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Moving mountains to serve cancer patients Steve Carchedi – CEO [email protected] 908-720-1786 APEX -1- Company Overview • Apexian is a clinical stage biotech company with first-in-class therapy targeting the APE1 protein • Our lead compound, APX3330 an oral anticancer agent has shown preclinical efficacy against a variety of APE1-expressing tumors • APX3330 safety has been confirmed in 10 Phase I/II human studies of non-cancer indications with over 422 patients • The phase I oncology study of APX3330 is ready for execution. IND approved by FDA, first site has IRB approval and clinical supplies are ready to ship • Pipeline of oral anticancer agents APX2009, APX2014. Additional oncology and nononcology indications could lead to broad clinical utility • Key value inflection points in the near term (2017-18) • Robust IP estate and plan seeking Orphan Drug Designation, Fast Track and Priority Review at the appropriate time • Experienced management team in discovery, development and commercialization of oncology products • Synergy between both company’s portfolios – Prostate, Lung, Inflammatory Programs APEX -2- Leadership Team Steve Carchedi - Chief Executive Officer • Mark Kelley, Ph.D. - Chief Scientific Officer • Former CMO of ProNAi Therapeutics, with a 25+ years of clinical and pre-clinical drug-development experience in industry (Endocyte, Eli Lilly), government (NCI, NIH) and academia (University of Michigan, Michigan State University). Roger Miller – Chief Operating Officer • Professor at Indiana University School of Medicine (IUSM); Betty and Earl Herr Chair of Pediatric Oncology Research; Professor in Departments of Pediatrics, Biochemistry & Molecular Biology and Pharmacology & Toxicology, Associate Director, IU Simon Cancer Center. Devoted more than 25 years exploring APE1/Ref-1 and its role in redox signaling, DNA repair, cancer and other diseases. Rich Messmann, M.D., M.H.S., M.Sc. - Chief Medical Officer • Former President and CEO of Cornerstone Pharma. 25+ years of specialty pharmaceutical executive experience in Fortune 500 companies (BMS, Eli Lilly, J&J and GE) as well as biotech firms (Endo and Sunesis). More than 40 years of experience at Eli Lilly, Targanta, BioCriteria, Beta Cat and Salarius leading development, manufacturing, quality and clinical trial operations. Bill Current, Ph.D. – Vice President, Regulatory Affairs • More than 30 years of experience at Eli Lilly, Targanta, BioCriteria and other companies leading regulatory affairs for multiple therapeutic areas. APEX -3- Board Members and Scientific Advisors John Barnard – chairman, BOD • David Broecker – member BOD and SAB • Professor at Indiana University School of Medicine (IUSM); Betty and Earl Herr Chair of Pediatric Oncology Research; Professor in Departments of Pediatrics, Biochemistry & Molecular Biology and Pharmacology & Toxicology, Associate Director, IU Simon Cancer Center. Devoted more than 25 years exploring APE1/Ref-1 and its role in redox signaling, DNA repair, cancer and other diseases. Martin Haslanger, Ph.D. – CEO Emeritus, member BOD and SAB • Named CEO of Apexian in 2016. Former CEO of Cornerstone Pharmaceuticals, with 25+ years of specialty pharmaceutical executive experience in several Fortune 500 companies, BMS, Lillly J & J, GE, Endo, as well as biotech firms. Mark Kelley, Ph.D. – Chief Scientific Officer • 35-year veteran of the pharmaceutical industry and former CEO and served as chairmen of the board for Bristol Myers Squibb. Prior to BMS, Mr. Cornelius served as chairman emeritus of the Guidant Board of Directors and member of the Board of Directors of Eli Lilly, a member of its Executive Committee and chief financial officer Steve Carchedi – CEO, member