Beijing Avistone Biotechnology Co., Ltd has announced that the U.S. Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for ANS03, a next-generation tyrosine kinase inhibitor (TKI) targeting both ROS1 and NTRK.
ANS03 is designed to address the urgent clinical need for novel Type II ROS1/NTRK TKIs capable of overcoming acquired resistance mutations, particularly solvent front (SF) mutations like ROS1-G2032R and ROS1-D2033N and NTRK1-G595R, as well as ROS1 central beta sheet #6 (Cβ6) mutation L2086F and NTRK1 xDFG mutation G667C. These mutations often lead to resistance against existing ROS1/NTRK inhibitors.
Overcoming Resistance with Type II Inhibition
As a type II inhibitor, ANS03 occupies the ATP-bound pocket of the kinase with the “DFG-out” inactive conformation and extends into the adjacent allosteric pocket. This mechanism is expected to provide a broader spectrum of resistance mutation inhibition, conferring ANS03 a distinctive pharmacodynamic advantage.
Clinical Development and Patient Enrollment
Avistone plans to initiate clinical trials in Q1 2025, focusing on patients with locally advanced or metastatic tumors harboring ROS1 or NTRK alterations. ANS03 is designed as an oral, small molecule therapy intended to effectively overcome the acquired drug resistance problems caused by type I TKIs and possesses a broader inhibitory range of ROS1/NTRK kinase activity, including wild-type ROS1/NTRK fusion and numerous acquired drug-resistant mutations.
The Current Landscape of ROS1/NTRK Inhibitors
Several ROS1/NTRK inhibitors, including crizotinib, entrectinib, larotrectinib, and repotrectinib, have already been approved by the FDA and China’s NMPA for treating patients with metastatic NSCLC whose tumors are ROS1/NTRK-positive. However, resistance invariably develops, highlighting the need for new therapeutic options like ANS03.
