Lorus Therapeutics Inc. 2 Meridian Road
Toronto, Ontario Canada M9W 4Z7 Phone: (416) 798-1200 Fax: (416) 798-2200 www.lorusthera.com
Attacking Cancer with Multiple Drug Candidates
Snapshot January 3, 2005
Lorus Therapeutics Inc. (“Lorus”) is a biopharmaceutical company specializing in the research, development, and commercialization of pharmaceutical products and technologies for the management of cancer†. With products in all stages of evaluation, from preclinical through Phase III, and a product approved for use in Mexico, the Company develops therapeutics for the purpose of managing cancer efficaciously and with low- toxicity. Lorus’ lead products span three classes of anti-cancer therapies: (1) immunotherapies, based on macrophage-stimulating biologic response modifiers; (2) antisense therapies, based on synthetic segments of deoxyribonucleic acid (DNA), designed to bind to the messenger ribonucleic acid (mRNA) that is responsible for the production of proteins over-expressed in cancer cells; and (3) small-molecule chemotherapies, targeting biochemical pathways that are key to the development of cancer, and are potentially anti-angiogenic, anti-proliferative, and anti-metastatic. Lorus has also developed a tumor suppressor/gene therapy approach and a U-sense technology that have demonstrated preclinical anti-cancer potential. The most advanced candidate in the Company’s pipeline, Virulizin®, is an immunotherapy that mobilizes the body’s immune system to attack and eliminate cancer cells. Virulizin® is currently sold in Mexico through Mayne Pharma for the treatment of malignant melanoma and is in a Phase III trial for the treatment of advanced pancreatic cancer, having received Orphan Drug status, special protocol assessment, and Fast Track designation by the U.S. Food and Drug Administration (FDA). Lorus is collaborating as well with the U.S. National Cancer Institute (NCI) to conduct multiple Phase II clinical trials with its lead antisense drug, GTI-2040, which is in a Phase II clinical trial program for the treatment of cancers of the breast, colon, prostate, lung, various solid tumors, and leukemia. This drug is also in Phase II to treat renal cell carcinoma (RCC), the most common form of kidney cancer. Lorus is additionally pursuing the development of a number of small molecule compounds, which are currently undergoing extensive preclinical study.
Recent Financial Data
1 LRP (AMEX)/ Ticker (Exchange) LOR (TSX) Recent Price (01/03/05) $0.60
52-Week Range $1.00-0.45 Shares Outstanding (mm) 172.0 Market Cap. (mm) $103.2 Avg. 3-month volume (AMEX) 24,590
Avg. daily volume (TSX) 171,000 Institutional Owners ~30%
EPS (as of 08/31/04) ($0.04) 1All amounts are in Canadian dollars, except pricing data, Employees 80 which is in U.S. dollars.
Key Points
Lorus is developing cancer drugs, which cause fewer demonstrated side effects than current treatments, and are targeted for large markets including, but not limited to, malignant melanoma, pancreatic, lung, breast, prostate, colorectal cancer, and leukemia. Together, these account for over half of all cancers. Lorus’ most advanced development candidate, Virulizin®, is progressing through a pivotal Phase III clinical trial in pancreatic cancer, having recently completed enrollment of patients from over 100 clinical sites. Rarely curable, pancreatic cancer is the fourth leading cause of cancer death in the U.S., and has an overall survival rate of <1% at 5 years, with most patients dying within one year.
EXECUTIVE INFORMATIONAL OVERVIEW Lorus pursues a multi-mechanistic approach to treating cancer, believing that cancer will continue to be treated by many different drugs through a variety of mechanisms of action. This approach could reduce the risks that are inherent in the development of cancer therapeutics. The Company maintains a solid financial position with approximately CDN$25 million in cash and a quarterly cash burn rate of approximately CDN$5.8 million.
†BOLD WORDS ARE REFERENCED IN GLOSSARY ON PAGES 43-46.
Table of Contents
Snapshot ...... 1
Recent Financial Data ...... 1
Key Points ...... 1
Executive Overview...... 3
Growth Strategy...... 5
Intellectual Property...... 5
Management and Board Members...... 7
Core Story ...... 12
Cancer ...... 12
Immunotherapy and Macrophages...... 15
Antisense Therapy...... 21
Small Molecule Discovery Program ...... 27
Recent Milestones ...... 29
Key Points to Consider...... 30
Historical Financial Results ...... 31
Risks...... 34
Recent Events ...... 37
Glossary of Lesser-Known Terms ...... 43
Executive Informational Overview Page 2
Executive Overview
Lorus Therapeutics Inc. (“Lorus”) is a biopharmaceutical company specializing in the research, development, and commercialization of pharmaceutical products and technologies for the management of cancer. With products in all stages of evaluation, from preclinical through Phase III trials, and a product approved for use in Mexico, the Company develops therapeutics that have demonstrated lower toxicity than current compounds on the market, and have been shown to improve patients' quality of life.
The lead products in the Company's pipeline span three classes of anti-cancer therapies: (1) immunotherapies, based on macrophage-stimulating biological response modifiers; (2) antisense therapies, based on synthetic segments of deoxyribonucleic acid (DNA) designed to bind to the messenger RNA (mRNA) responsible for the production of proteins over-expressed in cancer cells; and (3) small-molecule chemotherapies targeting biochemical pathways that are key to the development of cancer, and are potentially anti-angiogenic, anti-proliferative, and anti-metastatic.
By developing cancer therapeutics using different mechanisms of action that could prove effective against a broad spectrum of cancers, Lorus may be able to reduce the risk inherent in the drug development process, and consequently maximize its opportunity to address a variety of cancer markets. Each of the Company’s key areas of focus are illustrated in Figure 1 and are briefly described below, with extensive details contained within this Executive Informational Overview™ (EIO™).
Figure 1 Lorus Therapeutics Inc. DRUGS IN CLINICAL DEVELOPMENT PIPELINE Research Preclinical Phase I Phase II Phase III Approved
VIRULIZIN® (Malignant Melanoma) (Launched in Mexico by Mayne Pharma) VIRULIZIN® (Advanced Pancreatic)
NEO-VIRULIZIN (2nd Generation)
GTI-2040 (Renal cell carcinoma)
GTI-2040 (Unresectable colon cancer)
GTI-2040 (Non-small cell lung cancer)
GTI-2040 (Advanced breast cancer)
GTI-2040 (Solid tumors)
GTI-2040 (Acute myeloid leukemia)
GTI-2040 (Prostate cancer)
GTI-2501 (Prostate cancer)
GTI-4006 (IGFII)
GTI-3611 (VEGFR)
GTI-3008 (TR)
GTI-2601 (TRX)
NC381 (Cyclacel)
NC-383, NC-384
Tumor suppressor technology
New small molecule
U-sense
Source: Lorus Therapeutics Inc.
Executive Informational Overview Page 3
® Immunotherapy. Lorus’ lead drug candidate in development, Virulizin , is a novel biological response modifier that mobilizes the body’s immune system to recognize and attack cancer cells. The compound is in a Phase III clinical trial for the treatment of pancreatic cancer after having demonstrated anti-tumor efficacy and an excellent safety profile in clinical trials. Pancreatic cancer is the fourth leading cause of cancer death in U.S. It is seldom curable, and is frequently diagnosed too late for surgical intervention. In four out of five cases the disease spreads beyond the pancreas. Pancreatic cancer has an overall survival rate of <1% at 5 years, with most patients succumbing within a year of diagnosis. Virulizin® has received Orphan Drug status, special protocol assessment, a Fast Track designation by the U.S. Food and Drug Administration (FDA), and is currently available in Mexico for the treatment of malignant melanoma.
Antisense. GTI-2040 is in a Phase II clinical trial for the treatment of renal cell carcinoma (RCC), also known as kidney cancer, and in various other clinical trials in collaboration with the U.S. National Institutes of Health’s (NIH) National Cancer Institute (NCI) developmental therapeutics program. Also in the antisense class is GTI-2501, which is currently in a Phase II clinical trial for hormone-refractory prostate cancer.
Small molecule compounds. Lorus has several small molecules that are being investigated in preclinical studies. The Company has out-licensed development and commercialization of its clotrimazole (CLT) analog, NC 381, to U.K.-based Cyclacel Ltd. The agreement extends to other drug candidates that Cyclacel may identify from a library of clotrimazole analogs licensed by Lorus’ NuChem Pharmaceuticals Inc. subsidiary by Harvard Medical School in 1997. These small molecules were derived from an existing anti-fungal agent known to have anti-proliferative, anti-angiogenic, and anti-metastatic properties in cancer when tested in cell line and animal studies. Lorus is also actively developing new drug candidates in another small molecule preclinical research program that demonstrates both anti-cancer and antibacterial activity by targeting enzyme or receptor-binding sites to inhibit the activity of disease-causing proteins.
Additional preclinical work includes gene-based therapeutics [gene therapy, U-Sense therapy (proprietary to Lorus) and further antisense molecules] and a second generation immunotherapeutic program.
In 2003, the Centers for Disease Control and Prevention (CDC) estimated that approximately 1.3 million new cases of cancer were diagnosed, and that more than 556,500 Americans (about 1,500 people per day) were dying from the disease. In total, the NCI estimates that there are nearly 9.6 million people with a history of cancer in the U.S. This figure represents tremendous economic ramifications. According to the NIH, in 2002 the overall annual cost of cancer in the United States was $171.6 billion, increasing from $156.7 billion in 2001. This amount included $60.9 billion for direct medical expenses, compared with $56.4 billion in 2001; $15.5 billion for lost worker productivity due to illness versus $15.6 billion in 2001; and $95.2 billion for lost worker productivity due to premature death, up from $84.7 billion in 2001.
Headquarters and Employees
Founded in 1986, Lorus Therapeutics is headquartered in Toronto, Ontario, and currently employs approximately 80 people. In 1999, Lorus merged with GeneSense Technologies Inc., a company with drug development programs concentrating on genetic approaches for discovering new anti-cancer drugs, including the design of second-generation antisense compounds with exceptional anti-tumor properties.
Executive Informational Overview Page 4
Growth Strategy
Lorus’ strategy for the near-term (2-5 years) is to license the marketing rights for its drug candidates to pharmaceutical partners, or to co-develop drugs with strategic partners who can share the risk and costs of later-phase development and commercialization. Lorus’ objective is to maximize and retain a large proportion of the value it creates, and when feasible, assume greater responsibility for late-stage clinical development of its internally developed drug candidates.
The Company plans to exploit its core capabilities through in-house discovery programs, collaborative research agreements that have the potential to generate new product candidates, and licensing and acquisition activities to obtain high potential oncology compounds that have completed preclinical and Phase I studies.
To date, Lorus has out-licensed the development and commercialization of small molecule compounds, most notably the clotrimazole analog NC 381, to U.K.-based Cyclacel Ltd. The agreement extends to other drug candidates that Cyclacel may identify from a library of clotrimazole analogs licensed to Lorus’ NuChem subsidiary by Harvard Medical School in 1997. Under the terms of this agreement, Lorus received an upfront payment of USD$400,000 and is to receive future milestone payments, assuming that all milestones are achieved, of USD$11.6 million. Similar milestones are to be paid for each of the other compounds developed from the library. Lorus will also receive royalties based on product sales. Cyclacel is responsible for all future drug development costs.
Intellectual Property
Lorus has assembled an extensive portfolio of issued and pending patents that cover its lead drugs. Some of these patents were issued to GeneSense Technologies, which merged with Lorus, and others were issued to NuChem Pharmaceuticals, Lorus’ subsidiary. Table 1 (page 6) provides a summary of Lorus’ portfolio of issued patents.
Executive Informational Overview Page 5
Table 1 Lorus Therapeutics Inc. ISSUED PATENTS Patent Description Countries Issued Issued and Expiration Dates GeneSense Antitumor Antisense Sequences Directed Against R1 and R2 U.S., Singapore, Australia, New Most Recent Issued: Components of Ribonucleotide Reductase (GTI-2040) Zealand July 15, 2003 Expires: Feb. 11, 2019
Suppression of Malignancy Utilizing Ribonucleoside Reductase U.S., Singapore, Australia, Europe Most Recent Issued: R1 (Gene Therapy) (Great Britain, France, Germany, Italy, May 12, 2004, Spain) Expires: March 18, 2018 Antisense Oligonucleotide Sequences as Inhibitors of U.S., Canada Issued: April 8, 2003 Microorganisms Expires: July 10, 2018 Neuropilin Antisense Oligonucleotide Sequences and Methods Australia Issued: Aug. 19, 2002 of Using Same to Modulate Cell Growth (GTI-3611) Expires: April 23, 2019
Oligonucleotide sequences Complementary to Thioredoxin or U.S., Australia Most Recent Issued: Thioredoxin Reductase Genes and Methods of Using Same to Aug. 28, 2003 Modulate Cell Growth (GTI-2601/3008) Expires: Feb. 11, 2019 Antitumor Antisense Sequences Directed Against R1 and R2 U.S. Issued: Sept. 19, 2000 Components of Ribonucleotide Reductase (GTI-2501) Expires: Feb. 11, 2019 Insulin-Like Growth Factor II Antisense Oligonucleotide U.S., Australia Most Recent Issued : Sequences and Methods of Using Same to Modulate Cal Growth Oct. 17, 2002 (GTI-4006) Expires: April 23, 2019 Lorus Virulizin® (Family Composition) (Immunomodulating U.S., Canada, Europe (Germany, Issued: various dates between Dec. Compositions from Bile) Spain, France, Great Britain, Italy), 29, 1998 and July 9, 2003 Expires: Australia, Korea, Mexico, New various dates between Sept. 9, 2014 Zealand, China, Hong Kong and May 16, 2016.
Virulizin® (Family Use) (Immunomodulating Compositions [from U.S., Canada, Australia, Singapore, Issued: various dates between Jan. Bile] for the Treatment of Immune System Disorders) New Zealand 20, 2000 and July 22, 2003 Expires: various dates between March 16, 2015 and July 13, 2018
Immunomodulating Compositions for the Treatment of Viral South Africa Issued: July 28, 1999 Disorders Expires: July 13, 2018 NuChem Substituted 11-Phenyl Dibenzazepine Compounds Useful for the U.S., Australia, China, New Zealand Issued: various dates between Oct. Treatment or Prevention of Disease Characterized by Cell 17, 2002 and April 18, 2003 Proliferation Expires: various dates between Nov. 20, 2017 and Nov. 20, 2018
Substituted Diphenyl Indanaone, Indane and Indole Compounds Australia Issued: July 11, 2002
Trianyl Methane Compounds, their Analogues and Uses Thereof U.S., Canada, Australia, Mexico, New Issued: various dates between Dec. Zealand 7, 2000 and Feb. 21, 2002 Expires: various dates until March 19, 2017
Use of Aromatic Halides for Treating Mammalian Cell Europe, Australia Issued: various dates between July Proliferation 15, 1999 and Nov. 27, 2002
Cancer Treatments U.S. Issued: May 27, 1997 Expires: May 27, 2014 Treatment for Diseases Characterized by Neovascularization U.S. (3 Patents), Europe (Germany, Most Recent Issued August 27, Spain, France, Great Britain, Italy) 2003 Expires February 18, 2014
Imidazole Compounds for use as a Medicament Against Pre- Israel Issued: April 13, 2003 Cancerous Lesions Expires: April 21, 2016 A Method of Treating Epithelial Pre-Cancerous Lesions with U.S. Issued: Sept. 17, 1996 Topical Imidazole Expires: April 25, 2015
* Patents licensed to Cyclacel. Source: Lorus Therapeutics Inc.
Executive Informational Overview Page 6
Management and Board Members
Management
Table 2 summarizes Lorus’ key management, with detailed biographies following.
Table 2 Lorus Therapeutics Inc. MANAGEMENT Jim A. Wright, Ph.D. President and Chief Executive Officer Aiping Young, M.D., Ph.D. Chief Operating Officer W. Bruce Rowlands Senior Vice President, Planning and Public Affairs Shane Ellis, B.A., LL.M. Vice President, Legal Affairs and Corporate Secretary Paul J. Van Damme, C.A. MBA Chief Financial Officer
Source: Lorus Therapeutics Inc.
