TopoTarget A/S Symbion Science Park 3 Fruebjergvej DK-2100 Copenhagen, Denmark Phone: +45 39 17 83 90 www.TopoTarget.com

Unique Oncological Biopharmaceutical Opportunity

Snapshot January 26, 2005

TopoTarget A/S is a privately held biopharmaceutical company focused on developing novel pharmaceuticals for cancer† and cancer-related indications, as well as on the identification of new indications for existing compounds. The Company’s first internally developed product, Topotect, is in Phase III as an antidote for extravasation, a severe form of tissue damage resulting from an incorrect administration of cytotoxic anthracyclines or chemotherapy drugs. Pending approval, the Company could launch Topotect in winter 2005/2006. This product, based on the concept of deoxyribonucleic acid (DNA) damage control, would provide TopoTarget access to profitable, lower-risk markets. TopoTarget is also developing Topotect for the treatment of brain metastases, a life-threatening condition that affects approximately 60% of primary small cell lung cancer (SCLC) patients. Topotect recently entered Phase I/II clinical trials for this indication. Additionally, TopoTarget is heavily involved in the management of chromatins, the proteins responsible for the formation of DNA-containing chromosomes. The Company’s expertise in this area has led to the development of PXD101, a Phase I anti-cancer histone deacetylase (HDAC) inhibitor that interferes with cell cycle arrest and angiogenesis, and has demonstrated anti-tumor activity in vivo. TopoTarget expects to employ this drug to target a variety of cancer indications, including multiple myeloma, malignant lymphoma, and ovarian, colorectal, and prostate cancer. TopoTarget also has a library of diverse HDAC inhibitors that have demonstrated efficacy in a variety of cancer and non-cancer indications.

Key Points

TopoTarget has three products in clinical trials, as well as approximately a half-dozen preclinical stage compounds. The Company’s most advanced product, Topotect, was granted Orphan Drug designation as an antidote for anthracycline extravasation in Europe in 2001 and could receive approval within the next 12 months. Orphan Drug designation was also granted by the U.S. Food and Drug Administration (FDA) in 2004. Following approval, TopoTarget expects to sell the product in Europe and partner it outside of Europe with a large pharmaceutical company.
In May 2004, the National Cancer Institute (NCI) and TopoTarget signed a letter of intent to enter into a Cooperative Research and Development Agreement (CRADA) to conduct the preclinical and clinical development of PXD101, TopoTarget’s proprietary HDAC inhibitor. The agreement involves the determination of the most appropriate anti-cancer agents for use in combination with PXD101. Also, the NCI and TopoTarget are collaborating on the identification of anti-cancer drug candidates from TopoTarget’s library of HDAC inhibitors.
In June 2004, TopoTarget and U.S.-based CuraGen Corporation (CRGN-NASDAQ) announced a license, collaboration, and commercialization agreement on a small molecule inhibitor program targeting HDAC in oncology.
TopoTarget was founded by clinical oncologists who have an understanding of the realities of clinical practice. This enables the Company to choose intelligently between an array of possibilities and targets. Additionally, the Company has proven in-house clinical trial capabilities.
TopoTarget’s leadership team is experienced in medical products, biopharmaceuticals, and pharmaceuticals, and has a track record of success over many decades in research, drug

EXECUTIVE INFORMATIONAL OVERVIEW development, clinical practice, and venture development.
The Company has achieved all of its key business and scientific milestones since its last funding round in June 2002. Over the next 24 months, TopoTarget could achieve more than a half-dozen separate potential revenue-generating milestones.

†BOLD WORDS ARE REFERENCED IN GLOSSARY ON PAGES 45-48.

Table of Contents

Snapshot ...... 1

Key Points ...... 1

Executive Overview...... 3

Growth Strategy...... 7

Intellectual Property...... 9

Management and Board of Directors ...... 12

Core Story ...... 15

Cancer ...... 15

The Cancer Cell Cycle ...... 15

Advanced Stage Development...... 20

Chemotherapy...... 20

Extravasation...... 21

Topotect for Extravasation ...... 26

Brain Metastases...... 30

Topotect for Brain Metastases ...... 31

Histone Deacetylase (HDAC) Inhibitors for Multiple Indications ...... 33

PXD101 ...... 34

Early Stage Development...... 36

HDAC Inhibitor Library ...... 36

In-licensed ...... 37

Potential Milestones Within Next 12-24 Months...... 38

Historical Financial Results ...... 39

Risks...... 42

Recent Events ...... 44

Glossary of Lesser-Known Terms ...... 45

Executive Informational Overview Page 2

Executive Overview

TopoTarget A/S is a privately held biopharmaceutical company focused on developing novel compounds for cancer and cancer-related indications. The Company’s development efforts employ a broad understanding of the molecular mechanisms of cancer and the realities of clinical practice to develop new and potentially effective approaches to combat the various manifestations of the disease.

Pipeline

TopoTarget’s pipeline is based on two pillars: (1) early revenues from specialty products, and (2) value growth from more broad indication products. With regard to the first pillar, the Company could launch its first product, Topotect for extravasation, in winter 2005/2006. Topotect could provide the Company with a base for top-line growth and profitability by 2007. Additionally, TopoTarget is developing Topotect (currently in Phase I/II) for brain metastases and PXD101 (currently in Phase I) for multiple indications. The Company also possesses a range of preclinical compounds targeted at a variety of indications.

Figure 1 provides a snapshot of the Company’s drug development pipeline, according to advanced stage and early stage development candidates. This is followed by an overview of its three leading and most advanced product candidates under development, as well as its earlier stage development candidates.

Advanced Stage Development

Figure 1 TopoTarget A/S DRUG DEVELOPMENT PIPELINE

Product Indication Lead ID Lead OP Preclin Phase I Phase II Phase III Reg filing Sales

Source: TopoTarget A/S.

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Topotect for extravasation. The Company’s first internally developed product, Topotect, is in Phase III as an antidote for extravasation, a severe form of tissue damage resulting from an adverse reaction to anthracyclines, a group of commonly used cytotoxic agents. Extravasation occurs when an anthracycline escapes from the vein at the injection site and induces extensive tissue necrosis (tissue damage) that may be life-threatening. Preclinicial and clinical trials of Topotect have demonstrated that prompt administration in both animals and humans prevented necrosis and eliminated the need for surgery. Topotect was granted Orphan Drug designation in Europe in 2001 and could receive approval within the next 12 months. Following approval, TopoTarget expects to sell the product in Europe, and partner it internationally, including the U.S., with a larger pharmaceutical company.

