ASN002: A Potent Dual SYK/JAK Inhibitor Currently in a Phase I/II Study Shows Strong Antitumor Activity in Preclinical Studies

ASN002 is an orally bioavailable potent dual inhibitor of spleen tyrosine kinase (SYK) and Janus kinases (JAK) with low nM IC50 values in biochemical assays.  It is currently under clinical evaluation in a phase I/II study for safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL) and Follicular lymphoma (FCL).  SYK and JAK are tyrosine kinases that play important roles in various types of lymphomas, solid tumors, myeloproliferative and inflammation disorders. Inhibition of these targets has been shown to suppress tumor growth in various preclinical and clinical studies. ASN002 showed anti-proliferative activity in a broad panel of cell lines representing both solid and leukemia/lymphoma tumor types. ASN002 potently induced apoptosis in a DLBCL cell-line and showed a strong dose dependent tumor growth inhibition in multiple DLBCL xenograft models.  ASN002 also showed strong anti-proliferative activity in an ibrutinib-resistant cell line.  In mechanistic cell-based studies, ASN002 strongly suppressed IgE and IL-6 stimulated responses that are thought to be mediated by SYK and JAK, respectively.  ASN002 exhibited good oral bioavailability and metabolic stability in animal models.  ASN002 is being evaluated in patients with solid tumors and hematological malignancies (excluding those with extensive marrow involvement) in the dose escalation phase which employs a 3+3 open label design.  Sequential doses of 10, 20, 30, 40 and 50 mg BID are planned.   Patient accrual is continuing and no dose limiting toxicities were identified in the first cohort.  Data on safety, tolerability, pharmacokinetics and pharmacodynamics will be presented.