MEI PHARMA, INC. This Quarterly Report on Form 10-Q 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 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
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We are currently operating in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by geopolitical instability due to the ongoing military conflict betweenRussia andUkraine . Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflict inUkraine or any other geopolitical tensions. • The ongoing military conflict betweenRussia andUkraine has affected our planned sites inUkraine andRussia for the COASTAL trial. Failure to replace those sites with new sites could have a materially detrimental effect on recruitment timelines. • 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 ongoing COVID-19 pandemic, 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; 21
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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; • 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. • We are not in compliance with the Nasdaq continued listing requirements. If we are unable to comply with the continued listing requirements of the Nasdaq Capital Market, our common stock could be delisted, which could affect our common stock's market price and liquidity and reduce our ability to raise capital; • 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; 22
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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.
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 Quarterly Report on
Form 10-Q 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 Note 1, "Restatement of Previously Issued Financial Statements," in the Notes to Condensed Financial Statements of this 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 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
As a result of the ongoing military conflict between
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to be moved elsewhere. Failure to find a replacement for those sites could have
a detrimental effect on recruitment timelines. It is possible this conflict may
further impact enrollment at study sites in neighboring countries (e.g.
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:
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Zandelisib, an oral phosphatidylinositol 3-kinase ("PI3K") delta inhibitor;
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Voruciclib, an oral cyclin-dependent kinase 9 ("CDK9") inhibitor; and
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ME-344, a mitochondrial inhibitor targeting the oxidative phosphorylation
("OXPHOS") complex.
[[Image Removed: img103133933_0.jpg]]
1.
Study evaluating patients with Indolent B-cell non-Hodgkin's lymphoma (iB-NHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström's macroglobulinemia (WM) conducted by Kyowa Kirin. 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 with FDA
Zandelisib: 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. Clinical studies are focused on the time-limited, intermittent dosing, of zandelisib in patients with relapsed or refractory ("r/r") indolent non-Hodgkin lymphomas and chronic lymphocytic leukemia ("CLL"). "Time-limited" therapy is treatment which is to be administered for a fixed period of time and not based on an event like disease progression.
In
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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. In
On
COASTAL is an ongoing Phase 3 study evaluating the intermittent dosing and
time-limited therapy of 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
Zandelisib:
While PI3K? inhibitors as a group are a clinically validated class for the treatment of B-cell malignancies, earlier entrants to the class have been challenged by 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 realize 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. Clinical and preclinical data demonstrate that 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 the evaluation of an innovative dosing ("ID") regimen. The ID regimen consists of daily dosing only in the first seven days of each 28-day dosing cycle. The unique zandelisib ID regimen 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 ID regimen 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
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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, and 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. Clinical evaluation is focused on the intermittent dosing of zandelisib as part of time-limited therapy.
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 the Phase 2 CORAL study evaluating zandelisib in combination with
venetoclax plus rituximab in patients with CLL in the first half of calendar
year 2022, 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 ID regimen 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
The abstract reports data from the evaluation of zandelisib in 69 patients with follicular lymphoma. In the 69 patients, zandelisib was administered at 60 mg daily for two 28-day cycles then on the ID regimen of 60 mg daily on days 1-7 of a 28-day cycle as a single agent (Group 1, n=18) or in combination with rituximab (Group 2, n=19). Group 3 (n=32) evaluated zandelisib 60 mg on ID regimen from cycle 1 and zanubrutinib 80 mg twice daily. Patients were generally heavily pretreated and had a median follow-up of 10.8 months (range 1.8-49.5).
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The overall response rate in 65 evaluable pts was 84.6% (55/65) and the complete response rate was 24.6% (16/65). The overall response rate was 77.8% (14/18) in Group 1, 94.7% (18/19) in Group 2, and 82.1% (23/28) in Group 3. The median duration of response was 31.1 months in Group 1, 25.8 months in Group 2, and not yet mature in Group 3, with median drug exposure of 17.1, 20.5, and 7.1 months, respectively.
Six patients (8.7%) discontinued therapy due to an adverse event. Grade 3 adverse events of special interest were rash in 6 patients (8.7%), ALT increased in 6 (8.7%), diarrhea in 3 (4.3%), colitis in 2 (2.9%), and AST increased in 3 (4.3%). No grade 4-5 adverse events of special interest were reported. One patient in Group 3 had reversible grade 4 drug rash with eosinophilia and systemic symptoms ("DRESS") syndrome. Grade 3-4 neutropenia was observed in 11 patients (16%).
