Tolero Pharmaceuticals has inked a pact to test its CDK9 inhibitor, alvocidib, in combination with AbbVie’s BCL-2 blocker Venclexta in relapsed/refractory acute myeloid leukemia (AML). The pair will equally share development costs.
Alvocidib inhibits CDK9, which controls the expression of the survival factor MCL-1, which, along with BCL-2, is co-opted by cancer cells to avoid cell death. Tolero and AbbVie reckon that Venclexta and alvocidib might complement each other as previous studies have shown that cancer cells can resist BCL-2 inhibition by using MCL-1 to prevent cell death.
"Preclinical data suggest that the mechanisms of action for venetoclax and alvocidib may synergistically drive apoptosis in cancer cells. We hope to further investigate this hypothesis with our planned trial of this combination therapy in patients with relapsed/refractory AML,” said Tolero CEO David Bearss, Ph.D., in a statement.
Alvocidib is currently in phase 2 for the treatment of MCL-1-dependent AML, while Venclexta (venetoclax) became the first FDA-approved treatment targeting the BCL-2 protein in 2016. It is indicated for patients with chronic lymphocytic leukemia (CLL) who also have a chromosomal abnormality where they lack a section of the chromosome that curbs cancer growth.
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"This is a unique opportunity to bring together and investigate two first and only in class compounds to help patients with AML," said Neil Gallagher M.D., Ph.D, vice president and head of global oncology development at AbbVie. "There is an urgent need for new therapies, particularly in patients who either did not respond well to initial therapy or who subsequently relapsed.”
There are two FDA-approved drugs for refractory AML: Pfizer’s Mylotarg, first approved for relapsed CD33-positive AML in 2000, and Agios’ Tibsovo, approved in July this year. Tibsovo became the only approved drug for the 6% to 10% of AML patients who have an IDH1 mutation, but it was approved with a black box warning detailing risks of differentiation syndrome. But SunTrust analyst Yatin Suneja wrote at the time that the warning is “unlikely” to be a barrier to uptake as doctors know how to manage that side effect.