UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): April 13, 2021
MEI Pharma, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 000-50484 | 51-0407811 | ||
| (State or other jurisdiction of incorporation or organization) |
(Commission File Number) |
(I.R.S. Employer Identification No.) |
11455 El Camino Real, Suite 250
San Diego, California 92130
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area code: (858) 369-7100
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions ( see General Instruction A.2. below):
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading Symbol |
Name of each exchange on which registered | ||
| Common stock, $0.00000002 par value | MEIP | The NASDAQ Stock Market LLC |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
☐ Emerging growth company
☐ If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to section 13(a) of the Exchange Act.
Item 2.02. Results of Operations and Financial Condition.
The information set forth below under “Investor Presentation” in Item 8.01 below is incorporated by reference herein.
Item 8.01 Other Events.
Investor Presentation
MEI Pharma, Inc. (the “Company”) is furnishing this Current Report on Form 8-K in connection with the disclosure of information contained in an investor presentation to be used by the Company at various meetings with institutional investors and analysts. A copy of the presentation is filed herewith as Exhibit 99.1 and is incorporated into this Item 8.01 by reference.
Press Release
On April 13, 2021, the Company and Kyowa Kirin issued a press release titled “MEI Pharma Announces Completion of Patient Enrollment in Follicular Lymphoma Primary Efficacy Population of Global Phase 2 TIDAL Study Intended to Support Potential Accelerated Approval Application from U.S. Food and Drug Administration (FDA)”. A copy of the press release is filed herewith as Exhibit 99.2 and is incorporated into this Item 8.01 by reference.
Poster Presentation
On April 10, 2021, the Company posted a poster presentation titled “Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models” on the Company’s website. A copy of the press release is filed herewith as Exhibit 99.3 and is incorporated into this Item 8.01 by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
Signatures
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| MEI PHARMA, INC. | ||
| By: |
/s/ Daniel P. Gold | |
| Daniel P. Gold | ||
| Chief Executive Officer | ||
Dated: April 13, 2021
Building a Leading Oncology Franchise NASDAQ: MEIP April 13, 2021 Exhibit 99.1
Forward-Looking Statements This presentation contains, and our officers and representatives may from time to time make, statements that are “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Examples of forward-looking statements include, among others, statements regarding our development strategy; potential advantages of our product candidates; the initiation and completion of preclinical and clinical studies and the reporting of the results thereof; the timing of regulatory submissions and actions; the sufficiency of our existing cash; and all other statements relating to our plans, objectives, expectations and beliefs regarding future performance, operations, financial condition and other future events (including assumptions underlying or relating to any of the foregoing). These forward-looking statements rely on a number of assumptions concerning future events and are subject to a number of risks, uncertainties, and other factors, many of which are outside of our control. Important factors that could cause our actual results and financial condition to differ materially from those indicated in forward-looking statements include, among others: uncertainties relating to the initiation and completion of preclinical and clinical studies; whether preclinical and clinical study results will validate and support the safety and efficacy of our product candidates; the outcome of regulatory reviews of our product candidates; varying interpretation of research and development and market data; the impact of the COVID-19 pandemic on our industry and individual companies, including on our counterparties, the supply chain, the execution of our clinical development programs, our access to financing and the allocation of government resources; risks and uncertainties relating to intellectual property and the other factors discussed under the caption “Item 1A. Risk Factors” in our most recent annual report on Form 10-K and our most recent quarterly report on Form 10-Q. Any forward-looking statement made by us in this presentation is based only on information currently available to us and speaks only as of the date on which it is made. In addition, we operate in a highly competitive and rapidly changing environment, and new risks may arise. Accordingly, you should not place any reliance on forward-looking statements as a prediction of actual results. We disclaim any intention to, and undertake no obligation to, update or revise any forward-looking statement. You are urged to carefully review and consider the various disclosures in our most recent annual report on Form 10-K, our most recent Form 10-Q and our other public filings with the SEC since the filing of our most recent annual report.
MEI Pharma: Who We Are Clinical Development Company Building a Leading Oncology Franchise with 4 Clinical-Stage Programs: Focus On HemOnc Zandelisib (f/k/a ME-401) Potential Best-in-Class PI3Kδ Inhibitor in Phase 2 Study Intended to Support Accelerated Approval Application with U.S. FDA Well Capitalized with ~$164.6 Million* * As of March 31, 2021, MEI had preliminary $164.6 million in cash, cash equivalents, and short-term investments with no outstanding debt (Unaudited).