Jim A. Wright, Ph.D., President and Chief Executive Officer
Dr. Jim A. Wright, president and chief executive officer (CEO) of Lorus Therapeutics, was a co-founder of the biotechnology company, GeneSense Technologies Inc. At various times during his tenure at Lorus, he has served as a member of the board, president and chief scientific officer (CSO), and is currently serving as president and CEO and is on the board of directors of the company. For GeneSense, he served at various times as its president, chairman of the board, and CSO. Dr. Wright is recognized internationally for his work in cancer biology. He has been professor of microbiology in the faculty of science, professor of biochemistry and molecular biology in the faculty of medicine, and adjunct professor of internal medicine in the faculty of medicine at the University of Manitoba. He has also been senior scientist, associate director, and acting director at the Manitoba Institute of Cell Biology, Manitoba Cancer Treatment and has also held the position of professor of medical biophysics at the University of Toronto. Dr. Wright has also been a Terry Fox Scientist, a senior scientist of the National Cancer Institute of Canada, and until recently, has been a Terry Fox Senior Scientist of the National Cancer Institute of Canada. Dr. Wright has approximately 200 scientific publications to his credit and has co-authored numerous patent applications. He has served as an advisor for various journals, agencies, and companies.
Aiping H. Young, M.D., Ph.D., Chief Operating Officer
Dr. Aiping Young, chief operating officer (COO), was a co-founder with Dr. Wright (see biography above) of GeneSense Technologies Inc. She has served as a member of the board of directors of GeneSense and held the position of senior vice president and chief technology officer (CTO) at Lorus, and previously as vice president of research and development at GeneSense until its merger with Lorus. Dr. Young previously held the positions of senior scientist, group leader, and medical and scientific advisor of Pias Corporation in Japan, where she was in charge of medical activities for that company. She has published two books and numerous scientific papers in diverse bioscience areas (e.g., physiology, molecular biology, pharmacology, and cell biology). Dr. Young has co-authored several key patent applications. She graduated from Jiangxi Medical College in China in 1979 and holds a Ph.D. in Pharmcology from Toyama Medical and Pharmaceutical University in Japan in 1989. She was a research associate at the University of Manitoba and has held the position of adjunct scientist at the Manitoba Institute of Cell Biology in the Manitoba Cancer Treatment and Research Foundation in Winnipeg, Canada.
Executive Informational Overview Page 7
W. Bruce Rowlands, Senior Vice President, Planning and Public Affairs
Mr. Bruce Rowlands, senior vice president, planning and public affairs, has extensive industry experience in the areas of corporate finance, institutional equity sales, and investor communications. Most recently, he served as vice president and director at Dominick & Dominick Securities Canada, an affiliate of Dominick & Dominick LLC in New York City. During the past eight years Mr. Rowlands has participated in financings involving more than CDN$300 million for emerging North American companies, including biotechnology companies. Since 1997, he has been involved in all of Lorus’ financing transactions, totaling approximately CDN$100 million.
Shane A. Ellis, B.A., LL.M, Vice President, Legal Affairs and Corporate Secretary
Mr. Shane Ellis, vice president legal affairs and corporate secretary, joined Lorus with over 19 years of legal experience, to guide the Company’s legal activities and regulatory compliance on corporate governance issues. From 1994 to 1997, he lectured in business law at the School of Business Management at Ryerson Polytechnical University. From 1996 to 1998, Mr. Ellis acted as counsel for the Bennett & Wright Group of companies. He also has extensive and broad experience as counsel with companies such as the Dehavilland Aircraft Company and Journey’s End Corporation, and he has co- authored a textbook on Canadian business law. Mr. Ellis provides expertise in intellectual property and licensing, particularly in the area of technology transfer.
Paul J. Van Damme, C.A, MBA, B.Comm., Chief Financial Officer
Mr. Van Damme joined Lorus as chief financial officer (CFO) in September 2004. Mr. Van Damme has more than 20 years of financial strategy and operations experience in the biotechnology sector, and other industries. He began his biotechnology career at GlycoDesign Inc. as vice president of finance. He subsequently assumed the position of senior vice president, finance and CFO at Allelix Biopharmaceuticals Inc., where he was responsible for all aspects of financial management and investor relations. He participated in the sale of the company to NPS Pharmaceuticals Inc. (NPSP-NASDAQ) in Salt Lake City, UT. Mr. Van Damme has held senior finance positions in several other public companies in diversified industries. He is a chartered accountant and holds MBA and B.Comm. degrees from the University of Toronto. He is a member of several professional associations including the Canadian Institute of Chartered Accountants and Financial Executives International.
Board of Directors
Lorus’ board of directors oversees the conduct of and supervises the Company management. Table 3 provides a summary of board members, followed by detailed biographies.
Table 3 Lorus Therapeutics Inc. BOARD OF DIRECTORS Graham Strachan (Chairman) President, GLS Business Development Inc., Toronto J. Kevin Buchi Senior Vice President and Chief Financial Officer, Cephalon Inc. Gregory A. Curt, M.D. Medical Director, Field Medical Group, AstraZeneca Donald W. Paterson President, Cavandale Corporation, Toronto Elly Reisman Chief Executive Officer, The Great Gulf Group, Toronto Alan Steigrod Managing Director, Newport HealthCare Ventures, Newport Beach, CA Jim A. Wright, Ph.D. President and Chief Executive Officer, Lorus Therapeutics Inc.
Source: Lorus Therapeutics Inc.
Executive Informational Overview Page 8
Graham Strachan, Chairman
Mr. Strachan is president of GLS Business Development Inc., a life-science consulting firm, located in Etobicoke, Ontario. Prior to 1999, Mr. Strachan was president, CEO, and director of Allelix Biopharmaceuticals Inc.
J. Kevin Buchi, Director
Mr. Buchi is senior vice president and CFO of Cephalon Inc. (CEPH-NASDAQ), an international biopharmaceutical company. Mr. Buchi is responsible for finance, accounting, manufacturing, and information systems, and has been involved in raising significant financing for Cephalon. He is a certified public accountant and has received a master’s degree in management from the J. L. Kellogg Graduate School of Management at Northwestern University.
Gregory A. Curt, M.D., Director
Dr. Curt is medical director, field medical group, oncology at AstraZeneca PLC (AZN-NYSE). Prior to assuming this role, Dr. Curt was a clinical director at the United States NCI and led the intramural program increasingly towards new therapeutic modalities, including anti-cancer drugs, immunotoxins, and vaccines. He was awarded the Outstanding Service medal of the U.S. Public Health Service in 1992.
Donald W. Paterson, Director
Mr. Paterson is president of Cavandale Corporation, a firm principally engaged in providing strategic corporate consulting to emerging growth companies within the technology industry. Prior to founding Cavandale Corporation, Mr. Paterson was a director and vice president of Wood Gundy Inc., a Canadian investment bank, where he was directly involved in leading the firm’s activities in financing Canadian and international high technology companies.
Elly Reisman, Director
Mr. Reisman is the president, CEO, and founder of Great Gulf Group, a Toronto-based real estate company.
Alan Steigrod, Director
Mr. Steigrod is managing director of Newport Healthcare Ventures, a consulting firm for the healthcare industry, located in Newport Beach, CA. Mr. Steigrod has held that position since 1996. Previously, Mr. Steigrod has served as president and CEO of Cortex Pharmaceuticals, Inc. (COR-AMEX), a neuroscience research and development company, and as executive vice president of marketing/sales of Glaxo SmithKline PLC (GSK-NYSE).
Jim A. Wright, Ph.D., Director
Dr. Wright is president and CEO of Lorus Therapeutics Inc., (see biography on page 7).
Executive Informational Overview Page 9
Medical and Scientific Advisory Board
Table 4 Lorus Therapeutics Inc. MEDICAL AND SCIENTIFIC ADVISORY BOARD Dr. Donald P. Braun, Ph.D. (Chairman) Professor, Department of Surgery at the Medical College of Ohio in Toledo, Ohio, and Administrative Director of the Cancer Institute Dr. Jaime G. de la Garza Salazar, M.D. Member of the Mayo Graduate School of Medicine, has been the Director General of the National Cancer Institute of Mexico Dr. Robert Kerbel, Ph.D. Director of Biological Sciences and the Division of Cancer Biology Research Bishnu D. Sanwal, Ph.D., D.Sc., F.R.S.C. Professor Emeritus and former Chairman of the Department of Biochemistry at the University of Western Ontario Dr. Lesley Seymour, MBBCh, FCP (SA) Co-Director of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group Louis Siminovitch, O.C., Ph.D., D.Sc., F.R.S.C., Former founder and director of the Department of Medical Genetics, F.R.S., (Chairman M.S.A.B.) University of Toronto, the Department of Genetics, Hospital for Sick Children, the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, former Director and President of the National Cancer Institute of Canada and is presently on the Scientific Advisory Board of the Canadian Medical Discoveries Fund
George R. Stark, Ph.D., F.R.S. Sherwin-Page Chairman of the Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio Mace L. Rothenberg, M.D. (Medical Advisor) Internationally Recognized Oncologist
Source: Lorus Therapeutics Inc.
Dr. Donald P. Braun, Ph.D., Chairman
Dr. Donald Braun is a professor in the Department of Surgery at the Medical College of Ohio in Toledo, Ohio, and administrative director of the Cancer Institute. Dr. Braun is a member of the Scientific Advisory Committee on Immunology of the ACS and is Chair of Lorus’ Medical and Scientific Advisory Board.
Dr. Jaime G. de la Garza Salazar, M.D.
Dr. Jaime de la Garza, a member of the Mayo Graduate School of Medicine, has been the director general of the National Cancer Institute of Mexico since 1993. He is also the president of the Mexican Oncology Board. Prior to his appointment as director, Dr. de la Garza was associate director in clinical research at the NCI.
Dr. Robert Kerbel, Ph.D.
Dr. Robert Kerbel obtained his Ph.D. in microbiology and immunology from Queen’s University, Canada, in 1972. Dr. Kerbel is currently the director of biological sciences and the division of cancer biology research at the Sunnybrook Health Science Centre in Toronto and is also the John & Elizabeth Tory Professor of Experimental Oncology at the University of Toronto. He is a member of the editorial board of many international scientific journals and is editor-in-chief of Cancer Metastasis Review.
Bishnu D. Sanwal, Ph.D., D.Sc., F.R.S.C.
Dr. Bishnu Sanwal is a professor emeritus and former chairman of the Department of Biochemistry at the University of Western Ontario, London, Ontario. With over 146 publications, Dr. Sanwal is a member of, or advisor to, numerous scientific committees and journals such as the editorial board of Archives of Biochemistry and Biophysics, member of the Royal Society of London, and Fellow of the Royal Society of Canada. He received a Ph.D. from the University of Delhi and a Doctor of Sciences from the Federal Institute of Technology in Zurich.
Executive Informational Overview Page 10
Dr. Lesley Seymour, MBBCh, FCP (SA)
Dr. Lesley Seymour is a co-director of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. She received her M.D. at the University of the Witwatersrand in South Africa in 1978 and subsequently completed specialist training in internal medicine, in addition to clinical hematology and medical oncology.
Louis Siminovitch, O.C., Ph.D., D.Sc., F.R.S.C., F.R.S.
Dr. Louis Siminovitch is a former founder and director of the Department of Medical Genetics, University of Toronto; the Department of Genetics, Hospital for Sick Children; and, the Samuel Lunenfeld Research Institute at Mount Sinai Hospital. He is a former director and president of the National Cancer Institute of Canada and is presently on the scientific advisory board of the Canadian Medical Discoveries Fund, as well as several biotechnology companies and institutes. He is a founding member and former Senior Editor of Virology, a founding member and former member of the editorial board of Cell, the editorial board of Annual Review of Genetics, a founding member and former senior editor of Molecular and Cellular Biology, a former member of the editorial board of Genetics, and of the advisory board of Molecular Biology and Medicine. Dr. Siminovitch received a Ph.D. from McGill University and was awarded a Doctor of Science, Honoris Causa, for his distinguished scientific research contributions from several Canadian universities, including Memorial University, McMaster University, the University of Montreal, McGill University, the University of Western Ontario and the University of Toronto. Dr. Siminovitch is a Companion of the Order of Canada and was inducted into the Canadian Medical Hall of Fame in 1997.
George R. Stark, Ph.D., F.R.S.
Dr. George Stark is the Sherwin-Page Chairman of the Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio. He received a Ph.D. from Columbia University and completed postdoctoral studies at Rockefeller University. Dr. Stark has made fundamental contributions to molecular biology; (Stark led the development of the Northern and Western Blot techniques for analysis of specific RNAs and proteins). Much of his work has focused on the process of gene amplification in mammalian cells, leading to an appreciation both of the mechanisms that generate amplified structures in cell lines and tumor cells and the regulatory processes that prevent amplification from occurring in normal cells. Very recent work has led to the key discovery of a new signal pathway that regulates gene expression in cancer cells. A former professor of biochemistry at Stanford University, he moved to London, England, to become the associate director of research at the Imperial Cancer Research Fund, (1983-1992). Dr. Stark received the H. A. Sober award of the American Society of Biological Chemists in 1986, was elected to the U.S. National Academy of Science in 1986, and to the Fellowship of the Royal Society in Britain in 1990.
Mace L. Rothenberg, M.D. (Medical Advisor)
Dr. Rothenberg is an internationally recognized oncologist. His research focuses on the evaluation of the effects of new drugs in humans from clinical, pharmacologic, biologic, and genetic perspectives. His work has been vital to the development and eventual U.S. FDA approval of irinotecan (CPT-11, Camptosar®), oxaliplatin (Eloxatin®) for colorectal cancer, and gemcitabine (Gemzar®) for pancreatic cancer. Dr. Rothenberg is an Ingram Professor of Cancer Research at the Vanderbilt-Ingram Cancer Center, as well as professor of medicine at the Vanderbilt University Medical Center, and a Director of Drug Development. The Vanderbilt-Ingram Cancer Center in Nashville, Tennessee is one of the world's leading institutions in cancer prevention, care, and research.
Executive Informational Overview Page 11
Core Story
Cancer
Cancer develops from abnormal cells that have circumvented the body’s immune system, and is characterized by uncontrolled growth and eventual spread to distal sites within the body. Although the human immune system has evolved to recognize aberrant “self” cells, there are a number of mechanisms by which cancer cells evade recognition. Once cancer cells escape the body’s immune system responses, they can spread throughout the body in a variety of ways, invading healthy human tissue and eventually causing widespread cell death.
Cancer is manifested as either solid tumors or blood-borne cancerous cells, which, over time, tend to invade or metastasize to other tissues and organs of the body. Typically, cancer that is diagnosed in the early stages of the disease has the best prognosis. In this event, if the cancer has not yet spread to other organs and tissues, surgical removal of the tumor can be effective. Conversely, cancer that is detected at a later stage has a much worse prognosis, as it has often already spread to other organs and tissues within the body.
Even when detected early, cancer cannot always be remedied through surgery. In many situations, the expansion of cancer to other parts of the body will preclude surgical removal of the entire tumor, or afflicted area, significantly compromising the patient’s prognosis. In such cases, even if most of the tumor is removed, the prognosis may be poor due to the spread of undetectable cancer cells or micrometastasis. As a result, even if the cancer is discovered at an early stage, it may have already entered the blood or lymphatic system and established new tumors at other sites. Cells and tumors formed at these new sites are extremely difficult to treat.
Prevalence
Cancer is a global health threat, with an estimated 10 million new diagnoses and approximately 6 million deaths annually, 40% of which occur in the developed world. The American Cancer Society (ACS) estimates that there are currently 8.9 million people in North America with a history of cancer, with approximately 3 million additional diagnoses projected this year. Specifically, in the U.S., approximately 1.4 million new cancer cases are estimated to be detected this year, with the most common forms being lung (173,770 cases per/year), breast (217,440), colorectal (106,370), and prostate (230,110). Table 5 (page 13) provides figures of the estimated new cases of cancer and estimated deaths, projected by the ACS for 2004.
