MEI PHARMA, INC. This Amended Quarterly Report on Form 10-Q/A includes forward-looking statements
within the meaning of Section 27A of the Securities Act of 1933, as amended (the
"Securities Act") and Section 21E of the Securities Exchange Act of 1934, as
amended (the "Exchange Act"). All statements other than statements of historical
facts contained in this Amended Quarterly Report, including statements regarding
the future financial position, business strategy and plans and objectives of
management for future operations, are forward-looking statements. The words
"believe," "may," "will," "estimate," "continue," "anticipate," "intend,"
"should," "plan," "expect," and similar expressions, as they relate to us, are
intended to identify forward-looking statements. We have based these
forward-looking statements largely on current expectations and projections about
future events and financial trends that we believe may affect our financial
condition, results of operations, business strategy and financial needs. These
forward-looking statements are subject to a number of risks, uncertainties and
assumptions, including, without limitation, those described in "Risk Factors" in
our 2021 Amended Annual Report on Form 10-K/A, as filed with the
•
We will need substantial additional funds to progress the clinical trial
programs for our drug candidates, to commercialize our drug candidates, and to
develop new compounds. The actual amount of funds we will need will be
determined by a number of factors, some of which are beyond our control;
•
We are a late stage clinical research and development stage company and are
likely to incur operating losses for the foreseeable future;
•
The results of pre-clinical studies and completed clinical trials are not
necessarily predictive of future results, and our current drug candidates may
not have favorable results in later studies or trials;
•
The outbreak of the novel coronavirus disease, COVID-19, or other pandemic,
epidemic or outbreak of an infectious disease may materially and adversely
impact our business, including our preclinical studies and clinical trials;
•
Changes in drug candidate manufacturing or formulation may result in additional
costs or delay;
•
If KKC or other parties with whom we collaborate on the development and
commercialization of our drug candidates do not satisfy their obligations, do
not otherwise pursue development or commercialization of our drug candidates or
if they terminate their agreements with us, we may not be able to develop or
commercialize our drug candidates;
•
We are subject to significant obligations to Presage in connection with our
license of voruciclib, and we may become subject to significant obligations in
connection with future licenses we obtain, which could adversely affect the
overall profitability of any products we may seek to commercialize, and such
licenses of drug candidates, the development and commercialization for which we
are solely responsible, may never become profitable;
•
Our business strategy may include entry into additional collaborative or license
agreements. We may not be able to enter into collaborative or license agreements
or may not be able to negotiate commercially acceptable terms for these
agreements;
•
Final approval by regulatory authorities of our drug candidates for commercial
use may be delayed, limited or prevented, any of which would adversely affect
our ability to generate operating revenues;
•
The FDA may determine that our drug candidates have undesirable side effects
that could delay or prevent their regulatory approval or commercialization;
•
If we experience delays or difficulties in the enrolment of patients in clinical
trials, our completion of clinical trials and receipt of necessary regulatory
approvals could be delayed or prevented;
•
Changes in funding for the FDA and other government agencies or future
government shutdowns could cause delays in the submission and regulatory review
of marketing applications, which could negatively impact our business or
prospects;
•
Failure to obtain regulatory approval in foreign jurisdictions would prevent us
from marketing our products internationally;
•
Any designation granted by the FDA for any of our product candidates may not
lead to a faster development or regulatory review or approval process, and does
not increase the likelihood that our product candidates will receive marketing
approval. We may also not be able to obtain or maintain any such designation;
•
Any orphan drug designations we receive may not confer marketing exclusivity or
other benefits;
•
Even if we or our licensees receive regulatory approval to commercialize our
drug candidates, our ability to generate revenues from any resulting products
will be subject to a variety of risks, many of which are out of our control;
•
If any products we develop become subject to unfavorable pricing regulations,
third-party reimbursement practices or healthcare reform initiatives, our
ability to successfully commercialize our products will be impaired;
•
Our drug candidates are subject to ongoing government regulation both before and
after regulatory approval;
•
We may not be able to establish the contractual arrangements necessary to
develop, market and distribute our drug candidates;
•
Our commercial opportunity will be reduced or eliminated if competitors develop
and market products that are more effective, have fewer side effects or are less
expensive than our drug candidates;
•
Our product candidates may face competition sooner than anticipated;
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•