Zandelisib Topline TIDAL Study Data on Track to be Reported in the Fourth Quarter of CY2021 Announced Today: Enrollment Complete in Follicular Lymphoma Primary Efficacy Population of Global Phase 2 TIDAL The complete Phase 2 TIDAL study data are intended to be submitted to FDA to support accelerated approval applications
Voruciclib: Oral CDK Inhibitor with Potent CDK9 Activity Preclinical Data
CDK9 Regulates MYC and MCL1 Transcription by RNA POL II DSIF HEXIM NELF Pol II DSIF Pol II Inhibitory Complex Productive elongation of RNA Pol II transcription of target genes (e.g., MYC, MCL1) Promoter proximal pausing relieved by PTEFb & CDK9 activity CDK9 P P PTEFb CDK9 PTEFb voruciclib Transcription of MYC and MCL1 MePCE LARP7 Wiley et al, AACR 2021
Voruciclib Induces Rapid Down Regulation of RNA POL II Associated Proteins That Control MYC and MCL1 Transcription Summary of Phosphoproteomics Analysis Total Peptides 98,140 Total Proteins 5,753 Phosphoproteins (n) 4,806 Phosphosites (n) 21,384 Voruciclib (min) Downreg Phospho-peptides (n) Downreg Phospho-proteins (n) 5 72 67 15 33 28 30 237 174 60 159 117 Database ID Gene Symbol Role in RNA Pol II Regulation P24928 POLR2A RNA Pol II complex Q96ST2 IWS1 RNA Pol II complex O60885 BRD4 pTEFb complex Q03111 MLLT1 pTEFb complex Q7L2J0 MEPCE pTEFb regulation O00267-2 SUPT5H RNA Pol II regulation Q15648 MED1 RNA Pol II regulation P23193 TCEA1 RNA Pol II transcription elongation Q9UHB7 AFF4 SEC regulation of RNA Pol II 5 min 30 min 16-plex TMT labelling, IMAC phosphopeptide enrichment, HPLC fractionation, and analysis by LC-MS/MS. Wiley et al, AACR 2021
CDK9 Regulates MYC Protein Stability Cell Stimulatory Signals KRAS PI3K GSK3β CDK9 RAF MEK MYC MYC MYC protein degradation by proteasome SCF-Fbw7 Ubiquitin sotorasib adagrasib pT58 Pin1 Pin1 PP2A pS62 pS62 pT58 (unstable) voruciclib (stable) Transcriptional activation of MYC target genes MYC MYC ERK1 CDK9 Wiley et al, AACR 2021
Voruciclib Causes Rapid Inhibition of MYC pSer62 Phosphorylation and Reduces MYC Protein Levels 0 min 5 min 15 min 30 min CON VOR AZD CON VOR AZD CON VOR AZD CON VOR AZD MYC β-actin p-MYC (S62) 1.0 0.9 1.1 1.0 0.4 0.4 1.0 0.8 0.9 1.0 1.1 1.0 1.0 0.3 0.3 1.0 0.3 0.3 1.0 1.0 1.1 1.0 0.9 1.1 β-actin MYC 45 min CON VOR AZD 60 min CON VOR AZD 120 min CON VOR AZD 240 min CON VOR AZD p-MYC (S62) 1.0 0.2 0.2 1.0 0.2 0.1 1.0 0.9 0.9 1.0 0.9 1.1 1.0 0.2 0.2 1.0 0.2 0.2 1.0 0.8 1.0 1.0 0.5 0.6 Wiley et al, AACR 2021
Voruciclib Inhibits KRAS Mutant Cell Growth In Vitro and In Vivo in Xenograft Mice Cell Line Indication KRAS Mut IC50 (µM) Gp2D CRC G12D 0.8 HCT-116 CRC G13D 1.8 LS-513 CRC G12D 0.6 SW-480 CRC G12V 3.9 SW837 CRC G12C 2.1 KYSE-410 Esoph G12C 1.9 RPMI-8226 MM G12A 2.4 A-549 NSCLC G12S 1.5 Calu-1 NSCLC G12C 2.0 HCC1171 NSCLC G12C 3.0 HCC44 NSCLC G12C 0.8 NCI-H460 NSCLC Q61H 3.1 NCI-H1373 NSCLC G12C 1.2 NCI-H1792 NSCLC G12C 1.4 NCI-H2030 NSCLC G12C 1.1 NCI-H23 NSCLC G12C 1.2 NCI-H358 NSCLC G12C 0.6 TOV-21G Ovarian G13C 1.7 AsPC-1 PDAC G12D 2.3 HPAF-II PDAC G12D 1.9 MIA PaCa-2 PDAC G12C 1.1 Panc 04.03 PDAC G12D 1.4 Time (days) Ave tumor weight (mg) 600 500 400 100 200 300 0 0 2 4 6 8 10 12 14 1800 1600 1400 1200 1000 800 600 400 200 0 0 2 4 6 Time (days) Ave tumor weight (mg) 8 10 12 Control VOR 100 mg/kg VOR 50 mg/kg VOR 200 mg/kg 6000 5000 4000 3000 2000 1000 0 0 2 4 6 Time (days) Ave tumor weight (mg) 8 10 12 Control VOR 100 mg/kg VOR 50 mg/kg VOR 200 mg/kg Control VOR 100 mg/kg VOR 200 mg/kg HCT-116 (CRC, KRAS G13D) SW-480 (CRC, KRAS G12V) H460 (NSCLC, KRAS Q61H) Wiley et al, AACR 2021
