Tolero Pharmaceuticals Presents Nonclinical Data Demonstrating Alvocidib Provides Multiple Drug Combination Strategies Due To The Targeting Of MCL-1

Poster presented at the AACR Annual Meeting 2016

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, demonstrated profound synergistic activity with agents rendered less active due to myeloid cell leukemia 1 (MCL-1) dependence. The data were presented in a poster entitled "Targeting MCL-1 expression, through the inhibition of CDK9 and super enhancer driven transcription, offers multiple opportunities for rational drug combinations," at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans, Louisiana.

“Targeting MCL-1 expression, through the inhibition of CDK9 and super enhancer driven transcription, offers multiple opportunities for rational drug combinations”

Alvocidib, a potent cyclin-dependent kinase-9 (CDK9) inhibitor, has proven to be a clinically active agent, particularly in acute myeloid leukemia (AML). Tolero has previously demonstrated that the primary mechanism responsible for this activity is the CDK9-dependent downregulation of MCL-1. To further explore additional clinical development strategies for alvocidib, nonclinical combination studies with chemotherapy agents, hypomethylating agents, and compounds targeting other B-cell lymphoma 2 (BCL-2) family members were evaluated. The drug combinations led to synergistic activities 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 numerous therapies.

"MCL-1 dependence has become a serious resistance mechanism to both chemotherapy and targeted agents in many forms of cancer," said David J. Bearss, Ph.D., Chief Executive Officer at Tolero. “The increased activity of combining alvocidib with such agents confirms our understanding that alvocidib is a potent inhibitor of CDK9 which controls the expression of MCL-1. The results of our preclinical study supports the further research of alvocidib and other potential drug combinations."

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.

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 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.