SALT LAKE CITY--(BUSINESS WIRE)--Tolero Pharmaceuticals, Inc., a clinical-stage pharmaceutical company developing treatments for serious hematological diseases, today announced that data for its lead clinical candidate, alvocidib, was presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida. The data in the presentation describe the mechanistic rationale for the FLAM regimen, which combines alvocidib in a time-sequential regimen with cytarabine and mitoxantrone. This alvocidib-containing regimen has demonstrated consistent activity in front-line and relapsed/refractory acute myeloid leukemia (AML) patients. The results presented demonstrate that alvocidib, a cyclin-dependent kinase-9 (CDK9) inhibitor, blocks super enhancer-regulated transcription of MCL-1 and places AML cells in a heightened state of sensitivity to apoptosis-inducing agents such as cytarabine and mitoxantrone. The nonclinical data presented are validated by the clinical activity of the FLAM regimen in multiple AML clinical trials. These conclusions are also supported by the previously reported finding that AML cells dependent upon MCL-1 are uniquely sensitive to the alvocidib-containing regimen. These patients can be identified through an assay called NOXA priming. NOXA is a protein antagonist of MCL-1 and sensitivity of cells to NOXA is a direct functional measurement of MCL-1 dependency. AML patients that have a dependency on MCL-1 may likely be sensitive to alvocidib and respond to the FLAM regimen.
"MCL-1 expression and function has long been known to be an escape mechanism for cancer cells to evade apoptosis. Alvocidib represents a clinically advanced agent that clearly functions through a mechanism of MCL-1 downregulation and sensitizes AML cells to cell death," said David J. Bearss, Ph.D., Chief Executive Officer at Tolero. "These findings provide the foundation for our current NOXA-priming driven clinical development strategy allowing us to prospectively confirm that this assay allows us to identify patients most likely to respond to the FLAM regimen in AML."
Currently, Tolero is validating these findings in a prospective randomized Phase 2 biomarker-driven clinical trial in patients with relapsed or refractory AML (clinicaltrials.gov - NCT02520011).
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.
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.