Following cardiovascular diseases, cancer remains the most common cause of death in the U.S., with approximately one out of every four U.S. deaths linked to this disease. The relative lifetime risk of a male developing cancer is one in two; for women the risk is one in three. A synopsis of the estimated U.S. cases and deaths due to cancer by gender as estimated by the ACS is provided in Figures 2 and 3 (page 14), respectively, as a point of reference.
Market
The global cancer treatment market represents the most extensive pharmaceutical market in the world. According to Datamonitor (a business information company specializing in industry analysis), annual global cancer expenditure has been estimated at approximately $20 billion as of 2003, and could increase to more than $45 billion by 2011. This expansion is forecast to occur as demand increases as a result of improvements in traditional therapies combined with the introduction of new and innovative treatments that display improved efficacy and lower toxicity, while at the same time taking a more targeted approach at eliminating specific forms of cancer.
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Table 5 ESTIMATED NEW CANCER CASES AND DEATHS FOR ALL SITES, 2004* Estimated New Cases Estimated Deaths Both Sexes Male Female Both Sexes Male Female All Sites 1,368,030 699,560 668,470 563,700 290,890 272,810 Oral cavity & Pharynx 28,260 18,550 9,710 7,230 4,830 2,400 Tongue 7,320 4,860 2,460 1,700 1,100 600 Mouth 10,080 5,410 4,670 1,890 1,070 820 Pharynx 8,250 6,330 1,920 2,070 1,460 610 Other oral cavity 2,610 1,950 660 1,570 1,200 370 Digestive System 255,640 135,410 120,230 134,840 73,240 61,600 Esophagus 14,250 10,860 3,390 13,300 10,250 3,050 Stomach 22,710 13,640 9,070 11,780 6,900 4,880 Small Intestine 5,260 2,750 2,510 1,130 610 520 Colon 106,370 50,400 55,970 56,730 28,320 28,410 Rectum 40,570 23,220 17,350 Anus, ana canal, & anorectum 4,010 1,890 2,120 580 210 370 Liver & intrahepatic bile duct 18,920 12,580 6,340 14,270 9,450 4,820 Gallbladder & other billiary 6,950 2,960 3,990 3,540 1,290 2,250 Pancreas 31,860 15,740 16,120 31,270 15,440 15,830 Other digestive organs 4,740 1,370 3,370 2,240 770 1,470 Respiratory System 186,550 102,730 83,820 165,130 95,460 69,670 Larynx 10,270 8,060 2,210 3,830 3,010 820 Lung & bronchus 173,770 93,110 80,660 160,440 91,930 68,510 Other respiratory organs 2,510 1,560 950 860 520 340 Bones & Joints 2,440 1,230 1,210 1,300 720 580 Soft Tissue (including heart) 8,680 4,760 3,920 3,660 2,020 1,640 Skin (excluding basal & squamous) 59,350 31,640 27,710 10,250 6,590 3,660 Melanoma-skin 55,100 29,900 25,200 7,910 5,050 2,860 Other nonepithelial skin 4,910 2,400 2,510 2,340 1,540 800 Breast 217,440 1,450 215,990 40,580 470 40,110 Genital system 323,210 240,660 82,550 59,250 30,530 28,720 Uterine cervix 10,520 0 10,520 3,900 0 3,900 Uterine corpus 40,320 0 40,320 7,090 0 7,090 Ovary 25,580 0 25,580 16,090 0 16,090 Vulva 3,970 0 3,970 850 0 850 Vaginal & other genital, female 2,160 0 2,160 790 0 790 Prostate 230,110 230,100 0 29,900 29,900 0 Testis 8,980 8,980 0 360 360 0 Penis & other genital, male 1,570 1,570 0 270 270 0 Urinary System 98,400 68,290 30,110 25,880 17,060 8,820 Urinary bladder 60,240 44,640 15,600 12,710 8,780 3,930 Kidney & renal pelvis 35,710 22,080 13,630 12,480 7,870 4,610 Ureter & other urinary organ 2,450 1,570 880 690 410 280 Eye & orbit 2,090 1,130 960 180 110 70 Brain & other nervous system 18,400 10,540 7,860 12,690 7,200 5,490 Endocrine 23,600 6,950 18,570 2,440 1,140 1,300 Thyroid 23,600 5,960 17,640 1,460 620 840 Other endocrine 1,920 990 930 980 520 460 Lymphoma 62,250 33,180 29,070 20,730 11,090 9,640 Hodgkin's disease 7,880 4,330 3,550 1,320 700 620 Non-Hodgkin's 54,370 28,850 25,520 19,410 40,390 9,020 Multiple myeloma 15,270 8,090 7,180 11,070 5,430 5,640 Leukemia 33,440 19,020 14,420 23,300 12,990 10,310 Acute lymphocytic leukemia 3,830 2,110 1,720 1,450 820 630 Chronic lymphocytic leukemia 8,190 5,050 3,140 4,800 2,730 2,070 Acute myeloid leukemia 11,920 6,280 5,640 8,870 4,810 4,060 Chronic myeloid leukemia 4,600 2,700 1,900 1,570 940 630 Other leukemia 4,900 2,880 2,020 6,610 3,690 2,920 Other & unspecified primary sites‡ 37,090 15,930 15,160 45,170 22,010 23,160 * Rounded to the nearest 10; excludes basal and squamous cell skin cancers and in situs carcinomas except urinary bladder. Carcinoma in situ of the breast acounts for about 59,390 new cases annually, in situ melanoma accounts for about 40,780 new cases annually.
‡ Estimated deaths for colon and rectum cancers are combined. More deaths than cases suggests lack of specificity in recording underlying causes of death on death certificates. Note: Areas in bold are being focused on by Lorus Therapeutics. Source: American Cancer Society, Inc. (2004) and Crystal Research Associates.
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Figure 2 2004 ESTIMATED U.S. CANCER CASES*
Prostate 33% Men Women 32% Breast 699,560 668,470 Lung & bronchus 13% 12% Lung & bronchus Colon & rectum 11% 11% Colon & rectum Urinary bladder 6% 6% Uterine corpus Melanoma of skin 4% 4% Ovary Non-Hodgkin 4% Non-Hodgkin lymphoma 4% lymphoma Kidney 3% 4% Melanoma of skin Oral Cavity 3% 3% Thyroid Leukemia 3% 2% Pancreas Pancreas 2% 2% Urinary bladder All Other Sites 18% 20% All Other Sites
Note: *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder Source: American Cancer Society, 2004.
Figure 3 2004 ESTIMATED U.S. CANCER DEATHS*
Lung & bronchus 32% Men Women 25% Lung & bronchus 290,890 272,810 Prostate 10% 15% Breast Colon & rectum 10% 10% Colon & rectum Pancreas 5% 6% Ovary Leukemia 5% 6% Pancreas Non-Hodgkin 4% 4% Leukemia lymphoma 3% Non-Hodgkin Esophagus 4% lymphoma Liver & intrahepatic 3% 3% Uterine corpus bile duct 2% Multiple myeloma Urinary bladder 3% 2% Brain/ONS Kidney 3% 24% All other sites All other sites 21%
Note: *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder ONS=Other nervous system. Source: American Cancer Society, 2004.
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Immunotherapy and Macrophages
The past two decades have witnessed widespread advances in cancer therapy, with the emergence of immunotherapy representing one of the most significant developments. Also called biological therapy, immunotherapy is a clinical approach with the goal of stimulating the body’s natural defenses against cancer by employing biological response modifiers.
The intention of cancer immunotherapy is to bolster the patient’s immune system, either directly or indirectly, and enable it to fight the cancer and ameliorate any unfavorable side effects of the treatment. Clinical data have indicated that solid tumors have antigens that are recognized by cells of the immune system, including a certain type of white blood cell called a macrophage. Macrophages are located throughout the body and serve as an important line of defense against the development of cancer.
The immune system responds to the presence of antigens on solid tumors by stimulating macrophages, which in turn, stimulate the production of cytokines. Cytokines enhance the immune system by either killing tumor cells directly, or stimulating anti-tumor activity in other cell types. Macrophages influence tumor cell destruction through the release of cytokines, nitric oxide, and other anti-tumor molecules.
Pancreatic Cancer
Pancreatic cancer is one of the deadliest forms of cancer, with a 5-year survival rate of <1% and a post- diagnosis life expectancy of 3-6 months, largely due to the fact that the disease is not typically diagnosed until its later stages. According to the ACS, there will be an estimated 31,860 new cases and 31,270 deaths from pancreatic cancer in 2004 (Table 5).
Pancreatic cancer occurs when malignant cells form in the pancreas, (a tube-shaped gland that lies behind the stomach, helps with digestion, and regulates how food is stored and used). The cause of pancreatic cancer is unknown, and the disease often shows no symptoms in its early development. The location of the pancreas itself also makes tumors there difficult to detect.
The primary treatments for pancreatic cancer include surgery, radiation therapy, and chemotherapy. Despite the high risk and invasive approach, surgical treatments remain one of the favored options for treating pancreatic cancer, and are usually performed only when the cancer is contained entirely within the pancreas at the time of diagnosis, (occurring in only about 10% of all cases). Once the tumor spreads, however, surgery is usually not an option. Even when the cancer remains restricted to the pancreas, a small number of cancer cells may have spread to other parts of the body, but have not yet formed detectable tumors. As this condition is almost always untreatable through surgery, Lorus is actively pursuing a viable alternative to halt tumor cell proliferation via the immune system.
In cases of advanced disease, radiation therapy and/or chemotherapy may be used. Palliative surgery may be performed also, for example, to bypass areas obstructed by tumor growth (such as blockages in the bile duct or small intestine). Within the pancreatic cancer market, a variety of new approaches are now under evaluation to bolster the immune system against malignant cells to suppress hormones that might cause further malignant cell proliferation. These approaches include immunotherapy and hormone therapy.
Potential Treatments
As immunotherapeutic alternatives remain in the development stage, the market for pancreatic cancer drugs is currently a niche market, characterized by a number of clinical stage corporations pursuing development through several different methods of production. Table 6 (page 16) provides an overview of the companies that are currently pursuing the pancreatic cancer market, in addition to Lorus’ Virulizin®, with many entering more advanced development stages. Should these drugs prove effective in treating the condition, immunotherapeutics may gain a significant share of the pancreatic cancer treatment market.
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Table 6 KEY COMPETITORS IN THE PANCREATIC CANCER MARKET Company Drug Development SuperGen Inc. (SUPG-NASDAQ) Orathecin Phase III Aphton Corp. (APHT-NASDAQ) Gastrimmune (anti-gastrin 17) Phase III ImClone Systems, Inc. (IMCL-NASDAQ) IMC-C225 Phase III AVI BioPharma (AVI-NASDAQ) Avicine Phase II Pharmacyclics, Inc. (PCYC-NASDAQ) Xcytrin Phase II Antigenics Inc.(AGEN-NASDAQ) Oncophage Investigational Cell Genesys, Inc. (CEGE-NASDAQ) GVAX Phase II
Source: ResearchAndMarkets.
At present, the most widely used drug for treating pancreatic cancer is Gemzar (gemcitabine) produced by Eli Lilly & Company (LLY-NYSE). Gemzar, a nucleoside analog, is administered by infusion therapy and ameliorates the conditions of some patients by enhancing their comfort, though extending life only by about six weeks. In addition to Eli Lilly & Company, several companies are currently developing drugs for treating pancreatic cancer. A comprehensive list of drugs in clinical trials for pancreatic cancer appears on the website, www.pancreatica.org.
Gemzar
Eli Lilly & Company’s Gemzar is the current standard chemotherapy used for the treatment of pancreatic cancer, despite a <20% objective response rate in the clinic. Gemzar is approved for the first-line treatment of both pancreatic cancer and non-small cell lung cancer (NSCLC) in the U.S. and Europe. The drug became a billion-dollar product in 2003 with worldwide sales of $1.02 billion, of which slightly more than half ($524 million) was generated by the U.S. market.
Due to the relative shortcomings of current treatments for pancreatic cancer patients, the need for a new agent with lower toxicity and superior efficacy has been recognized. Lorus is developing a novel formulation with low toxicity for the treatment of pancreatic cancer.
Virulizin®
Virulizin® is Lorus’ leading drug candidate in development for the treatment of pancreatic cancer. The compound works by activating the body’s immune system to recognize and attack cancer cells as an immunomodulatory activator of human macrophages. The drug is administered via intramuscular (IM) injection, making it possible for treatment to be provided on an outpatient basis. The drug has been evaluated in hundreds of patients who have received more than 16,000 injections. To date, Virulizin® has demonstrated an excellent safety profile, with only a small number of mildly adverse events reported.
Virulizin® has been evaluated both alone and in combination with other chemotherapeutic agents. In addition to its most advanced indication in development, which is for pancreatic cancer, Virulizin® may also have potential applications in the treatment of a broad range of other cancer types, including malignant melanoma, as well as lung, breast, uterine, ovarian, and cervical cancers. Possible non-cancer indications may also include immune system disorders and viral diseases.
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Mechanism of Action
The mechanism of action for Virulizin® is the subject of ongoing research, described below.
® Virulizin treatment activates Figure 4 macrophages, which are attracted ® to tumor cells, where they release VIRULIZIN MECHANISM OF ACTION anti-tumor molecules.
Activated macrophages release molecules that activate natural feedback NK Cells killer (NK) cells and promote on
migration of these NK cells to i Activation vat tumors, where they release i ct molecules with antitumor activities. A Macrophage tumor-killing molecules The NK cells, in turn, also release Activation molecules that activate more Virulizin Tumor cell macrophages. tumor-killing By exploiting this unique activity, molecules Virulizin® is able to “jump start” a process that activates macrophages and NK cells, which have Source: Lorus Therapeutics Inc. demonstrated anti-tumor activity. An illustration of this process is provided in Figure 4.
While some questions have been posed regarding the drug’s activity, Virulizin® has demonstrated significant characteristics of an effective medication as described above, and listed in Table 7.
Table 7 Lorus Therapeutics Inc. KEY FEATURES DEMONSTRATED BY VIRULIZIN® Safe and non-toxic immunotherapeutic drug Formulated as sterile pryogen-free injectable aqueous solutions for intramuscular (IM) injection Equivalency release criteria: analytical assay (e.g., LC/MS) and biopotency assays A unique and distinct mechanism of action Stimulates macrophage-mediated NK cell activation/recruitment to tumors Convincing Phase I and Phase II clinical results Strong preclinical anti-tumor efficacy in a variety of tumors Highly effective in a gemcitabine-resistant pancreatic cancer xenograft model Insensitive to prostaglandin-mediated immunosuppression
Source: Lorus Therapeutics Inc.
Macrophage Activation at the Tumor Site
Virulizin®’s use as an immunotherapy is based on its potent, non-specific activation of human macrophages. The compound has been shown to be a non-toxic immunotherapy that recruits monocytes and macrophages with the intention of attacking tumor cells. Monocytes and macrophages are key contributors to the body’s immune response to invasion, including that by tumor cells.
The drug has also demonstrated the ability to stimulate immune system cells and fuel the release of cytokines, including tumor necrosis factor (TNF) and interleukin one beta (IL-1B), inducing apoptosis (cell death). Virulizin® has further been shown to stimulate the macrophage-mediated destruction of tumors in patients undergoing chemotherapy, and has been found to prolong survival and improve the quality of life in patients with advanced pancreatic cancer, without causing significant toxicity. Essentially,
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Virulizin® works by stimulating the immune system to attack the cancer, rather than by actually killing the cancer cells directly, and it has shown fewer negative side effects than commonly used chemotherapy agents.
Preclinical Studies
Preclinical studies of Virulizin® have demonstrated that the drug activates macrophages and NK cells, producing significant reduction in tumor growth, and increasing survival across a broad range of animal xenograph models of human carcinoma. In a gemcitabine-resistant pancreatic tumor model in mice, treatment with Virulizin® was associated with a delay in tumor growth and a significant reduction in tumor size, compared with controls.
A summary of the preclinical test results of Virulizin® is provided in Table 8. Pharmacologic studies in healthy volunteers, as well as in cancer patients, indicate that peripheral blood monocytes have an enhanced capacity to kill tumor cell targets when stimulated with Virulizin®.