Leveraging CDK9 Regulation of MYC: Exploring Synergy with Direct KRAS Inhibitors Synergy Scores Cell Line KRAS mut Sensitivity to G12C Inhibitors Voruciclib + Sotorasib Voruciclib + Adagrasib NCI-H23 G12C High HCC1171 G12C High MIA Paca-2 G12C High SW837 G12C Moderate - High NCI-H2030 G12C High Calu-1 G12C Moderate - High HCC-44 G12C Moderate - High NCI-H1373 G12C Moderate - High NCI-H358 G12C High NCI-H1792 G12C Moderate - High KYSE-410 G12C Low - High Panc 04.03 G12D Low Gp2D G12D Low LS-513 G12D Low - Moderate AsPC-1 G12D Low HPAF-II G12D Low TOV-21G G13C Low Low High Moderate Esophageal cancer cell line Colorectal cancer cell lines Non-small cell lung cancer cell lines Pancreatic adenocarcinoma cell lines Ovarian cell line VORUCICLIB SYNERGIZES WITH KRAS G12C INHIBITORS IN VITRO Wiley et al, AACR 2021
Leveraging CDK9 Regulation of MYC: In Vivo Synergy with Sotorasib in MIA PaCa-2 Tumors Con VOR SOTO Combo 40X Representative IHC images of DAPI and H&E staining in a Murine Xenograph Model CIVO GLO Fluorescent tracking microspheres Intratumoral injection of drugs & fluorescent microspheres with Presage CIVO technology Processing of tumors for IHC & staining with DAPI, CC3, H&E Wiley et al, AACR 2021
Leveraging CDK9 Regulation of MYC: In Vivo Synergy with Sotorasib in MIA PaCa-2 Tumors VOR Combo SOTO Con CC3 Radial Distance from Injection Center (μm) % of Cell Area Cleaved Caspase 3+ 24% 20% 16% 12% 8% 4% 0 500 1000 1500 22% 18% 14% 10% 6% 2% SOTO + VOR VOR SOTO Con Data represents 5 tumors with duplicate combination and SOTO injection sites per tumor, single injection sites other conditions; 4 sections imaged per tumor (Murine Xenograph Model) . Wiley et al, AACR 2021
CONCLUSIONS MYC is implicated in KRAS mutant tumors. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation at Ser62 Treatment of KRAS G12C mutant MIA PaCa-2 pancreatic cancer cells with voruciclib resulted in a rapid decrease in both phosphorylation of proteins that regulate transcription of MYC, and in phosphorylation of MYC protein on Ser62 that was followed by a reduction in total MYC protein In in vitro and in vivo preclinical models, voruciclib demonstrated single agent activity against multiple KRAS mutant cancer cell lines harboring various G12, G13, and Q61 mutations Voruciclib acted synergistically with KRAS G12C inhibitors in killing KRAS G12C mutant cancer cell lines, both in vitro and in vivo Collectively, these experiments suggest that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC Wiley et al, AACR 2021
Voruciclib: Oral CDK Inhibitor with Potent CDK9 Activity Clinical Experience
Piramal Monotherapy Phase 1 Studies in Solid Tumors 2 weeks on, 1 week off schedule 75 to 850 mg 29 pts in dose escalation / expansion at 600 mg cohorts 41% disease control rate 1 PR and 8 SD lasting 2 to 6 months Daily continuously schedule 75 to 500 mg 39 pts in dose escalation / expansion at 350 mg cohorts 31% disease control rate 12 SD lasting a median of 15 weeks Safety profile Most common AEs involved GI tract 9 Drug related SAEs 2 at doses <350 mg: infectious diarrhea, hematuria due to low platelets 7 at doses 350-850 mg: Diarrhea (2), renal failure (2), death/hypokalemia, death/abdominal pain, increased INR No evidence of myelosuppression Data on file.
Decreased c-MYC Expression in Solid Tumors 10 gene biomarkers evaluated in Phase 1 daily dosing study c-MYC expression decreased in 17/25 patients (68%) tested Data on file.
Piramal Study of Voruciclib + Vemurafenib in BRAF-mut Advanced/Inoperable Malignant Melanoma Voruciclib 150 mg daily plus vemurafenib 720 mg or 960 mg BID in 28-day cycles 9 pts treated before study termination for business reasons 8 patients evaluable for efficacy 5 patients were BRAFi refractory Best Response = PD 3 patients were BRAF/MEK naïve 1 CR and 2 PR ongoing for 3 to 14 months Most common AEs were fatigue, constipation, diarrhea, arthralgia and headache 1 DLT = grade 3 fatigue No SAEs related to voruciclib Diab et al, ASCO 2015
CR in a Patient with Pulmonary Metastases Data on file.
