Laboratory abnormalities in the Phase 1b trial were infrequent. Grade
³
3 laboratory abnormalities reported were: neutropenia 10% (4/31) and AST/ALT increase 6% (2/31). Myelosuppression was not associated with febrile neutropenia. Based on the data, we determined that no further
dose escalation was required. An expansion cohort of up to 30 patients with FL, CLL and SLL was added to further evaluate the safety and efficacy of
ME-401
as a single agent at the 60 mg dose. An additional 15
patients are enrolled in the study arm evaluating
ME-401
(60 mg) in combination with rituximab (marketed as Rituxan
®
) in patients with various B cell
malignancies, including diffuse large
B-cell
lymphoma (DLBCL).
In October 2018, we
announced a clinical collaboration with BeiGene. In connection with the BeiGene collaboration, we will amend the ongoing Phase 1b trial to evaluate the safety and efficacy of ME-401 in combination with BeiGenes zanubrutinib, an investigational
inhibitor of BTK, for the treatment of patients with B-cell malignancies. The cost of the combination study will be equally shared. Each company will supply its own compound. We retain all commercial rights to ME-401 and BeiGene retains all
commercial rights to zanubrutinib.
Phase 2 Accelerated Approval Study
In July 2018, the Company discussed with FDA a
ME-401
monotherapy accelerated approval strategy in
patients with relapsed or refractory follicular lymphoma. The FDA communicated support for the Companys proposed randomized Phase 2 trial. Accelerated approval of
ME-401
will be subject to FDA review of
the improvement provided by
ME-401
over other therapies available at the time of the regulatory action.
Informed by our communications with the FDA, we are planning to initiate by the end of calendar year 2018, a global randomized Phase 2 study
to evaluate the efficacy, safety, and tolerability of
ME-401
in patients with FL after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. The study will
evaluate two different
ME-401
single agent dosing regimens; in one arm,
ME-401
will be administered once daily continuously and in the other arm,
ME-401
will be administered once daily for two cycles (i.e., eight weeks) followed by an intermittent schedule whereby
ME-401
will be administered once daily for the first
seven days of a
28-day
cycle followed by 21 days placebo. Approximately 150 patients will be randomized in the study and the primary efficacy endpoint will be the rate of objective response to therapy.
Voruciclib: CDK Inhibitor with CDK9 Inhibition in Phase 1 Studies
Voruciclib is an orally administered CDK inhibitor differentiated by its potent in vitro inhibition of CDK9 in addition to CDK6, 4 and 1.
Voruciclib is currently being evaluated in a Phase 1b dose ranging study in patients with
B-cell
malignancies.
Voruciclib Scientific Overview: Cell Cycle Signaling
The CDK family of proteins are important cell cycle regulators. CDK9 is a transcriptional regulator of the myeloid leukemia cell
differentiation protein (MCL1), 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 MCL1, which is an established resistance
mechanism to the
B-cell
lymphoma (BCL2) inhibitor venetoclax (marketed as Venclexta).
In
pre-clinical
studies voruciclib shows dose-dependent suppression of MCL1; in December 2017 a study
of voruciclib published in the journal Nature Scientific Reports reported that the combination of voruciclib plus the
BCL-2
inhibitor venetoclax was capable of inhibiting two master regulators of cell
survival,
MCL-1
and
BCL-2,
and achieved synergistic antitumor efficacy in an aggressive subset of DLBCL
pre-clinical
models.
(Scientific Reports. (2017) 7:18007.
DOI:10.1038/s41598-017-18368-w).
CDK9 is also a transcriptional regulator of MYC, a transcription factor regulating cell proliferation and growth which contributes to many
human cancers and is frequently associated with poor prognosis and unfavorable patient survival. Targeting MYC directly has historically been difficult, but CDK9 is a transcriptional regulator of MYC and is a promising approach to target this
oncogene.
Clinical Program
In January 2018, we announced the FDA cleared the voruciclib Investigational New Drug Application (IND) for hematologic
malignancies. In August 2018 we dosed our first patient in a dose ranging Phase 1b clinical trial of voruciclib as a single agent in patients with relapsed and/or refractory
B-cell
malignancies after failure
of prior standard therapies to determine the safety, preliminary efficacy and maximum tolerated dose. We also plan to evaluate voruciclib in combination with venetoclax to assess synergies and the opportunity for combination treatments across
multiple indications.
Voruciclib was previously evaluated in more than 70 patients in multiple Phase 1 studies with a tolerability
profile consistent with other drugs in its class. In
pre-clinical
studies, voruciclib shows dose-dependent suppression of MCL1 at concentrations achievable with doses that appear to be generally well tolerated
in earlier Phase 1 studies.
Pre-clinical
studies additionally show inhibition of MYC protein expression.
ME-344:
Mitochondrial Inhibitor with Combinatorial Potential
ME-344
is our novel and tumor selective, isoflavone-derived mitochondrial inhibitor drug candidate. It
directly targets the OXPHOS complex 1, a pathway involved in ATP production in the mitochondria.
ME-344
is currently in an ongoing investigator-initiated, multi-center, randomized study in combination with the
vascular endothelial growth factor (VEGF) inhibitor bevacizumab (marketed as Avastin
®
) in a total of 40 patients with HER2
negative breast cancer.
ME-344
Scientific Overview: Cancer Metabolism
Tumor cells often display a high metabolic rate to support cell division and growth. This heightened metabolism requires a continual supply of
energy in the form of adenosine triphosphate (ATP). The two major sources of ATP are the specialized cellular organelles termed mitochondria and through the metabolism of carbohydrates, proteins and lipids.
ME-344
was identified through a screen of more than 400 new chemical structures originally created
based on the central design of naturally occurring plant isoflavones. We believe that some of these synthetic compounds, including our drug candidate
ME-344,
interact with specific mitochondrial enzyme
targets, resulting in the inhibition of ATP generation. When these compounds interact with their target, a rapid reduction in ATP occurs, which leads to a cascade of biochemical events within the cell and ultimately to cell death.
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