Table 8 Lorus Therapeutics Inc. PRECLINICAL RESULTS OF VIRULIZIN® IN NUDE MICE Demonstrates anti-tumor activity in a variety of mouse tumor xenograft models Highly effective in a gemcitabine-resistant pancreatic cancer xenograft model Potentiates anti-tumor effect of various chemotherapeutic compounds in several mouse tumor xenograft models (dacarbazine, gemcitabine, 5-FU, Taxol, cisplatin, and Taxotere) Well-tolerated by animals with no apparent toxicity except a reduced body weight gain in male rats at a high dose (about 20x the human dose) No evidence for mutagenic potential as assessed by reverse bacterial mutagenicity assay Source: Lorus Therapeutics Inc.
Phase I/II Clinical Test Results
Phase I/II clinical trial results have demonstrated that Virulizin® performs equal to or better than the currently available products for the treatment of pancreatic cancer. Pancreatic cancer patients treated with Virulizin® in Phase I/II studies showed an increase of six and 12 months survival versus historical controls, with the maximum tolerated dose of Virulizin® not reached in clinical trials. Table 9 summarizes the results of Phase I/II trials.
Table 9 Lorus Therapeutics Inc. EFFICACY IN PANCREATIC CANCER PATIENTS Virulizin® (Phase I/II) Gemzar® All Patients Evaluable Patients (Phase II) Number of patients 61 49 63 Median survival (months) 4.6 5.7 3.9 6-month survival rate 38% 48% 31% 9-month survival rate 25% 31% 15% 12-month survival rate 18% 22.5% 4% Source: Lorus Therapeutics Inc.
Pivotal Fully Enrolled Phase III Trial
Lorus initiated a Phase III clinical trial of Virulizin® for the treatment of pancreatic cancer in November 2001 and in June 2004 announced the completion of patient enrollment. The end points for this trial are listed in Table 10 (page 19).
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Table 10 Lorus Therapeutics Inc. VIRULIZIN® PHASE III END POINTS Primary Efficacy Endpoint Survival, defined as the time from baseline/treatment day 1 to the time of death from any cause Secondary Efficacy Endpoint Time to increase in pain, time to deterioration in ECOG performance status, and time to weight loss from baseline/treatment day 1 Safety Endpoints Adverse events, laboratory tests, and vital signs. Adverse events will be graded according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC)
Source: Lorus Therapeutics Inc.
According to the study protocol, there will be patient follow-up for a period of one year, followed by a database lock and data analysis. The results of the study are anticipated in late 2005. This clinical study report is to be pivotal in the application for marketing approval of Virulizin®, which is planned for submission to the FDA in the first half of 2006. Virulizin® has obtained Special Protocol Assessment and has been designated both Fast Track and Orphan Drug Status for pancreatic cancer by the U.S. FDA.
Phase III Update
In June 2004, full patient enrollment was achieved for a 400-patient pivotal Phase III trial of Virulizin® for treating patients with advanced pancreatic cancer. The study is being conducted at over 100 clinical test sites in the U.S., Canada, Brazil, Europe, and Russia. The primary efficacy endpoint is overall survival, while secondary endpoints include progression of symptoms of pain, deterioration of performance status, and weight loss, as shown in Table 10.
This multi-center, double-blind clinical study compares the safety and efficacy of Virulizin® when combined with gemcitabine with a placebo combined with gemcitabine in the first-line treatment setting. The activity of NK cells will be evaluated throughout the study. The correlation between NK cell activity profiles and clinical outcome will be assessed.
The FDA had suggested that the Phase III study be a first-line comparison in combination with gemcitabine as patients in the second-line situation have such poor prognosis that there is unlikely to be sufficient time for the drug to demonstrate its full survival advantage.
A Phase III study of Virulizin® in combination with 5-fluorouracil (5-FU) is also underway as a second-line treatment, as compared with 5-FU and placebo. The primary endpoint of the study is survival. Secondary endpoints in the study include time to treatment progression, which analyzes the effect of Virulizin® on key clinical benefit parameters such as pain, analgesic consumption, changes in weight, and performance status. The study also correlates immune parameters with clinical outcome. Virulizin® was shown to increase NK cell activity in an earlier Phase II clinical study. This clinical study report will be key for the application for marketing approval of Virulizin®, which is planned for submission to the FDA by the first half of 2006.
Production and Composition of Virulizin®
Virulizin® is derived from purified bovine bile through Lorus’ proprietary production process, and consists of an aqueous solution containing approximately 5% weight/weight (w/w) solid materials that are comprised of 95-99% inorganic ions and 1-5% organic compounds. The organic compounds include various amino acids with trace amounts of peptides, short chain fatty acids, alcohols, organic phosphates, and amines. The active components of the drug have yet to be fully identified and the Company’s scientists are seeking to identify all components and their corresponding mechanisms of action. Levels of TNF-alpha produced by cells stimulated with Virulizin® in vitro, efficacy in in vivo animal
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models of human tumor growth, and fingerprinting with high-performance liquid chromatography (HPLC) are measures that are used to ensure consistency of batch composition.
Virulizin® for Treating Malignant Melanoma
Virulizin® is currently being sold in Mexico by Mayne Pharma for use in treating malignant melanoma (a cancerous tumor that develops from melanocytes, which are melanin-producing cells in the skin). In three Mexican Phase II studies, the median survival rate of over six months was greater than of the historical survival interval of 3.1 months. Another Mexican Phase II study showed that two out of three patients, for whom data were available, achieved a partial tumor response. The latter study also indicated that a combination of Virulizin® and Dacarbazine might be effective.
Presentations on Virulizin® at Immunology, Lustgarten, ASCO, and AACR Conferences
® A paper entitled “Virulizin : A Novel Biological Response Modifier, Activates NK Cells and Induces Anti-tumor Activity,” was presented at the 4th Annual Conference of the Federation of Clinical Immunology Societies, held in Montreal, Canada in July 2004. The study was also published in a supplement to the Clinical Investigative Medicine Journal.
th Lorus was an education sponsor of the 6 Annual Lustgarten Foundation Scientific Conference held in San Francisco, CA, in June 2004. The conference targeted clinical researchers, oncologists, post- doctorate fellows, and allied medical professionals worldwide. The Lustgarten Foundation for Pancreatic Cancer Research is the largest private foundation exclusively dedicated to the support of pancreatic cancer research. An abstract entitled “Virulizin® Induces Anti-tumor Activity Through Activation and Interaction of Innate Immunity,” was presented at the conference and published in the meeting proceedings.
The Lustgarten Foundation concentrates on helping the scientific community work toward finding a cure for pancreatic cancer. The Foundation has awarded USD$9 million in support of promising pancreatic research, and has sponsored four international scientific meetings at leading institutions. The Foundation also provides patient information through the dissemination of handbooks and a comprehensive website, and promotes public awareness through a public service announcement campaign featuring former U.S. President Jimmy Carter, who also serves as honorary chairman of the Foundation’s corporate advisory board.
Lorus participated in the American Society of Clinical Oncology (ASCO) annual meeting in June 2004 in New Orleans, LA. Virulizin® was the subject of an abstract entitled “Stimulation of NK Cell and Macrophage Infiltration in Pancreatic Cancer with Virulizin®, an Immunotherapeutic Agent.” The ASCO annual conference is an important event in clinical oncology worldwide, attracting researchers, clinicians, and members of the pharmaceutical industry. The conference provides oncology professionals with the most current information on recent developments in cancer research, prevention, and treatment.
Lorus presented at ASCO’s Gastrointestinal Cancers Symposium in San Francisco in January 2004 an abstract entitled, “Induction of NK Cell and Macrophage Infiltration into Tumors may Contribute to Anti-tumor Activity of Virulizin®.” These studies were conducted through a collaboration between Lorus’ scientists and researchers at the Calcium Research Laboratory, Department of Medicine, McGill University.
Two presentations were delivered at the annual meeting of the American Association for Cancer Research (AACR) in Orlando, Florida in March 2004. The presentations were entitled “Virulizin® Increases Infiltration of NK Cells to Tumors Via Activation of Macrophages,” and “GTI-2040 Displays Cooperative Anti-tumor Activity when Combined with Standard Chemotherapeutic Drugs.”
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Antisense Technology
Lorus is researching and developing compounds designed to interact specifically with cellular targets responsible for the uncontrolled proliferation of cancer cells, with the goal of potentially producing safer and more effective cancer drugs. The complex processes underlying cancer progression are controlled through modifications in the regulation of a large group of transforming genes or oncogenes, and through the inactivation of tumor suppressor genes. Lorus’ scientists have discovered that specific genes, described as malignant determinants, can be inhibited with antisense technology, and lead to significant tumor suppression and regression.
Human metabolism is controlled by proteins produced by the body. Virtually all human diseases are associated with inadequate or faulty protein production. Proteins are complex molecules necessary for the structure and physiological functioning of human beings, and infectious organisms such as viruses and bacteria. Infectious organisms carry their own genetic materials (DNA and/or RNA), which direct the production of (or “codes for”) proteins that are needed for the survival and proliferation, leading to the progression of infectious disease in humans. (Non-infectious diseases, such as cancer, develop through altered expression of proteins that are inherent to mammalian physiology).
The information that enables the human body to produce proteins in the correct Figure 5 amount and at the appropriate time is THE HUMAN BODY AND ITS GENETIC COMPOSITION found in the human genome, which comprises 46 chromosomes in the nucleus of human cells and contains a network of approximately 100,000 genes. Each gene is comprised of DNA in the form of a pair of entwined strands, cells nucleus chromosome DNA DNA known as a double helix. In each set, pair helices helix with the building blocks of DNA, called base pairing nucleotides, are paired with Source: Lorus Therapeutics Inc. complementary nucleotides on the other strand. A brief summary of the human body and its genetic composition is provided in Figure 5.
Nucleotide sequences code for the Figure 6 synthesis of proteins. The sequence SENSE AND ANTISENSE SEQUENCES and repetition of bases (A-adenine; C- cytosine; G-guanine; and T-thymine) spell out the cell’s genetic information. In general, each gene has sufficient information to code for the synthesis of a single specific protein. The precise sequence of a nucleotide chain that is the blueprint for the information used during protein synthesis is called the “sense” sequence. The sequence of a nucleotide chain that is precisely complementary to a given sequence is called its “antisense” sequence. An illustration of this is provided in Figure 6. Source: Lorus Therapeutics Inc.
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The sequence of nucleotides that lies adjacent to the sense sequence, but does not directly code for a protein, is called the untranslated region. There are two untranslated regions, one at each end of the sense sequence, designated as the 5’-region and the 3’-region. A sequence of nucleotides that is identical or equivalent to, as opposed to complementary to, the untranslated region is referred to as “U- Sense” and was coined by Lorus’ president and CEO, Dr. Jim Wright.
Two genes that are the targets of the antisense and U-sense technologies code for components of ribonucleotide reductase (RNR), a multi-subunit enzyme that is crucial for the synthesis of DNA and the proliferation of cells, including tumor cells. As over-expression of RNR is important in mechanisms of cancer transformation and disease progression, reducing gene expression through the application of antisense and U-sense molecules and has the potential to produce new classes of anti-cancer drugs.
RNR is a highly regulated cell cycle-controlled enzyme that is essential for DNA synthesis and repair. The enzyme catalyzes the formation of deoxyribonucleotides by removing an oxygen molecule from the corresponding ribonucleotides in a process called ribonucleotide reduction. Cancer cells require deoxyribonucleotides as the building blocks to manufacture DNA. The only direct route to these precursors is by reduction of ribonucleotides, making RNR the essential element for DNA synthesis and cell proliferation. Lorus’ Drs. Jim A. Wright, and Aiping H. Young, COO, have been studying RNR since 1973 and 1990, respectively.
Table 11 Approximately 90% of cancer patient deaths are due to the Lorus Therapeutics Inc. development of increased ADVANTAGES OF ANTISENSE TECHNOLOGY malignant characteristics of Promise of high specificity and affinity the primary tumor (tumor Rational design by targeting a given nucleotide sequence progression), which ultimately leads to the metastasis of An approach to treating a variety of diseases including cancer tumor cells to other sites in Mode of action: interferes with transcription, translocation, and translation the body. Translation: binding to mRNA activates RNAse activity Single molecule can bind to many mRNA molecules RNR is a newly discovered Prevents the production of a specific protein type of genetic determinant that can profoundly alter the Source: Lorus Therapeutics Inc. malignant potential of cancer cells, and it is an important target for drug intervention. There are several noteworthy therapeutic advantages to antisense technology, listed in Table 11
Competitive Efforts in Antisense Technology
Antisense compounds are made up of repeating subunits linked together to form a polymer and are referred to as the antisense backbone. Each antisense subunit carries a genetic letter that matches with its pair on the gene target. Although genetic letters are common to all antisense compounds, the chemical structure of the subunits and the linkages that string them together vary widely.
Early antisense backbones were made from natural genetic materials and linkages. These compounds were easily degraded or broken down by enzymes in the blood and within cells, and had difficulty crossing cellular membranes to enter the cells that contained their genetic target.
Subsequently, modified backbones were designed, which resist degradation by enzymes, and provide enhanced entry to tissues and cells. The most common of these second-generation antisense molecules used natural DNA subunits linked together by a negatively charged backbone.
As further modifications, synthetic subunits are being used in place of modified natural materials, and linkages that are used to string the subunits together are uncharged molecules, a feature which is believed to increase clinical safety potential.
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While several companies are working to develop drugs based on antisense technology for therapeutic applications, none have been commercialized to date in oncology, though Isis Pharmaceuticals Inc. (ISIS- NASDAQ) has commercialized a product for retinitis. The intended applications for these antisense drugs are different from Lorus’ GTI-2040 and GTI-2501, as described below. Companies that are developing antisense therapeutics include AVI BioPharma Inc., Isis Pharmaceuticals, Hybridon Inc. (HBY- AMEX), MethylGene Inc. (MYG-TSX), and Genta Inc. (GNTA-NASDAQ).
GTI-2040 and GTI-2501
Antisense oligonucleotides are short DNA molecules that can interfere with gene expression by forming duplexes with complementary sequences of target messenger RNAs (mRNAs). Antisense oligonucleotides are under evaluation for their use as therapeutic agents for a variety of diseases, including cancer. The oligonucleotides can inhibit protein production by causing mRNA inactivation in the following ways:
Sterically hindering mRNA interaction with ribosomes, spliceosomes, and/or regulatory binding proteins;
Facilitating degradation of RNA/DNA hybrids by the action of RNase H; and
Binding to DNA, resulting in the formation of DNA triplexes which, in turn, prevents transcription.
Lorus is developing a line of antisense drugs, summarized in Figure 7. Its leading candidates, GTI-2040 and GTI-2501, are 20-mer phosphorothioate oligonucleotides anti-tumor agents. Phosphorothioates have one of the nonbridging oxygen molecules replaced with a sulfur atom. This modification increases the in vivo stability of the compound by making it more resistant to degradation by nucleases.
Figure 7 Lorus Therapeutics Inc. ANTISENSE DEVELOPMENT PIPELINE Research Preclinical Phase I Phase II Phase III
GTI-2040 (Renal cell carcinoma)
GTI-2040 (Unresectable colon cancer)
GTI-2040 (Non-small cell lung cancer)
GTI-2040 (Advanced breast cancer)
GTI-2040 (Solid tumors)
GTI-2040 (Acute myeloid leukemia)
GTI-2040 (Prostate cancer)
GTI-2501 (Prostate cancer)
GTI-4006 (IGFII)
GTI-3611 (VEGFR)
GTI-3008 (TR)
GTI-2601 (TRX)
Source: Lorus Therapeutics Inc.
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RNR is composed of two subunits, R1 and R2. GTI-2040 and GTI-2501 target the R2 and R1 subunits of human RNR, respectively, which are required for DNA synthesis and tumor cell growth. RNR activity is elevated in a wide range of tumors. In addition, the R2 component appears to act as a signal molecule in cancer cells and increases the activity of a biochemical pathway that plays an important role in tumor progression. Both GTI-2040 and GTI-2501 have shown sequence/target specificity for each target in vitro and in vivo, and exhibit effective anti-tumor activity in a broad spectrum of human cancers in mouse models, including, lung, breast, colon, kidney, ovarian, pancreatic, skin, prostatic, and cervical cancers.