Leveraging CDK9 Regulation of MCL1: Phase 1 Study in R/R B-Cell Malignancies and AML Study population Relapsed/Refractory B-cell malignancies Relapsed/Refractory AML Dose escalation with standard 3+3 design Endpoints Safety and tolerability Pharmacokinetics Biologic correlative studies BH3 profiling, MCL-1 expression (Dana Farber) Molecular mutations analysis (City of Hope) Response rates Voruciclib single agent dose escalation/optimization - Enrolling 100 mg 150 mg 200 mg 50mg
Phase 1 Study in Hematologic Malignancies 24 pts treated in 3 dose levels 10 AML and 14 B-cell malignancies No drug related GI toxicity or neutropenia at doses studied Favorable PK profile across all voruciclib studies Half life 24-28 hours supports once-a-day dosing Dose proportional Cmax and AUC High volume of distribution indicates broad entry into tissues Doses of 150-200 mg projected to achieve plasma concentrations sufficient to inhibit molecular target Data on file.
HCT-116 CRC cell xenograft in SCID mice. 8 mice per time point (2 control, 6 orally dosed with voruciclib at 100 mpk). Voruciclib fold increase in tumors relative to plasma are indicated. Voruciclib Shows Preferential Tumor Accumulation in Preclinical Model Data on file.
Evidence of Biologic Activity in AML Suspected Differentiation syndrome seen in 5 pts (50%) Increased WBC without increased in blasts, bone pain, and/or pulmonary symptoms Response to corticosteroids Differentiation syndrome reported with ATRA, IDHi, and other AML targeted therapies Data on file.
Voruciclib Synergizes with Venetoclax in Venetoclax Sensitive and Resistant Cell Lines Ven Sensitive Ven Resistant Luedtke, et al. Nat Sign Trans and Targ Ther. 2020
Phase 1 Study of Voruciclib + Venetoclax in AML Planned Amendment Study population Relapsed/Refractory B-cell malignancies Relapsed/Refractory AML Dose escalation with standard 3+3 design Endpoints Safety and tolerability Pharmacokinetics Biologic correlative studies BH3 profiling, MCL-1 expression (Dana Farber) Molecular mutations analysis (City of Hope) Response rates Voruciclib single agent dose escalation/optimization – Enrolling Voruciclib + Venetoclax dose escalation (Pending FDA approval) 100 mg 150 mg 200 mg 100 mg 150 mg 200 mg V2 50 mg
Key Upcoming 12 Month Milestones Across Portfolio Zandelisib TIDAL, study intended to support accelerated approval application for R/R follicular lymphoma: Announce top-line data fourth quarter CY2021 New clinical studies to expand development, including: COASTAL, intended confirmatory Phase 3 study + Rituxan® in 2L FL/MZL TIDAL study arm: 3L MZL 1L DLBCL + RCHOP (IIT) Initial data of Phase 1b evaluating zandelisib with zanubrutinib under clinical collaboration with BeiGene: Mid CY2021 Voruciclib Initial data, Phase 1 monotherapy and +BCL2i data updates ME-344 Institute plan to leverage clinically demonstrated anti-tumor activity in combination with anti-VEGF Pracinostat Program / Phase 2 MDS Helsinn Update All Timing subject to developments related to the COVID-19 pandemic
Q&A NASDAQ: MEIP
Building a Leading Oncology Franchise NASDAQ: MEIP April 13, 2021
Exhibit 99.2
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MEI Pharma and Kyowa Kirin Announce Completion of Patient Enrollment in Follicular Lymphoma Primary Efficacy Population of Global Phase 2 TIDAL Study Intended to Support Potential Accelerated Approval Application from U.S. Food and Drug Administration (FDA)
Topline TIDAL Study Data on Track to be Reported in the Fourth Quarter
SAN DIEGO, April 13, 2021 — MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing potential new therapies for cancer, and Kyowa Kirin Co., Ltd. (TSE:4151, Kyowa Kirin), a global specialty pharmaceutical company that strives to create new value through the pursuit of advances in life sciences and technologies, today announced completion of enrollment in the follicular lymphoma primary efficacy population of the global Phase 2 TIDAL study. Topline data from the study is on track to be reported in the fourth quarter. If successful, the complete Phase 2 TIDAL study data are intended to be submitted to FDA to support accelerated approval applications under 21 CFR Part 314.500, Subpart H.
Following discussions with FDA, MEI finalized the sample size to evaluate zandelisib in patients with follicular and marginal zone lymphomas in the global Phase 2 TIDAL study. The primary efficacy population sample size for follicular lymphoma is 91 patients and the primary efficacy population sample size for marginal zone lymphoma is 64 patients. To provide a robust safety database, MEI will maintain the total study enrollment of approximately 120 follicular lymphoma patients and 64 marginal zone lymphoma patients.
“The completion of enrollment in the follicular lymphoma efficacy population arm of the TIDAL study is an important milestone for the zandelisib program, and we are grateful to the patients and healthcare providers that are participating in the TIDAL study as we diligently work to advance the program towards potential U.S. marketing authorization,” said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. “In collaboration with our partner, Kyowa Kirin, we are committed to exploring zandelisib’s full potential, both as a monotherapy and in combination with other agents, for patients with B-cell malignancies.”
“I am truly pleased with this news that the enrollment for the patients with the follicular lymphoma has been successfully completed,” said Yoshifumi Torii, Ph.D., Executive Officer, Vice President, Head of Global R&D Division of Kyowa Kirin. “One of our big missions is to steadily advance this drug, which we believe has the potential to provide new value to patient suffering from the follicular lymphoma. We are looking forward to working closely with MEI Pharma to ensure that we fulfill that mission and our responsibilities.”
