Preclinical Data Supporting Tolerability and Activity of Low-dose Infigratinib in Treating Achondroplasia Presented at ASHG 2019 Annual Meeting
QED Therapeutics, Inc. and parent company BridgeBio Pharma, Inc announced the presentation of preclinical data supporting the potential of low-dose infigratinib for the treatment of achondroplasia. The data were presented during the ASHG 2019 Annual Meeting in a poster entitled “Low dose, daily or intermittent administration of infigratinib (BGJ398), a selective FGFR inhibitor, as treatment for achondroplasia in a preclinical mouse model.”
Achondroplasia is the most common cause of dwarfism and is caused by mutation of the gene for fibroblast growth factor receptor 3 (FGFR3). FGFR3 has been shown to be crucial for the process of bone elongation.1,2 Infigratinib, an investigational agent, binds to FGFR3 and has been previously shown to increase bone growth in preclinical mouse models of achondroplasia.3 The data presented today showed a positive dose-response relationship between infigratinib and bone growth.
“Observing a dose-response relationship is an important step in developing infigratinib as a therapy for achondroplasia,” said Laurence Legeai-Mallet, Ph.D., head of research team at Imagine Institute, INSERM U1163, Université de Paris, who led the research, in a press release. “We also observed better organization within the hypertrophic zone of the growth plate, which is responsible for bone formation and elongation, indicating that a low dose of infigratinib had a positive effect.”
The preclinical study used a dwarf mouse model (Fgfr3Y367C/+), which mimics achondroplasia. In each of the three dose groups, treatment with infigratinib led to an increase in all nine measures of bone size studied compared to the control group (See figure). At the highest dose examined (0.5 mg/kg/day), treatment with infigratinib demonstrated a statistically significant (P < 0.01) improvement in bone length of 7-14% in the upper limbs, 10% to 17% in the lower limbs and 12% in the foramen magnum (an opening at the base of the skull). No apparent toxicity of infigratinib was noted in this study.
Read the full press release here.
1Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J.M., Maroteaux, P., Le Merrer, M., Munnich, A. “Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia”. Nature 371 (1994): 252–254.
2Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. “Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.” Cell 78 (1994): 335–342.