We rely on third parties to conduct our clinical trials and pre-clinical studies. If those parties do not successfully carry out their contractual duties or meet expected deadlines, our drug candidates may not advance in a timely manner or at all; • We will depend on third party suppliers and contract manufacturers for the manufacturing of our drug candidates and have no direct control over the cost of manufacturing our drug candidates. Increases in the cost of manufacturing our drug candidates would increase our costs of conducting clinical trials and could adversely affect our future profitability; • We rely on acquisitions or licenses from third parties to expand our pipeline of drug candidates; • Our commercial success is dependent, in part, on obtaining and maintaining patent protection and preserving trade secrets, which cannot be guaranteed; • Claims by other companies that we infringe on their proprietary technology may result in liability for damages or stop our development and commercialization efforts; • We may be subject to claims by third parties asserting that our employees or we have misappropriated their intellectual property, or claiming ownership of what we regard as our own intellectual property; • We may be subject to substantial costs stemming from our defense against third-party intellectual property infringement claims; • We face a risk of product liability claims and claims may exceed our insurance limits; • Our employees, independent contractors, consultants, commercial partners, principal investigators, or CROs may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could have a material adverse effect on our business; • Our business and operations would suffer in the event of system failures; • Our efforts will be seriously jeopardized if we are unable to retain and attract key employees; • NegativeU.S. and global economic conditions may pose challenges to our business strategy, which relies on funding from the financial markets or collaborators; • Laws, rules and regulations relating to public companies may be costly and impact our ability to attract and retain directors and executive officers; • We have identified a material weakness in our internal control over financial reporting and determined that our disclosure controls and procedures were ineffective as ofJune 30, 2021 , as a result of the restatement of our financial statements as of and for the years endedJune 30, 2021 and 2020. Relevant unaudited interim financial information for each of the quarterly periods endedSeptember 30, 2020 throughDecember 31, 2021 have also been restated. In the future, we may identify additional material weaknesses or otherwise fail to maintain an effective system of internal control over financial reporting or adequate disclosure controls and procedures, which may result in material errors of our financial statements or cause us to fail to meet our periodic reporting obligations. • Security breaches and other disruptions could compromise our information and expose us to liability, which would cause our business and reputation to suffer; • If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could harm our business; • We or the third parties upon whom we depend may be adversely affected by natural disasters and our business continuity and disaster recovery plans may not adequately protect us from a serious disaster; • Limitations on the deductibility of net operating losses could adversely affect our business and financial condition; • The trading price of the shares of our common stock has been and may continue to be highly volatile and could decline in value and we may incur significant costs from class action litigation; • Future sales of our common stock, including common stock issued upon exercise of outstanding warrants or options, may depress the market price of our common stock and cause stockholders to experience dilution; • Because we do not intend to pay, and have not paid, any cash dividends on our shares of common stock, our stockholders will not be able to receive a return on their shares unless the value of our common stock appreciates and they sell their shares; • We will have broad discretion over the use of the net proceeds from any exercise of outstanding warrants and options; • We are authorized to issue blank check preferred stock, which could adversely affect the holders of our common stock; • Anti-takeover provisions contained in our amended and restated certificate of incorporation and third amended and restated bylaws, as well as provisions ofDelaware law, could impair a takeover attempt; • Our third amended and restated bylaws require, to the fullest extent permitted by law, that derivative actions brought in our name, actions against our directors, officers, other employees or stockholders for breach of fiduciary duty and other similar actions may be brought only in theCourt of Chancery in theState of Delaware and, if brought outside ofDelaware , the stockholder bringing the suit will be deemed to have consented to service of process on such stockholder's counsel, which may have the effect of discouraging lawsuits against our directors, officers, other employees or stockholders; and • Our executive officers and directors may sell shares of their stock, and these sales could adversely affect our stock price. 23
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These risks are not exhaustive. Other sections of this report and our other
filings with the
You should not rely upon forward-looking statements as predictions of future
events. We cannot assure you that the events and circumstances reflected in the
forward-looking statements will be achieved or occur. Although we believe that
the expectations reflected in the forward-looking statements are reasonable, we
cannot guarantee future results, levels of activity, performance or
achievements. Past performance may not be an indicator of future results. The
following discussion is qualified in its entirety by, and should be read in
conjunction with, the more detailed information set forth in the financial
statements and the notes thereto appearing elsewhere in this Amended Quarterly
Report on Form 10-Q/A and the audited financial statements and notes thereto
included in our 2021 Amended Annual Report on Form 10-K/A, as filed with the
The following information has been adjusted to reflect the restatement of our financial statements as described in the "Explanatory Note" at the beginning of this Amended Quarterly Report and in Note 1, "Restatement of Previously Issued Financial Statements," in the Notes to Condensed Financial Statements of this Amended Quarterly Report.
