MEI Pharma Reports Update from Clinical Study Evaluating Oral CDK9 Inhibitor Voruciclib in Combination with Venetoclax in Patients with Relapsed and Refractory Acute Myeloid Leukemia
MEI Pharma, Inc. initiates enrollment in an expansion cohort for a Phase 1 study evaluating voruciclib and venetoclax in R/R AML patients. Positive anti-leukemic activity and Mcl-1 decreases observed with no dose-limiting toxicities. Promising early results show good treatment tolerance and safety.
Positive
MEI Pharma, Inc. initiates enrollment in a 12-patient expansion cohort for Phase 1 study
Evaluation of voruciclib and venetoclax in R/R AML patients
Observation of anti-leukemic activity and Mcl-1 decreases
No dose-limiting toxicities or overlapping toxicity reported
Positive safety results and good treatment tolerance
Promising early clinical activity in heavily pretreated AML patients
The expansion of the Phase 1 study by MEI Pharma concerning voruciclib in combination with venetoclax represents a noteworthy development in the treatment of acute myeloid leukemia (AML). AML is a rapidly progressing cancer of the blood and bone marrow, which often requires aggressive treatment. The standard treatment has been challenged by resistance issues, particularly in relapsed or refractory cases.
From an oncological perspective, the combination of a CDK9 inhibitor like voruciclib, which can reduce Mcl-1, a protein associated with poor prognosis, with a BCL2 inhibitor such as venetoclax, is a strategic approach. It targets two different survival mechanisms of leukemia cells. The lack of overlapping toxicity is significant because it suggests a potential for a more tolerable treatment regimen, which is critical in heavily pretreated patients who often have fewer options and a lower tolerance for adverse effects.
As an oncologist, the early signs of synergistic activity are encouraging, but it's important to remember that these are preliminary results. We must await more comprehensive data from the expansion cohort to truly understand the efficacy and safety profile of this combination therapy.
In the context of drug development, the progression to an expansion cohort in a Phase 1 study is an indicator of potential therapeutic promise. It is important to note that Phase 1 studies are primarily concerned with safety and dosing, rather than efficacy. However, the observation of anti-leukemic activity in this context is promising and warrants further investigation.
The absence of dose limiting toxicities (DLTs) thus far is a positive sign. DLTs are a critical factor in determining the maximum tolerated dose, which in turn informs dosing for subsequent phases of clinical trials. The favorable safety results to date may facilitate a smoother transition into later-stage trials, which can be a bottleneck in oncological drug development.
For stakeholders, including investors, the progression of this study is a signal of potential future value, but it is also a reminder of the inherent risks and long timelines associated with pharmaceutical research. The commercial success of the drug will depend on the outcomes of future trials, regulatory approval processes and eventual market competition.
The initiation of an expansion cohort in MEI Pharma's Phase 1 study is an event of interest to investors, as it reflects progress in the company's pipeline. The market for AML treatments is competitive and the development of a new therapy that can overcome resistance mechanisms could capture significant market share, particularly if it demonstrates a strong safety and efficacy profile.
Investors should consider the potential market implications of a successful treatment. AML has a high unmet medical need and new treatments can command premium pricing. However, the road to market approval is long and uncertain. It is essential to monitor the ongoing results of the clinical trials and the responses from regulatory bodies.
From a financial perspective, the costs associated with advancing clinical trials are substantial and the company's financial health and ability to secure additional funding or partnerships will be important in determining its ability to bring the drug to market. Investors should weigh these factors against the potential long-term returns of a successful novel AML therapy.
03/26/2024 - 08:00 AM
– Enrollment Initiated in 12-Patient Expansion Cohort Evaluating Voruciclib Plus Venetoclax in Ongoing Phase 1 Study –
– Anti-leukemic Activity Across Multiple Heavily Pretreated Patients Demonstrated Along with Anticipated Decreases in Mcl-1 –
– No Evidence of Overlapping Toxicity, and No Dose Limiting Toxicities Observed to Date in Dose Escalation Cohorts –
SAN DIEGO --(BUSINESS WIRE)--
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 reported initiation of enrollment in a 12-patient expansion cohort in the ongoing Phase 1 study evaluating voruciclib, an investigational selective oral cyclin-dependent kinase 9 (“CDK9”) inhibitor, in combination with venetoclax (Venclexta® ), a B-cell lymphoma 2 (“BCL2”) inhibitor, in relapsed and refractory (“R/R”) acute myeloid leukemia (“AML”) patients. The Safety Review Committee recommended initiating the expansion cohort after observing anti-leukemic activity in multiple heavily pretreated patients in the dose escalation cohorts, including responses, anticipated decreases in myeloid leukemia cell differentiation protein (“Mcl-1”) in available patient samples, no overlapping toxicity or dose limiting toxicities, and favorable safety results to date.
