Eli Lilly's Selective FGFR3 Inhibitor LOXO-435 Receives IND Approval in China for Advanced Solid Tumors with FGFR3 Alterations

Intelligent Finance APP learned that recently, according to the CDE official website, Eli Lilly and Company's (LLY.US) clinical trial application for the FGFR3 inhibitor LOXO-435 tablets has been tacitly approved for the treatment of advanced malignant solid tumors with FGFR3 mutations. It is reported that FGFR3 is a member of the highly conserved FGFR family of membrane receptors, consisting of an extracellular ligand-binding region, a transmembrane domain, and an intracellular tyrosine kinase. After the extracellular region binds to high-affinity ligands, it induces receptor dimerization, thereby activating the PI3K-AKT, RAS-MAPK-ERK, and STAT pathways, playing an important role in various biological processes.

FGFR3 abnormalities include point mutations, fusions, amplifications, and overexpression, which may be associated with various tumors, occurring in approximately 15%-20% of advanced urothelial carcinoma, ~15% of uterine carcinosarcoma, ~5% of endometrial cancer, and other solid tumors. However, most FGFR-targeted therapies currently on the market are pan-FGFR inhibitors rather than highly selective for FGFR3. Inhibition of FGFR1 and FGFR2 may lead to dose-limiting off-target toxicity and susceptibility to drug resistance mutations.

LOXO-435, as a highly selective FGFR3 inhibitor, was designed to reduce dose-limiting hyperphosphatemia caused by FGFR1 inhibition and address intolerance issues associated with pan-FGFR inhibitors. It has already demonstrated significant anti-tumor efficacy in preclinical models while retaining activity against FGFR3 gatekeeper resistance mutations.

In addition, according to the Insight database, LOXO-435 initiated its first clinical trial in November 2022, planning to enroll 140 participants. The first participant was enrolled in January this year. The trial regions include the United States, Japan, Australia, and South Korea. In the phase 1a dose-escalation stage of the trial, DLT is the primary endpoint for evaluating the safety of LOXO-435. The phase 1b dose-expansion stage also includes a combination group with Keytruda (pembrolizumab).