Overview and Recent Developments
We are a late-stage pharmaceutical company committed to the development and
commercialization of novel cancer therapies intended to improve outcomes for
patients. Our portfolio of drug candidates has three clinical-stage assets,
including zandelisib, currently in multiple ongoing clinical studies intended to
support marketing applications with the
Our approach to building our pipeline is to license or acquire promising cancer agents and build value in programs through development, commercialization and strategic partnerships, as appropriate.
As a result of the ongoing and rapidly evolving COVID-19 pandemic, various
public health orders and guidance measures have been implemented across much of
While we continue to enroll and dose patients in our clinical trials, certain of
our clinical trials evaluating zandelisib and voruciclib have been delayed due
to COVID-19, and our clinical development program timelines may continue to be
subject to potential negative impacts from the ongoing pandemic in the
Clinical Development Programs
We build our pipeline by licensing or acquiring promising cancer agents and creating value in programs through development, commercialization and strategic partnerships, as appropriate. Our objective is to leverage the mechanisms and properties of our pipeline drug candidates to optimize the balance between efficacy and tolerability to meet the needs of patients with cancer. Our drug candidate pipeline includes:
•
Zandelisib (f/k/a ME-401), an oral phosphatidylinositol 3-kinase ("PI3K") delta
inhibitor;
•
Voruciclib, an oral cyclin-dependent kinase 9 ("CDK9") inhibitor; and
•
ME-344, a mitochondrial inhibitor targeting the oxidative phosphorylation
("OXPHOS") complex.
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After a thorough review of the Phase 3 AML and Phase 2 MDS data, we and
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1.
Phase 2 study intended to support accelerated approval marketing applications
with the FDA.
2.
Study arm initiated under clinical collaboration with BeiGene, Ltd.
3.
Investigator-initiated trial.
4.
Initiation of clinical studies is subject to opening of a new Investigational
New Drug Application ("IND") with the FDA.
Zandelisib (f/k/a ME-401): PI3K? Inhibitor in Multiple Trials Intended to Support Marketing Approvals in Relapsed or Refractory Follicular and Marginal Zone Lymphomas
Zandelisib is an oral, once-daily, selective PI3K? inhibitor in clinical
development for the treatment of B-cell malignancies. In
We are conducting multiple ongoing studies evaluating zandelisib. Our studies include TIDAL, a Phase 2 study evaluating zandelisib as a monotherapy in patients with r/r FL and marginal zone lymphoma ("MZL") patients who have received at least two prior lines of treatment. Enrollment in the FL cohort of the study is complete. Enrollment of the MZL cohort remains ongoing. Subject to the results, data from TIDAL are intended to support submissions for accelerated approval marketing applications with the FDA in r/r FL and MZL patients receiving at least two prior lines of treatment.
Also ongoing is COASTAL, a Phase 3 study evaluating zandelisib in combination
with rituximab in patients with r/r FL and MZL who have received at least one
prior line of treatment. COASTAL is intended to support full marketing
applications in the
We are also conducting a multi-arm, open-label, Phase 1b dose finding and
expansion trial evaluating zandelisib as a monotherapy and in combination with
other therapies in patients with relapsed or refractory B-cell malignancies.
Other initiated studies include Phase 1 and Phase 2 studies being conducted by
KKC evaluating zandelisib as a monotherapy in patients in
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Zandelisib:
While PI3K? inhibitors as a group are a clinically validated class for the treatment of B-cell malignancies, the FDA approved orally administered products, idelalisib (marketed as Zydelig®), duvelisib (marketed as COPIKTRA®), umbralisib (marketed as UKONIQ™), and the intravenously administered PI3K?/? inhibitor copanlisib (marketed as Aliqopa®), are challenged by dose-limiting toxicities, modest efficacy and/or inconvenience of administration route. We believe this provides an opportunity for the development of a next-generation candidate with pharmaceutical properties that may better maximize the therapeutic potential of PI3K? inhibition by limiting toxicities and improving upon modest efficacy, which together hinder clinical utility.