Topotect for Brain Metastases. Brain tumors may either be primary, such as glioblastomas, or secondary, which is a metastasis from a primary cancer not located in the brain. More than 90% of all malignant brain tumors are metastatic. The two most common cancers capable of spreading to the brain are lung and breast cancer, which reach the brain via the blood in up to 60% of cases of SCLC and in 20% of breast cancer patients. These metastatic tumors are difficult to treat because the blood brain barrier restricts the cytotoxic treatments from reaching the brain. Preclinical testing of Topotect has demonstrated that the drug, when used in combination with etoposide (a well-established chemotherapeutic agent), allows the use of elevated cytotoxic poison and aids in the treatment of brain metastases in animals. As such, Phase I clinical trials are now underway to investigate the efficacy of a combination therapy of Topotect and etoposide. The Company hopes to advance into a randomized Phase II or Phase III trial for the prevention of brain metastases following primary SCLC in 2006.

PXD101. PXD101 is a Phase I anti-cancer histone deacetylase (HDAC) inhibitor being investigated for the treatment of various solid and hematological cancers, including colorectal and ovarian cancer, multiple myeloma, and Non-Hodgkin Lymphoma. PXD101 has been shown to interfere with cell cycle arrest and angiogenesis and has demonstrated anti-tumor activity in vivo. The drug is based on the Company’s solid position in the management of chromatin, the substance responsible for the conformation of DNA in the chromosomes. PXD101 entered Phase I clinical trials in October 2003 and pharmacodynamic proof of principle in humans was achieved, even at the lowest dose.

TopoTarget is also testing an oral formulation of PXD101 within the current Phase I trial. In 3/3 patients, an oral bioavalilability of approximately 35% was achieved using simple gelatin capsules. A Phase II trial for multiple myeloma is due to commence in Copenhagen, Denmark in the first quarter 2005 and further Phase II trials in ovarian, prostate, and colorectal cancer are planned for 2005. In addition, the U.S. National Cancer Institute (NCI) has recently solicited for multiple Phase I/II trials under a CTA (Clinical Trial Agreement) with CuraGen Corp.

o Agreement between TopoTarget and the National Cancer Institute (NCI). The NCI and TopoTarget are currently finalizing a Cooperative Research and Development Agreement (CRADA) to conduct the preclinical development of PXD101 as well as on the identification of anti-cancer drug candidates from TopoTarget’s library of HDAC inhibitors.

o Agreement between Curagen Corporation and the NCI. On August 24, 2004, TopoTarget announced that its licensing partner, CuraGen Corporation, had signed a CTA with the Division of Cancer Treatment and Diagnosis (DCTD) at the NCI for PXD101. Under the agreement, the NCI will sponsor several clinical trials evaluating the activity of PXD101, either alone or in combination with other anti-cancer therapies, for the treatment of solid and hematologic cancers.

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Early Stage Development

HDAC inhibitors for psoriasis/parasitic disease. TopoTarget has identified HDAC compounds that have marked anti-proliferative effects on aberrantly proliferating keratinocytes. The Company has a collaboration with Leo Pharma, a Danish pharmaceutical company largely involved in the psoriasis market in Europe, to develop HDAC inhibitors as therapeutics in psoriasis.

HDAC Second Generation for cancer. The second generation HDAC inhibitor program is aimed at identifying compounds with different pharmacokinetic, HDAC subtype selective chemical properties to PXD101.

Cardioprotective non-catalytic Inhibitors. TopoTarget has a collaboration with Professor Brian Hasinoff from the University of Manitoba to develop dexrazoxane analogues without catalytic inhibition of topoisomerase II, but with retained ability to protect against myocardial damage caused by the free radical effects of anthracyclines. A lead compound has been identified and animal studies are planned.

HSP90. A newly established and validated target for anti-cancer therapy, HSP90, has been found to be primarily drug sensitive in malignant cells due to mutations in the enzyme. Experimental HSP90 drugs, such as 17-AAG and 17-DMAG are in the clinic, but have experienced problems with liver toxicity. Using the published crystal structure of HSP90, its experience with topoisomerase II ATPase, which resembles that of HSP90, as well as an arrangement with Inhibox Ltd., a molecular modeling company, TopoTarget believes that it can design and test efficient HSP90 inhibitors for targeted treatment. Synthesis of a candidate drug has begun at TopoTarget’s contract research facility in Riga, Latvia.

E2F for cancer. E2F is a transcription factor that regulates whether cells progress to cell growth and division. Restoration of E2F control causes cancer cell death in a variety of models.

DUBS. De-ubiquinating systems (DUBS) are a potential angiogenesis target in cancer therapy. TopoTarget owns intellectual property (IP) in the field, derived from a collaboration with Professor Rene Bernards at the Netherlands Cancer Institute. A particularly promising DUBS, VDU1, which inhibits the angiogenesis signal HIF-1α, is being cloned and expressed for compound screening.

In-licensed

Endovion. In an announcement made in mid-August 2004, TopoTarget entered into a collaboration with NeuroSearch A/S (NEUR.COP) to develop the NeuroSearch compound Endovion (NS3728), an orally active chloride channel blocker for the treatment of cancer.

Acquisition of Prolifix

In May 2002, TopoTarget purchased UK-based Prolifix Ltd., which now operates as a wholly owned subsidiary of TopoTarget. Prolifix was founded by Professor La Thangue in 1994 (biography on page 12) and is based on his discovery of the cancer control protein E2F while at the UK Medical Research Council‘s (MRC) laboratories in London. Prolifix was built on specific targets coming out of human genome research, specifically focused on cancer.

Executive Informational Overview Page 5

History, Headquarters, Manufacturing, and Employees

TopoTarget was founded in 2000 by Dr. Peter Buhl Jensen, Dr. Maxwell Sehested, Neil Goldsmith, and Dr. Seppo W. Langer and is based on discoveries relating to cell protection mechanisms against DNA damage. Their focus was to build predictive clinical models using the knowledge of the topoisomerase enzymes and their function and interaction. Such data provided a unique tool for regulating the effect of drugs that have been on the market for 2-3 decades. Their research was conducted at The Danish National University Hospital in Copenhagen.