Positive results that have been demonstrated include significant tumor growth inhibition, disease stabilization, and tumor regression. Toxicology studies in rodents and monkeys of GTI-2040, and preliminary results with GTI-2501, indicate that these compounds are likely to be safe in humans at concentrations that exceed therapeutic doses.
GTI-2040 targets the R2 component of RNR, a novel malignant determinant that can cooperate with a type of cancer causing genes, known as oncogenes. Preclinical animal models have demonstrated that GTI-2040 has particular efficacy in inhibiting tumor growth in animal tumor models of RCC, alone or in combination with other agents. GTI-2040 received approval of its Investigational New Drug (IND) application in 1999 and entered a Phase I clinical trial in June 2000 at the University of Chicago Cancer Research Center.
GTI-2501 has shown complete tumor regression in mice containing human breast cancer and human kidney cancer cells. The FDA approved an IND for Phase I clinical trials in February 2001 for use on patients with solid tumors or lymphoma.
GTI-2040 Combined with Capecitabine (Xeloda) for Treating Advanced Renal Cell Carcinoma (RCC)
RCC is a devastating disease with a high mortality rate and restricted therapeutic options. Immunotherapies have been used with very limited success in a subset of patients. One of the primary barriers to the efficacy of these therapies has been the number of serious toxicity concerns that have precluded their therapeutic usefulness.
RCC is the most common type of kidney cancer, with more than 190,000 cases diagnosed annually throughout the world. The majority of patients are over the age of 40. More than 90,000 patients die annually from this disease worldwide and the age-adjusted world incidence has been increasing steadily at an annual rate of approximately 2%. Advanced RCC is typically resistant to chemotherapy, with reported response rates of less than 10%. Current immunotherapeutic treatments include the cytokines, interferon, and interleukin-2. Tumor response rates for these agents are low, however, in the range of 15%.
GTI-2040 is being studied in clinical trials in combination with capecitabine (Xeloda from Roche Holdings) for the treatment of advanced RCC in patients who have failed previous chemotherapies. Capecitabine is a well-known oral anti-cancer treatment. The design of the trial was developed by Dr. Walter Stadler of the University of Chicago, who has published extensively on the subject of treatments for RCC.
In January 2004, interim data were analyzed from the Phase II clinical trial of GTI-2040 in combination with capecitabine for patients with advanced RCC. The majority of patients had failed two or more prior therapies before entering the study, exhibited extensive metastases, and were representative of a population with a very poor prognostic outcome.
In August 2004, Lorus announced findings from the dose escalation stage of its Phase II clinical trial of GTI-2040 and capecitabine in metastatic kidney cancer patients at seven test sites in the U.S. These findings demonstrated that GTI-2040 was well tolerated in combination with capecitabine, with no reduction in the starting capecitabine dose required, up to and including the target GTI-2040 dose that was previously established as a monotherapy in a Phase I clinical investigation. The clinical findings were presented in August 2004 by Dr. Apurva Desai, an oncology investigator at the University of Chicago, at the First International Congress on Kidney and Bladder Cancer, held in Orlando, FL. A Phase II/III registration clinical program for GTI-2040 in RCC is presently being designed.
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In September 2004, Lorus presented new clinical results of a study in metastatic RCC with GTI-2040 in combination with capecitabine at the ENA meeting, a leading forum for presenting clinical oncology research, in Geneva, Switzerland. The ENA is organized jointly by the European Organization for Research and Treatment of Cancer (EORTC), the United States National Cancer Institute (NCI), and the American Association for Cancer Research (AACR). In this clinical trial, GTI-2040, a novel oligonucleotide with specificity for the R2 component of ribonucleotide reductase that is elevated in RCC and many other cancers, was investigated in combination with capecitabine. Of 29 patients reported, including 25 evaluable for best response, all had advanced metastatic RCC that had either failed or was ineligible for standard therapies, and are representative of a population with very poor prognostic outcome. Data presented from the ongoing clinical study reported that at the recommended Phase II dose, more than 50% of patients with advanced metastatic RCC showed disease stabilization. The greatest tumor shrinkages included a 39% reduction in a patient with a significant partial response and a 23% reduction in a patient who had durable stabilization of disease of 10 months duration. Adverse events were consistent with those expected with the drug combination studied, and demonstrated that GTI-2040 is well tolerated when combined with a cytotoxic agent like capecitabine.
GTI-2040 Combined with Gemcitabine for Treatment of Solid Tumors
In February 2004, Lorus initiated a Phase II clinical trial of GTI-2040, in combination with gemcitabine, in patients with solid tumors. The study is designed to determine the recommended dose of GTI-2040 when administered with gemcitabine, and is part of a larger clinical development program sponsored and coordinated by the NCI in collaboration with Lorus. Dr. Chris Takamoto, the principal investigator, is an oncology researcher and director of pharmacokinetics at the Institute for Drug Development, Cancer Therapy, and Research Center in San Antonio, Texas where the study will be conducted.
The study is to evaluate the plasma pharmacokinetics and pharmacodynamics of each drug, and examine cellular biomarkers that may correlate with clinical outcomes. One such biomarker is R2, the gene target of GTI-2040, and an essential component of RNR, an enzyme required for cell division. The R2 component is elevated in many tumor types and, as such, suppression of R2 by GTI-2040 may serve as a biomarker for clinical response. A number of clinical correlates are to be investigated, in particular, markers for apoptosis, which may represent an additional mechanism by which GTI-2040 selectively kills tumor cells.
GTI-2040 and gemcitabine have complementary intracellular mechanisms of action for blocking DNA synthesis and subsequently inhibiting the growth of tumor cells. This convergence of drug mechanisms of action provides the potential for enhanced or synergistic effects when used in combination.
GTI-2040 in Treatment of Advanced Colon Cancer
The ACS identifies colon cancer as the third most common cancer in both men and women, with an estimated 106,370 new cases and 56,730 deaths expected to occur in 2004 in the U.S. (Table 5, page 13). While advances have come from earlier diagnoses, patients with metastatic colon cancer have achieved only modest improvement from advances in combination chemotherapies, emphasizing the need for new therapeutic combination strategies encompassing multiple targeted therapies.
In May 2004, Lorus initiated a Phase II clinical trial of GTI-2040 in combination with oxaliplatin and capecitabine in patients with advanced unresectable colon cancer. A major objective of this clinical study is to establish the optimal dose of this combination for colon cancer patients, and investigate the pharmacodynamic effects on cellular markers of anti-tumor activity when these agents are combined.
The study is under the direction of Dr. Stephen Shibata at the City of Hope Comprehensive Cancer Center in Duarte California, together with Dr. Heinz-Joseph Lenz at the University of Southern California in Los Angeles, Dr. David Gandara at the Davis Cancer Center, University of California in Sacramento, and Dr. Mark McNamara, at the City of Hope Medical Group in Pasadena, California. Capecitabine and oxaliplatin are FDA approved therapies for colon cancer, the former for first-line therapy and the latter in combination with 5-fluorouracil/Leucovorin.
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Other Programs Underway for GTI-2040
There are a total of seven clinical studies in Phase II programs for GTI-2040 in combination with other agents in various cancers described in the preceding sections. In addition to the studies described on the preceding page, clinical programs are underway for the treatment of metastatic breast cancer at the University of California, Davis Cancer Center; acute myeloid leukemia at the Ohio State University Medical Center; and non-small cell lung cancer (NSCLC) at Princess Margaret Hospital in Toronto, Ontario. A clinical trial was recently initiated to investigate GTI-2040 in prostate cancer sponsored by the Cancer Therapy Evaluation Program (CTEP), an NCI program that sponsors clinical trials of novel compounds to accelerate their development. The objective is to determine against which tumors GTI- 2040 is most effective, and to identify patient populations that will benefit the most from treatment.
In preclinical studies, GTI-2040 has demonstrated a reduction in the size of human adenocarcinoma tumors of the colon by 80% when injected into mice, compared with those in untreated mice using the standard mouse xenograft model. It has also demonstrated a broad spectrum of activity in vivo in preclinical models across many tumor types, and a 65-95% inhibition of lung metastases in two animal models. In similar animal models, when combined with 5-FU (the active metabolite of capecitabine) or oxaliplatin, GTI-2040 has shown increased anti-tumor activity when compared with either agent alone.
Summary of GTI-2040 NCI Clinical Trials
The NCI has sponsored several GTI-2040 clinical trials in multiple locations throughout the U.S. and Canada. Lorus believes these trials may provide it with an opportunity to demonstrate GTI-2040’s efficacy in combination with a variety of proven anti-cancer therapies. Table 12 provides a summary of each trial and its current stage of development.
Table 12 Lorus Therapeutics Inc. GTI-2040 NCI CLINICAL TRIALS Indication Phase Combination Planned Accrual Principal Investigator Solid Tumor I Gemcitabine 18-40 Chris Takimoto, MD Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX Breast II Capecitabine 23-29 Helen K. Chew, MD University of California Davis Cancer Center, Sacramento, CA Colorectal I Capecitabine 15-20 Stephen Shibata, MD Oxaliplatin City of Hope National Medical Center, Duarte, CA Prostate II Docetaxel 18-46 Malcolm J. Moore, MD Prednisone Princess Margaret Hospital, Toronto, ON Non-Small Cell Lung Carcinoma I/II Docetaxel 42-48 Natasha Leighl, MD Princess Margaret Hospital, Toronto, ON Acute Myeloid Leukemia I Cytarabine 12-33 Guido Marcucci, MD Ohio State University, Columbus, OH Source: Lorus Therapeutics Inc.
GTI-2501 for Prostate Cancer
Prostate cancer is the most frequently diagnosed cancer among men in the U.S., with 230,110 new cases diagnosed and 29,900 deaths each year, second only to lung cancer, according to the 2004 estimates recently released by the ACS (Table 5, page 13).
Lorus’ GTI-2501 is a novel investigational antisense drug, which has shown a favorable safety profile in preclinical studies and in a Phase I clinical trial. Initial testing has demonstrated strong anti-tumor activity in preclinical studies in prostate cancer and a variety of other tumor types. GTI-2501 is designed to exert its activity by specific down-regulation of the R1 component of RNR, an enzyme essential for DNA replication and cell proliferation.
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In July 2004, Lorus expanded its Hormone Refractory Prostate Cancer (HRPC) Phase II trial of GTI-2501 in combination with docetaxel to two additional test sites in Canada. Docetaxel is a chemotherapeutic agent extensively studied for the treatment of prostate cancer. The combination of GTI-2501 and docetaxel in this clinical trial is being investigated in patients with asymptomatic or symptomatic HRPC in which disease progression is uncontrolled.
The principal investigators at the new sites are Dr. Peter Venners, Director of the Division of Medical Oncology at the Cross Cancer Institute in Edmonton, Alberta, and Dr. Scott Ernst, Associate Professor, Division of Medical Oncology, at the London Regional Cancer Centre in London, Ontario. Both are leading researchers in the field, representing major centers for prostate cancer research in Canada, and have contributed to many trials and publications in the treatment of this disease. Dr. Venners and Ernst are collaborating with Sunnybrook and Women’s Health Centre in Toronto, where the clinical trial has been ongoing under the direction of Dr. Scott Berry and Dr. Lawrence Klotz.
GTI-2040 and GTI-2501 Presented at 2nd Annual Antisense and siRNA Technologies Conference
A presentation on Lorus’ GTI-2040 and GTI-2501 antisense drug candidates was given at the Second Annual Antisense and siRNA Technologies Conference in London, England in February 2004. The conference brings together leading industry experts to track the new developments in antisense and siRNA technologies and examine new clinical trial results and approaches
An oral presentation, entitled “Lorus Therapeutics Antisense Drug Development: Update on GTI-2040 and GTI-2501,” was given at the TIDES Conference that was held in Las Vegas, Nevada in April 2004.
Small Molecule Discovery Program
Lorus has created a library of low molecular compounds that are structurally related to the anti-fungal agent, clotrimazole (CLT), a known inhibitor of cell proliferation by interfering with cell cycle progression. The anti-cancer activity of CLT was discovered by Dr. José Halperin at the Harvard Medical School, who reported on the unique mechanism of action by which CLT depletes cells of calcium, and therefore inhibits the production of factors required for cell growth.
Based on the structural feature (pharmacophore) found to be responsible for the anti-proliferative effect of CLT, chemical analogs of CLT have been designed and tested. Lorus believes that these analogs (e.g., NC-381, NC-383, and NC-384) could have very similar biological properties, with remarkably less toxicity than the parent compound.
Lorus has obtained a licensing agreement to develop the CLT analogs as anti-cancer agents and has designed and synthesized variations or analogs of CLT. In preclinical trials conducted in partnership with the NCI, these analogs have demonstrated low or no toxicity in animal models and have inhibited cancer growth in cell culture and animal models.
NC-381 and Library of Clotrimazole Analogs with Cyclacel Ltd.
NC-381, an analog of CLT, is an orally-administered compound that inhibits growth of tumor cells through the same mechanism as CLT. NC-381 has been designed to retain the triphenyl configuration of CLT with the intent of developing a more efficacious entity. In September 2003, Lorus entered into a worldwide exclusive out-licensing agreement for NC-381 with Cyclacel Ltd, a leading private biotechnology company in the UK. The agreement extends to other drug candidates that Cyclacel may identify from a library of CLT analogs.
Collaborative Program with University of Toronto on Anti-Proliferative Small Molecules
In addition to the CLT analog library, Lorus is actively developing new drug candidates in another small molecule preclinical research program. In May 2004, after three years of research by its scientists in a small molecule discovery program, Lorus signed a collaboration agreement with the University of Toronto to provide a further development and delivery strategy for several proprietary compounds. The development is to be partially funded by a grant awarded to Lorus and the University of Toronto from the
Executive Informational Overview Page 27
Natural Sciences and Engineering Research Council of Canada/Collaborative Research and Development (NSERC/CRD), entitled “Development of Polymeric Delivery Systems for a Novel Series of Hydrophobic Therapeutic Agents.” The study is to be performed in collaboration with Dr. Christine Allen of the Department of Pharmaceutical Sciences at the University of Toronto.
The anti-proliferative properties of the newly discovered compounds were corroborated in an in vitro anti- cancer screen provided by the Developmental Therapeutics Program (DTP) at the NCI. In addition, the compounds exhibited in vivo activity in animal models. Preliminary evaluation of their in vivo efficacy in a xenograft model of human colon adenocarcinoma showed potent anti-cancer activity. Although these compounds exhibit wide spectrum anti-proliferative activity, no apparent acute or chronic toxicity was observed in preliminary animal tests.
The formal research agreement with the University of Toronto to optimize a drug delivery system focuses on the synthesis and characterization of novel structural-based formulations specifically designed for a number of lead compounds identified by Lorus as having anti-cancer and antibacterial activity. The collaboration is to evaluate the in vivo pharmacokinetics and biodistribution of the formulated compounds, as well as efficacy in animal models of human disease. Of particular interest were compounds that inhibited the growth of several human tumor cell lines, including hepatocellular carcinoma, pancreatic carcinoma, ovarian carcinoma, breast adenocarcinoma, and metastatic melanoma. These compounds have also demonstrated activity against multi-drug resistant bacteria, which are responsible for a number of life-threatening infections in hospitalized and immune-compromised individuals.
Lorus introduced this novel series of anti-cancer small molecules (aryl imidazoles) in a poster presented at the IBC’s 9th Annual World Congress Drug Discovery Technology 2004 meeting, held in Boston in August 2004. These compounds demonstrated potent anti-proliferative activity against a variety of human cancer cell types. Promising cancer cell growth inhibition was exhibited in the NCI’s 60-cell line tumor panel. In animal models of human colon cancer and liver cancer, treatment with several compounds resulted in significant inhibition of tumor growth. The lead compound, ML-220, suppressed the growth of most cancer cell types. Studies using HT-29 colon cancer cells demonstrated the alteration of the cell cycle by ML-220 through induction of a partially reversible arrest in the G0/G1 phase.