The molecular structure and pharmacodynamic characteristics of zandelisib are distinct from the FDA approved PI3K? inhibitors. Zandelisib's distinct characteristics include prolonged target binding, preferential cellular accumulation, high volume of distribution throughout the body tissues, and an approximately 28-hour half-life suitable for once daily oral administration. The properties of zandelisib support an innovative dosing regimen, known as Intermittent Dosing Therapy, or "IDT." The IDT consists of daily dosing only in the first seven days of each 28-day dosing cycle. The unique zandelisib IDT is hypothesized to allow for the recovery of regulatory T cells, which in turn may lead to fewer and/or less severe immune-related adverse events. This may provide long-term disease control through maintenance therapy, without the need for dose reductions or premature discontinuations. Clinical evaluation of the IDT to date has demonstrated the potential to maintain clinical benefit while minimizing immune-related toxicities common to other PI3K? agents, either as a monotherapy or in combination with other therapies.
KKC License, Development and Commercialization Agreement
In
KKC will be responsible for the development and commercialization of zandelisib
in the Ex-
Under the terms of the KKC Commercialization Agreement, KKC paid us an initial
payment of
Zandelisib Scientific Overview: at the Crossroads of B-cell Signaling Pathways
The PI3K/AKT/mTOR pathway is an important signaling pathway for many cellular functions such as cell survival, cell cycle progression and cellular growth. PI3Ks are a family of enzymes within this pathway that have been shown to play a critical role in the proliferation and survival of certain cancer cells.
There are several isoforms of PI3K that are expressed in different types of cells. The PI3K? isoform is at the crossroads of B-cell receptor signaling pathways that are major drivers of survival and proliferation of many B-cell malignancies. Because the ? isoform is often overexpressed in cancer cells of the B-lymphocyte lineage, such as B-cell leukemias and lymphomas, it is understood to be important for survival of these cells. Zandelisib displays high selectivity for the PI3K delta isoform and functions to inhibit its activity.
Clinical Program Overview
We are conducting multiple ongoing studies evaluating zandelisib including TIDAL, a global Phase 2 trial evaluating patients with r/r FL and MZL with at least two prior of lines of therapy that is intended to support FDA marketing applications for accelerated approval. Also ongoing is COASTAL, a global Phase 3 study evaluating patients with r/r FL and MZL with at least one prior line of therapy that is intended to support full marketing authorization with the FDA as well as regulatory authorities globally.
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Additionally, we are conducting a multi-arm, open-label, Phase 1b dose
escalation and expansion trial as a monotherapy and in combination with
rituximab or zanubrutinib in patients with FL and other B-cell malignancies. The
Phase 1b trial continues enrollment in the study arm exploring zandelisib in
combination with zanubrutinib (marketed as BRUKINSA®), an inhibitor of Bruton's
tyrosine kinase developed by BeiGene, Ltd. ("BeiGene"). This study arm completed
the safety evaluation stage in patients with B-cell malignancies and has
expanded into disease specific B-cell malignancy cohorts. The evaluation of
zandelisib in combination with zanubrutinib is conducted under a collaboration
established with BeiGene in
Ongoing clinical trials also include Phase 1 and Phase 2 studies conducted by
KKC evaluating zandelisib as a monotherapy in patients in
In addition to other planned clinical studies sponsored by us, such as
initiation of a Phase 2 study evaluating zandelisib plus venetoclax in patients
with chronic lymphocytic leukemia ("CLL"), we also plan to support select
investigator-initiated studies, including one being conducted at the
All ongoing studies, as well as planned studies, utilize zandelisib's unique Intermittent Dosing Therapy, or "IDT," intended to optimize zandelisib's therapeutic profile and also support its potential as a backbone for combination approaches with other modalities in the treatment of B-cell malignances.
Phase 1b Multi-arm Trial
In
Data were reported from 37 patients with r/r FL administered zandelisib 60 mg once daily for two 28-day cycles and then on an intermittent schedule ("IS") of once daily dosing for the first seven days of each subsequent 28-day cycle. The objective of this data presentation was to evaluate the safety, tolerability and efficacy of zandelisib as monotherapy or in combination with rituximab in patients with FL who had disease progression within 24 months after initial chemoimmunotherapy ("POD24") or disease progression beyond 24 months ("non-POD24").