TopoTarget’s first funding round took place in November 2000 and allowed the Company to fully establish itself in custom fitted laboratories at the Symbion Science Park in Copenhagen. Along with Prolifix Ltd., the combined company now operates from two sites in Copenhagen, Denmark and Oxford, UK, and employs a total of 65 individuals. The Company occupies 348 m2 of office and laboratory facilities at Symbion and 300 m2 at the National University Hospital (Rigshospitalet), Copenhagen. The two facilities are a 10-minute bike ride apart. Management, administrative, regulatory, clinical, Drug Metabolism and Pharmacokinetics (DMPK), and synthetic chemistry activities are located at Symbion, with all other activities (including animal work), located at Rigshospitalet. Additionally Topotarget occupies 600 m2 of custom fitted laboratory/office space in Milton Park, Oxfordshire for molecular biology, computational chemistry, and drug screening. Finally, 15 full time chemists are employed under a rolling contract at the Latvian Institute of Organic Synthesis (LIOS) at a salary of roughly one-third the salary of a western country. Thus, the Company has an extremely cost-effective way of producing new small molecules for in vitro and in vivo testing.

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Growth Strategy

TopoTarget’s top line growth strategy is predicated upon the achievement of both organic growth as well as growth through mergers and acquisitions as opportunities arise. In an effort to enhance its current efforts, TopoTarget is focused on seeking out companies that offer complementary expertise and product portfolios to that of its own. TopoTarget’s growth strategy is summarized below.

Outlicensing. Products with large earnings potential could be partnered to provide the most beneficial risk/reward profile.

o Non-oncology indications of existing oncology pipeline, including psoriasis and tropical diseases in its library of HDAC inhibitors, could be partnered.

o Non-European marketing rights to the Company’s portfolio of niche cancer products, such as Topotect for extravasation, could be out-licensed.

o Oncology compounds with significant product potential but with relatively higher development risk and/or compounds that require significant sales forces could be partnered during the development process; and

o For distribution outside of Europe, the Company is exploring out-licensing options with larger pharmaceutical companies.

Collaborations. Collaborations with organizations such as the NCI and/or the World Health Organization (WHO) could prove beneficial.

In-licensing. TopoTarget seeks to broaden its portfolio of niche cancer products and ensure full use of its European sales and marketing facility through the in-licensing of products and late stage projects within its specifically targeted areas.

Commercial Strategy

With regard to the Company’s business model, TopoTarget is focused on feeding its pipeline through (1) developing a portfolio of cancer drug candidates that are a balance between niche products with low development risk that can more expeditiously drive the Company toward sustainable profitability, and (2) larger products that have a greater risk/reward profile but with the potential to generate significant profits. The first of these strategies is representative of the near term focus by TopoTarget, specifically within Europe.

The Company’s goal is to produce a Phase I candidate annually, either through an internal process or through successful in-licensing opportunities. This strategy is in place as an attempt to ensure a full pipeline and additional mid-term revenue.

Figure 2 (page 8) illustrates the Company’s continuously fed Product Pipeline. The funnel begins on the left with early preclinical discovery, such as testing in animals and on targets with intellectual property, sourcing where the Company is receiving its drug developing work. It then illustrates the validation and chemical screens. Next are the clinical trials at the far right, with the most advanced drugs in the point of the arrow, with three products in clinical trials.

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Figure 2 TopoTarget A/S CONTINUOUSLY FED PIPELINE

MRC (UK)

E2F PXD 104 NCI (US) DUB’S PXD 101 Cyclin D1 HDACi (Six Series) Lead Topotect Topotect Sourcing

JMY WBCIs III Myc/Miz Cardio-2’s II

NCI (NL) I Clinic MDRCIs HSP90 P53 prot Lead Rigshosp Optimisation & – italet (DK) Lead ID Pre-Clinical Target Validation Predictive clinical models New Targets Note: Rigshospitalet is TopoTarget's department situated at the National Hospital, Rigshospitalet. Source: TopoTarget A/S.

Executive Informational Overview Page 8

Intellectual Property

TopoTarget’s patent strategy is focused on securing intellectual property that underpins its drug discovery programs. Proprietary patents are relevant to all parts of the Company’s business, thus patent protection is sought for:

Novel indications for more mature drugs;

Innovative targets identified for the Company’s academic collaborators and their related assays; and

Composition-of-matter protection for chemical entities and clinical candidates that have been identified by TopoTarget’s internal expertise in drug discovery.

Priority applications are generally filed in Denmark and the UK; international applications are filed a year later, taking advantage of the priority year to file additional data supporting and strengthening the priority filing where appropriate.

Preliminary international examination is requested during the international phase (referred to as PCT) and claim amendments are made in response to the comments made during the international examination. Applications are then filed in the major international territories 30 months after the proprietary filing.

The patent portfolio is under continuous review and evaluation, both internally and through the Company’s patent attorneys, to monitor progress and the relevance of competing intellectual property. A full overview of the Company’s patent position can be found in Table 1 (page 10).

Other Patent Applications

Table 2 (page 11) provides a snapshot of other programs unrelated to TopoTarget’s current program, though potentially a basis for future programs.

