Overview
TY-2136b is a new generation ROS1/NTRK/ALK multi-target small molecule broad-spectrum tyrosine kinase inhibitor, which is independently developed by TYK Medicines, Inc. Preclinical studies have shown that TY-2136b can target ROS1/NTRK/ALK mutation-driven cancers, and potentially overcome drug resistance triggered by acquired ROS1/NTRK/ALK mutations including G2032R, G595R, G667C, G623R, G1202R, and double mutations, etc. Moreover, it has better potential for brain penetration. TY-2136b is a potent inhibitor for the treatment of lung cancer and other advanced solid tumors with ALK/ROS1/NTRK alterations or ALK/ROS1/NTRK resistant mutations. On August 31, 2020, TYK signed a patent transfer and technology exclusive license agreement with Livzon Pharmaceutical Group Inc. for TY-2136b in greater China. Currently, the phase I dose-escalation and dose-extension study is being conducted in the United States and China.
Mechanism of Action
Lung cancer is one of the leading cause of cancer death worldwide, with about 85% of cases are patients with non-small cell lung cancer (NSCLC). According to the classification of oncogenic driver genes, ROS1 positive accounted for about 2% of the NSCLC patients, with over half of these patients developing drug resistance mutations such as G2032R and D2033N after receiving therapy with existing targeted drugs. NTRK gene fusion mutations account for about 0.5-1% of NSCLC patients, which can also cause a variety of cancers including appendix cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, melanoma, pancreatic cancer, thyroid cancer and many other 17 types of solid tumors. Larotrectinib (LOXO-101) is a first-generation targeted therapy that is effective against multiple types of cancer caused by NTRK gene fusions, but since its launch in the United States in 2018, patients have developed resistance mutations such as TRKA (G595R, G667C) and TRKC (G623R, G696A). ALK-positive accounts for about 5-8% of NSCLC patients, and after treatment with ALK inhibitors, especially second-generation ALK inhibitors, will produce a large number of G1202R resistant mutations. At present, except for Lorlatinib, Pfizer's third-generation ALK inhibitor, there is no other ALK inhibitor that has been able to effectively overcome this resistance mutation worldwide. TY-2136b, benchmarked against Repotrectinib (TPX-0005), a drug candidate from Turning Point Therapeutics, shows excellent activity against the above gene mutations and drug resistance mutations, and has potentially better brain penetration. It is the second drug candidate in the world after TPX-0005 and the first in China to demonstrate this potential.