The overall response rate in the 37 patients with r/r FL was 87%, with 27% achieving a complete response. The overall response rate was 78% in 18 patients administered zandelisib as a monotherapy and 95% in 19 patients administered zandelisib in combination with rituximab. The overall response rate in nine evaluable patients with CLL, previously reported separately, was 89%.
Overall Response Rates ("ORR")
POD24 Non-POD24 Total FL
n = 22 n = 15 n = 37
Overall response rate (ORR) 18 (82%) 14 (93%) 32 (87%)
Regimen
Monotherapy 8/11 (73%) 6/7 (86%) 14/18 (78%)
Combination with rituximab 10/11 (91%) 8/8 (100%) 18/19 (95%)
Prior lines of therapy
1 prior 5/7 (71%) 9/9 (100%) 14/16 (88%)
? 2 prior 13/15 (87%) 5/6 (83%) 18/21 (86%)
CR rate, n (%) 4 (18%) 6 (40%) 10 (27%)
Median duration of response in the 37 patients with FL, as reported in a poster
presentation at the 16th
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Duration of Response: Follicular Lymphoma Patients
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Zandelisib was generally well-tolerated. The rate of drug related grade 3 Adverse Events of Special Interest ("AESI") in the 37 patients with r/r FL was: diarrhea 5% (2/37); colitis 5% (2/37); rash 8% (3/37); alanine aminotransferase ("ALT")/ aspartate aminotransferase ("AST") elevation 8% (3/37); The discontinuation rate due to adverse events was 8% (3/37).
Data from the arm of the Phase 1b study evaluating 20 patients receiving
zandelisib in combination with zanubrutinib was also reported in a poster
session at the ASCO 2021 Annual Meeting. In this arm of the study two treatment
dosing regimens were explored:
The overall response rate in all evaluable patients with r/r indolent B-cell
malignancies and CLL was 100%. No response was noted in the two patients with
DLBCL/HGBCL. Responses were durable with median follow up for all patients was
6.6 months (0.6 to 21.3 months) with the majority of responders still on
treatment.
Overall Response Rate
Evaluable FL CLL/SLL MZL MCL DLBCL/HGBCL
n = 18 (n = 8) (n = 5) (n = 2) (n = 1) (n = 2)
ORR*, n (%) 8 (100%) 5 (100%) 2 (100%) 1 (100%) 0 (0%)
Group A 1 (100%) 3 (100%) 1 (100%) 1 (100%) 0 (0%)
Group B 7 (100%) 2 (100%) 1 (100%) 0 (0%) 0 (0%)
*CR/CRi in two of eight patients with FL (25%) and in two of five patients with CLL (40%).
Imaging scans were taken at months 3, 7, 13, and then every six months until
disease progression. Response reported based on Lugano criteria and
Group B, which received zandelisib 60 mg orally, daily on days 1-7 of each 28-day cycle starting Cycle 1 and zanubrutinib 80 mg, orally, twice daily, was well tolerated across the various B-cell malignancies in the completed part of the study. The combination administered on the optimized, Group B, dosing regimen did not result in additive toxicity to each agent alone. One of the two patients with Grade 3 AST/ALT increases in Group B was successfully retreated and continued therapy.
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Treatment-Emergent Adverse Events of Special Interest
Group A Group B
Grade 3-4 AESI, n (%) (n = 7) (n = 13)
ALT / ALT increased 2 (29%) 2 (15%)
Rash 1 (14%) 0 (0%)
CMV colitis 1 (14%) 0 (0%)
Pneumonia *1 (14%) 0 (0%)
Diarrhea 0 (0%) 0 (0%)
Atrial fibrillation 0 (0%) 0 (0%)
* 1 DLBCL patient had several Grade 3 AEs on Day 1 attributed to prior therapy and discontinued treatment on Day 17.
The Phase 1b study is continuing to enroll expansion cohorts in r/r FL and r/r MCL to further evaluate the combination of zandelisib 60 mg administered on days 1-7 starting Cycle 1 and zanubrutinib administered at 80 mg twice daily.