BOD and SAB • CEO of APEX from 2014 to 2016. Former CEO of Alkermes and has served in executive leadership positions at Eli Lilly and Company and several biotech firms. Currently he is CEO of Indiana Bioscience Research Institute Jim Cornelius – Investor, Advisor and member of SAB • Founder of Barnard Associates and Pearl Street Venture Funds. Former financial executive at Eli Lilly and Company. Has assisted in the formation of many successful new companies. CEO of APEX from founding until 2014. Former discovery and development executive at Eli Lilly and Company, Squibb and Schering-Plough. Homer Pearce, Ph.D. – member BOD and chairman, SAB • . Former Vice President, Cancer Research and Clinical Investigation and Distinguished Research Fellow at Eli Lilly & Company. Led discovery and development of Gemzar™ and Alimta™ APEX -4- APE1/Ref-1 Overview • APE1 (apurinic/apyrimidinic endonuclease), also called Ref-1 (redox effector factor 1), is a multifunctional cellular protein with two distinct and separate functions: • APE1 Redox Function: Redox regulation of transcription factors (TFs) effecting critical aspects of cancer cell survival and growth including HIF-1, STAT3, NF-KB, and others. We can target multiple signaling pathways relevant to various cancers with one protein— as APE1 regulates transcription factors (TFs) HIF1a, STAT3, NFkB and others. APX3330 inhibits only the APE1 redox signaling activity. • DNA Repair Function: DNA base repair caused by oxidative stress, alkylating agents, and ionizing radiation • Various cancers, including treatment resistant tumors, have shown elevated expression of APE1 suggesting adaptation and unique survival mechanisms through this pathway. APEX -5- APE1/Ref-1 Overview (Cont.) • The drug has a direct and selective interaction with APE1 as demonstrated by chemical foot-printing, mass spectrometry, and other biochemical data. • Although multiple pathways may be modulated, unacceptable toxicity following APE1 inhibition has not been observed in animal or human studies. • Preclinical data supports the use of the drug as a single agent; future directions indicate partnering APX3330 with various clinical agents such as JAK2 inhibitors (Ruxolitinib, LY3009104. etc), STAT3 inhibitors, gemcitabine and Abraxane (nab-paclitaxel). APEX -6- APE1/Ref-1 protein has demonstrated relevance in the following cancers: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Non-small cell lung cancer Colorectal cancer Breast cancer Prostate cancer Gynecologic cancers (ovarian, cervical) Pancreatic cancer Glioblastoma multiforme, meduloblastoma Renal cancer Gastric cancer Germ cell tumors Head-and-neck cancers Multiple myeloma (hematologic cancer) Osteosarcoma and Rhabdomyosarcoma (pediatric) Green = Mark Kelley’s Laboratory Black = APE1 expression validated independently in multiple labs references available in Diligence Files APEX -7- Why is APE1 Important? APE1 Protein is a node that controls the downstream signaling multiple transcription factors APX3330 (reduced APE1) C65 C93 Redox active site X HIF-1a NFkB STAT3 AP-1 NRF2 (oxidized APE1) X APEX TF X (oxidized APE1) TF (oxidized TF) (reduced TF) (reduced TF binds to target DNA) Target gene expression: Growth Inflammation Angiogenesis X -8- APX3330 Inhibits APE1 Redox Function and Downstream Transcription Factors APX3330 DNA Stat3 APX3330 uM APEX APX3330 uM APX3330 uM Luciferase APX3330 uM -9- APX3330 Reduces Tumor Growth and Metastasis in a Variety of Tumor Types PaCa-2 Human PDAC Metastasis Number of lymph node metastases # of Lymph Node Metastases 18 16 Individual Mice Average 14 12 10 8 * 6 4 2 * p<0.01 0 Vehicle E3330 APX3330 Preclinical Results and Conclusions: • 3+ fold reduction in PaCa-2 or Panc254 tumors • Significantly less PDAC metastasis • Multiple models, consistent results SOURCE: Fishel ML, et al Kelley MR. (2011). Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth. Molecular Cancer Therapeutics. Sep;10(9):1698-708 and Lou et al Aberrant expression of redox protein Ape1 in colon cancer stem cells.Oncol. Letters 2014 Apr;7(4):1078-1082. Epub 2014 Feb 10. APEX - 10 - Ratio to Actin APE1 Redox Inhibition with APX3330 Reduces Pro-survival Downstream Target Proteins in Prostate Cancer Cell Lines APX3330 APX3330 * * * * * * APX3330 PC3 C4-2 E7 • PC3, C4-2, and noncancerous E7 cells were treated with the redox-function inhibitor APX3330. • Further, APX3330 preferentially inhibited the expression of survival proteins in prostate cancer lines relative to benign lines. APEX - 11 - APX3330 Provides Synergistic Anti-tumor Effect When Added to a JAK2 Inhibitor APEX - 12 - APX3330 Provides Synergistic Anti-tumor Effect When Added to a JAK2 Inhibitor Patient-derived Pa03C (pancreatic cancer) and patient-derived cancer associated fibroblasts (CAF) cells in 3D spheroid model: 2500000 Tumor area – Tumor area – Co-culture Tumor alone Rux only uM^2 2000000 Rux+APX 1500000 1000000 CAF area – Co-culture 500000 0 Ruxolitinib (uM) APEX - 13 - Prior Development of APX3330 Eisai conclusion: • • • No significant acute toxicity on neurologic, cardiovascular, or pulmonary function in patients administered APX3330 Improvements in transaminase levels in patients with hepatitis B and C Eisai ended APX3330 development after in-licensing Revovir® (clevudine) for the treatment of hepatitis B and Humira (adalimumab) for treatment of rheumatoid arthritis, IBD and other indications. Note: Eisai detected human serum concentrations of APX3330 at 147µM; a level well above that required for anti-tumor effect in our xenograft models of pancreatic cancer. APEX - 14 - Apexian Clinical Plans for APX3330 • Apexian will complete a two-part phase I oncology study: • Increasing doses in patients with treatment-refractory solid tumors 20-40 patients Phase 1 expansion strategy • • • • Evidence of anti-tumor effect; indications for which therapy is synergistic/additive with APX3330; indications that require neurotoxic chemotherapy; biomarker evidence of APX3330 effect Study details: • • • Identify the RP2 dose of APX3330 POC within 12 months Based upon • • • • IND accepted by the FDA: • • tolerability of the agent evidence of anti-tumor effect pharmacokinetic and pharmacodynamic Contracts pending completion of the funding round Sites include START (Tolcher and Lakhani) & IU (O’Neil) * APEX Involves Big 10 Consortium - 15 - External Validation of APE1 as a Cancer Target • Ovarian • • • • • • • • • Osteosarcoma Hepatocellular Carcinoma (HCC) Glioblastoma Bladder Triple Negative BC Breast cancer Head and Neck Endothelial Cell Tumor Pancreatic • • • • Colorectal Retinoblastoma Multiple Myeloma Non-small cell lung (NSCLC) • • • • Locally advanced rectal cancer Pediatric Ependymona Prostate Cervical APEX Wen et al 2016, Kong et al 2016; Londero et al 2014; Zhang et al 2009; Tanner et al 2004 Jiang et al 2015; Wang et al 2007 DiMaso et al 2015; Yang et al 2014; Avellini et al 2010 Montaldi et al 2015 Shin et al 2015 Lee et al 2015 Woo et al 2014; Puglisi et al 2002 Koukourakis et al 2001 Biswas 2015 Jiang et al, 2015; Chen 2013; Zou et al 2008; Ziong et al 2010; Zou et al 2009; Jiang et al 2015 Lou et al 2014; Noike et al 2008 Sudhakar et al 2014 Xie et al 2010; Yang et al 2007 Kang et al 2012; Wang et al 2009; Yoo et al 2008; Kakolyris et al 2000 Kim et al 2012 Bobola et al 2011 Gray et al 2005 Hedley et al 2004; Herring et al 1998 - 16 - APX3330 Combination Studies APEX - 17 - Biomarker Strategy: Goal to Identify Patients Most Likely to Benefit from Treatment • APE1 