Overview
TY-9591 is an orally, irreversible, third-generation inhibitor of Epidermal Growth Factor Receptor (EGFR), individually developed by TYK Medicines, Inc. TY-9591 is a potent inhibitor and is intended for use in the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation (including exon 19 deletions or exon 21 L858R substitution mutation), or for the treatment of adult patients with advanced EGFR mutation positive NSCLC with central nervous system metastases. TY-9591 received the clinical trial approval notification from the NMPA in 2019, and the phase I dose-escalation and dose-extension study has been completed. Currently, it is being evaluated in a phase III study versus Osimertinib as first-line treatment in patients with EGFRm+ NSCLC and a phase II study in patients with EGFRm+ NSCLC with brain metastases.
Mechanism of Action
Epidermal Growth Factor Receptor (EGFR), a member of the ErbB receptor family, is a receptor for Epithelial Growth Factor (EGF) cell proliferation and signal transduction, and is related to tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and inhibition of cell apoptosis. EGFR-activating mutations are one of the main driving factors for NSCLC with the proportion of EGFR mutation-positive in patients as high as 30%-50% in Asian patients. Mutations are mainly concentrated in exons 18~21, with classical mutations including the L858R mutation in exon 21 and deletion in exon 19, accounting for about 90%. The rate of brain metastases in advanced lung adenocarcinoma with EGFR mutations is about 44%-63%. At present, EGFR TKI has become the main therapeutic drug for patients with EGFR+ NSCLC.
TY-9591 is a highly effective, ATP-competitive, non-reversible, oral available third-generation EGFR TKI. It has good stability, similar efficacy and development characteristics compared with the marketed drug Osimertinib, but with different drug metabolism characteristics, which can significantly reduce the production of toxic metabolite AZD5104 (TY-9591-D1) and lower the side effects, thus has a wider clinical therapeutic window. Preclinical studies indicated that TY-9591 tablets had high bioavailability, and could penetrate the blood-brain barrier, showing potential advantages for clinical development in patients with NSCLC with brain metastases. NSCLC brain metastases are life-threatening and severely affect the quality of life, and the current treatment effect is limited. There is no effective drug that has been approved worldwide for this indication, which poses unmet clinical needs and difficulties. TY-9591 is expected to become the first drug with significant curative effect for this indication in China, to fill the urgent clinical gap.
