On December 21, 2017 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported that a study of voruciclib, an orally available CDK9 inhibitor, was published in the journal Nature Scientific Reports (Press release, MEI Pharma, DEC 21, 2017, View Source [SID1234522756]). Researchers found that voruciclib when combined with the BCL-2 inhibitor Venclexta (venetoclax) was capable of inhibiting two master regulators of drug resistance, MCL-1 and BCL-2, and achieved synergistic antitumor efficacy in an aggressive subset of Diffuse Large B-cell Lymphoma (DLBCL). A phase 1 study of voruciclib in relapsed/refractory B-cell malignancies is planned to begin in the first half of 2018.
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"As an orally available CDK9 inhibitor with a favorable pharmacokinetic profile and the ability to regulate MCL-1 expression, voruciclib is an ideal candidate to test in combination with a BCL-2 inhibitor such as venetoclax in patients with high risk hematological malignancies," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "The fact that overexpression of MCL-1 is a known mechanism of resistance to venetoclax suggests that the combination of MCL-1 and BCL-2 inhibitors may pave the way for a novel treatment strategy for high-risk DLBCL."
Approximately 40% of patients with DLBCL do not respond or relapse following standard chemotherapy. The evasion of apoptosis is primarily due to over expression of BCL-2, a pro-survival protein, in response to chemotherapy. The selective inhibition of BCL-2 has been achieved with the BH3 mimetic, venetoclax, resulting in high response rates in certain malignancies. However, exclusive targeting of BCL-2 with venetoclax in relapsed or refractory DLBCL has yielded only a modest 18% response rate with a one-month median progression free survival1. A primary mechanism of resistance to venetoclax is overexpression of MCL-1 which compensates for loss of BCL-2 functionality. The combined targeting of BCL-2 and MCL-1 is a potential treatment strategy for lymphomas that are refractory to standard chemotherapy.
Key findings reported in the study:
Differentiated structure of voruciclib confers greater selectively for CDK9 compared to other CDK9 inhibitors, with less off-target liability
Voruciclib significantly decreased MCL-1 expression in a dose dependent manner at concentrations achievable with doses that appeared to be generally well tolerated in Phase 1 solid tumor studies
The combination of voruciclib and venetoclax was more effective than either drug alone, with the best responses in the more aggressive subtypes of DLBCL
The published study is available online at View Source
Voruciclib (formerly P1446A) has been tested in more than 70 patients with solid tumors in multiple Phase 1 studies and has been associated with manageable side effects consistent with other drugs in its class, including nausea, vomiting and diarrhea. In pre-clinical studies, voruciclib alone induces cell death in multiple patient-derived chronic lymphocytic leukemia (CLL) samples2.