Tolero Pharmaceuticals Presents Preclinical Data Demonstrating Synergistic Activity With A Combination Of Alvocidib And Azacytidine

Poster presented at the 57^th ASH Annual Meeting and Exposition

SALT LAKE CITY--(BUSINESS WIRE)--Tolero Pharmaceuticals, Inc., a clinical-stage pharmaceutical company developing treatments for serious hematological diseases, today announced that its lead clinical candidate, alvocidib, demonstrated profound synergistic activity with 5-azacytidine in nonclinical models of hematological malignancies. These data were presented at the 57^th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida. Alvocidib, a potent cyclin-dependent kinase-9 (CDK9) inhibitor, has proven to be a clinically active agent, particularly when combined with cytarabine, an agent frequently used to treat acute myeloid leukemia (AML). To further explore additional clinical development strategies for alvocidib, the Company conducted nonclinical combination studies with the hypomethylating agent, 5-azacytidine the standard of care for the treatment of myelodysplastic syndromes (MDS). The drug combination led to synergistic activity when measuring both cell viability and apoptosis. The mechanism for the synergy relies on alvocidib’s ability to inhibit CDK9 and thereby downregulate MCL-1 expression which has emerged as a known marker of resistance to 5-azactydine.

“We are planning to further explore the medical utility behind these findings by conducting a clinical study with this drug combination in MDS patients, as part of a strategy to realize the broader therapeutic applications for alvocidib’s ability to inhibit CDK9 and suppress MCL-1.”

“The combined synergistic activity we have observed is consistent with our understanding that alvocidib is a potent inhibitor of CDK9 which controls the expression of MCL-1 and that it primes cells to more readily undergo apoptosis when combined with agents such as 5-azacytidine,” said David J. Bearss, Ph.D., Chief Executive Officer at Tolero. “We are planning to further explore the medical utility behind these findings by conducting a clinical study with this drug combination in MDS patients, as part of a strategy to realize the broader therapeutic applications for alvocidib’s ability to inhibit CDK9 and suppress MCL-1.”

Tolero is beginning to conduct a randomized Phase 2 biomarker-driven clinical trial with alvocidib, cytarabine, and mitoxantrone in patients with AML (clinicaltrials.gov - NCT02520011).

About Alvocidib

Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) in development as a combination therapy for frontline and relapsed/refractory 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.

About Tolero

Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological 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.