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Table 1 TopoTarget A/S PATENT PORTFOLIO Patent Family Case # Date Relevance to TopoTarget Status/key points TOPOISOMERASE PROGRAM ICRF 187 and topoisomerase II 16930 1/11/96 Covers the use of Topotect and related •Granted US, EP poison combination for treating compounds in combination with •Pending CA brain metastases topoisomerase poisons ICFR187 antidote 22386 3/12/99 Covers the use of Topotect for extravasation •Granted EP, AU, NZ, US •Pending BR, CA, CN, IN, JP, NO, MX, RU Succinimides + Maleimides 25886 3/29/01 Covers novel compounds for use as catalytic •Pending US, EP inhibitors and anti-cancer agents ICRF187 and etoposide and P52 2/3/04 Covers the use of Topotect in combination •Pending GB radiation for CNS tumors with etoposide and radiation for CNS tumors

HDAC PROGRAMS Group F (sulphonamides) P37 9/29/00 Each claims novel chemical series of •Pending CA, JP, EP, AU, NZ inhibitors Allowed US Group B (ethers and thioethers) P38 9/29/00 •Pending US, CA

Group E (aryl leaders) P39 9/29/00 •Pending US, CA, JP, EP Group I (piperazines) P46 4/3/02 •Pending US, CA, JP, EP, MX, BR, IN, AU, NZ Group H (esters and ketones) P45 1/17/03 •Pending PCT Group J (quinolines) P48 2/25/03 •Pending PCT PRAME P51 1/28/04 Covers genes regulating sensitivity to HDAC •Pending GB inhibitors

DEUBIQUITINASE PROGRAM VDU1/CYLD P49 1/17/03 Underpins deubiquitinase program. Covers •Pending PCT proteins regulating stability of key plays in cancer and inflammation.

E2F PROGRAM DP1 P1 1/29/02 Underpins E2F program; claims the assays •Gene claims granted US, AU, for discovering DP1 inhibitors; potential for NZ, SG gene therapy applications to be licensed out; •Assay claims granted EP possible licensing revenue from antibody •Antibody claims granted US claims DP1 phosphorylation assay P2 7/1/94 Describes novel aspect of E2F regulation •Granted US, AU, NZ, SG, EP

E2F-4 P4 11/15/94 Possible gene therapy/anti-sense •Granted US, AU applications; possible antibody revenue •Pending EP, JP E2F-5 P5 2/14/95 Possible gene therapy/anti-sense •Granted US, AU applications; possible antibody revenue •Pending EP, JP, CA DP3 E-region assay P9 5/15/96 Claims method of regulating DP proteins •Granted US, EP •Pending JP, CA DP3 sequence P11 9/30/96 Possible antibody revenue US application only filed- granted E2F proteolysis P10 8/23/96 Claims novel regulation of E2F proteins •Granted US Allowed EP E2F peptides P13 12/20/96 Proof of principle of E2F as a target in tumor •Granted US AU, NZ cells and cardiovascular cell lines; potential •Pending JP, CA, EP, IL for development of peptides as therapeutics e.g. for restenosis and/or solid tumors

Peptide inhibitors P23 1/26/99 Potential for development of peptides as •Allowed US therapeutics e.g. for restenosis and/or solid •Pending EP, CA tumors

Source: TopoTarget A/S .

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Table 2 TopoTarget A/S ADDITIONAL PATENT APPLICATIONS Patent Family Case # Date Relevance to TopoTarget Status/key points ER and cyclin D1 P8 4/19/96 Underpins Hormone Responsive Cancer •Granted US, EP program •Pending CA, JP Cyclin D1 and co-activators P20 2/12/98 Underpins Hormone Responsive Cancer •Granted US program •Allowed EP •Pending JP, CA Cdc25 repressor P3 8/26/94 Potential target for modulation of G2/M •Costs borne by Hoechst. phase transition Prolifix has a license to any CDF claims. JMY P15 10/21/97 Inhibition of JMY/p300 interaction to •Pending CA, JP, EP overcome chemotherapy side effects. •Granted US Potential target for gene therapy

STRAP P42 3/19/01 Inhibition of STRAP:JMY or STRAP:p300 •Pending PCT interactions to overcome chemotherapy side effects; potential for gene therapy BS69 P6 6/14/95 Originally identified as potential anti-viral •US gene claim allowed target, BS69 now known to be a transcriptional repressor (interacts with oncogene myb) Cyclin D1 degradation P29 5/12/00 Cyclin D1 is rapidly degraded in response to •Pending US, CA, EP DNA damage. Inhibitor of degradation would potentially complement activity of cytotoxics and radiotherapy RB acetylation P36 8/11/00 Novel regulation of a tumor suppressor •Pending US, CA, EP protein involved in tumorigenesis TBX2 P28 6/19/00 Protein which causes cell to overcome •Pending US, CA, EP senesence. Over-expressed in many tumors

Myc/Miz P27 4/30/97 Claims the interaction between Myc and Miz, •Gene claims granted US crucial in regulation of tumor cell apoptosis •Granted EP •Pending US, JP

Source: TopoTarget A/S.

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Management and Board of Directors

Management

Table 3 provides a snapshot of TopoTarget’s key management, followed by detailed biographies.

Table 3 TopoTarget A/S MANAGEMENT Peter Buhl Jensen, M.D., Ph.D. Managing Director Maxwell Sehested, M.D., Ph.D. Chief Scientific Officer Nicholas La Thangue, Ph.D. Chief Business Development Officer Annie Rasmussen Director of Clinical Research Paul Finn, Ph.D. Director, Research and Development Leif Hamø Chief Financial Officer Tim Corcoran Commercial Director, Investor Relations

Source: TopoTarget A/S.

Peter Buhl Jensen, M.D., Ph.D., Managing Director

Dr. Buhl Jensen is co-founder of TopoTarget, with 15 years of management experience in cancer research and translational drug development. He was previously chief of the Laboratory of Experimental Oncology and consultant medical oncologist at The National University Hospital, Copenhagen. Dr. Buhl Jensen is a board member of the Danish Society of Medical Oncology, The Danish Cancer Research Fund, and The Danish Lung Cancer Group, and has published more than 60 papers on cancer and its treatment in high impact journals. He obtained his M.D. from the University of Copenhagen.

Maxwell Sehested, M.D., Ph.D., Chief Scientific Officer

Dr. Sehested is co-founder of TopoTarget and has pioneered the field of multi-drug resistance with more than 20 years of experience in preclinical drug evaluation. He is head of the Laboratory of Experimental Pathology at the National University Hospital of Denmark and was chairman of the Danish Society of Pathology (1997-2001). Dr. Sehested has published more than 70 scientific papers and has been a guest researcher at the NCI, U.S. (2000-2001).

