Eli Lilly's Selective FGFR3 Inhibitor LOXO-435 Receives CDE Approval for Clinical Trials in China
Eli Lilly
Global Pharmaceutical R&D and Production Company
Recently, according to the CDE official website, Eli Lilly and Company submitted an FGFR3 inhibitorLOXO-435 Tablets Clinical Trial Application Granted Implicit Approval, for the treatment of advanced malignant solid tumors with FGFR3 mutations.
Source: CDE Official Website
FGFR3 is a member of the highly conserved FGFR family of membrane receptors, consisting of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase. Ligand binding with high affinity to the extracellular region induces receptor dimerization, thereby activating the PI3K-AKT, RAS-MAPK-ERK, and STAT pathways, playing crucial roles in various biological processes.
Source: Corporate Official Website
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.
Comparison of FGFR Inhibitor Dosing, Efficacy, and Adverse Reactions
Source: 2021 AACR (Unless otherwise specified, the source is the same as below)
And LOXO-435, as a highly selective FGFR3 inhibitor, serves to reduceDesigned to address dose-limiting hyperphosphatemia caused by FGFR1 inhibition and intolerance issues associated with other pan-FGFR inhibitors,Significant antitumor efficacy has been demonstrated in preclinical models, retaining activity against FGFR3 gatekeeper mutations.
LOXO-435 Selectivity Compared to Other Pan-FGFR Inhibitors
Eli Lilly had previously disclosed the preclinical data of LOXO-435 (LOX-24350) at the 2021 AACR-EORTC.
According to the Insight database, LOXO-435 initiated its first clinical trial in November 2022 (Registration Number:NCT05614739）, planning to enroll 140 cases. The first case was successfully enrolled in January this year. The trial regions include the United States, Japan, Australia, and South Korea.Phase 1a Dose Escalation of the TrialThe phase evaluates the safety of LOXO-435 with DLT as the primary endpoint, and the Phase 1b dose expansion also includes a combination group with pembrolizumab (K药).
From:EnterpriseOfficial Website
References:
1. Loxo@Eli Lilly and Company Official Website
https://www.lillyloxooncologypipeline.com/molecule/fgfr3-inhibitor
https://www.lillyloxooncologypipeline.com/flashcards/loxo_435_flash_card_q2_2023.pdf
2、AACR-EORTC
https://www.loxooncology.com/docs/publications/EORTC_2021_Ballard_Josh_Preclinical_Characterization_of_FGFR3_Website.pdf