TIDAL: A Phase 2 Trial Intended to Support Accelerated Approval of Marketing Applications
TIDAL is a global Phase 2 trial evaluating zandelisib as a monotherapy across
two study cohorts: the first study cohort for the treatment of adults with r/r
FL and the second study cohort for r/r MZL, in both cases after failure of at
least two prior systemic therapies including chemotherapy and an anti-CD20
antibody. Subject to the results and discussions with the FDA, data from each
study cohort are intended to be submitted to the FDA to support marketing
applications for accelerated approval. The study is evaluating zandelisib
administered once daily at 60 mg for two 28-day cycles and then on an
intermittent schedule of once daily dosing for the first seven days of each
subsequent 28-day cycle (i.e.,
COASTAL: A Phase 3 Trial Intended to Support Full FDA and Global Marketing Authorizations
COASTAL is a global, randomized, two-arm Phase 3 trial comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab, in patients with r/r FL or MZL who received at least one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL is expected to enroll 534 patients. Zandelisib will be administered once daily for two 28-day cycles followed by an intermittent schedule of once daily dosing for seven days of each subsequent 28-day cycle for a total of 24 months, in combination with rituximab (R) in the first six months only. The control arm will consist of six cycles of the standard chemoimmunotherapy regimens R-CHOP or R-bendamustine. The primary efficacy endpoint is progression-free survival; secondary endpoints include overall response rate, overall survival, patient reported outcomes assessments, and safety and tolerability.
COASTAL is intended to support full marketing applications in the
Impact of COVID-19 on the TIDAL and COASTAL Studies
The extent to which the COVID-19 pandemic will impact the progress of the
zandelisib development program, including the enrollment and completion of the
COASTAL and TIDAL studies, is subject to future developments, which are highly
uncertain and cannot be predicted with confidence. Currently, we believe that
the integrity of the program and individual studies remains intact; however, the
pandemic did have a negative impact on the rate of enrollment in the TIDAL
study. Enrollment in the FL cohort of the TIDAL study was completed in
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Voruciclib: Potent Orally Administered CDK9 Inhibitor in Phase 1 Studies
Voruciclib is a potent orally administered CDK9 inhibitor. Voruciclib is being evaluated in a Phase 1b trial evaluating dose and schedule in patients with acute myeloid leukemia ("AML") and B-cell malignancies. Voruciclib is also being evaluated in pre-clinical studies to explore the potential synergistic activity in various solid tumor cancers of voruciclib in combination with drug-candidates that targets in the RAS signaling pathway, including KRAS.
Voruciclib Scientific Overview: Cell Cycle Signaling
CDK9 has important functions in cell cycle regulation, including the modulation of two therapeutic targets in cancer:
•
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®). • CDK9 is a transcriptional regulator of the MYC proto-oncogene protein ("MYC") which 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.
Voruciclib: Inhibition of MCL1
In pre-clinical studies voruciclib shows dose-dependent suppression of MCL1; in
Additionally, a peer reviewed manuscript published in 2020 by Luedtke et al, concluded that the inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia.
The research presented suggests that voruciclib could be an attractive therapeutic target for treating cancers in combination with venetoclax or other BCL-2 inhibitors.
Voruciclib: Inhibition of MYC
Many cancers are associated with overexpression of MYC, a transcription factor
regulating cell proliferation and growth. CDK9 is a known regulator of MYC
transcription and a modulator of MYC protein phosphorylation. Data reported at
the
•
Results in a rapid decrease in the phosphorylation of proteins that promote MYC transcription; • Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in stabilizing MYC in KRAS mutant cancers; • Possesses single agent activity against multiple KRAS mutant cancer cell lines both in vitro and in vivo; • Synergistically inhibits KRAS G12C mutant cancer cell lines in combination with KRAS G12C inhibitors, both in vitro and in vivo.
The research presented suggests that voruciclib could be an attractive therapeutic agent for cancers, including solid tumors, dependent on the activity of MYC.
Clinical Program
We are evaluating patients with hematological malignancies in a Phase 1b clinical trial evaluating the dose and schedule of voruciclib. The trial is initially intended to evaluate the dose and schedule of voruciclib as a monotherapy in patients with relapsed and refractory B-cell malignancies and AML after failure of prior standard therapies to determine the safety, preliminary efficacy and maximum tolerated dose. Once dose levels and schedules have been explored and established, we plan in parallel, subject to FDA agreement, to evaluate the dose and schedule of voruciclib in combination with a BCL2 inhibitor such as venetoclax to assess synergies and the opportunity for combination treatments, initially in patients with AML and subsequently across multiple indications.