Protein levels are measurable in blood and tissue • Anti-APE1 antibody already developed and commercially available • Tissue and radiographic imaging techniques are options • Strategy: • Pretreatment Tissue samples being collected • Pre and Post Treatment Blood samples being collected • Circulating tumor cells to be collected APE1 levels and downstream effects on transcription factors and other biomarkers will be analyzed for evidence of anti-tumor effect and potential selection criteria for future studies. APEX - 18 - APX3330 Manufacturing and Supply Chain • APX3330 Drug Substance • Robust 4-step synthesis (replicated from Eisai) Scaled up at Strides Shasun under cGMP to > 3 Kg scale Ongoing 36 month ICH stability • • APX3330 MW 378.47 • APX3330 Drug Product • Common excipients (replicated from Eisai) o Lactose, Microcrystalline Cellulose, Starch, Sodium Carboxymethylcellulose 60 mg 120 mg and Magnesium Stearate • • • Manufactured, packaged and labeled 60 mg and 120 mg coated tablets at Catalent Pharma Solutions under cGMP to supply phase 1 study Ongoing 36 month ICH stability APX3330 Clinical Supply Chain • • APEX Packaged inventory stored a controlled room temperature at Catalent Catalent providing distribution to the clinical sites - 19 - APX3330: Robust Global IP Portfolio, Orphan Drug Designation & Near Term Approval US Patent No. 9,040,505 US Patent No. 9,089,605 “Use of APX3330 in treatment of cancer and angiogenesis” “Composition of matter for quinone derivatives” Expiration Date: 2030 Expiration Date: 2029 US Patent No. 9,193,700 “Composition of matter for quinone compounds for treating APE1 diseases” Expiration Date: 2032 US Patent No. 9,315,481 “Methods and compounds for ref-1 inhibition in leukemia” Expiration Date: 2033 Application No. PCT US2016/0309045 “Use of APX3330 in treatment of ChemotherapyInduced Peripheral Neuropathy” Earliest Projected Expiration Date: 2036 Portfolio Patent Estate Over 70+ issued or filed patents worldwide APX3330 is IP protected until 2030 and beyond across US, Australia, EU, Japan, China, Brazil and other key countries Seeking orphan drug designation by the US FDA for the treatment of relapsed and refractory solid tumors APX3330 near term approvals within 2019 – 2020 APEX - 20 - Sustainable Horizons for Growth APX3330 Targeting Large Unmet Need in Terms of Patient Pool Step 3 Business Plan Phase 3 Program Step 2 Phase 2 Program Step 1 Phase I Program R/R Solid Tumors (Accelerated Path to Approval) Phase 1B Phase 1A Safety Study 20-30 Patients 2017 APEX (APE1 Expressing Targeted Indications) 10 patients Pilot Single Agent & Combination Studies Proof of Concept Studies Registration Studies Pursue Other High Unmet Need Tumors 2018-19 2020 - 21 - Apexian Company Summary Company Our Lead Compound Privately held, Indiana based, clinical stage, biotech company with first-in-class therapy targeting the APE1 protein APX3330 an novel oral anticancer agent has shown preclinical efficacy against a variety of APE1-expressing tumors Near to market opportunity Phase I oncology study of APX3330 is ready for execution. IND approved by FDA and IRB approval by 1st clinical site Clinical Plan Robust manufacturing process with clinical supplies available APX3330 safety has been confirmed in 10 Phase I/II human studies of non-cancer indications with over 422 patients Strong Portfolio Robust IP Our Management APEX Pipeline of oral anticancer agents (APX2009, APX2014). Additional oncology and nononcology indications could lead to broad clinical utility Robust IP estate and plan seeking Orphan Drug Designation Extensive experience in discovery, development and commercialization of oncology products - 22 - “Moving mountains to serve cancer patients” www.ApexianPharma.com APEX - 23 -