The subcellular localization of ML-220 in cancer cells was investigated by fluorescent microscopy, which demonstrated that ML-220 localizes in the perinuclear area closely associated with the endoplasmic reticulum subcellular network of membranes responsible for manufacture and transfer of secretory proteins. ML-220 was also found to be an inhibitor of kinases, enzymes involved in many cell-signaling pathways. Altered expression of these enzymes is often associated with abnormal cell growth and development of tumors.
Targeting cancer-related kinase activity presents novel opportunities for the development of new cancer therapies designed to be less toxic than conventional chemotherapeutic drugs. The subcellular distribution and morphological changes induced by these compounds in cancer cells, as well as their selective pattern of kinase inhibition, suggest that they target novel mechanisms of signal transduction. Further studies are currently in progress to identify the precise mechanisms.
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Recent Milestones
Lorus has completed full patient enrolment with over 400 patients in the pivotal Phase III FDA registration clinical trial of its lead immunotherapeutic drug, Virulizin®, for the treatment of advanced pancreatic cancer in June 2004.
The Company received a commitment from the NCI to sponsor an expanded Phase II clinical trial program with GTI-2040. They have also initiated six clinical trials in collaboration with the NCI for a Phase II clinical program of GTI-2040 in patients with AML, breast cancer, NSCLC, prostate cancer, solid tumors, and advanced unresectable colon cancer.
A Phase II clinical trial has been initiated in hormone refractory prostate cancer patients with GTI- 2501, one of the Company’s lead antisense drug candidates, at three prominent Canadian cancer centers.
Audited interim data were analyzed from the Phase II clinical trial of GTI-2040 in combination with capecitabine for patients with advanced end-stage RCC who had failed two or more prior therapies before entering the study, exhibited extensive metastases, and were representative of a population with very poor prognostic outcome. The data demonstrated that more than half of the 25 evaluable patients in this study exhibited disease stabilization, ranging up to eight months. Tumor shrinkages of index tumors compared to baseline measurements were also observed in some patients.
Lorus was awarded Orphan Drug status by the FDA for GTI-2040 for the treatment of advanced RCC.
After three years of research, the Company discovered novel low molecular weight compounds with anti-cancer and antibacterial activities. Lorus subsequently signed a collaboration agreement with the University of Toronto to provide further development of the compounds.
The Company has entered into a worldwide exclusive outlicensing agreement for NC-381 and a library of Clotrimazole analogs for an upfront fee of USD$400,000, with potential for each compound developed in the library of 100 compounds of up to USD$11.6 million of milestone payments if all milestones are achieved, as well as a royalty fee.
An agreement has been entered into to raise aggregate net proceeds of CDN$14.4 million through the issuance of CDN$15 million of secured convertible debentures on October 6, 2004. The Company received CDN$4.4 million on October 6, 2004, and is expected to receive additional proceeds of CDN$5.0 million on January 14, 2005 and April 15, 2005, respectively.
Lorus raised net proceeds of CDN$29.9 million by way of a public offering of units at a price of CDN$1.25 per unit, with each unit consisting of one common share and one-half of one purchase warrant.
The Company obtained approval to list on the American Stock Exchange (AMEX) and commenced trading on the exchange on February 23, 2004, under the symbol LRP.
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Key Points to Consider
Lorus has a pipeline of cancer therapeutics that employs diverse technologies including: (1) immunotherapies that are based on macrophage-stimulating biological response modifiers; (2) antisense therapies based on synthetic segments of DNA; and (3) small-molecule chemotherapies. Their diverse pipeline also includes a gene therapy potential application, and a U-sense research approach.
Lorus’ cancer therapies have fewer demonstrated side effects than current treatments, and are targeted for large markets which include, but are not limited to, pancreatic, lung, breast, prostate, colorectal cancers and malignant melanoma. Together, these markets account for more than half of all cancer cases.
® Lorus’ lead product, Viruzulin , is a proprietary formulation with low toxicity for the treatment of advanced pancreatic cancer. It is in a pivotal Phase III clinical trial in 100 North American, South American, and European sites. Virulizin® has been designated by the FDA for Fast Track approval and has obtained Special Protocol Assessment and Orphan Drug Status.
® The commercial potential for Viruzulin could prove significant as the American Cancer Society (ACS) estimates that 31,860 new cases of pancreatic cancer are expected to occur in the United States in 2004, with an estimated 31,270 deaths. The International Agency for Research on Cancer reports that worldwide incidents of pancreatic cancer are estimated to be 216,000, with almost 100% fatality. Due to the largely unmet need of pancreatic patients, a new agent with lower toxicity and better efficacy is required.
® Virulizin works by stimulating the immune system to attack the cancer, rather than by killing cancer cells itself. As a result, it has shown fewer negative side effects than commonly used chemotherapy agents. It is currently sold in the private market in Mexico for the treatment of malignant melanoma.
GTI-2040, Lorus’ lead antisense drug, has potentially broad applications as a cancer therapy. It is in Phase II clinical trials for the treatment of breast, colon, prostate, lung, and kidney cancers, as well as leukemia.
A number of small molecule compounds that target anti-angiogenic, anti-proliferative, and anti- metastatic pathways are undergoing extensive preclinical studies by Lorus.
Lorus operates under a multi-mechanistic approach to treating cancer, believing that cancer will continue to be treated by many different drugs through a variety of mechanisms of action. This approach could reduce the development risks that are inherent to developing cancer therapeutics.
The Company maintains a stable, liquid financial position with approximately CDN$25 million in cash and a quarterly cash burn rate of less than CDN$6 million.
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Historical Financial Results
Tables 13, 14, and 15 provide a summary of Lorus’ key historical financial statements, including its Statement of Operations, Balance Sheet, and Statement of Cash Flows.
Table 13 Lorus Therapeutics Inc. CONSOLIDATED STATEMENT OF OPERATIONS (amounts in 000’s Canadian dollars, except per common share data) May 31, 2004 2003 2002 Revenues $ 608 $ 66 —
Operating expenses Cost of sales 28 55 — Research and development 26,785 12,550 8,659 General and administrative 4,915 4,290 4,867 Depreciation and amortization 420 960 1,956 Operating expenses 32,148 17,789 15,482 Interest and other income (1,239) (1,155) (1,995) Loss for the period 30,301 16,634 13,487 Deficit, beginning of period 91,503 74,869 61,382 Deficit, end of period $ 121,804 $ 91,503 $ 74,869 Basic and diluted loss per common share $ (0.18) $ (0.12) $ (0.09) Weighted average number of common shares outstanding 171,628 144,590 143,480 used in the calculation of basic and diluted loss per share
Source: Lorus Therapeutics Inc.
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Table 14 Lorus Therapeutics Inc. CONSOLIDATED BALANCE SHEET (amounts in 000’s Canadian dollars) May 31, 2004 2003 ASSETS Current assets Cash and cash equivalents$ 1,071 $ 905 Short-term investments 25,657 24,219 Prepaid expenses and amounts receivable 1,697 1,104 Total current assets 28,425 26,228 Fixed assets 1,471 1,507 Goodwill 606 606 Acquired research and development 3,922 5,669 Deferred financing costs — 245 $ 34,424 $ 34,255 LIABILITIES AND SHAREHOLDERS' EQUITY
Current liabilities Accounts payable$ 2,429 $ 1,318 Accrued liabilities 3,396 4,042 Total current liabilities 5,825 5,360
Shareholders' equity Share capital Common shares Authorized unlimited number of shares; Issued and outstanding (000's): May 31, 2003 - 171,794 May 31, 2002 - 145,285 144,673 120,441 Warrants 4,325 — Compensation options 1,405 — Deferred stock-based compensation — (43) Deficit accumulated during development stage (121,804) (91,503) Total shareholders' equity 28,599 28,895 $ 34,424 $ 34,255
Source: Lorus Therapeutics Inc.
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Table 15 Lorus Therapeutics Inc. CONSOLIDATED STATEMENT OF CASH FLOWS (amounts in 000’s Canadian dollars) May 31, 2004 2003 2002 OPERATING ACTIVITIES Loss for the period$ (30,301) $ (16,634) $ (13,487) Add items not requiring a current outlay of cash: Depreciation and amortization 2,166 2,033 3,407 Stock-based compensation (43) 674 296 Other 245 — — Net change in non-cash working capital balances related to operations (129) 2,019 2,124 Cash used in operating activities (28,062) (11,908) (11,908)
INVESTING ACTIVITIES Sale (purchase) of short-term investments, net (1,438) 12,438 9,378 Acquisition, net of cash received — — — Acquired research and development — — — Additions to fixed assets (383) (1,260) (477) Cash proceeds on sale of fixed assets — — — Cash provided by (used in) investing activities (1,821) 11,178 8,901
FINANCING ACTIVITIES Issuance of warrants 4,537 — — Issuance of common shares 25,512 715 1,389 Additions to deferred financing costs — (245) — Cash provided by financing activities 30,049 470 1,389 Increase (decrease) in cash and cash equivalents during the period 166 (260) (1,618) Cash and cash equivalents, beginning of period 905 1,165 2,783 Cash and cash equivalents, end of period $ 1,071 $ 905 $ 1,165
Source: Lorus Therapeutics Inc.
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Risks
Some information in this report relates to future events or future business and financial performance. Such statements can be only predictions and the actual events or results may differ from those discussed due to, among other things, the risks described in Lorus’ reports in its Annual Information Form (AIF), press releases, and other forms filed from time to time. The content of this report with respect to Lorus has been compiled primarily from information available to the public and released by Lorus through news releases, American Stock Exchange (AMEX), and Toronto Stock Exchange (TSX) filings. Lorus is solely responsible for the accuracy of that information. Information about other companies has been prepared from publicly available documents and has not been independently verified by Lorus. For more complete information about Lorus, please refer to the Company’s Web site at www.lorusthera.com.
Competition
The biotechnology and pharmaceutical industries are characterized by rapidly evolving technology and intense competition. Lorus specializes in the development of drugs that help manage cancer. With products in late stage preclinical through to Phase III development, spanning three different platform technologies, the Company believes it has multiple opportunities for success.
There are a variety of companies in the cancer industry that are focusing their efforts on activities similar to Lorus. The cancer industry is very large, inviting widespread competition from established and highly profitable firms. Some of these companies have substantially greater financial and technical resources, more extensive research and development capabilities, and greater marketing, distribution, production, and human resources than Lorus.
Potential competitors to Lorus’ products include chemotherapeutic agents, monoclonal antibodies, antisense therapies, and immunotherapies with novel mechanisms of action. These are drugs that are delivered by specific means and are targeting cancers with large disease populations.
Lorus may face competition as well from other companies for opportunities to enter into collaborative agreements with biotechnology and pharmaceutical companies and academic institutions. A number of large pharmaceutical firms are actively partnering with development stage companies and licensing a number of cancer therapies similar to those developed by Lorus. Many of these other companies are not solely focused on cancer, as is the mission of Lorus’ drug development efforts. Virulizin® currently faces competition from a number of drugs in development for pancreatic cancer. The leading and most advanced competing drugs are listed in Table 6 (page 16).
Aside from antisense, a number of companies are actively developing oligonucleotide-based technology and relevant pharmaceuticals that employ the technology. These companies include specialized pharmaceutical firms and large pharmaceutical companies acting either independently or together with biopharmaceutical companies.
The Company also expects to experience competition from established and emerging pharmaceutical and biotechnology companies that have other forms of treatment for the cancers that it targets. There are many drugs currently in development for the treatment of cancer that employ a number of novel approaches for attacking these cancers.
Lorus’ ability to remain competitive in the cancer industry also depends upon its ability to attract and retain qualified personnel, obtain patent protection or develop proprietary products or processes, and secure sufficient capital resources for the often substantial period between technological conception and commercial sales.
Cancer is a complex disease with more than 100 indications requiring drugs for treatment. The drugs in competition with Lorus have specific targets for attacking the disease, targets which are not necessarily the same as Lorus’. These competitive drugs therefore could potentially be used together in combination therapies with Lorus’ drugs to manage the disease.
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Limited Product Revenues
Lorus not has produced or commercially marketed any product other than Virulizin®, which has been approved for sale and is being sold in the private market in Mexico. Although the Company has commenced commercial sales of Virulizin®, there can be no assurance that they will realize future revenues from the product. Lorus also cannot be assured that it will ever realize revenues from any of its products in development, or that the Company will ever be profitable.
Limited Funding
Lorus’ products are in various stages of development. The Company is not assured that it will have funds available to permit the successful commercialization of its products. Funding needs may vary depending on many factors including: the progress and number of research and drug development programs; costs associated with clinical trials and the regulatory process; costs related to maintaining drug manufacturing sources; costs of prosecuting or enforcing patent claims and other intellectual property rights; collaborative and license agreements with third parties; and opportunities to in-license or acquire new products.
Regulatory Process
In order to commercialize its products, Lorus must obtain regulatory approvals. Regulatory approvals can take a number of years and involve substantial expenditures. The Company cannot be assured that it will ever obtain necessary approvals or licenses for any of its products; that they will not encounter difficulties or excessive costs in its efforts to secure necessary approvals and licenses; or that it will be able to obtain sufficient funds to meet the necessary expenditures associated with obtaining regulatory approvals.
Market Acceptance
Even if its product candidates receive all necessary regulatory approvals and clearances, they may not gain market acceptance. Physicians, patients, third party payors, and the medical community may not accept or utilize its products, and if its products do not achieve significant market acceptance, Lorus’ business and financial condition will be materially adversely affected. Market acceptance is affected as well by the extent to which reimbursement for the cost of such products will be available from government health administration authorities, private health coverage insurers, and other organizations.
Reliance on Third Parties for Key Services
Lorus relies upon third parties to provide certain key services, including contract manufacturers to manufacture its products and independent investigators and contract research organizations to assist it in conducting its clinical trials. These third parties may encounter difficulties in meeting regulatory requirements and in maintaining quality control and quality assurance to meet the Company’s clinical development needs. If these third party service providers are unable to meet regulatory requirements or maintain quality control and quality assurance, or the Company is unable to retain such suppliers or obtain new third party suppliers, Lorus may not be able to effectively conduct clinical trials or ultimately commercialize its products. Lorus currently holds licenses from third parties for certain technologies, including its antisense platform. The Company cannot be assured that these licenses will not terminate or that they will remain in good standing.
Reliance on Corporate and Academic Collaborators
The Company’s strategy is to enter into various arrangements with corporate and academic collaborators, licensors, licensees, and others for the research, development, clinical testing, manufacturing, marketing, and commercialization of its products. The Company cannot be assured that it will be able to establish such additional collaborations on favorable terms, if at all, or that its current or future collaborative arrangements will be successful, or may not be terminated by its partners.
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No Sales, Marketing, or Distribution Infrastructure in Place
Lorus does not have any sales, marketing, or distribution capabilities. In order to commercialize its products if any are approved, the Company must either acquire or internally develop sales, marketing and distribution capabilities or make arrangements with third parties to perform these services for them. The inability to market its products could have a material adverse effect on its business and financial condition.
Risk of Liability Proceedings
The sale and use of the products Lorus develops could carry the risk of product liability proceedings. While the Company currently maintains limited product liability insurance, there can be no assurance that product liability insurance will continue to be available for Lorus on commercially reasonable terms. Product liability claims might also exceed the amounts of such coverage.
Risk of Contamination or Injury from Materials
Lorus’ discovery and development processes involve the controlled use of hazardous and radioactive materials. Although the Company believes that its safety procedures for handling and disposing of such materials comply with the standards prescribed by local laws and regulations, the risk of accidental contamination or injury from these materials cannot be completely eliminated. In the event of such an accident, the Company could be held liable for any damages that result and any such liability could exceed its resources.
Dependence on Key Patents
The Company’s success depends in part on its ability to obtain patents, maintain trade secret protection, and operate without infringing upon the proprietary rights of third parties. There can be no assurance that its pending patent applications will result in patents being granted, that they will be able to develop additional proprietary products that are patentable, that patents already granted to the Company will provide them with any competitive advantage, or that patents of others will not have an adverse effect on its ability to do business.