Nicholas La Thangue, Ph.D., Chief Business Development Officer

Dr. La Thangue is the scientific founder of Prolifix Ltd. and has been instrumental in the development of TopoTarget’s technologies. He currently serves as the endowed chair of biochemistry at the University of Glasgow. Previously, Dr. La Thangue served as senior scientist at the MRC National Institute for Medical Research. He is internationally recognized for his work on tumor suppressor genes and cell cycle control and has discovered the E2F transcription factor. Dr. La Thangue has published more than 100 scientific papers and is an elected member of European Molecular Biology Organization (EMBO) 2003.

Annie Rasmussen, Director of Clinical Research

Annie Rasmussen is the director of clinical research for TopoTarget and a registered nurse. Ms. Rasmussen has 15 years of experience from the National University Hospital in Copenhagen in cancer treatment and care, management and leadership, education and training, of which six years were dedicated to clinical research at an international level. She served six years as the president of the Danish Oncology Nursing Society, and was a member of several international cancer care and research organizations. For four years, at SmithKline Beecham’s Nordic Oncology Unit, Ms. Rasmussen was head

Executive Informational Overview Page 12

of oncology marketing in Denmark, head of marketing clinical trials in Scandinavia, and a member of SKB International Clinical Trials Group.

Paul Finn, Ph.D., Director, Research and Development

Dr. Finn has more than 15 years of experience in drug design and discovery. Previously, he served as section head of the Computational Chemistry Group at Pfizer Inc. (PFE-NYSE) after holding a similar position with SmithKline Beecham. He obtained his Ph.D. in biochemistry from the University of Manchester.

Leif Hamø, Chief Financial Officer

Mr. Hamø has been responsible for finance and funding in consumer finance companies for more than 15 years. Before joining TopoTarget, he served as chief executive officer (CEO) of AcceptFinance and played a key role in selling the Company to GE Capital. He graduated from Copenhagen Business School with a BSc in economics and business administration, receiving a graduate degree in business administration, finance, and organization and management.

Tim Corcoran, Commercial Director, Investor Relations

Before joining TopoTarget, Mr. Corcoran served as chief financial officer (CFO) of Prolifix. In New Zealand, Mr. Corcoran spent four years as chief executive of the commercial property and light engineering firm Brittco Group and worked for the international firm of accounts Deloitte & Touche. He studied law at Canterbury University, Christchurch, New Zealand.

Board of Directors

TopoTarget’s board of directors oversees the conduct and supervises the management and affairs at TopoTarget. Table 4 provides a snapshot of key board members followed by detailed biographies.

Table 4 TopoTarget A/S BOARD OF DIRECTORS Jesper Zeuthen Managing Director, BankInvest A/S Johan Christenson, Ph.D. Partner, Healthcap AB Anders Gersel Pedersen Clinical Research Director, Lundbeck A/S Peter Buhl Jensen, M.D., Ph.D. Managing Director, TopoTarget A/S Håkan Åstrøn Senior Vice President, Pharmacia Ingelise Saunders CEO, ACE Biosciences

Source: TopoTarget A/S.

Jesper Zeuthen, Managing Director, Bankinvest A/S

Dr. Zeuthen is managing director of BankInvest A/S. Previously, he served as head of research and development at Novo Nordisk (NVO-NYSE) and head of research at the Danish Cancer Society. He is author of more than 200 publications in immunology, cell biology, and molecular biology and serves as an adjunct professor of biotechnology at the University of Copenhagen.

Johan Christenson, Ph.D., Partner, Healthcap AB

Dr. Christenson is a partner at HealthCap AB. Prior to HealthCap, he was responsible for the healthcare portfolio with SEB, a venture capital firm. Previously, he had served as project director and global product director at AstraZeneca (AZN-NYSE) in the pain control area. Dr. Christenson has a Ph.D. in neuroscience and serves as a medical doctor at the Karolinska Institute.

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Anders Gersel Pedersen, Research Director, Lundbeck A/S

Dr. Pedersen is research director at Lundbeck A/S (HLUKF.PK). Previously, he served as research director with Eli Lilly & Company (LLY-NYSE), where he was responsible for the clinical development of Gemcitabine (Gemzar), which is one of the world’s most important cancer drugs.

Peter Buhl Jensen, M.D., Ph.D., Managing Director, TopoTarget

(Biography on page 12.)

Håkan Åström, Senior Vice President, Pharmacia

Håkan Åström is a board member of TopoTarget since May 2004. Mr. Åström holds an honorary doctorate in medicine from the Sahlgrenska Academy in Gothenburg, Sweden, 2003, and a M.Sc. in business administration and economics from the Stockholm School of Economics, 1972. Mr. Åström also is the chairman of the board of directors of Biolipox AB, Orexo AB, and ACO Hud AB. He also serves on the board of directors of Biovitrum AB and Scandinavian Life Sciences Ventures AB. Since graduating from the Stockholm School of Economics, Mr. Åström has worked in the pharmaceutical industry. He has been managing director of a number of companies, including Travenol AB (now owned by Baxter International Inc. [BAX-NYSE]), Astra Pharmaceuticals Ltd., UK, and Kabi Pharmacia AB. In his most recent position, Mr. Åström was senior vice president of Pharmacia Corporation (PHA-NYSE), in charge of the group’s strategy and communication. Concurrently, he was managing director of Pharmacia AB, Sweden.

Ingelise Saunders, CEO, ACE BioSciences

Ingelise Saunders, member of the board, is CEO of ACE BioSciences. Previously, she was CEO at Celltech Pharmaceuticals Ltd. Prior to Celltech, Ms. Saunders spent 15 years at Novo Nordisk A/S where she gained extensive international experience in various senior roles. Ms. Saunders was born in Denmark, gained her Cand Pharma at the Royal Danish School of Pharmacy and spent her early career working in sales and marketing roles for the Danish operations of Glaxo A/S, Schering Plough (SGP- NYSE), and Novo Farmeka Denmark.

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Core Story

Cancer

Cancer is an abnormal cell produced by the body that engages in uncontrolled growth by escaping the body’s immune system. Since abnormal cells are originally produced from within the body, they are not recognized as foreign. This means that the body does not respond through the typical immune response of destroying this foreign substance. Cancer cells that escape the body’s immune system can proliferate in a variety of ways, invading and destroying healthy human tissue and eventually causing cell death.

Cancer is composed of 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 detected early in its progression has the best prognosis. In this scenario, if the cancer has not spread to other organs and tissues, surgical removal of the tumor can be effective. In contrast, cancer that is detected at a later stage has the worst prognosis since it has often already spread to other organs and tissues within the body.

