‒ Voruciclib alone or in combination with venetoclax was generally well tolerated with no significant myelosuppression ‒
– Encouraging preliminary efficacy signal demonstrated with voruciclib alone and at the first dose level with voruciclib in combination with venetoclax –
MEI Pharma, Inc. (NASDAQ: MEIP), a clinical-stage pharmaceutical company focused on advancing new therapies for cancer, today announced an update to the Phase 1 study evaluating voruciclib, an orally administered cyclin-dependent kinase 9 (“CDK9”) inhibitor, in patients with relapsed and refractory (“R/R”) acute myeloid leukemia (“AML”) or B-cell malignancies. These results demonstrate that, as of the data cut off, voruciclib alone or in combination with venetoclax (Venclexta®), a BCL2 inhibitor, was generally well tolerated with no significant myelosuppression. The results further demonstrated encouraging clinical activity in heavily pretreated patients administered voruciclib alone and at the initial dose level in combination with venetoclax. These early results are consistent with the hypothesized ability of voruciclib to inhibit MCL-1 via CDK 9 inhibition to address a common venetoclax resistance mechanism. Dose escalation is continuing in the voruciclib and venetoclax combination arm in patients with R/R AML.
“These initial results provide encouraging support for the potential of voruciclib administered in combination with venetoclax to address a common resistance mechanism to venetoclax therapy and deliver improved clinical benefit to patients without significant myelosuppression,” said Dan Gold, Ph.D., president and chief executive officer of MEI Pharma. “We look forward to disclosing more data from this study around year-end, including data from patients receiving higher doses of voruciclib plus venetoclax, to further evaluate the potential of the combination to safely provide synergistic benefit to patients.”
Phase 1 Study Overview and Preliminary Safety and Efficacy Results
The Phase 1 study is a two stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib as a monotherapy and in combination with venetoclax, a BCL-2 inhibitor. The primary objectives of the study are to determine the safety and biologic effective dose of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary objectives of the study include assessing the preliminary efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib monotherapy or voruciclib in combination with venetoclax.
The first stage of the study evaluated the dose and schedule of voruciclib as a single-agent in patients with relapsed and refractory (“R/R”) acute myeloid leukemia (“AML”) or B-cell malignances after failure or standard therapies. Stage 2 of the study is evaluating voruciclib in combination with standard dose venetoclax in patients with R/R AML.
Part 1, the voruciclib monotherapy dose escalation/expansion stage of the study, enrolled 40 patients with R/R AML and B-cell malignancies, the first 16 dosed daily continuously at 50 and 100 mg and the following 24 dosed on an intermittent schedule (14 consecutive days on therapy in a 28-day cycle) at 100, 150 and 200 mg. All patients were heavily pretreated with a median of 3 prior therapies (range 1-7). The most common (≥5% of all patients) adverse events related to voruciclib were diarrhea (15%), nausea (10%) and fatigue (7.5%), all graded 1 or 2. On the intermittent dosing schedule selected for further development, no dose-limiting toxicities (“DLT”) were observed, there were no grade 3 or higher drug related toxicities, and dose escalation was stopped at 200 mg before reaching the maximum tolerated dose (“MTD”) because plasma concentrations reached levels considered sufficient for target inhibition. Of the 10 AML patients treated at the highest dose evaluated, 200 mg daily on the intermittent schedule, the disease control rate among these patients was 50%, with a median duration on therapy of 72 days (range 27-127).
Part 2 of the study is currently evaluating the combination of voruciclib and venetoclax in patients with R/R AML. The first cohort in the dose escalation phase enrolled 6 patients administered 50 mg of voruciclib every other day for 14 days followed by 14 days of no therapy in a 28-day cycle, plus standard dose venetoclax. All patients were heavily pretreated with a median of three prior therapies. Notably, all patients previously progressed after receiving treatment with venetoclax. No DLTs or overlapping bone marrow toxicities were observed. The disease control rate was 50%, including one patient who received 5 prior therapies including stem cell transplant and who achieved a partial response after the 1st cycle of therapy and a 2nd patient with stable disease and a reduction in transfusion requirement. The study Safety Review Committee cleared enrollment in the next dose level: 50 mg administered daily for 14 consecutive days followed by 14 days of no therapy in a 28-day cycle.
