ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK). We commenced a phase 1 trial in patients with B-cell malignancies refractory to other therapeutic options in July of 2017.
B-cell malignancies, like chronic lymphocytic lymphoma (CLL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are driven by BTK. The only approved BTK inhibitor, ibrutinib, is irreversible and makes a covalent bond with the C481 residue of the targeted protein. Although ibrutinib has demonstrated excellent responses in patients with elevated BCR signaling, clinical resistance has been observed, and the BTK-C481S mutation is emerging as a predominant mechanism of resistance. As a reversible inhibitor, ARQ 531 does not require interaction with the C481 residue, a binding site essential for irreversible ibrutinib binding to BTK, thus positioning ARQ 531 as a targeted therapy for CLL, DLBCL, MCL patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.
Patients with tumors harboring the BTK-C481S mutation could benefit from being targeted by ARQ 531, a potent inhibitor of that mutation. There is an emerging body of evidence that is defining the potential clinical need related to BTK resistance, and new molecules are needed to treat patients who have developed resistance.
In February of 2017, The Ohio State University published a study in the Journal of Clinical Oncology that identified an increasingly significant number of Chronic Lymphocytic Leukemia (CLL) patients relapsing after ibrutinib. The study found at year four roughly 20% of patients on ibrutinib clinically progressed. Of these patients who relapsed, 85% acquired the BTK-C481S mutation. Additionally, these mutations were detected, on average, over nine months before a relapse.
Given the role of BTK in B-cell malignancies including B-cell lymphomas, chronic lymphocytic leukemia, and Waldenstrom’s macroglobulinemia, initial clinical trials will enroll patients refractory to current therapeutic options. The phase 1a portion of the trial will be a dose escalation study open to all refractory patients, with the aim of establishing a recommended dose. Upon completion of the phase 1a trial, the company plans to begin the phase 1b portion of the trial that will consist of a number of expansion cohorts including patients with the C481S mutation who are refractory to other approved therapies. The goal of the phase 1b portion would be to establish proof of concept and early signs of activity.