On June 5, 2017 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that clinical data from its product candidate CB-1158, a first-in-class arginase inhibitor, will be presented in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper), in Chicago, Illinois (Press release, Calithera Biosciences, JUN 5, 2017, View Source [SID1234519364]). The data demonstrate the safety, tolerability and target engagement of CB-1158 (INCB01158) in patients with advanced solid tumors. Schedule your 30 min Free 1stOncology Demo! "Arginase-expressing tumor-infiltrating myeloid cells have been shown to play an important role in suppressing the immune system in the tumor microenvironment. In this first-in-human Phase 1 trial of the oral arginase inhibitor CB-1158, we have demonstrated CB-1158’s bioavailability and near complete inhibition of plasma arginase activity," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We look forward to completing the monotherapy dose expansion in tumor types of interest, and initiating combination cohorts with other immune-modulatory therapies."
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As of the data cut off of April 24, 2017, a total of 17 patients with advanced solid tumors had received single agent doses ranging from 50 to 150 mg twice a day (BID) in the ongoing Phase 1 trial. CB-1158 was generally well tolerated with no drug-related serious adverse events. Treatment related adverse events were limited to one case each of Grade 1 anemia, fatigue, increased ALT and myalgia. No Grade 3 treatment related adverse events were reported. Reversible, asymptomatic elevations of urinary orotic acid, a highly sensitive marker of urea cycle inhibition, were observed in two patients at 150 mg bid. Plasma levels of arginase were inhibited >90% in all patients, and in 10 of 11 patients plasma arginine increased 1.5 fold or more. The pharmacokinetics support BID dosing of CB-1158, as currently tested doses continuously maintained targeted levels of arginase inhibition. Preliminary observation of peripheral immune modulation will be further explored.
"CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients with solid tumors," by lead author Kyriakos Papadopoulos from South Texas Accelerated Research Therapeutics is in the developmental therapeutics session at 1:45 p.m. CT Monday, June 5, 2017 (Abstract #3005).
About Arginase
Arginase is an enzyme produced by immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs) and neutrophils, which prevents T-cell and natural killer (NK) cell activation in tumors. Arginase exerts its immunosuppressive effect by depleting the amino acid arginine in the tumor microenvironment, which subsequently prevents activation and proliferation of the immune system’s cytotoxic T-cells and NK-cells. Inhibition of arginase activity reverses this immunosuppressive block and restores T-cell function. In preclinical models, arginase inhibition has been shown to enhance anti-tumor immunity and inhibit tumor growth. CB-1158 (INCB01158) is being developed in a global collaboration with Incyte Corporation.