ARQ 531 - ArQule


ARQ 531 is an orally bioavailable, potent and reversible dual inhibitor of Bruton’s tyrosine kinase (BTK) inhibitor rationally designed and selected for its ability to inhibit both wild type and C481S-mutant BTK.  The C481S mutation is the predominant mechanism for the emerging resistance to irreversible inhibitors of BTK. C481S-mutant patients currently have poor prognoses with limited treatment options. We commenced a phase 1 trial in patients with refractory B-cell malignancies, including but not limited to ibrutinib, in July of 2017. Recently published data from this ongoing clinical trial at the American Society of Hematology (link here) demonstrate a good safety profile, predictable PK, profound pharmacodynamic effects and emerging signs of dose-proportional clinical activity.

Mechanism of Action

B-cell malignancies, such as chronic lymphocytic lymphoma (CLL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are often driven by BTK, a component of the B-cell receptor (BCR) pathway. Preclinical and clinical research have demonstrated that small molecule inhibitors of BTK possess anti-tumor activity. The approved BTK inhibitors, ibrutinib and acalabrutinib, are irreversible and form a covalent bond with the C481 residue of the targeted protein. Although they have demonstrated excellent responses in patients with elevated BCR signaling, clinical resistance to ibrutinib treatment has been observed. The C481S mutation is emerging as a predominant mechanism of resistance associated with irreversible BTK treatment. ARQ 531 was rationally designed to reversibly bind BTK independent of the mutational status at the C481 residue, a binding site essential for irreversible binding to BTK.

Precision Medicine

ARQ 531 may provide benefit to patients harboring the C481S mutation as it inhibits BTK independent of the mutational status at the C481 residue. The emergence of resistance to irreversible BTK inhibitors has led to a population of patients with very poor outcomes in need of new treatment options.

The need for treatments to address this resistance was addressed in a February 2017 Journal of Clinical Oncology study from researchers at The Ohio State University. This work identified a significant increase in the number of Chronic Lymphocytic Leukemia (CLL) patients relapsing after ibrutinib. At year four, roughly 20% of patients on ibrutinib clinically progressed. Of these patients who relapsed, approximately 85% had acquired the C481S mutation. Additionally, these mutations were detected, on average, about nine months before a relapse. This work highlights the emergence of a patient population requiring new treatment options beyond irreversible BTK inhibitors.

Planned Clinical Trial Indications

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 (or have enrolled) patients refractory to current therapeutic options.  The phase 1a portion of the clinical trial, initiated in July of 2017, is a dose escalation study open to all relapsed or refractory patients, with the aim of establishing a recommended dose. Upon completion of the phase 1a trial, the company plans to identify a recommended phase 2 dose and initiate mutiple expansion cohorts including patients with the C481S mutation who have progressed on an irreversible BTK inhibitor, such as ibrutinib. The goal of the phase 1b study will be to establish proof-of-concept and convincing signs of clincal activity.

Current Clinical Trials

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