Merck's BTK-C481S Inhibitor MK-1026 Receives IND Approval in China to Address Resistance in B-Cell Malignancies

On May 18, according to the official website of the CDE, the clinical trial application for MSD’s MK-1026 tablets has been accepted by the National Medical Products Administration (NMPA), making it the third BTK-C481S inhibitor to submit a clinical trial application in China.

Currently, several small-molecule BTK inhibitors have been successfully applied in the clinical treatment of B-cell lymphoma. Existing marketed BTK inhibitors primarily exert their enzymatic inhibitory effects by forming covalent bonds with the cysteine residue at the active site of BTK. However, covalent binding is prone to inducing resistance mutations, which has become a major challenge in clinical practice. The C481S mutation is a known resistance mechanism against first-generation irreversible BTK inhibitors.

MK-1026 is an orally active and reversible BTK inhibitor capable of inhibiting both wild-type and C481S mutant BTK. Originally developed by ArQule under the code name ARQ 531, MK-1026 was acquired by MSD on January 18, 2020, as part of the approximately $2.7 billion acquisition of ArQule, which secured a portfolio of small-molecule drugs including ARQ 531.

At the 2019 American Society of Hematology (ASH) Annual Meeting, ArQule presented Phase I clinical trial data for ARQ 531: 47 patients with relapsed/refractory B-cell malignancies were treated with ARQ 531 at varying doses (5, 10, 15, 20, 30, 45, 65, and 75 mg once daily). The objective response rate (ORR) was 89% in 9 efficacy-evaluable patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated with ARQ 531 at doses ≥65 mg. Notably, 7 of these 9 efficacy-evaluable CLL patients harbored the BTK C481S mutation.

Among investigational drugs globally targeting the BTK-C481S mutation, Eli Lilly's pirtobrutinib and Roche's fenebrutinib are advancing the fastest; both are currently in Phase III clinical trials and have already received clinical trial approval in China.