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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 • Currently seeking funding or clinical development partnership 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, PhD – 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 as well as biotech firms. Mark Kelley, Ph.D. – Chief Scientific Officer • 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 Steve Carchedi – CEO, member BOD and 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 footprinting, 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- Alteration of APE1/Ref-1 protein expression has been shown to be elevated in: 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) APEX -7- APX3330 inhibits APE1 Redox Function Blocking TF Activity APX3330 (reduced APE1) C65 C93 Redox active site X HIF-1a NFkB STAT3 AP-1 NRF2 X (oxidized APE1) (oxidized APE1) TF APEX (oxidized TF) X TF (reduced TF) (reduced TF binds to target DNA) Target gene expression: Growth Inflammation Angiogenesis X -8- APX3330 inhibits APE1 redox function in tumor cells APX3330 DNA Stat3 APX3330 uM APEX APX3330 uM APX3330 uM Luciferase APX3330 uM -9- APX3330 Reduces Tumor Growth and Metastasis Panc253 Patient-derived cells PaCa-2 % Growth (Mean ± SEM) 800 700 Control APX3330 600 500 400 300 200 25 mg/kg 100 0 1 4 8 11 15 18 22 25 29 Day 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 • • • • Overall Preclinical Results and Conclusions: 3+ fold reduction in PaCa-2 tumors 2+ fold reduction in Panc254 tumors Significantly less metastasis PDAC Multiple models, consistent results E3330 APX3330 SOURCE: Fishel ML, Jiang Y, Rajeshkumar NV, Scandura G, Sinn AL, He Y, Shen C, Jones DR, Pollok KE, Ivan M, Maitra A, Kelley MR. (2011). Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth. Molecular Cancer Therapeutics. Sep;10(9):1698-708. APEX - 10 - APX3330 Enhances Gemcitabine 1200 Mean Tumor Volume (mm3) 1000 Vehicle 800 APX3330 25mg/kg All drug treatments stopped on day 30 APX3330 25+Gem Gem 35mg/kg 600 400 * 200 * 0 APX3330 12 Gem 16 22 29 34 37 41 Days after Implantation APEX 44 * * 49 55 63 Error bars were removed from graph for clarity. * =p<0.05 between Gem+APX3330 and Gem alone. All drug treatments were significantly different from the vehicle control p<0.01. - 11 - Role of APE1 in Cancer Immunotherapy • PD-L1 and APE1 …findings suggest that high expression of PD-L1 and APE1 is a risk factor of gastric cancer and a new biomarker to predict the prognosis of gastric cancer…. • …findings suggest that targeting the PD-L1 and APE1 signaling pathways may be a new strategy for cancer immune therapy and targeted therapy for gastric cancer… Kaplan–Meier analysis demonstrated that PD-L1 and APE1 co-positivity was significantly related to a poor prognosis (P=0.003). Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Qing, et al. PMC4338255. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338255/ APEX - 12 - 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 - 13 - 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 Study endpoint: • • Identify the RP2 dose of APX3330 Based upon • • • • IND accepted by the FDA (July 2016): • • • tolerability of the agent evidence of anti-tumor effect pharmacokinetic and pharmacodynamic All study documents are ready and sites identified Contracts pending completion of the funding round Additional safety, tolerability and efficacy POC APEX - 14 - 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 - 15 - 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 - 16 - Apexian Company Summary Company Privately held, clinical stage, biotech company with first-in-class therapy targeting the APE1 protein Our Lead Compound APX3330 an novel oral anticancer agent has shown preclinical efficacy against a variety of APE1-expressing tumors 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 non-oncology 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 - 17 - “Moving mountains to serve cancer patients” www.ApexianPharma.com APEX - 18 -