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– Safety Profile Observed to Date as Monotherapy and in Combination with Venetoclax Suggests no Overlapping Toxicity –
– Initial Results from Correlative Studies Demonstrate On-target Reductions in Mcl-1 and RNA Pol II p-S2 –
MEI Pharma, Inc. (NASDAQ:MEIP), a clinical-stage pharmaceutical company evaluating novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, today announced clinical data from the monotherapy dose escalation stage of the ongoing Phase 1 study evaluating voruciclib, a selective oral cyclin-dependent kinase 9 ("CDK9") inhibitor, alone and in combination with venetoclax (Venclexta®), a B-cell lymphoma 2 ("BCL2") inhibitor, in patients with acute myeloid leukemia ("AML") or B-cell malignancies, is highlighted in a poster session at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.
The poster can be viewed on the MEI Pharma website here: https://meipharma.com/ash2023.html.
"The potential to use an oral CDK9 inhibitor such as voruciclib to reduce Mcl-1 protein, an established resistance factor for the BCL-2 inhibitor venetoclax, is a promising approach to improve therapeutic options for patients with hematologic malignancies," said Matthew S. Davids, MD, MMSc., Director, Clinical Research, Division of Lymphoma, Dana-Farber Cancer Institute, and study chair of the monotherapy stage of the Phase 1 study. "The data reported today, along with the experience with voruciclib in combination with venetoclax to date, provides encouraging support for the approach of this combination to address a common resistance mechanism to venetoclax therapy and improve clinical response without overlapping toxicity."
"I'd like to recognize the support and high level of engagement by our investigators, and the participation of the patients enrolling in this study, as we advance the evaluation of voruciclib in combination with venetoclax in patients with AML," said David M. Urso, president and chief executive officer of MEI Pharma. "We look forward to disclosing additional data in early 2024 from the dose escalation portion of the ongoing Phase 1 clinical trial evaluating voruciclib in combination with venetoclax in patients with AML."
Clinical Data from the Monotherapy Dose Escalation Stage of the Ongoing Phase 1 Study Evaluating Voruciclib in Combination with Venetoclax
Phase 1 Study Details
The Phase 1 study is a two stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, a CDK9 inhibitor, as a monotherapy and in combination with venetoclax (marketed as Venclexta®), a BCL2 inhibitor. The first stage of the study, evaluating 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 of standard therapies, is complete. The second stage of the study is ongoing and is evaluating voruciclib in combination with venetoclax in patients with R/R AML.
A total of 40 patients, median age 75 years (range 63-80), were enrolled in the first stage of the study evaluating voruciclib as a monotherapy. The majority of patients (n=21) had AML and the remaining patients (n=19) had B-cell malignancies. Enrolled patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-9) and 5 patients had prior hematopoietic stem cell transplant.
Patients enrolled in Cohort 1 (n= 16) of the monotherapy stage of the study were administered voruciclib once daily continuously at doses of 50 mg and 100 mg. Patients enrolled in Cohort 2 (n=24) were administered voruciclib on an intermittent schedule (IS) on days 1-14 in a 28-day cycle implemented after 2 dose limiting toxicities (DLT) were observed at 100 mg daily continuously. Dose escalation in Cohort 2 was stopped at 200 mg before reaching the maximum tolerated dose (MTD) at this schedule to focus on evaluation of venetoclax in combination with voruciclib.
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.
Monotherapy Safety and Tolerability
Voruciclib at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle (Cohort 2) was well tolerated with no DLT reported. The most common adverse events (≥20% of patients) were diarrhea, nausea, anemia and fatigue. The large majority of adverse events were Grade 1-2; of note, the only Grade 3-4 adverse events in Cohort 2 were diarrhea (n=1) and anemia (n=5).
Pharmacokinetics were dose proportional and mean half-life of approximately 24 hours supports once daily dosing.
Monotherapy Efficacy
In the 21 patients enrolled with AML, 1 patient at 100 mg achieved a morphologic leukemia-free state and 9 patients had disease stabilization, which lasted at least 3 months in 2 patients. In the 19 patients enrolled with B-cell malignancies, 4 patients had stable disease with a decrease in tumor size.
Initial results from correlative studies assessing myeloid leukemia cell differentiation protein ("Mcl-1") and RNA Pol II phosphorylation on Ser2 ("RNA Pol II p-S2") demonstrated reduction in expression consistent with the anticipated on-target pharmacodynamic effect of voruciclib on Mcl-1 and RNA Pol II p-S2 (Figures A and B, respectively, below).
Voruciclib Plus Venetoclax Combination: Initial Data
Voruciclib at doses up to 200 mg on the intermittent schedule have been administered in combination with venetoclax in patients with relapsed or refractory AML. Dose escalation is continuing.
No DLTs have been reported and no evidence of overlapping toxicity has been observed to date. Anti-tumor activity has been demonstrated by objective responses and reductions in transfusions, with multiple patients continuing on therapy for ≥ 4 months.
About Voruciclib
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: Mcl-1 and the MYC proto-oncogene protein ("MYC")
Mcl-1 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.
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