Tolero Pharmaceuticals Announces Mechanistic Data Describing the Activity of Alvocidib within a Time-sequential Regimen at Two Hematology Conferences

SALT LAKE CITY--()--Tolero Pharmaceuticals, Inc., a late-stage pharmaceutical company developing treatments for serious hematological diseases, today announced that data for its lead clinical candidate, alvocidib, was presented at the Society of Hematologic Oncology (SOHO) 2015 Annual Meeting and the 2015 American Society of Hematology (ASH) Meeting on Hematology Malignancies. The presentations describe the nonclinical data supporting the mechanistic rationale for combining alvocidib in a time-sequential regimen with cytarabine and mitoxantrone (FLAM) in the setting of acute myeloid leukemia (AML). The results from these studies demonstrate that alvocidib, as a CDK9 inhibitor, exerts its activity through a cell cycle-independent mechanism. Alvocidib inhibits super enhancer-regulated transcription of MCL-1 that places AML cells in a heightened state of sensitivity to apoptosis-inducing agents, such as cytarabine and mitoxantrone. These findings are supported by the validated clinical activity of the FLAM regimen in multiple Phase I and Phase II clinical trials. These data are also consistent with the finding that the MCL-1-dependent biomarker of high NOXA sensitivity predicts for response to FLAM in AML patients. NOXA is a protein antagonist of MCL-1 and sensitivity of cells to NOXA is a direct functional measurement of MCL-1 dependency.

“These findings are extremely complementary with our current biomarker-driven clinical development strategy to enhance the response to the FLAM regimen in AML by enriching for patients that are highly NOXA primed.”

“The history of alvocidib development has often focused on its activity of inhibiting cell cycle progression; however, our analysis of clinical data combined with supporting nonclinical data, clearly point to a mechanism that is dependent upon MCL-1 downregulation,” said Steven L. Warner, PhD, Vice President of Discovery and Development at Tolero. “These findings are extremely complementary with our current biomarker-driven clinical development strategy to enhance the response to the FLAM regimen in AML by enriching for patients that are highly NOXA primed.”

Tolero will be further validating these findings in a prospective randomized Phase II biomarker-driven clinical trial in patients with AML (clinicaltrials.gov - NCT02520011), expected to initiate in the second half of 2015.

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 late 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.

Contacts

Tolero Pharmaceuticals, Inc.
Joe Nilson, 801-285-6003
bizdev@toleropharma.com