“MCL-1 overexpression has been associated with a poor prognosis and development of resistance to BCL-2 inhibition by venetoclax in patients with AML and CLL. Voruciclib is a potent, oral CDK9 inhibitor that indirectly also suppresses MCL-1. We are participating in the ongoing multicenter phase 1 study, where preliminary results are demonstrating good treatment tolerance and safety to date,” said Yesid Alvarado-Valero, M.D., Associate Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center and study chair of the combination therapy stage of the Phase 1 study. “When Voruciclib is used in combination with venetoclax, the combination appears to have no added toxicity, in addition there is evidence of synergistic, early clinical activity, with disease responses, in a group of heavily pretreated acute myeloid leukemia patients.”
“Increasingly, venetoclax is being used as a standard treatment in patients with AML, but resistance to salvage therapy after venetoclax use is common and yields limited benefit upon relapse; only about 10% of patients respond to salvage therapy after venetoclax failure, representing a significant need for patients with AML,” said Richard Ghalie, M.D., chief medical officer of MEI Pharma. “We see the voruciclib data to date demonstrating anti-leukemic activity as promising, particularly alongside the consistent reductions of Mcl-1 that provide evidence we are eliciting the anticipated biological response in patients, and we are excited to share additional updates as appropriate in the second half of 2024.”
Dr. Ghalie continued: “As we enroll the expansion cohort evaluating the potential of voruciclib in combination with venetoclax among a larger group of patients, I would like to thank and recognize the continued engagement of our investigators, and the participation of the patients enrolling in this study.”
Phase 1 Study Details
The Phase 1 study is a multiple stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, an oral CDK9 inhibitor, as a monotherapy and in combination with venetoclax, a BCL2 inhibitor. The first stage of the study evaluated the dose and schedule of voruciclib as a single-agent in patients with AML or B-cell malignances after failure of standard therapies. This stage is complete.
The second stage of the study, evaluating voruciclib in combination with standard dose venetoclax in patients with R/R AML, has completed enrollment in the dose escalation cohorts evaluating seven voruciclib dose levels from 50 mg every other day to 300 mg daily for two weeks in a four-week cycle. The study is currently enrolling a 12-patient expansion cohort evaluating voruciclib administered at 300 mg daily for two weeks in a four-week cycle in combination with venetoclax. Considering the tolerability results for the combination to date, another arm of the study will evaluate escalating doses of voruciclib administered over three weeks in a four-week cycle in combination with venetoclax to increase dose intensity and potentially optimize patient response.
A total of 29 patients with R/R AML, median age 67 years (range 34-89), enrolled in the dose escalation stage of the study evaluating voruciclib in combination with venetoclax. These patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-7), and 15 (52% ) patients had ≥3 prior lines. Almost all patients (28/29) were treated with venetoclax in an earlier line of therapy. Additionally, 21 (72% ) patients were noted as being in an adverse 2017 ELN Risk Category due to adverse cytogenetics and molecular mutations.
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.
Voruciclib Plus Venetoclax Combination: Initial Safety and Tolerability Data
Voruciclib at doses up to 300 mg administered on 14 consecutive days in a 28-day cycle in combination with standard dose venetoclax was well tolerated with no dose limiting toxicities observed. The maximum tolerated dose of voruciclib administered on this schedule with venetoclax has not been established. There were no discontinuations due to drug-related adverse events. No evidence of overlapping toxicity has been observed to date. The most common (≥5% of patients) grade 3 adverse events were myelosuppression associated with AML. Only 1 patient was observed as having a non-hematologic grade 3 drug-related adverse event (diarrhea).
Voruciclib Plus Venetoclax Combination: Initial Efficacy Data
In the 20 patients administered voruciclib at a dose of 100 mg or more, three patients achieved a response, including two patients that achieved a complete response with incomplete hematologic recovery (CRi) and one patient that achieved a morphologic leukemia-free state (MLFS), in each case having received venetoclax in an earlier line of treatment. Responses lasted 7 months in one patient, 5 months and ongoing in the second patient, and the third patient was referred to stem cell transplant. Further, an additional 14 patients had stable disease which lasted more than 90 days in 5 patients.
In the patients administered voruciclib at a dose of 100 mg or more, initial results from correlative biomarker assay studies of available samples from patients treated with the combination demonstrate the anticipated decrease of Mcl-1. Further, the available assays from the dose escalation cohorts demonstrated dose proportional decreases in Mcl-1. Reductions in Mcl-1 are consistent with the known mechanism of action of CDK9, which regulates Mcl-1.
About Voruciclib
Voruciclib is an investigational 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").
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
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David A. Walsey
investor@meipharma.com
Source: MEI Pharma, Inc.
MEI Pharma, Inc. is initiating enrollment in a 12-patient expansion cohort.
Voruciclib, a CDK9 inhibitor, and venetoclax, a BCL2 inhibitor, are being evaluated.
Anti-leukemic activity and anticipated decreases in Mcl-1 were observed.
No dose-limiting toxicities have been reported to date.
The Safety Review Committee recommended initiating the expansion cohort.
MCL-1 overexpression has been associated with poor prognosis and resistance to BCL-2 inhibition by venetoclax.
Voruciclib indirectly suppresses MCL-1 and shows good treatment tolerance and safety in combination with venetoclax.
Venetoclax is increasingly used as a standard treatment in AML patients.
The combination shows no added toxicity and evidence of synergistic early clinical activity in heavily pretreated AML patients.