Even when detected early, cancer cannot always be cured through surgery. In many situations, the cancer has spread to other parts of the body and surgery cannot remove the entire tumor, making the patient’s prognosis bleak. In such cases, even if the primary tumor is removed, the prognosis may be poor due to the spread of undetectable cancer cells (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.

The Cancer Cell Cycle

Cancer is a cell cycle disease, caused by the genetic mutation of normal cells into cancer cells. This unique evolutionary process is characterized by a tightly regulated cycles of growth and division that can be divided into four distinct stages, which include two gap phases (G1 and G2), an S phase (when DNA is synthesized and replicated), and an M phase (when cells undergo mitosis and divide). This cycle is illustrated in Figure 3.

Figure 3 TopoTarget A/S THE CANCER CYCLE

Replication of DNA S G2 and Chromosomes Decision to Enter Mitosis

Decision to Replicate DNA M G1 Mitosis Protein Synthesis and Cell Growth

Source: TopoTarget A/S

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Topoisomerases

In normal cells, the balance between old and new cells is maintained by an intricate system of “brakes” (suppressor genes) and “accelerators” (oncogenes). These mechanisms serve the function of inhibiting cell division and maintaining stasis in the cells. In tumor cells, however, this core function is defective. For example, in normal cells, the brakes are encoded by a tumor suppressor gene, such as retinoblastoma (RB) gene, while in tumor cells, mutated forms of this gene inhibit its growth-suppressing activities and cause cells to proliferate invariably.

Figure 4 As a cell progresses through the cell cycle and divides, the TopoTarget A/S chromosomal DNA untangles. CATALYTIC INHIBITOR This process is carried out by a unique group of enzymes called topoisomerases. Topoisomerase II cuts gaps in one strand of double-stranded DNA, passes the other strand through the gap, and subsequently reseals the break. An illustration of this process is provided in Figure 4.

When the DNA is cleaved, it is a dangerous situation where the anti-cancer agents— specifically doxorubicin and all the topoisomerase poisons—are dangerously blocking the enzymes once they have made the cleavage. Consequently, the enzyme changes from an essential enzyme to a highly lethal enzyme that kills the cells. However, cancer cells are more sensitive due to their faulty DNA damage-sensing and repair systems.

Topoisomerases represent one of many enzymes that are Source: TopoTarget A/S. crucial to the expressions of genes throughout the cell cycle. Since an abnormal gene is universally demonstrated in tumor cells, scientists are attempting to identify gene-regulating enzymes that may control the proliferation of malignant tumors via the cell cycle.

TopoTarget’s first catalytic inhibitor (CI), Topotect, is a novel tool that beneficially regulates the utility of a range of clinically effective drugs—potentially allowing for a 3-4-fold increase in doses of cancer drugs (secondary brain metastases, pages 31-33) and providing the solution to a feared chemotherapy accident (extravasation, pages 21-29).

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Prevalence

Cancer is a global health threat, with an estimated 10 million new diagnoses each year and approximately 6 million deaths, 40% of which occur in the developed world. The incidence is expected to increase by 50% over the next 20 years. The American Cancer Society (ACS) estimates that there are currently 8.9 million people in North America with a history of cancer, accompanied by approximately 3 million predicted diagnoses this year. In the U.S. this year, approximately 556,000 people or more than 1,500 per day, are predicted to die from cancer. The most common forms of cancer are lung (1.24 million cases/year), breast (1.050 million/year), colorectal (944,000/year), stomach (876,000/year), liver (564,000/year), prostate (543,000/year), uterine (470,000/year), and esophageal cancer (412,000/year).

Following cardiovascular diseases, cancer remains the most common cause of death, 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. Furthermore, the NCI anticipates that cancer may exceed cardiovascular disease as the leading cause of death in the next decade. Table 7 (page 18) provides an overview of the estimated new cases of cancer and estimated deaths, projected by the ACS in 2004.

The Cancer Market

The global cancer market represents the most far-reaching pharmaceutical market in the world. According to Datamonitor (a premium business information company specializing in industry analysis), the global cancer market is predicted to be worth approximately $20 billion as of 2003, and could increase to more than $45 billion by 2011. This expansion is forecasted to occur as a result of improvements in traditional therapies combined with the introduction of new and innovative treatments that display improved efficacy and lower toxicity, and take a more targeted approach at eliminating a specific form of cancer.

Cytotoxic Agents

The most important poisons on the market used to treat cancer include doxorubicin, etoposide, teniposde, etopofos, daunorubicin, idarubicin, epirubicin, mitoxantrone, topotecan, adriamycin, and irinotecan. A snapshot of the worldwide market size for these respective drugs, according to IMS Health, Inc. (RX- NYSE) in the year 2003, is provided in Table 5. On a more broad scale, Table 6 provides a snapshot of the worldwide market for antineoplastic agents. Companies selling such drugs include Pfizer Inc., Bristol-Myers Squibb Company (BMY-NYSE), Aventis SA (AVE-NYSE), Immunex, Wyeth (WYE-NYSE), and GlaxoSmithKline PLC.

Table 5 Table 6 WORLDWIDE MARKET FOR SELECT WORLDWIDE MARKET FOR ANTINEOPLASTIC CYTOTOXIC AGENTS, 2003 ($000) AGENTS, 2003 ($000) doxorubicin $123,361 Total antineoplastics $4,206,154 daunorubicin 15,073 Total vinca alkaloids 250,729 epirubicin 342,069 Total antimetabolites 3,065,498 etoposide 105,695 Total antibiotics 84,810 etoposide phosphate 9,651 Total topoisomerase poisons 2,082,794 idarubicin 63,937 Total taxanes 2,276,896 irinotecan 859,535 Total alkylating agents 2,592,871 mitoxantrone 130,687 Total $14,559,752 topotecan 165,576 Source: IMS Health Inc. Source: IMS Health Inc.

Development strategies for cancer therapeutics are focused on creating and marketing pharmaceuticals to address more than 200 different forms of cancer, including those described in Table 7 (page 18). Six recently introduced drugs currently account for approximately 46% of total sales, suggesting that the market may continue its solid expansion in congruence to the influx of less toxic new drugs to replace the older treatments.