“We are gratified to see preliminary evidence of clinical activity with voruciclib in combination with venetoclax at the lowest dose level evaluated,” stated Richard Ghalie, M.D., chief medical officer of MEI Pharma. “These results are supportive of the hypothesis that voruciclib may reverse a mechanism of resistance to venetoclax.”
Voruciclib is an orally administered cyclin-dependent kinase 9 (“CDK9”) inhibitor with potential to treat both hematological malignancies and solid tumors. It is in clinical development for acute myeloid leukemia and B-cell malignancies. Applications in solid tumors are also being considered.
The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells: myeloid leukemia cell differentiation protein ("Mcl-1") and the MYC proto-oncogene protein ("MYC")
MCL1 is 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 Mcl-1, which is an established resistance mechanism to the B-cell lymphoma 2 ("BCL2") inhibitor venetoclax (marketed as Venclexta®).
MYC regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.
About Acute Myeloid Leukemia and B-cell Malignancies
Acute myeloid leukemia (“AML”) is a fast-growing hematologic cancer in which too many myeloblasts (a kind of immature white blood cell) are found in the bone marrow and blood. AML usually gets worse quickly if it is not treated. It can spread outside the blood to other parts of the body, including the lymph nodes, spleen, liver, central nervous system (brain and spinal cord), skin, gums, and testicles. AML is most common in older adults.*
B-cell malignancies are a type of hematologic cancer that forms in B cells (a kind of immune system cell). B-cell lymphomas may be either indolent (slow-growing) or aggressive (fast-growing). Most B-cell lymphomas are non-Hodgkin lymphomas. There are many different types of B-cell non-Hodgkin lymphomas, such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.**
About MEI Pharma
MEI Pharma, Inc. (Nasdaq: MEIP) is a pharmaceutical company focused on developing potential new therapies for cancer. MEI Pharma’s portfolio of drug candidates includes clinical stage candidates with differentiated mechanisms of action intended to address unmet medical needs and deliver improved benefit to patients, either as standalone treatments or in combination with other therapeutic options. For more information, please visit www.meipharma.com. Follow us on Twitter @MEI_Pharma and on LinkedIn.
Under U.S. law, a new drug cannot be marketed until it has been investigated in clinical studies and approved by the FDA as being safe and effective for the intended use. Statements included in this press release that are not historical in nature are "forward-looking statements" within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995 including, without limitation, statements regarding: the potential, safety, efficacy, and regulatory and clinical progress of zandelisib and our other product candidates, including the anticipated timing for initiation of clinical trials and release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals and timing thereof, our business strategy and plans; and the sufficiency of our cash, cash equivalents and short-term investments to fund our operations. You should be aware that our actual results could differ materially from those contained in the forward-looking statements, which are based on management's current expectations and are subject to a number of risks and uncertainties, including, but not limited to our failure to successfully commercialize our product candidates; the availability or appropriateness of utilizing the FDA’s accelerated approval pathway for our product candidates; final data from our pre-clinical studies and completed clinical trials may differ materially from reported interim data from ongoing studies and trials; costs and delays in the development and/ or FDA approval, or the failure to obtain such approval, of our product candidates; uncertainties or differences in interpretation in clinical trial results; adverse effects on the Company's business as a result of the restatement of our previously issued financial statements; uncertainty regarding the impact of rising inflation and the increase in interest rates as a result; the impact of the COVID-19 pandemic on our industry and individual companies, including on our counterparties, the supply chain, the execution of our clinical development programs, our access to financing and the allocation of government resources; our inability to maintain or enter into, and the risks resulting from our dependence upon, collaboration or contractual arrangements necessary for the development, manufacture, commercialization, marketing, sales and distribution of any products; competitive factors; our inability to protect our patents or proprietary rights and obtain necessary rights to third party patents and intellectual property to operate our business; our inability to operate our business without infringing the patents and proprietary rights of others; general economic conditions; the failure of any products to gain market acceptance; our inability to obtain any additional required financing; technological changes; government regulation; changes in industry practice; and one-time events. We do not intend to update any of these factors or to publicly announce the results of any revisions to these forward-looking statements.
* National Cancer Institute (2023, May 17). Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/aml
** National Cancer Institute (2023, May 17). Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/b-cell-lymphoma
David A. Walsey