About Zandelisib
Zandelisib (formerly called ME-401), a selective PI3Kd inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. In March 2020 the U.S. FDA granted zandelisib Fast Track designation for treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies.
In April 2020, MEI and Kyowa Kirin entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin will co-develop and
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co-promote zandelisib in the U.S., with MEI booking all revenue from the U.S. sales. Kyowa Kirin has exclusive commercialization rights outside of the U.S. and will pay MEI escalating tiered royalties on ex-U.S. sales.
Ongoing zandelisib studies include a Phase 2 pivotal study in Japan in patients with indolent B-cell non-Hodgkin’s lymphoma (iNHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström’s macroglobulinemia (WM) conducted by Kyowa Kirin.
About the TIDAL Phase 2 Study
The TIDAL study (Trials of PI3K DeltA in Non-Hodgkin’s Lymphoma) is a global Phase 2 study evaluating zandelisib as a monotherapy across two study arms: the first study arm for the treatment of adults with relapsed and refractory follicular lymphoma and the second study arm for marginal zone lymphomas, in both cases after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. The primary endpoints of the study are the objective response rate and the tolerability of zandelisib.
Subject to the results and discussions with FDA, data from each study arm are intended to be submitted to FDA to support separate accelerated approval marketing applications under 21 CFR Part 314.500, Subpart H.
The study is evaluating zandelisib administered once daily at 60 mg 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. Approximately 120 follicular lymphoma and 60 marginal zone lymphoma patients will be enrolled and treated with the IS regimen. The primary efficacy endpoint will be the rate of objective responses to therapy and other endpoints will include duration of response and tolerability of zandelisib.
More information about this trial is available at ClinicalTrials.gov.
About Follicular and Marginal Lymphomas
Follicular lymphoma (FL) is the most common indolent lymphoma, comprising about 20-30% of all non-Hodgkin lymphomas. The disease also forms on B cells, is chronic in most cases and tends to progress slowly. Most people diagnosed with FL are over 65 years of age. Sometimes follicular lymphomas can change into diffuse large B-cell lymphoma, a fast-growing (aggressive) type of NHL.
Marginal zone lymphoma (MZL) is a group of indolent, or slow growing, lymphomas. The disease forms on B-cells, a type of white blood cell called a lymphocyte. MZL accounts for approximately eight percent of all non-Hodgkin lymphoma cases; over 77,000 cases of non-Hodgkin lymphoma are diagnosed in the U.S. each year. The average age at diagnosis is 60 years, and it is slightly more common in women than in men.
About MEI Pharma
MEI Pharma, Inc. (Nasdaq: MEIP) is a late-stage pharmaceutical company focused on developing potential new therapies for cancer. MEI Pharma’s portfolio of drug candidates contains four clinical-stage assets, including zandelisib, currently in an ongoing Phase 2 clinical trial which may support an accelerated approval marketing application with the U.S. Food and Drug Administration. Each of MEI Pharma’s pipeline candidates leverages a different mechanism of action with the objective of developing therapeutic options that are: (1) differentiated, (2) address unmet medical needs and (3) deliver
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improved benefit to patients either as standalone treatments or in combination with other therapeutic options. For more information, please visit www.meipharma.com.
About Kyowa Kirin
Kyowa Kirin strives to create and deliver novel medicines with life-changing value. As a Japan-based Global Specialty Pharmaceutical Company with a heritage of 70+ -years, we apply cutting-edge science including an expertise in antibody research and engineering, to address the needs of patients and society across multiple therapeutic areas including Nephrology, Oncology, Immunology/Allergy and Neurology. Across our four regions – Japan, Asia Pacific, North America and EMEA/International – we focus on our purpose, to make people smile, and are united by our shared values of commitment to life, teamwork/Wa, innovation, and integrity. You can learn more about the business of Kyowa Kirin at: https://www.kyowakirin.com.
Forward-Looking Statements
Under U.S. law, a new drug cannot be marketed until it has been investigated in clinical studies and approved by the FDA as being safe and effective for the intended use. Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. You should be aware that our actual results could differ materially from those contained in the forward-looking statements, which are based on management’s current expectations and are subject to a number of risks and uncertainties, including, but not limited to, our failure to successfully commercialize our product candidates; costs and delays in the development and or FDA approval, or the failure to obtain such approval, of our product candidates; uncertainties or differences in interpretation in clinical trial results; the impact of the COVID-19 pandemic on our industry and individual companies, including on our counterparties, the supply chain, the execution of our clinical development programs, our access to financing and the allocation of government resources; our inability to maintain or enter into, and the risks resulting from our dependence upon, collaboration or contractual arrangements necessary for the development, manufacture, commercialization, marketing, sales and distribution of any products; competitive factors; our inability to protect our patents or proprietary rights and obtain necessary rights to third party patents and intellectual property to operate our business; our inability to operate our business without infringing the patents and proprietary rights of others; general economic conditions; the failure of any products to gain market acceptance; our inability to obtain any additional required financing; technological changes; government regulation; changes in industry practice; and one-time events. We do not intend to update any of these factors or to publicly announce the results of any revisions to these forward-looking statements.