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Table 7 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, anal 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.

Source: American Cancer Society, Inc. (2004) and Crystal Research Associates.

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Current Research and Development Efforts

The modern pharmaceutical industry is voraciously pursuing the research and development of innovative and effective cancer treatments. According to the ACS, greater than 300 companies are involved in the development of more than 1,000 drugs to treat cancer worldwide. Aside from the development of proven chemotherapies and monotherapies, scientists are now pursuing the development of a new generation of cancer therapeutics, which include anti-angiogenesis agents, monoclonal antibodies (immunotherapeutics), light-activated drugs, and genetic-based therapeutics. Additionally, more established products are being reformulated to improve efficacy, reduce side effects, and improve the drug-delivery profile.

Progressing Toward Prevention

While death rates from the most common cancers continue to decline, global incidence has remained stable. Some preventative measures have directly contributed to lower rates, such as anti-smoking measures and lower fat consumption. Additionally, the use of screening tests for cervical and colorectal cancers is increasing, aiding in early detection and eliminating potential cancer-related mortality.

Despite these encouraging trends, several significant areas continue to demand attention. According to the NCI, the incidence of cancers of the breast and lung in women, non-Hodgkin lymphoma, melanoma of skin, and liver in men and women is rising, with lung cancer death rates in women continuing to grow.

Strategies for Treating Cancer

While there are a wide variety of cancers, with each requiring specialized treatments, several unifying factors exist regarding the origin of the disease. By understanding the basic evolution of malignant cancers, scientists are seeking to develop new and innovative ways to treat the disease. TopoTarget recognizes the following areas, which have yet to be effectively addressed by cancer therapies:

Proliferation. While many known cancer drugs inhibit proliferation, they do so through shared mechanisms used by normal cells and tumor cells, causing them to affect cancer cells only marginally more than normal cells. This results in a narrow therapeutic window and a variety of unpleasant side effects. Therefore, there remains an urgent need to widen the therapeutic window available to cancer treatments and increase the efficacy of conventional therapeutics. This strategy is employed by TopoTarget.

Redundancy. A cancer cell uses genes that are often only one part of a complete network of inter- locking mechanisms. Therefore, if one pathway is blocked, another is capable of assuming its responsibility. Such redundancy leads to immense pharmaceutical problems, as most or all pathways have to be blocked to achieve meaningful treatment. Many of the most favored targets of modern anti-cancer drug development, which include apoptosis, metastasis, and angiogenesis, suffer from this problem. New methods of cancer drug development (including those of TopoTarget) involve finding targets where redundancy does not have a significant effect. Topoisomerases and E2F appear to represent non-redundant targets. This strategy is employed by TopoTarget.

Resistance. Cancers are often able to gain resistance to anti-cancer drugs by adapting to the treatment. Eventually, the high resistance of the cancer makes the needed dose of the relevant drug unattainable due to high side effects. TopoTarget is seeking to develop drugs in which resistance is very rare. To date, the Company has achieved clinical success for its HDAC inhibitor program.

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Advanced Stage Development

Chemotherapy

Chemotherapy is the most widely used medical cancer treatment. Often employed in combination with surgery and radiation therapy, chemotherapeutic drugs work by selectively targeting fast-dividing cells and blocking cell division. While chemotherapy is often able to inhibit the proliferation of malignant cells, scientists have yet to locate significant targets that would enable them to more effectively combat malignant cell proliferation. In fact, many fast-dividing stem cells responsible for hair growth, replacement of the epithelium in the intestine, as well as repopulation of the bone marrow are also affected, which leads to a variety of unpleasant side effects (page 21).

Chemotherapeutic Agents

Chemotherapy encompasses a variety of drugs, each possessing unique modes of action. The following agents represent some of the most common chemotherapeutic drugs.

Alkylating agents. Alkylating agents are highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning.

Anti-metabolites. Anti-metabolites are chemically similar to purine and pyrimidine, which are the building blocks of DNA. By masquerading as these substances, anti-metabolites inhibit them from being incorporated into DNA during the S phase (Figure 3, page15) of the cell cycle, which halts normal development and division.

Plant Alkaloids. Plant alkaloids consist of two drug classes, both of which act on tublin, a protein necessary for cell division. Vinca alkaloids, such as vincristine, act by de-stabilizing tubulin, and taxanes such as Taxol, conversely act by stabilizing tubulin.

Topoisomerase I and II poisons. Topoisomerases are enzymes responsible for cleaving and relegating DNA. Drugs that interfere with this reaction at a step where the DNA is cleaved are called topoisomerase poisons.

Chemotherapy Administration

Chemotherapy is administered in a variety of ways. Table 8 provides an overview of the common methods of administration.

Table 8 METHODS OF CHEMOTHERAPY ADMINISTRATION Method Approach Orally Given in the form of a pill or liquid, taken by mouth Intravenously (IV) Injected through a needle or catheter into the vein Intrathecal (IT) Injected into the spinal canal either directly into the spine or into a reservoir under the scalp Intraarterial Injected directly into an artery to treat a single area (e.g. liver, arm, or leg) Intracavitary Given through a catheter into the abdominal cavity or chest cavity Intramuscular (IM) Injected through a needle into the muscle Topical Applied directly to a cancerous area on the skin

Source: American Cancer Society.

Based upon the broad array of treatments and methods of administration, a variety of strategies exist regarding the treatment regimens for chemotherapy. Combined modality chemotherapy remains one of the most widely used methods. This method involves combining the use of chemotherapeutic drugs with additional cancer treatments, such as radiation or surgery. Combination therapy is a similar practice that employs a variety of different chemotherapeutic agents simultaneously. Since each drug differs in mechanism and side effects, this approach may minimize the possibility of the patient developing a

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resistance to the therapy. Adjuvant chemotherapy is primarily employed after the tumor has been removed and there is no evidence of cancer present, but a risk of recurrence remains. This approach also assists in reducing the chances of resistance developing if a tumor does develop and is useful in killing any cancer cells that may have spread to other parts of the body.

