The US Food and Drug Administration (FDA)  has cleared ArQule's Investigational New Drug (IND) application to conduct a phase 1 clinical trial with ARQ 531 in patients with B-cell malignancies who are refractory to other therapeutic options. ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton's tyrosine kinase (BTK).

ArQule plans to initiate a phase 1a/b dose escalation and signal generation trial by Q3 of 2017. The phase 1a portion will be a dose escalation study open to patients with B-cell malignancies, with the aim of establishing a recommended dose. Upon completion of the phase 1a trial, the company plans to begin a phase 1b trial in a number of expansion cohorts that will include patients with the C481S mutation who are refractory to other therapies. The goal would be to establish target engagement and early proof of concept.

"Given the emerging data on BTK resistance and the extensive preclinical work the team at The Ohio State University have done with ARQ 531, we are looking forward to moving this drug from the bench to the bedside," said Dr. Jennifer Woyach, M.D., of The Ohio State University College of Medicine. "A clear need is emerging for a BTK inhibitor that addresses resistance."

"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," said Dr. Brian Schwartz, M.D., head of research and development and chief medical officer at ArQule. "We have been working with The Ohio State University in the preclinical development of ARQ 531, and we are looking forward to extending that partnership into clinical testing."

B-cell malignancies, like chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma and mantle cell lymphoma 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 B-cell receptor 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 patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.

ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton's tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to initiate a phase 1 trial by the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.

ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases.