Alvocidib; CDK9 Inhibitor
Alvocidib is a cyclin-dependent kinase (CDK) inhibitor with selective activity against CDK9 and also CDK4/6. Recent cell-based studies have shown that the cancer cell killing activity of alvocidib is independent of the cell cycle, demonstrating that CDK9 is the primary pharmacological target of alvocidib. The primary function of CDK9 is to activate transcription elongation by phosphorylating the C-terminal domain of RNA polymerase II. CDK9, as part of a protein complex called PTEFb, is recruited to DNA regulatory elements called enhancers, which play key roles in the control of cell type-specific gene expression programs. Super-enhancers (large clusters of enhancers) are associated with key genes that control cellular identity and they have become a key target for new cancer therapies. Alvocidib is the most potent known inhibitor of CDK9 and has demonstrated remarkable activity at down-regulating super-enhancer mediated transcription. The down-regulation of super-enhancer regulated genes, such as c-myc and mcl-1, is responsible for the clinical anti-cancer activity observed with alvocidib.
Alvocidib has demonstrated clinical activity in multiple types of cancer including both solid tumors and hematological malignancies. Tolero’s primary focus is the development of alvocidib in acute myeloid leukemia (AML). Alvocidib has been evaluated in multiple Phase II clinical trials in AML, involving more than 400 patients. The most significant activity has been seen when alvocidib is combined in a sequential dosing regimen that includes the standard of care agents cytarabine and mitoxantrone (ACM).
Alvocidib's most recently completed Phase II clinical trial was a randomized study comparing ACM to the standard-of-care (7+3) in frontline, high-risk AML patients. In this study, ACM demonstrated a statistically significant improvement in the complete remission (CR) rate of high-risk AML compared to the standard-of-care. Moreover, the ACM regimen is highly effective in relapsed/refractory AML patients that have progressed on prior therapies, including the standard of care, 7+3.
Tolero has initiated a randomized Phase II biomarker-driven clinical trial (TPI-ALV-201
) comparing alvocidib, cytarabine, and mitoxantrone (ACM) to cytarabine and mitoxantrone (AM) in patients with relapsed or refractory AML.