Preliminary data to date from the Phase 1b study evaluating voruciclib as a monotherapy at the doses studied demonstrates that voruciclib has not been associated with drug related gastrointestinal toxicity or neutropenia. Also, favorable pharmacokinetics have been observed, including a half-life supporting once-a-day oral dosing and dose proportional C-max. Our projections suggest that doses of 150-200 mg may be sufficient to achieve plasma concentrations sufficient to inhibit the molecular target. Early signs of biological activity have also been observed in patients with AML.
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Voruciclib was also previously evaluated in more than 70 patients with solid tumors in multiple Phase 1 studies. The totality of the clinical data, along with data from pre-clinical studies, suggests voruciclib's ability to inhibit its molecular target at a projected dose as low as 150 mg daily. In one clinical study, voruciclib was evaluated in combination with vemurafenib (marketed as Zelboraf®) in nine patients with BRAF mutated advanced/inoperable malignant melanoma. Three of three BRAF/MEK naive patients achieved a response: two partial responses and one complete response. In this study voruciclib was dosed at 150 mg daily plus vemurafenib 720 mg or 960 mg twice daily in 28-day cycles. The most common adverse events were fatigue, constipation, diarrhea, arthralgia and headache. One instance of grade 3 fatigue was dose limiting and no serious adverse events related to voruciclib were reported. Other clinical studies evaluated voruciclib at doses up to 850 mg in patients with solid tumors, demonstrating additional evidence of potential biologic activity and an adverse event profile generally consistent with other drugs in its class.
We are exploring opportunities to clinically evaluate voruciclib in solid tumors where MYC may play an important role in tumor growth.
Impact of COVID-19 on the Voruciclib Clinical Development Program
While the extent to which the COVID-19 pandemic will impact the progress of the voruciclib clinical development program, including the ongoing Phase 1b study, is subject to future developments, which are highly uncertain and cannot be predicted with confidence, the study remains ongoing and is continuing to enroll patients; however, the rate of enrollment of patients has been negatively impacted by the pandemic. We will continue efforts to be proactive in managing the impact from the pandemic, including various actions to communicate with sites and investigators, and making accommodations to patients consistent with FDA guidance as we may deem appropriate.
ME-344: Clinical Stage 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 adenosine triphosphate ("ATP") production in the mitochondria. ME-344 was studied in an investigator-initiated, multi-center, randomized clinical trial in combination with the vascular endothelial growth factor ("VEGF") inhibitor bevacizumab (marketed as Avastin®) in a total of 42 patients with human epidermal growth factor receptor 2 ("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 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.
Clinical Program
ME-344 demonstrated evidence of single agent activity against refractory solid tumors in a Phase 1 trial, and in pre-clinical studies tumor cells treated with ME-344 resulted in a rapid loss of ATP and cancer cell death. In addition to single agent activity, ME-344 may also have significant potential in combination with anti-angiogenic therapeutics. In pre-clinical studies, it was shown that one outcome of anti-angiogenics was to reduce the rate of glycolysis in tumors as a mechanism to slow tumor growth. However, tumor metabolism was able to shift to mitochondrial metabolism for energy production to support continued tumor proliferation. In such cases of tumor plasticity in the presence of treatment with anti-angiogenics, targeting the alternative metabolic source with ME-344 may open an important therapeutic opportunity.
Support for this combinatorial use of ME-344 was first published in the
Results published in the
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The primary objective of the trial was to show proof of ME-344 biologic activity as measured by Ki67 reductions in the presence of the nuclear protein Ki67 (expression of which is strongly associated with tumor cell proliferation and growth) from days 0 to 28 compared to the control group who received bevacizumab alone. Secondary objectives included determining whether ME-344 biologic activity correlates with vascular normalization. The data demonstrate significant biologic activity in the ME-344 treatment group:
•
In ME-344 treated patients, mean absolute Ki67 decreases were 13.3 compared to an increase of 1.1 in the bevacizumab monotherapy group (P=0.01). • In ME-344 treated patients, mean relative Ki67 decreases were 23% compared to an increase of 186% in the bevacizumab monotherapy group (P < 0.01). • The mean relative Ki67 reduction in patients experiencing vascular normalization in the ME-344 treated patients was 33%, compared to an increase of 11.8% in normalized patients from the bevacizumab monotherapy group (P=0.09). Approximately one-third of patients in each arm had vascular normalization.
Treatment was generally well tolerated; three grade 3 adverse events of high blood pressure were reported, two in the ME-344 arm and one in the bevacizumab monotherapy arm.