The Phase 1b study is enrolling the r/r MCL expansion cohort, and will continue 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 Evaluating Zandelisib as a Single-Agent in Follicular and Marginal Zone Lymphoma Patients
TIDAL is an ongoing global Phase 2 trial evaluating the intermittent
administration of 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. 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.,
In
The EHA abstract reports that ORR was 70.3% (N=64), with 32 patients (35.2%) achieving a complete response. Responses occurred early: 85.5% (N=56) achieved a response in the first two cycles of therapy and 75% of CRs (N=24) achieved the first four cycles. Patients were generally heavily pretreated: the median number of prior therapies was three (range 2-8), 21 patients (23%) received prior stem cell transplant, 42 patients (46%) were refractory to last therapy, 31 patients (34%) had tumors ?5 cm, and 51 patients (56%) were POD24. The data are still immature to estimate accurately the DOR.
With a median follow-up of 9.4 months (range 0.8-24) in the safety population of 121 pts, 12 patients (9.9%) discontinued therapy due to any drug-related AE. Grade 3 adverse events of special interest (AESI) were diarrhea in 6 patients (5%), colitis in two (1.7%), cutaneous rash in four (3.3%), stomatitis in three (2.5%), and one (0.8%) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (15 of 18, 83%) occurred in cycles 1-3, during daily dosing, with only three cases reported on ID regimen in Cycles ?4.
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 the intermittent and time-limited administration of 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
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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
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
In a peer reviewed manuscript published in 2020 by Luedtke et al, it was reported that the inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of AML. The data demonstrated that voruciclib synergizes with venetoclax to induce apoptosis in both AML cell lines and primary patient samples. It was also demonstrated that voruciclib downregulates MCL1, which is relevant for the synergy between voruciclib and venetoclax, and further that voruciclib also downregulates MYC, which also contributes to the synergies with venetoclax.
The research presented suggests that voruciclib is an attractive therapeutic target for treating cancers in combination with venetoclax or other BCL-2 inhibitors, and is supportive of our ongoing clinical evaluation of voruciclib in B-cell malignancies and AML.
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
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Results in a rapid decrease in the phosphorylation of proteins that promote MYC
transcription;
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Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in
stabilizing MYC in KRAS mutant cancers;
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Possesses single agent activity against multiple KRAS mutant cancer cell lines
both in vitro and in vivo;
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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.
As reported at the
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. We also plan to initiate a Phase 1b study evaluating voruciclib in combination with venetoclax in patients with AML mid calendar year 2022.
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.
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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
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
Additionally, ME-344 may also have clinical potential against hematological malignancies. At the AACR Annual Meeting 2022, a poster presentation reported results from preclinical studies exploring the ability of ME-344 to enhance the activity of venetoclax against AML. Data from the in vitro and in vivo preclinical studies evaluating the combination of ME-344 with venetoclax in standard-of-care-resistant AML cell lines and relapsed or refractory AML patient samples suggest that ME-344, both alone and in combination with venetoclax, inhibits purine biosynthesis, suppresses oxidative phosphorylation, induces apoptosis and decreases Mcl-1, which together target metabolic vulnerabilities of AML cells. The data demonstrated that ME-344 and venetoclax prolong survival in MV4-11- and MV4-11/AraC-R-derived xenograft AML models. The poster concludes that ME-344 enhances venetoclax activity against AML cells including resistant AML.
Results of Operations
The following information has been adjusted to reflect the restatement of our financial statements as described in Note 1, "Restatement of Previously Issued Financial Statements," in the Notes to Condensed Financial Statements of this Quarterly Report.
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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
March 31,
Research and development expenses 2022 2021
Zandelisib $ 13,071 $ 11,460
Voruciclib 1,364 694
ME-344 382 212
Other 7,501 5,518
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
General and Administrative: General and administrative expenses increased by
Other income or expense: We recorded a non-cash gain of
Comparison of nine 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.
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Nine Months Ended
March 31,
Research and development expenses 2022 2021
Zandelisib $ 40,082 $ 36,350
Voruciclib 3,950 2,215
ME-344 2,166 433
Other 17,604 14,106
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
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 nine months ended
Net cash used in investing activities for the nine months ended
Net cash provided by financing activities during the nine months ended
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Table of Contents 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.
We have leased approximately 32,800 square feet of office space in
In
Presage License Agreement
In
COVID-19
As a result of the ongoing 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.
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In light of the ongoing COVID-19 pandemic, the FDA issued a number of new
guidance documents. Specifically, as a result of the potential effect of the
ongoing COVID-19 pandemic 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 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 Annual Report. There
have been no changes in our significant accounting policies or critical
accounting estimates since
Recent Accounting Pronouncements
There are no recent accounting pronouncements that we anticipate adopting.
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