SALT LAKE CITY--(BUSINESS WIRE)--Tolero Pharmaceuticals, Inc., a clinical-stage pharmaceutical company developing treatments for oncology and hematologic diseases, today announced that its lead clinical candidate, alvocidib, demonstrates high synergistic activity with the B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax (ABT-199) in nonclinical models of acute myeloid leukemia (AML) through a mechanism that involves targeting myeloid cell leukemia-1 (MCL-1) expression. The data were presented in a poster entitled "Alvocidib Potentiates the Activity of ABT-199 in Nonclinical Models of Acute Myeloid Leukemia" at the 21st European Hematology Association (EHA) Congress in Copenhagen, Denmark, June 9 through 12, 2016.
Alvocidib, a potent cyclin-dependent kinase-9 (CDK9) inhibitor, has proven to be a clinically active agent, particularly in AML. Tolero has previously demonstrated that the primary mechanism responsible for this activity is the CDK9-dependent downregulation of MCL-1. MCL-1 overexpression or a switch to MCL-1 dependency is a known mechanism of resistance to BCL-2 inhibitors. To further explore the rationale of dual targeting BCL-2 and MCL-1, alvocidib and venetoclax were co-administered in combination studies. The drug combination led to synergistic activities when measuring both cell viability and apoptosis. The combination demonstrated profound synergy in difficult to treat AML cells taken directly from patients and in animal xenograft studies.
"Developing MCL-1 dependency has become a critical mechanism of resistance to BCL-2 targeted agents in many forms of cancer," said David J. Bearss, Ph.D., Chief Executive Officer at Tolero. "Increasing the activity of BCL-2 inhibitors by adding alvocidib confirms our understanding that alvocidib is a potent inhibitor of CDK9 which controls the expression of MCL-1."
Tolero has initiated a randomized Phase 2 biomarker-driven clinical trial comparing alvocidib, cytarabine, and mitoxantrone (ACM) to cytarabine and mitoxantrone (AM) in patients with relapsed or refractory AML.
Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) in development as a combination therapy for relapsed/refractory acute myeloid leukemia (AML). CDK9 is a protein critical to the regulation of gene expression including the MCL-1 gene and other important genes involved in cancer. Given the key role CDK9 de-regulation plays in expression of cancer-associated genes related to cell division and proliferation, CDK9 is an attractive target for the treatment of various cancers.
Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with cancer and blood diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control.