Results from our earlier, first-in-human, single-agent Phase 1 clinical trial of
ME-344 in patients with refractory solid tumors were published in the
Results of Operations
The following information has been adjusted to reflect the restatement of our financial statements as described in the "Explanatory Note" at the beginning of this Amended Quarterly Report and in Note 1, "Restatement of Previously Issued Financial Statements," in the Notes to Condensed Financial Statements of this Amended Quarterly Report.
Comparison of three months ended
We had a loss from operations of
Revenue: We recognized revenue of
Research and Development: The following is a summary of our research and development expenses to supplement the more detailed discussion below. The dollar values in the following table are in thousands.
Three Months Ended
September 30,
Research and development expenses 2021 2020
Zandelisib $ 12,392 $ 7,996
Voruciclib 1,041 784
ME-344 640 65
Other 5,880 4,151
Total research and development expenses
Research and development expenses consist primarily of clinical trial costs
(including payments to contract research organizations "CROs"), pre-clinical
study costs, and costs to manufacture our drug candidates for non-clinical and
clinical studies. Other research and development expenses consist primarily of
salaries and personnel costs, share-based compensation, legal costs, and other
costs not allocated to specific drug programs. Research and development expenses
were
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the three months ended
General and Administrative: General and administrative expenses increased by
Other income or expense: We recorded a non-cash gain of
Liquidity and Capital Resources
We have accumulated losses of
To date, we have obtained cash and funded our operations primarily through equity financings and license agreements. In order to continue the development of our drug candidates, at some point in the future we expect to pursue one or more capital transactions, whether through the sale of equity securities, debt financing, license agreements or entry into strategic partnerships. There can be no assurance that we will be able to continue to raise additional capital in the future.
Sources and Uses of Our Cash
Net cash used in operating activities for the three months ended
Net cash provided by investing activities for the three months ended
Net cash used in financing activities during the three months ended
Contractual Obligations
We have contracted with various consultants and third parties to assist us in pre-clinical research and development and clinical trials work for our leading drug compounds. The contracts are terminable at any time, but obligate us to reimburse the providers for any time or costs incurred through the date of termination. Additionally, we have employment agreements with certain of our current employees that provide for severance payments and accelerated vesting for share-based awards if their employment is terminated under specified circumstances.
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We have leased approximately 32,800 square feet of office space in
Presage License Agreement
In
COVID-19
As a result of the ongoing and rapidly evolving COVID-19 pandemic, various
public health orders and guidance measures have been implemented across much of
While we continue to enroll and dose patients in our clinical trials, our
clinical development program timelines may continue to be subject to potential
negative impacts from the ongoing pandemic in the
We may experience enrollment delays and suspensions, patient withdrawals, postponement of planned clinical or preclinical studies, redirection of site resources from studies, and study deviations or noncompliance. We may also need to maintain or implement study modifications, suspensions, or terminations, the introduction of additional remote study procedures and modified informed consent procedures, study site changes, direct delivery of investigational products to patient homes or alternative sites, which may require state licensing, and changes or delays in site monitoring. The foregoing may require that we consult with relevant review and ethics committees, Institutional Review Boards ("IRBs"), and the FDA. The foregoing may also impact the integrity of our study data. The COVID-19 outbreak may further increase the need for clinical trial patient monitoring and regulatory reporting of adverse effects, and may delay regulatory authority meetings, inspections, or the regulatory review of marketing or investigational applications or submissions.
The COVID-19 pandemic may also impact our ability to procure the necessary supply of our investigational drug products, as well as any ancillary supplies necessary for the conduct of our studies. Third party manufacturers may also need to implement measures and changes, or deviate from typical manufacturing requirements that may otherwise adversely impact our product candidates.
In light of the COVID-19 outbreak, the FDA issued a number of new guidance
documents. Specifically, as a result of the potential effect of the COVID-19
outbreak on many clinical trial programs in the
Critical Accounting Policies and Management Estimates
We describe our significant accounting policies in Note 1A, The Company and
Summary of Significant Accounting Policies, of the notes to the financial
statements included in our 2021 Amended Annual Report. We discuss our critical
accounting estimates in Item 7, Management's Discussion and Analysis of
Financial Condition and Results of Operations, in our 2021 Amended Annual
Report. There have been no changes in our significant accounting policies or
critical accounting estimates since
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Recent Accounting Pronouncements
There are no recent accounting pronouncements that we anticipate adopting.
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