– 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
- Presentation Title: A Phase 1 Study of the Oral CDK9 Inhibitor
Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or
Acute Myeloid Leukemia (AML)
- Session Title: Acute Myeloid Leukemias: Investigational
Therapies, Excluding Transplantation and Cellular Immunotherapies:
Poster III (616)
- Presenter: Matthew S. Davids, MD, MMSc., Associate Professor,
Harvard Medical School, Director, Clinical Research, Division of
Lymphoma, Dana-Farber Cancer Institute
- Date: Monday, December 11, 2023, 6:00-8:00 PM (Pacific
Time)
- Publication Number: 4286
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.
About MEI Pharma
MEI Pharma, Inc. (Nasdaq: MEIP) is a clinical-stage
pharmaceutical company committed to developing novel and
differentiated cancer therapies. We build our pipeline by acquiring
promising cancer agents and creating value in programs through
development, strategic partnerships, out-licensing and
commercialization, as appropriate. Our approach to oncology drug
development is to evaluate our drug candidates in combinations with
standard-of-care therapies to overcome known resistance mechanisms
and address clear medical needs to provide improved patient
benefit. The drug candidate pipeline includes voruciclib, an oral
cyclin-dependent kinase 9 ("CDK9") inhibitor, and ME-344, an
intravenous small molecule mitochondrial inhibitor targeting the
oxidative phosphorylation pathway. For more information, please
visit www.meipharma.com. Follow us on X (formerly Twitter)
@MEI_Pharma and on LinkedIn.
Forward-Looking Statements
Certain information contained 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 our 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; the sufficiency of our cash, cash
equivalents and short-term investments to fund our operations; and
our ability to fund future capital returns. 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; uncertainty regarding the impact of rising inflation and
the increase in interest rates as a result; potential economic
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version on businesswire.com: https://www.businesswire.com/news/home/20231211089962/en/
David A. Walsey MEI Pharma Tel: 858-369-7104
investor@meipharma.com
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