Contacts:
MEI Pharma:
David A. Walsey
VP of IR and Corporate Communications
Tel: 858-369-7104
investor@meipharma.com
Jason I. Spark
Canale Communications for MEI
Tel: 619-849-6005
jason.spark@canalecomm.com
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Kyowa Kirin Co., Ltd.:
Hiroki Nakamura
Corporate Communications Department
media@kyowakirin.com
Lauren Walrath
VP, Public Affairs-Kyowa Kirin North America
Tel: 646-526-4454
lauren.walrath.g4@kyowakirinc.om
Exhibit 99.3
Exhibit 99.3 Poster: # 1962 Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models Sandra Wiley*, Yongwei Su**, Yubin Ge** *MEI Pharma Inc, 11455 El Camino Real, Suite 250, San Diego, CA , 92130 **Department of Oncology and Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine. ABSTRACT Mutations in KRAS at G12, G13, and Q61 are oncogenic drivers in many cancers, including lung, colorectal, pancreatic, bone marrow, and endometrial carcinomas.1 KRAS mutations are frequently accompanied by stabilization of the MYC oncoprotein through increased MYC transcription and decreased protein degradation that is mediated by phosphorylation of MYC on Ser 62 by ERK and CDK9 kinases.2,3 Voruciclib is a novel oral inhibitor of CDKs 9, 4, 6, and 1 that is currently being tested in Phase 1B clinical trials (NCT03547115) for B-cell malignancies and acute myeloid leukemia.4 Voruciclib inhibition of CDK9 leads to decreased expression of transcriptional targets of RNA Pol II, such as MCL1 and MYC.5 Phosphoproteomics analysis revealed that voruciclib treatment resulted in a reduction in phosphorylation of proteins that regulate Pol II. To investigate MYC protein stability, MIA PaCa-2 (KRAS G12C) cells were treated with voruciclib, followed by Western Blot analysis with α-MYC and α-pSer62-MYC antibodies. Voruciclib treatment resulted in a reduction in phosphorylation of MYC on Ser 62. A 60% decrease in pSer62 was observed after 5 min that reached 80% by 60 min. In contrast, there was no decrease in total MYC protein at either 5 or 15 min. A 10% reduction in total MYC was observed at 60 min that reached 50% at 240 min. To test if voruciclib could be effective in cancers driven by dysregulated KRAS-MYC signaling, 22 cancer cell lines with KRAS mutations (G12A, G12C, G12D, G12S, G12V, G13C, G13D, Q61H) were treated in preclinical studies with voruciclib in vitro. Voruciclib decreased viability in all cell lines tested and inhibited tumor growth in vivo in murine xenograft models using KRAS mutant human cancer cells: HCT-116 (CRC, KRAS G13D), SW-480 (CRC, KRAS G12V), and H-460 (NSCLC, KRAS Q61H). Voruciclib also demonstrated synergy in vitro with the KRAS G12C inhibitors sotorasib (AMG 510) and adagrasib (MRTX849) in cell lines from multiple indications and in vivo within a MIA PaCa-2 murine xenograft model. Collectively, these data demonstrate that voruciclib inhibition of CDK9 leads to reduced phosphorylation of MYC on Ser62 followed by a decrease in total MYC protein in MIA PaCa-2 cells, and inhibition of growth in multiple KRAS mutant cancer cell lines in vivo and in vitro. This suggests that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC,possibly in combination with KRAS G12C inhibitors. CDK9 REGULATES TRANSCRIPTION OF MYC BY RNA POL II AND MYC PROTEIN STABILITY A. Transcription of MYC B. MYC protein stability MePCE LARP7 HEXIM PTEFb voruciclib PTEFb Transcription of MYC P P DSIF DSIF NELF sotorasib adagrasib KRAS MYC protein degradation by proteasome RAF SCF-Fbw7 Ubiquitin pT58 MEK (unstable) ERK1 pS62 pS62 pT58 Pin1 (stable) PP2A voruciclib Pin1 Transcriptional activation of MYC target genes Figure 1. Schematic illustrating (A) P-TEFb regulation of RNA Pol II driven transcription of MYC and (B) KRAS-ERK1 signaling pathway and bility by phosphorylation of Ser 62. Proteins with decreased phosphorylation after voruciclib treatment are circled hibition by voruciclib are noted.