Dependence on Key Personnel
Lorus’ success depends in large part upon its ability to attract and retain highly qualified scientific and management personnel. The Company faces competition for such personnel from other companies, academic institutions, government entities, and other organizations. There can be no assurance that Lorus will retain its current personnel and will be able to continue to attract qualified personnel.
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Recent Events
11/18/2004—Announced the initiation of a clinical trial of its antisense drug, GTI-2040, in combination with docetaxel and prednisone in hormone refractory prostate cancer (HRPC) at Princess Margaret Hospital in Toronto.
11/16/2004—Announced the signing of a commercial supply agreement with Diagnostic Chemicals Limited operating as BioVectra dcl (BioVectra) for the commercial manufacture of Virulizin®.
11/10/2004—Announced that it’s wholly owned subsidiary, GeneSense Technologies Inc., has been allowed a patent by the Canadian Patent Office entitled “Anti-tumor Antisense Sequences Directed Against R1 and R2 Components of Ribonucleotide Reductase.” The patent protects Lorus' antisense molecules that target R1 and R2, including its lead anti-cancer drugs in the clinic, GTI-2401 and GTI- 2501.
10/08/2004—Announced a net loss for the quarter ended August 31, 2004 totaled CDN$6.2 million ($0.04 per share) compared with a loss of CDN$8.2 million ($0.05 per share) for the same quarter last year. The decrease in net loss is due to a reduction of CDN$2.2 million in research and development expenses and CDN$200,000 in administrative expenses.
10/07/2004—Announced the closing of the first tranche of a CDN$15 million private placement of convertible secured debentures with The Erin Mills Investment Corporation (TEMIC). The proceeds of the private placement will be used to finance the Company's research and development and on-going operations.
09/30/2004—Announced it will present new clinical results of a study in metastatic RCC with GTI-2040 in combination with capecitabine at a major international conference in Geneva, Switzerland. In this clinical trial, GTI-2040 was investigated in combination with capecitabine, an established chemotherapeutic agent that has also been studied in renal cell cancer.
09/23/2004—Scientists at Lorus published the results of experimental studies with Virulizin®. The results currently appear online in an article entitled, “NK cell activation and tumor infiltration are involved in the anti-tumor mechanism of Virulizin®” in the electronic publication of Cancer Immunology, Immunotherapy, and are to subsequently appear in the printed version of the journal later in the month.
09/07/2004—Announced the appointment of Mr. Paul J. Van Damme as CFO. Mr. Van Damme has more than 20 years of financial strategy and operations experience in the biotechnology sector and in other industries. He was previously senior vice president, finance and CFO of Allelix Biopharmaceuticals Inc., where he was responsible for all aspects of financial management and investor relations, and participated in its sale to NPS Pharmaceuticals, Inc.
08/13/2004—Announced findings from the dose escalation stage of the Phase II trial of GTI-2040 in combination with capecitabine for the treatment of advanced RCC. These findings demonstrated that GTI-2040 is well tolerated in combination with capecitabine, with no reduction in the starting capecitabine dose required. These results are to be presented at the First International Congress on Kidney and Bladder Cancer to be held in Orlando, FL.
08/09/2004—Announced the presentation of results of a novel series of anti-cancer small molecules at the IBC’s 9th Annual World Congress Drug Discovery Technology 2004 held in Boston, from August 18-24 2004. The abstract, to be published in the meeting’s proceedings, is entitled “Anti-proliferative Activity of Novel Aryl-imidazoles and their Possible Mechanism of Action.” The compounds have demonstrated potent anti-proliferative activity against a variety of human cancer cell types.
07/23/2004—Announced the presentation on Virulizin® at the joint 12th International Congress of immunology and the 4th Annual Conference of the Federation of Clinical Immunology Societies held in Montreal, Canada July 18-23, 2004. The abstract, to be published as a supplement to the Clinical
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Investigative Medicine Journal, is entitled “Virulizin®, a Novel Biological Response Modifier, Activates NK Cells and Induces Anti-tumor Activity.”
07/23/2004—Announced financial results for the year ending May 31, 2004. The net loss in fiscal 2004 was CDN$30.3 million, compared with CDN$16.6 million in fiscal 2003. Research and development expenses increased to CDN$26.8 million in 2004 from CDN$12.6 million in 2003, due primarily to higher clinical trial and regulatory expenditures.
07/08/2004—Announced that it has expanded its Hormone Refractory Prostate Cancer (HRPC) trial to two additional sites in Canada. The combination of GTI-2501 and docetaxel in this clinical trial is being investigated in patients with asymptomatic or symptomatic HRPC where disease progression is uncontrolled.
06/24/2004—Announced that Lorus will be an education sponsor of the 6th Annual Lustgarten Foundation Scientific Conference held in San Francisco, CA, from June 25-26, 2004. The conference targets clinical researchers, oncologists, post-doctorate fellows, and allied medical professionals worldwide. The Lustgarten Foundation for Pancreatic Cancer Research is the largest private foundation exclusively dedicated to supporting pancreatic cancer research. An abstract entitled, "Virulizin® Induces Anti-tumor Activity Through Activation and Interaction of Innate Immunity" was accepted for presentation at the conference and be published in the meeting proceedings.
06/17/2004—Dr. Jim Wright, CEO of Lorus Therapeutics was invited to ring the opening bell for trading at the American Stock Exchange (Amex) on June 18, 2004. Bruce Rowlands, senior vice-president, also attended the ceremony. As part of the welcoming ceremony, Amex conducted an interview with Lorus which was transmitted via web cast on the Amex website, www.amex.com, on June 21.
06/17/2004—Announced full enrollment of the Company’s Phase III FDA registration clinical trial of Virulizin® in combination with gemcitabine for the treatment of advanced pancreatic cancer. Over 400 patients have been enrolled into the study globally, exceeding the original target enrollment. Study sites are located in North America, South America, and Europe. The study was designed to examine Virulizin® in both the first line setting and also in the second line treatment setting in combination with 5FU.
06/07/2004—Announced its participation and presentation at the BIO 2004 Annual International Convention in June 2004. Dr. Jim A. Wright, president and CEO, Lorus provided an overview of the Company’s business strategy and product development programs.
06/04/2004—Announced its participation at the American Society of Clinical Oncology annual meeting in June 2004 in New Orleans, NY. Virulizin® was the subject of an abstract entitled “Stimulation of Natural Killer (NK) Cell and Macrophage Infiltration in Pancreatic Cancer with Virulizin®, an Immunotherapeutic Agent.”
06/01/2004—Announced that Lorus’ wholly owned subsidiary, GeneSense Technologies Inc., had been allowed a patent by the European Patent Office for its discovery of a gene, which suppresses the growth of malignant tumors. The patent titled, “Suppression of Malignancy Utilizing Ribonucleotide Reductase R1,” protects an innovative approach to inhibiting tumor growth in mammals, including humans. The European patent follows previous patents issued by both the United States Patent Office and the Australian Patent Office.
05/13/2004—Announced that Lorus would be presenting at the Rodman & Renshaw Techvest Healthcare Conference from May 12-14, 2004 at Claridge’s Hotel in London, UK. Dr. Jim Wright, president and CEO of Lorus, presented a comprehensive review of Lorus’ oncology pipeline on May 13th.
05/12/2004—Announced the discovery of novel low molecular weight compounds with anti-cancer and antibacterial activity. After three years of research by its scientists, Lorus signed a collaboration agreement with the University of Toronto to provide a further development and delivery strategy for the compounds.
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05/04/2004—Announced the initiation of a clinical trial of GTI-2040 in a novel combination with oxaliplatin and capecitabine in patients with advanced unresectable colon cancer. A key objective of this clinical study is to establish the optimal dose of this combination in colon cancer patients and the pharmacodynamic effects on cellular markers of anti-tumor activity when these agents are combined.
04/29/2004—Announced its presentation at the TIDES Conference being held in Las Vegas, NV, from April 25-29, 2004. The oral presentation, entitled "Lorus Therapeutics Antisense Drug Development: Update on GTI-2040 and GTI-2501," was presented in the program under the heading "Updates on Oligonucleotide-Based Therapeutics in Clinical Development."
04/23/2004—Announced financial results for the third quarter ended February 29, 2004. Net loss for the quarter totaled CDN$8 million ($0.05 per share) compared with a loss of CDN$3.8 million ($0.02 per share) for the same quarter last year. Product, royalty and license revenue was CDN$2,000 for the quarter compared with CDN$27,000 for the same period last year. Research and development expenses were CDN$7.3 million compared with CDN$2.9 million for the same quarter last year.
03/30/2004—Announced its participation at the AACR Annual Conference in Orlando, Florida, on March 27-31, 2004. Two presentations were accepted and will be published in the meeting proceedings. The presentations were entitled “Virulizin® Increases Infiltration of NK Cells to Tumors Via Activation of Macrophages,” and “GTI-2040 Displays Cooperative Anti-tumor Activity when Combined with Standard Chemotherapeutic Drugs.”
02/18/2004—Announced that Lorus has been approved for trading on the American Stock Exchange under the symbol "LRP," subject to the fulfillment of certain conditions.
02/17/2004—Announced that Lorus would be presenting a comprehensive review of the development of GTI-2040 and GTI-2501 antisense drugs at the 2nd Annual Antisense and siRNA Technologies Conference in London, England.
02/10/2004—Announced the initiation of a clinical trial aimed at examining the clinical application of GTI- 2040, in combination with gemcitabine in patients with solid tumors. The study will determine the recommended dose of GTI-2040 when administered with gemcitabine. This study is part of a larger clinical development program sponsored and coordinated by the NCI in collaboration with Lorus. Dr. Chris Takamoto, the principal investigator, is an oncology researcher and director of pharmacokinetics at the Institute for Drug Development, Cancer Therapy and Research Center in San Antonio, where the study will be conducted.
01/29/2004—Announced financial results for the second quarter, ended November 30, 2003. Net loss was CDN$6.0 million ($0.03 per share) compared with a loss of CDN$4.0 million ($0.03 per share) for the same quarter last year. Research and development expenses increased to CDN$5.6 million, compared with CDN$3.3 million for the same quarter last year. General and administrative expenses increased to CDN$1.2 million, compared with CDN$0.8 million for the same quarter last year.
01/22/2004—Announced that Lorus will be attending the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco on January 22-24, 2004 An abstract entitled, “Induction of NK cell and macrophage infiltration into tumors may contribute to anti-tumor activity of Virulizin®, “ was presented. The abstract will also be published in the meeting proceedings. These studies were conducted as a collaboration between Lorus scientists and researchers at the Calcium Research Laboratory, Department of Medicine, McGill University.
01/12/2004—Announced interim results from a recently conducted exploratory Phase II clinical trial of GTI-2040 in patients with advanced, end-stage RCC in the United States. This trial was a single-arm pilot study examining the safety and efficacy of GTI-2040 used in combination with the anti-cancer agent capecitabine.
01/12/2004—Announced promising interim results from the Phase II clinical trial of GTI-2040 in combination with capecitabine for the treatment of advanced RCC.
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10/10/2003—Announced first quarter results for fiscal year 2004. Net proceeds of approximately CDN$30 million were raised at a per unit price of CDN$1.25, consisting of one common share and one-half of one purchase warrant. Net loss for the quarter was CDN$8.1 million ($0.05 per share), compared with a loss of CDN$4.1 million ($0.03 per share) for the same quarter in the prior year. R&D expenses increased to CDN$7.2 million from CDN$3.0 million a year ago.
10/09/2003—Announced presentation of results at the Human Proteome Organization (HUPO) 2nd Annual meeting of the International Union of Biochemistry and Molecular Biology XIX (IUBMB) Joint World Congress in Montreal of preclinical studies designed to assess the therapeutic feasibility of RI gene therapy for treatment of colon cancer. An abstract entitled “Adenovirus Mediated R1 Tumor Suppressor Gene Therapy Potential Demonstrated in a Human Colon Adenocarcinoma Model” was presented and published in the proceedings.
10/08/2003—Announced the presentation at the American Association of Cancer Research Special Conference in Cancer Research: Advances in Breast Cancer Research; Genetics, Biology, and Clinical Implications of preclinical studies aimed at assessing the potential therapeutic application of GTI-2040 for the treatment of breast cancer. The abstract is entitled “GTI-2040, An Antisense Oligonucleotide Targeting the R2 Component of Human Ribonucleotide Reductase Displays Cooperative Anti-tumor Activity when Combined with Standard Chemotherapeutic Drugs in Murinee Models of Human Breast Cancer.”
10/03/2003—Announced that Dr. Jim Wright, CEO, would present a comprehensive review of Lorus’ oncology pipeline at BioContact Quebec 2003.
10/01/2003—Announced the publication in Clinical Cancer Research of an article published by Lorus’ scientists entitled “Adenovirus-mediated Ribonucleotide Reductase R1 Gene Therapy of Human Colon Adenocarcinoma.” This study is targeting the development of an anti-cancer gene therapy based on over- expression of a novel tumor suppressor gene in colon cancer cells. The results of this study demonstrate that the large subunit of ribonucleotide reductase, R1, acts as a novel tumor suppressor that, as a gene therapy, has the potential to treat colon cancer.
09/30/2003—Announced a global expansion of clinical sites to Europe and South America of its current Phase III clinical trial of Virulizin® in advanced pancreatic cancer.
09/24/2003—Announced that Lorus’ subsidiary, NuChem Pharmaceuticals Inc., had entered into an exclusive worldwide license agreement for the development and commercialization of its preclinical compound, NC-381, and a library of clotrimazole analogs with Cyclacel Ltd. Lorus will receive upfront fees of USD$400,000 and milestone payments totaling USD$11.6 million.
09/15/2003—Announced that approval has been granted by Health Canada for initiation of a clinical trial of GTI-2040 in combination with docetaxel for the treatment of advanced non-small cell lung cancer, as part of a Phase II clinical program of GTI-2040 in collaboration with the NCI. The study is supported by the Cancer Therapy Evaluation Program, an NCI agency that is providing program coordination and financial sponsorship as part of its mission to support the development of novel cancer drugs,
08/20/2003—Announced that Lorus’ NuChem Pharmaceuticals Inc, subsidiary, through an exclusive license with Harvard University, has been allowed a patent by the European Patent Office. This patent protects Lorus’ intellectual property interests with regard to certain molecules that inhibit cancer progression characterized by abnormal vascularization.
08/13/2003—Announced positive clinical results from the dose escalation stage of the ongoing Phase II clinical trial of its antisense drug, GTI-2040, combined with capecitabine in metastatic kidney cancer. The clinical findings were presented at the First International Congress on Kidney and Bladder Cancer in Orlando, FL.
08/12/2003—Announced that the FDA had approved the NCI’s Investigational New Drug Application (IND) to begin a Phase II clinical trial to investigate Lorus’ leading antisense drug, GTI-2040, as a treatment for metastatic breast cancer in combination with capecitabine (Xeloda from Roche).
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07/28/2003—Announced that the Canadian Patent Office had allowed a patent which protects Lorus’ intellectual property as it relates to the discovery and use of potential anti-tumor oligonucleotide molecules that target the stability of messenger RNA molecules that code for proteins involved in essential cellular functions.
07/18/2003—Announced financial results for the year ended May 31, 2003. The loss for the year was CDN$16.6 million compared with the year earlier loss of CDN$13.5 million. Research and development expenses for this period increased from CDN$8.7 million to CDN$12.6 million. CDN$32.8 million was raised in a public offering of units at a price of CDN$1.25 per unit with each unit consisting of one common share and one-half of one purchase warrant.
07/07/2003—Announced the FDA’s approval of the NCI-sponsored IND application for a clinical trial of its lead antisense drug, GTI-2040, in combination with cytarabine in patients with refractory or relapsed acute myeloid leukemia. The study will be conducted under the sponsorship of the Division of Cancer Treatment and Diagnosis of the NCI.
06/24/2003—Announced the receipt of a notice from the European Patent Office of allowance of a patent, entitled “Immunomodulating Compositions from Bile,” which protects Lorus’ intellectual property for its lead immunotherapeutic anti-cancer drug, Virulizin®.
