CB-839 has the potential to be an important new therapeutic agent with a novel mechanism of action for the treatment of a broad range of cancers.
Genetically mandated alterations in the fundamental metabolic pathways of tumors often cause a dramatic rise in the uptake of the nutrients glucose and glutamine. Removal of glutamine leads to a substantial reduction in cell growth or induces cell death in certain types of cancer cells, indicating that these cells are dependent on, or “addicted” to, glutamine. Normal cells do not show this pronounced dependence on glutamine. The enzyme glutaminase, which converts glutamine to glutamate, has been identified as a critical choke point in the utilization of glutamine by cancer cells. CB-839 is a potent, selective, reversible and orally bioavailable inhibitor of human glutaminase.
Inhibition of glutaminase also results in accumulation of glutamine in tumors. Glutamine, which is frequently depleted in the tumor microenvironment due to uptake by tumor cells, has been shown to be an important nutrient for T-cell growth. CB-839 could potentially have a “one-two punch” in the treatment of cancer by first starving the tumor cell and second facilitating the activation of T-cells in the nutrient-deprived tumor microenvironment.
In preclinical studies, CB-839 has been shown to halt the growth of or kill cancer cells across a range of tumor types. The compound has demonstrated antitumor activity in several different tumor models in animals. In preclinical toxicology studies, CB-839 was well tolerated in animals at doses above those shown to inhibit tumor growth. CB-839 has also shown strong synergy with immunomodulatory agents and several kinase inhibitors that target growth factor pathways.
Calithera’s clinical program seeks to identify cancers that will be most sensitive to CB-839 to allow the greatest benefit for patients and to pursue the most efficient path to regulatory approval. Based on our preclinical data, we believe several specific tumor types will be sensitive to glutaminase inhibition and benefit from treatment with CB-839.These tumor types include triple-negative breast cancer, renal cell carcinoma, non-small cell lung cancer, and acute myelogenous leukemia. Some of these tumor types may offer the potential for rapid development pathways. We are also utilizing our expertise to identify relevant biomarkers for CB-839 that may predict which patients will be sensitive to treatment with CB-839.
Calithera is currently conducting three Phase 1 dose escalation trials of CB-839 in solid and hematological tumors. The objective of these trials is to assess the safety and tolerability of CB-839. Each trial includes a dose escalation stage to identify the optimal dose for future clinical trials. This dose will be determined by the extent of glutaminase inhibition in blood and tumors, or by identifying a maximum tolerated dose. Each trial will also have an expansion stage in which additional patients with specific tumor types will be enrolled to further evaluate the safety of CB-839 as a monotherapy and in combination with other approved agents, and to seek preliminary evidence of efficacy. Initial data from our single agent trials and from our combination trial in multiple myeloma were presented in 2015. Combination data from the Phase I renal cell carcinoma and triple negative breast cancer cohorts were presented at the 2016 American Society of Clinical Oncology Annual Meeting. CB-839 is the only selective glutaminase inhibitor currently in clinical trials.
Results of Calithera’s preclinical studies of CB-839 have been presented at several scientific conferences and these data may be viewed on our Publications page. Additional details regarding our Phase 1 program can be found on www.clinicaltrials.gov.