Poster: # 1962 Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models Sandra Wiley*, Yongwei Su**, Yubin Ge** *MEI Pharma Inc, 11455 El Camino Real, Suite 250, San Diego, CA , 92130 **Department of Oncology and Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine. VORUCICLIB INDUCES RAPID DOWN REGULATION OF RNA POL II ASSOCIATED PROTEINS THAT CONTROL MYC TRANSCRIPTION A. Summary of PhosphoproteomicsAnalysis Total Peptides 98,140 Total Proteins 5,753 Phosphoproteins (n) 4,806 Phosphosites (n) 21,384 C. Downreg Downreg Voruciclib Phospho- Phospho-(min) peptides (n) proteins (n) 5 72 67 15 33 28 30 237 174 60 159 117 Role in Database Gene RNA Pol II ID Symbol Regulation P24928 POLR2A RNA Pol II complex Q96ST2 IWS1 O60885 BRD4 pTEFb complex Q03111 MLLT1 pTEFb Q7L2J0 MEPCE regulation O00267-2 SUPT5H Q15648 MED1 RNA Pol II regulation P23193 TCEA1 Q9UHB7 AFF4 Figure 2. Landscape of the voruciclib-sensitive phosphoproteome in MIA Paca-2 cells reveals rapid downregulation of phosphoproteins controlling transcription of MYC. Cells were treated with voruciclib (4 µM) for 5, 15, 30, 60 min, followed by lysis, 16-plex TMT labelling, IMAC phosphopeptide enrichment, and analysis by LC-MS/MS. (A) Summary of total and phosphopeptide quantification for combined samples after MS. (B) Volcano plots of phosphosites (log2 fold change vs –log10 p-value). Significantly downregulated phosphosites are shown in red. Significantly upregulated phosphosites are shown in green (p £0.05. Fold change ³2.0). (C) Summary of significantly down-regulated phosphoproteins and phosphopeptides over time. (D) Downregulated phosphoproteins with a role in regulation of RNA Pol II activity. UniProt database ID and gene symbols noted. A. 0 min 5 min 15 min 30 min p-MYC (S62) 1.0 0.9 1.1 1.0 0.4 0.4 1.0 0.3 0.3 1.0 0.3 0.3 MYC 1.0 0.8 0.9 1.0 1.1 1.0 1.0 1.0 1.1 1.0 0.9 1.1 β-actin 45 min 60 min 120 min 240 min p-MYC (S62) 1.0 0.2 0.2 1.0 0.2 0.1 1.0 0.2 0.2 1.0 0.2 0.2 MYC 1.0 0.9 0.9 1.0 0.9 1.1 1.0 0.8 1.0 1.0 0.5 0.6 β-actin B. 240 min p-MYC (S62) 1.0 0.4 0.4 0.3 1.6 0.8 0.5 0.2 MYC 1.0 0.9 0.8 0.5 0.5 0.4 0.4 0.4 β-actin Figure 3. Immunoblot analyses of c-MYC, phospho-c-MYC (Ser62), and actin in MIA Paca-2 KRAS G12C mutant PDAC cells. (A) Cells were treated with vehicle control, voruciclib (VOR, 4 µM), or AZD4573 (AZD, a CDK9 inhibitor, 400 nM) for the indicated times. (B) Cells were treated with various concentrations of voruciclib or AZD4573 for 4 hours. Relative densitometry values are indicated.
Poster: # 1962 Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models Sandra Wiley*, Yongwei Su**, Yubin Ge** *MEI Pharma Inc, 11455 El Camino Real, Suite 250, San Diego, CA , 92130 **Department of Oncology and Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine. VORUCICLIB INHIBITS PROLIFERATION OF KRAS MUTANT CANCER CELL LINES IN VITRO AND IN VIVO A. IC50 Cell Line Indication KRAS Mut (µM) Gp2D CRC G12D 0.8 HCT-116 CRC G13D 1.8 LS-513 CRC G12D 0.6 SW-480 CRC G12V 3.9 SW837 CRC G12C 2.1 KYSE-410 Esoph G12C 1.9 RPMI-8226 MM G12A 2.4 A-549 NSCLC G12S 1.5 Calu-1 NSCLC G12C 2.0 HCC1171 NSCLC G12C 3.0 HCC44 NSCLC G12C 0.8 NCI-H460 NSCLC Q61H 3.1 NCI-H1373 NSCLC G12C 1.2 NCI-H1792 NSCLC G12C 1.4 NCI-H2030 NSCLC G12C 1.1 NCI-H23 NSCLC G12C 1.2 NCI-H358 NSCLC G12C 0.6 TOV-21G Ovarian G13C 1.7 AsPC-1 PDAC G12D 2.3 HPAF-II PDAC G12D 1.9 MIA PaCa-2 PDAC G12C 1.1 Panc 04.03 PDAC G12D 1.4 B. HCT-116 Control 1800 (mg) 1600 VOR 50 mg/kg 1400 VOR 100 mg/kg weight 1200 VOR 200 mg/kg 1000 800 tumor 600 400 Ave 200 0 0 2 4 6 8 10 12 Time (days) Control SW-480 (mg) 600 VOR 50 mg/kg 500 VOR 100 mg/kg weight 400 VOR 200 mg/kg 300 tumor 200 Ave 100 0 0 2 4 6 8 10 12 14 Time (days) Control H460 (mg) 6000 5000 VOR 100 mg/kg VOR 200 mg/kg weight 4000 3000 tumor 2000 Ave 1000 0 0 2 4 6 8 10 12 Time (days) Time (days) Figure 4. (A) Voruciclib IC50 values in multiple cell lines with KRAS mutations. (B) Murine xenograft experiment showing tumor growth over time in mice bearing HCT-116 (CRC, KRAS G13D), SW-480 (CRC, KRAS G12V) or H-460 (NSCLC, KRAS Q61H) tumors after treatment with voruciclib (VOR) at various doses (QD, p.o.) for 11-14 days. VORUCICLIB SYNERGIZES WITH KRAS G12C INHIBITORS IN VITRO Synergy Scores Cell Line KRAS mut Sensitivity to G12C Inhibitors Voruciclib + Sotorasib Voruciclib + Adagrasib