The U.S. Food and Drug Administration (FDA) has approved ArQule‘s Investigational New Drug (IND) application to begin clinical testing of the BTK inhibitor ARQ 531 in patients with B-cell malignancies.
ArQule, based in Burlington, Mass., plans to initiate a Phase 1a/b dose escalation trial by the third quarter of 2017.
“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,” Brian Schwartz, MD, chief medical officer at ArQule, said in a press release. “We have been working with 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 (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and Waldenström’s macroglobulinemia, a form of non-Hodgkin lymphoma, are driven by the Bruton’s tirosine kinase (BTK) signaling pathway.
Currently, the only approved BTK inhibitor is Imbruvica (ibrutinib), a drug that binds irreversibly to the protein in the cystein amino acid in position 481 (C481). While this drug has shown promising responses in patients with high B-cell receptor signaling, some patients develop resistance. Mutations in the C481 residue that hamper Imbruvica’s irreversible binding are the predominant mechanism of resistance.
ArQule, in collaboration with OSU, is developing a new BTK inhibitor for Imbruvica-resistant patients. The new drug, ARQ 531, is an orally available reversible inhibitor that does not require any interaction with the C481 residue, offering promise for CLL, DLBCL or MCL patients with the C481S-mutant BTK who are resistant to Imbruvica.
ARQ 531 will now be assessed in a future Phase 1a/b trial to be conducted in two parts. Phase 1a will enroll patients into different dosing cohorts to establish the recommended dose of ARQ 531. Then, in Phase 1b, expansion cohorts will include patients with the C481S BTK mutation who are resistant to other therapies.
“We are looking forward to moving this drug from the bench to the bedside,” said Jennifer Woyach, MD, of OSU’s College of Medicine. “A clear need is emerging for a BTK inhibitor that addresses resistance.”