06/17/2003—Announced that data on the mode of action of Virulizin® was accepted for presentation at the 5th Annual Lustgarten Foundation Scientific Conference held in Boston, MA. The poster presentation of preclinical and clinical findings was entitled “Stimulation of Natural Killer Cell Function in Pancreatic Cancer with Virulizin®, an Immunotherapeutic Agent.”
06/06/2003—Announced the publication in Cancer Research of results of studies in mouse models bearing human tumors that were treated with GTI-2040. The article was entitled, GTI-2040, an Antisense Agent Targeting the Small Subunit Component (R2) of Human Ribonucleotide Reductase, Shows Potent Anti-tumor Activity against a Variety of Tumors.” GTI-2040 exhibited highly specific anti-tumor activity against twelve different human tumors.
06/02/2003—Announced the presentations of data on GTI-2040 and Virulizin® at the 39th annual meeting of the American Society of Clinical Oncology in Chicago, IL. The papers were entitled “A Phase I Study of GTI-2040 Given by Continuous Intravenous Infusion in Patients with Advanced Malignancies” and a poster is entitled “Virulizin®, a Novel Immunotherapeutic Agent Stimulates Natural Killer Cell Function in Implanted Human Tumors – Potential Biologic Marker of Clinical Response.”
05/21/2003—Announced the initiation of a Phase II trial in the Fall 2003 for GTI-2040 for the treatment of advanced metastatic prostate cancer. A Letter of Intent to conduct this study was signed with Dr. Laurence Klotz of the Sunnybrook and Women’s College of Health Sciences Center in Toronto, Canada.
05/13/2003—Announced that the U.S. Patent Office allowed a patent that protects the antimicrobial component of Lorus’ antisense drug that targets specific gene sequences. The patent is entitled “Antisense Oligonucleotide Sequences as Inhibitors of Microorganisms.”
04/23/2003—Announced the publication in Anti-cancer Drugs of results of experimental studies demonstrating the anti-tumor activity of Virulizin® as a monotherapy and in combination with standard chemotherapy drugs. The article was entitled “Preclinical Efficacy of Virulizin® in human breast, ovarian, and prostate tumor models.”
04/16/2003—Announced that the pivotal Phase III clinical trial of Virulizin® for the treatment of advanced pancreatic cancer was being expanded to include approximately 50 clinical trial sites, 40 of which are major cancer centers in the U.S. and 10 are major oncology centers in Canada and Mexico.
04/09/2003—Announced that the Canadian Patent Office had allowed a patent which protects a new component of Lorus’ antisense drug that shows promising antimicrobial activity and targets specific microbial gene sequences. The patent is entitled “Antisense Oligonucleotide Sequences as Inhibitors of Microorganisms.” The two gene targets covered by the patent are SecA and Ribonucleotide reductase, which are necessary for the growth and viability of organisms.
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04/02/2003—Announced the receipt of notice from the U.S. Patent and Trademark Office of the allowance of a patent, which protects Lorus’ lead immunotherapeutic anti-cancer drug, Virulizin®. The patent is entitled “Immunomodulating Compositions for Treatment of Immune System Disorders.”
03/27/2003—Announced the publication in Cancer Chemotherapy and Pharmacology of the results of experimental studies in mouse models bearing human tumors treated with Virulizin®. The article was entitled “Anti-tumor Activity of Virulizin®, a Novel Biological Response Modifier, in a Panel of Human Pancreatic Cancer and Melanoma Xenografts.” Virulizin® showed significant anti-tumor activity as a monotherapy and enhanced anti-tumor effects when used in combination with standard chemotherapy agents against a panel of human pancreatic tumors and melanoma.
03/24/2003—Announced that the FDA awarded Orphan Drug status to GTI-2040 for the treatment of advanced kidney cancer. The FDA will help to facilitate the drug’s development process by providing financial incentives and granting seven years of market exclusivity in the U.S. upon approval of the drug in the U.S.
03/10/2003—Announced that the U.S. Patent and Trademark Office had allowed a patent to protect Lorus’ intellectual property involving a lead anti-cancer agent, the R1 component of ribonucleotide reductase.
02/21/2003—Announced that Lorus’ clinical investigators and scientific advisors would present results of discovery and clinical programs related to Virulizin® at a symposium at the 20th National Medical Meeting of the Instituto Nacional de Cancerologia in Mexico City.
02/17/2003—Announced that a patent had been allowed by the Mexican Patent Office to protect Virulizin®. The patent, entitled “Immunomodulator Composition, Process for Preparation, Pharmaceutical Compositions that Contain it and Uses of Same,” protects both the composition and use of Virulizin®.
02/11/2003—Announced a clinical trial agreement between the NCI and Lorus in which the NCI will financially sponsor a series of Phase II clinical trials to investigate the safety and efficacy of GTI-2040 in six different cancer indications. Dr. Helen Chew of the University of California Davis Center will be the lead investigator. This is the second clinical trial initiated in collaboration with the NCI to be approved by the FDA, the first was a clinical trial study with GTI-2040 in combination with cytarabine for the treatment of acute myeloid leukemia.
02/05/2003—Announced the expansion of the ongoing clinical trial of GTI-2040 to five major oncology centers in the U.S. GTI-2040 is being studied in combination with capecitabine (Xeloda from Roche Holdings) for the treatment of advanced RCC in patients who have failed previous chemotherapies.
01/15/2003—Announced the retention of Mr. Bruce Rowlands as senior advisor with responsibilities in investor relations.
01/14/2003—Announced the appointment of Dr. Robert L. Capizzi to Lorus’ Board of Directors. Dr. Capizzi is the president of Capizzi Clinical Resources, Inc., a company that specializes in pharmaceutical drug development and regulatory affairs.
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Glossary of Lesser-Known Terms
Acute Myeloid Leukemia—A rapidly progressing form of leukemia in which the body has an overabundance of immature blood forming cells in the blood and bone marrow. As the mature forms of these cells are directly responsible for giving rise to disease-fighting granulocytes and monocytes, the body is less efficient in preventing infection.
Adenocarcinoma—Cancer that begins in cells that line certain internal organs and that has glandular (secretory) properties.
Alcohols—Organic chemicals featuring one or more hydroxyl (OH) groups that are attached to carbon atoms in place of hydrogen atoms.
Amines—Chemical compounds containing nitrogen. Amines are derived from ammonia.
Anti-Angiogenic—Describes a class of drugs that halt the development of new blood vessels (angiogenesis). Angiostatin is a piece of a larger and very common protein, plasminogen, which the body uses in blood clotting. Endostatin is a piece of a different protein, collagen 18, which is in all blood vessels. Both angiostatin and endostatin are normally secreted by tumors. This process provides the basis for anti-angiogenesis drugs.
Antigens—Any substances that are recognized by a component of the immune system as foreign. Infectious disease antigens consist of parts of pathogens such as bacteria or viruses.
Anti-Metastatic—Any agent that halts metastasis, the spread of cancer from one part of the body to another. Cells in metastic (secondary) tumors may not be antigenically similar to those in the original (primary) tumor.
Anti-Proliferative—Exhibiting the ability to inhibit the proliferation of cells.
Antisense Oligonucleotides—Short DNA molecules that can interfere with gene expression by forming duplexes with complementary sequences of target messenger RNAs (mRNAs).
Antisense Therapies—The use of antisense DNA, a DNA strand involved in replication, for the production of a therapeutic gene product.
Apoptosis—Programmed cell death. The physiological process is necessary for the elimination of superfluous, diseased, or damaged cells and the formation of new cells.
Biological Therapy—See Immunotherapy.
Cancer—Disease in which abnormal cells divide without control. Cancer cells can invade nearby tissue and spread through the blood stream and lymphatic system to other parts of the body.
Chemotherapy—Treatment with cytotoxic anti-cancer drugs.
Chromosomes—Rod-shaped structures located in a cell nucleus that carry the genetic material that determines an individual’s sex along with the traits they inherit from their parents.
Clotrimazole (CLT)—An anti-fungal agent known to inhibit cell proliferation by interfering with cell cycle progression.
Colon Cancer—Malignant growths found in the colon, rectum, or anus. Colon cancer is the third most common form of cancer and second leading cause of cancer-related death in the U.S.
Cytokines—Small, cellular proteins secreted by the lymph system that affect the interaction, communication, and behavior of cells.
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Deoxyribonucleic Acid (DNA)—Building block of living organisms, found in the nucleus of a cell, that carries the genetic information of a cell and is able to self replicate and synthesize RNA. DNA is a duplex of linear chains of deoxyribonucleotides.
Eastern Cooperative Oncology Group (ECOG)—Standardized clinical scale to assess the functional status of cancer patients.
Fatty Acids—Organic acids occurring naturally as fats and oils in plant and animal materials. Fatty acids consist of a straight chain of carbon atoms linked by single bonds, and ending in a carboxyl group.
Genome—A set of chromosomes and genes that an individual inherits from his or her parents.
Hepatocellular—Related to cells in the liver.
High-Performance Liquid Chromatography (HPLC)—A standard instrumentation/methodology for separation of chemical compounds. Commonly used as a fingerprinting measure to ensure a consistent composition from batch to batch.
Hormone Therapy—The use of drugs or surgery to decrease the production of hormones in an effort to suppress the progression of cancer.
Immunotherapy—Treatment with drugs that act by stimulating or enhancing an immune response against a specific disease.
Interferon—A naturally-occurring substance possessing the capability to interfere with the ability of viruses to reproduce. Consequently, interferon also serves as an immune stimulator.
Interleukin One Beta (IL-1B)—A cytokine that stimulates immune responses against certain antigens.
Interleukin-2—A protein factor that stimulates T lymphocytes to act against antigens.
Intramuscular (IM)—An injection given by needle into the muscle, as opposed to a medication that is given by a needle, for example, into the skin (intradermal) or just below the skin (subcutaneous) or into a vein (intravenous).
Kinases—Enzymes involved in many cell-signalling pathways. Altered expression of these enzymes is often associated with abnormal cell growth and development of tumors.
Macrophage—Any of various phagocytic cells that play a central role in controlling the body’s immune response.
Malignant Determinants—A term coined by Dr. Wright (page 7) that refers to genes or proteins that elevate malignancy through aberrant expression or regulation.
Malignant Melanoma—A cancerous tumor that develops from melanocytes, which are melanin- producing cells in the skin.
Metastasize—To spread from one part of the body to another. Cells in metastic (secondary) tumors may not be antigenically similar to those in the original (primary) tumor.
Micrometastasis—Spreading of undetectable cancer cells, usually occurring early in the process of metastasis.
Monocytes—White blood cells responsible for the digestion of foreign substances in the body. Monocytes are precursors to macrophages.
Monotherapy—The use of a single drug or other therapy.
Natural Killer (NK) Cells—White blood cells containing granules with enzymes that can kill tumor cells.
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Nucleases—Enzymes that are capable of cleaving phosphodiester bonds between nucleotide subunits of nucleic acids.
Nucleoside—Compounds produced by attaching a nitrogenous base to a ribose ring. Precursors to nucleotides.
Nucleotides—Nucleoside phosphates that are the basic components of RNA and DNA.
Oncogenes—Fragments of genetic material (DNA) that carry the potential to cause cancer (transform normal cells into malignant cells).
Organic Phosphates—An organic polyatomic ion (or radical) consisting of one phosphorous atom and four oxygen atoms. Phosphates can be formed by the reaction of a metal, alchohol, or other radical with phosphoric acid.
Palliative Surgery—Surgical procedure to relieve, but not cure a disease.
Pancreatic Cancer—The proliferation of a malignant tumor in the pancreas.
Peptide—Molecules consisting of two or more amino acids.
Prostate Cancer—A malignant tumor containing cells from the prostate gland.
Proteins—Complex organic macromolecules that contain carbon, hydrogen, oxygen, nitrogen and usually sulphur, and are composed of one or more chains of amino acids. Proteins are fundamental components of all living cells and include many substances, such as enzymes, hormones and antibodies that are necessary for the proper functioning of an organism. Amino acids and/or their precursor molecules are essential in the diet of animals for the growth and repair of tissue and can be obtained from foods such as meat, fish, eggs, milk, and legumes.
Pyrogen—Any substance capable of causing a rise in body temperature.
Radiation Therapy—The use of high-energy radiation from X-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials (radioisotopes) that produce radiation that are placed in or near a tumor in the area where cancer cells are found (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy involves giving a radioactive substance a radio-labeled monoclonal antibody that circulates throughout the body. This method is also called radiotherapy.
Renal Cell Carcinoma (RCC)—Cancer that develops in the lining of the renal tubules, which filter the blood and produce urine.
Retinitis—Inflammation of the retina.
Ribonucleic Acid (RNA)—A single-stranded molecule composed of a linear chain of ribonucleotides. RNA is an intermediary in the making of proteins and is the sole genetic material of retroviruses.
Ribonucleotide Reductase (RNR)—A multi-subunit enzyme complex composed of two proteins encoded by different genes. RNR is the enzyme responsible for the rate-limiting step in the synthesis of deoxyribonucleotides from the corresponding ribonucleotides. RNR is crucial for the synthesis of DNA and the proliferation of cells, including tumor cells. As the over-expression of RNR is important in mechanisms of cancer transformation and disease progression, reducing gene expression through the application of antisense or U-sense molecules has the potential to produce important new classes of anti- cancer drugs.
Ribonucleotides—Nucleotides in which a purine or pyrimidine base is linked to a ribose sugar molecule.
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RNase H—A ribonuclease enzyme that cleaves the 3'-O-P-bond of RNA in a DNA/RNA duplex to produce 3'-hydroxyl and 5'-phosphate terminated products. RNase H can be found in virtually all organisms.
Spliceosomes—Nuclear ribonucleoprotein complex that is responsible for excision and splicing reactions that remove introns (intervening sequences) from precursor messenger RNA molecules to produce mature messenger RNA.
Tumor Necrosis Factor (TNF)—A subgroup of molecules capable of initiating signalling cascades that increase cell proliferation, differentiation, and apoptosis.
Tumor Suppressor Genes—Genes that inhibit the formation of tumors in the body.
U-Sense Therapy—A therapeutic based on short oligonucleotides that are identical to sequences in the untranslated regions of mRNA molecules. The binding of these oligonucleotides to factors (i.e. proteins) that would otherwise bind to the mRNA has the potential to affect translation and/or stability of the mRNA and, as a result, alter expression of the protein product.
Untranslated Region—Sequences of nucleotides that are present in a mature messenger RNA molecule but do not code for amino acids. In general, a messenger RNA has two untranslated regions found at the 3’ and 5’ ends of the RNA.
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Jeffrey J. Kraws and Karen B. Goldfarb Phone: 212-201-6638 Fax: 212-838-4568 Email: [email protected] Web: www.crystalra.com
Legal Notes and Disclosures: This report has been prepared by Lorus Therapeutics Inc., (the “Company”) with the assistance of Crystal Research Associates, LLC. (“CRA”) based upon information provided by the Company. CRA has not independently verified such information. In addition, CRA has been compensated by the Company in cash of $35,000 for its services in creating this report, for updates, and for printing costs.
Some of the information in this report relates to future events or future business and financial performance. Such statements constitute forward-looking information within the meaning of the Private Securities Litigation Act of 1995. Such statements can be only predictions and the actual events or results may differ from those discussed due to, among other things, the risks described in Lorus Therapeutics Inc.’s, reports on Annual Information Forms, press releases, and other forms filed from time to time. The content of this report with respect to Lorus Therapeutics Inc. has been compiled primarily from information available to the public released by Lorus Therapeutics Inc. Lorus Therapeutics Inc. is solely responsible for the accuracy of that information. Information as to other companies has been prepared from publicly available information and has not been independently verified by Lorus Therapeutics Inc. or CRA. [Certain summaries of scientific activities and outcomes have been condensed to aid the reader in gaining a general understanding.] For more complete information about Lorus Therapeutics Inc., the reader is directed to the Company's website at www.lorusthera.com. This report is published solely for information purposes and is not to be construed as an offer to sell or the solicitation of an offer to buy any security in any state. Past performance does not guarantee future performance. Free additional information about Lorus Therapeutics Inc., and its public filings, as well as free copies of this report can be obtained in either a paper or electronic format by calling (416) 798-1200.
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