaluated in the Fgfr3Y367C/+ mouse model of ACH and the Fgfr3N534K/+ mouse model of HCH. In both models, TYRA-300 treatment increased naso-anal length, tibia and femur length, and partially restored the disproportionality of the long bones. Histologic analysis of the growth plate in Fgfr3Y367C/+ mice revealed that mechanistically TYRA-300 increased both proliferation and differentiation of chondrocytes. Micro-CT analysis of Fgfr3Y367C/+ mice revealed that TYRA-300 treatment increased bone mineral density and bone volume to tissue volume ratio of the femoral metaphyses, suggesting that TYRA-300 improved bone quality and strength in this model. Importantly, children with ACH can experience critical foramen magnum stenosis, and TYRA-300 significantly improved the size and shape of the skull and foramen magnum in Fgfr3Y367C/+ mice. Spinal stenosis is also a frequent complication, and TYRA-300 increased the lumbar vertebrae length and improved the shape of the intervertebral discs in both models. TYRA-300 is currently being evaluated in a Phase 2 trial in children with ACH. BEACH301 is a Phase 2, multicenter, open-label, dose-escalation/dose-expansion study evaluating TYRA-300 in children with ACH, ages 3 to 10, with open growth plates. The primary objectives of this study will be to assess safety and tolerability in children with ACH and evaluate change from baseline in annualized growth velocity to determine the dose(s) for further development. Secondary objectives will include evaluating change from baseline in height z-score, proportionality and pharmacokinetics. Presentation: Sunday, July 13, 2025