NCI-H23 G12C High HCC1171 G12C High G12C High G12C Moderate—High NCI-H2030 G12C High Calu-1 G12C Moderate—High HCC-44 G12C Moderate—High NCI-H1373 G12C Moderate—High NCI-H358 G12C High NCI-H1792 G12C Moderate—High G12C Low—High G12D Low G12D Low G12D Low—Moderate G12D Low G12D Low TOV-21G G13C Low Non-small cell lung cancer cell lines Esophageal cell line Pancreatic adenocarcinoma cell lines Ovarian cell line Colorectal cancer cell lines low Moderate high Figure 5. Heatmap of combination activity of voruciclib with KRAS G12C inhibitors in cancer cell lines after 72 hours. Cell lines are ranked by synergy score of voruciclib in combination with either sotorasib or adagrasib. HSA, Bliss, and Loewe analyses were performed to generate the synergy scores using Chalice Analyzer. High synergy scores are represented as dark green. Moderate synergy scores are represented in shades of green. Low to moderate synergy scores are represented in white. Cell sensitivity to KRAS G12C inhibitors are ranked by EC50 scores. High (<0.1 µM), Moderate (> 0.1 µM), low (>1 µM). Where sensitivities to the two inhibitors differ, a range of responses is given.
Poster: # 1962 Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models Sandra Wiley*, Yongwei Su**, Yubin Ge** *MEI Pharma Inc, 11455 El Camino Real, Suite 250, San Diego, CA , 92130 **Department of Oncology and Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine. VORUCICLIB SYNERGIZES WITH SOTORASIB IN AN IN VIVO MIA PaCa-2 TUMOR MODEL Intratumoral injection of drugs & fluorescent microspheres with Presage CIVO technology Processing of tumors for IHC & staining with DAPI, CC3, H&E Analysis & Quantification Figure 6. Voruciclib synergizes with sotorasib in vivo. (A) Presage CIVO technology4,6 was used to inject MIA PaCa-2 cell tumors in vivo in a murine xenograft model. Tumors were injected with either vehicle (Con), voruciclib (VOR), sotorasib (SOTO), or voruciclib + sotorasib (Combo). Tumors were harvested and processed for IHC 24 hr after drug injection. (B) Representative IHC images of DAPI and H&E staining. (C) Representative IHC images of cleaved caspase-3 staining (CC3). (D) Analysis of cell area with cleaved caspase-3 staining for each treatment. (Mean ± SEM) (C, E) Data represents 5 tumors with duplicate combination and SOTO injection sites per tumor, single injection sites other conditions; 4 sections imaged per tumor. Similar results were obtained for VOR + adagrasib combination (data not shown). CONCLUSIONS • MYC is implicated in KRAS mutant tumors. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation at Ser62. Treatment of KRAS G12C mutant MIA PaCa-2 pancreatic cancer cells with voruciclib, a potent inhibitor of CDKs 9/4/6/1, resulted in a rapid decrease in both phosphorylation of proteins that regulate transcription of MYC, and in phosphorylation of MYC protein on Ser62 that was followed by a reduction in total MYC protein. • In in vitro and in vivo preclinical models, voruciclib demonstrated single agent efficacy against multiple KRAS mutant cancer cell lines harboring various G12, G13, and Q61 mutations. • Voruciclib acted synergistically with KRAS G12C inhibitors in killing KRAS G12C mutant cancer cell lines, both in vitro and in vivo. • Collectively, these experiments suggest that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC. REFERENCES 1. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17-33. 2. Blake DR, et al. Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer. Sci Signal. 2019;12(590):eaav7259. 3. Kalkat M, et al. MYC deregulation in primary human cancers. Genes (Basel). 2017;8(6):151. 4. Dey Sci Rep. J, et 2017;7(1):18007. al. Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. 5. Luedtke DA, et al. Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. Signal Transduct Target Ther. 2020;5(1):17. 6. Klinghoffer RA, et al. A technology platform to assess multiple cancer agents simultaneously within a patient’s tumor. Sci Tranl Med. 2015;7(284):1-12. ACKNOWLEDGMENTS AND DISCLOSURES SW – employee of MEI Pharma, Inc. YS – nothing to disclose. YG – research grant received from MEI Pharma, Inc. This study was funded by MEI Pharma, Inc. Editorial support provided by BluPrint Oncology Concepts, LLC. Presented at American Association for Cancer Research (AACR) 10 – 15 Apr 2021.