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B-Cell Malignancies & AML
3 Evaluation in combination with venetoclax is subject to FDA approval
Voruciclib is an orally administered cyclin-dependent kinase (CDK) inhibitor differentiated by potent inhibition of CDK9 in addition to CDK6, 4 and 1. Voruciclib is currently being evaluated in a Phase 1b dose ranging study in patients with B-cell malignancies and acute myeloid leukemia (AML).
Because CDK9 blocks the production of the myeloid leukemia cell differentiation protein (MCL1), which is an established resistance mechanism to venetoclax, a B-cell lymphoma 2 (BCL-2) protein inhibitor, we also plan to evaluate voruciclib in combination with venetoclax to assess potential synergies and to explore the opportunity for combination treatments across multiple indications.
MEI holds worldwide rights to voruciclib.
MECHANISM OF ACTION
The CDK family of proteins are important cell cycle regulators. CDK9 is a transcriptional regulator of MCL1, a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the BCL2 inhibitor venetoclax.
CDK9 is also a transcriptional regulator of MYC, a transcription factor regulating cell proliferation and growth which contributes to many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. Targeting MYC inhibition directly has been difficult, but CDK9 is a transcriptional regulator of MYC and is a promising approach to target this oncogene.
ABOUT B-CELL MALIGNANCIES
B-cell malignancies are those that start in B lymphocytes, a type of white blood cell. They include both slow growing (indolent) diseases as well as aggressive diseases and represent a collection of different blood cancers. Examples include chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.
AML is the most common type of acute leukemia. It is a fast-growing form of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells or platelets. As a result, the number of healthy blood cells (red cells, white cells and platelets) is usually lower than normal.
We are conducting a Phase 1b clinical trial of voruciclib as a monotherapy in patients with relapsed and/or refractory B-cell malignancies and AML after failure of prior standard therapies to determine safety, preliminary efficacy and the maximum tolerated dose. We also plan to evaluate voruciclib in combination with venetoclax to assess potential synergies and to explore the opportunity for combination treatments across multiple indications.
Voruciclib was previously evaluated in more than 70 patients with solid tumors in multiple Phase 1 studies with a tolerability profile generally consistent with the class of CDK 4/6 inhibitors. In pre-clinical studies, voruciclib shows dose-dependent suppression of MCL1 at concentrations achievable with doses that appear to be generally well tolerated in earlier Phase 1 studies. Pre-clinical studies additionally show inhibition of MYC protein expression.
In December 2017 a study of voruciclib published in the journal Nature Scientific Reports reported that the combination of voruciclib plus the BCL-2 inhibitor venetoclax was capable of inhibiting two master regulators of cell survival, MCL-1 and BCL-2, and achieved synergistic antitumor efficacy in an aggressive subset of Diffuse Large B-cell Lymphoma pre-clinical models. (Scientific Reports. (2017) 7:18007. DOI:10.1038/s41598-017-18368-w).