Side Effects

While chemotherapy continues to be the most broadly implemented method of cancer therapy, a multiplicity of side effects abound, ranging from mild to severe. The primary problem associated with these side effects is that if they are severe enough, they prevent physicians from delivering the prescribed dose of therapy at the specific time and schedule of the treatment plan. This may alter the expected outcome of the therapy and limit Table 9 patients’ ability to achieve the best COMMON CHEMOTHERAPY SIDE EFFECTS possible outcome from treatment. SKIN GASTROINTESTINAL BONE MARROW

Table 9 illustrates the more common dryness/rash nausea/vomiting risk of infection side effects associated with hair thinning loss of appetite tiredness chemotherapy, including ailments of hair loss wieght loss risk of bleeding the gastrointestinal tract, bone hemorhage diarhea anemia marrow, and skin. However, one extravasation constipation lesser-known symptom, mouth sores extravasation, is quite severe in nature and is described below. Source: Oncologychannel.com

Extravasation

Also known as “IV burns,” extravasation is a severe form of tissue damage resulting from an adverse reaction to cytotoxic agents. Substances known to cause severe tissue damage include certain chemotherapeutic agents and notably the sub-group of anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin, and idarubicin).

Extravasation occurs when an intravenously administered cytotoxic agent leaks from the injection site and escapes the vein, spreading to the surrounding tissues. The high concentration of the poison in the tissue then causes severe and cumulative tissue necrosis, including serious damage of the skin, the subcutaneous tissue, muscles, and nerves. The extent of destruction depends on the properties of the substance, its concentration, and the amount applied.

This potentially life-threatening disorder occurs in approximately one in every 1,000 administrations and may cause aggressive skin necrosis along with significant scarring around the tendons, nerves, and joints, necessitating skin grafting and even amputation. When extravasation occurs, it is irreversible, as the drug cannot be removed from the tissues. Figure 5

To avoid a deeper necrosis, some of the skin and CHRONIC NECROTIC ULCER POST subcutaneous fat is removed and biopsied to determine EXTRAVASATION OF DOXORUBICIN IN whether there is fluorescence, since a key property of LEUKEMIA PATIENT chemotherapeutic drugs is that they are flourescent. This can determine how much of the skin and tissue should be removed in order to eliminate the entire drug from the affected area. Following the excision of the extravasation, a skin graft is then performed.

Figure 5 provides a snapshot of a hand of an extravasation patient where doxorubicin, a common chemotherapy was misadministered. Instead of being administered into the vein, the drug leaked into the subcutaneous tissue where it destroyed the surrounding tissues. Source: TopoTarget A/S.

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Stages of Extravasation

Since extravasation is a highly aggressive condition, it is very important to recognize the condition in the early stages. Figure 6 provides a snapshot of the specific stages of the condition where doxorubicin was administered.

Figure 6 STAGES OF EXTRAVASATION

Redness at the site of an implanted port where doxorubicin HCI extravasated.

Skin necrosis The healed area begins 14 days 10 months after later. extravasation.

Area of Granulation on extravasation outer edges of the following debrided area debridement approximately (32 days after 3 1/2 months after extravasation). extravasation.

Source: Oncology Nursing Forum.

Risk Factors

In order for a specific drug to cause damage, it must meet several chemical parameters, which include (1) the ability to bind directly to DNA; (2) the ability to kill replicating cells (e.g. cytotoxic or antiviral agents); (3) the ability to cause vascular dilation of tissue; and (4) a certain pH, osmolarity, and excipience in the formulation of the drug. Additionally, high concentration volumes of the drug drastically increase the risk of extravasation. Table 10 (page 23) provides an overview of some of the drugs that may potentially cause extravasation.

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Table 10 CLASSIFICATION OF DRUGS ACCORDING TO THEIR POTENTIAL FOR TISSUE DAMAGE Cytotoxic drugs Non-cytotoxic drugs with vesicant potential GROUP A GROUP B GROUP C GROUP D Vesicants Irritants Non-Vesicants Hyperosmolar agents Potentially damaging (Commonly associated with severe local necrosis) acid & alkaline agents Actinomycin D Busulphan Asparaginase Calcium Chloride Aciclovir Amsacrine Carboplatin Bleomycin Calcium gluconate 10% Allopurinol Carmustine (BCNU) Etoposide Cisplatin Hypertonic Glucose (10% or >) Aminophylline Dacarbazine Methotrexate Cladribine Hypertonic Saline (10% or >) Amiodarone Daunorubicin * Taxol Cyclophosphamide Magnesium sulphate 20% Amphotericin B Doxorubicin * Cytarabine Mannitol 10% & 20% Co-Trimoxazole Epirubicin * Fludarabine Parenteral Nutrition Diazepam injection Idarubicin * 5 - Fluorouracil Sodium Bicarbonate Erythromycin Mitomycin C Gemcitabine X-Ray Contrast Media Foscarnet Sodium Mustine Ifosfamide Ganciclovir Streptozotocin Irinotecan Vascular regulators GTW infusion Vinblastine Melphalan Adrenaline Methylene Blue Vindesine Oxaliplatin Dobutamine Phenytoin Vinorelbine Taxotere Dopamine Vancomycin Vincristine Thiotepa Noradrenaline Tomudex Prostaglandins Topotecan Vasopressin * Anthracyclines (Known to cause extravasation when administered improperly.) Source: The North West Oncology Pharmacy Group (NWOPG).

Patients at increased risk of extravasation include:

Very young or elderly patients who have fragile skin and veins;

Cannula sited on side of mastectomy or lymph node clearance, or where lymphoedema is present;

Unconscious, sedated, or confused patients who may be unable to report stinging or discomfort around the cannula site;

Patients who have had multiple venipuncture or cannula sites, causing thrombosed vessels. This also increases the risk of leakage of drugs;

Patients suffering from decreased sensation or poor circulation caused by peripheral neuropathy, diabetes, Raynauds phenomenon, or peripheral vascular disease; and

Patients with superior vena cava obstruction. Elevated venous pressure can cause leakage at the cannula site.

Treatments

In order to thwart the proliferation of extravasation and prevent further tissue damage, a variety of preventative measures can be taken. First, the infusion must be stopped immediately if there is any doubt as to the patency of an implanted port or other ventricular assist device, or if it is suspected that the vesicant is not infusing properly. One of the primary concerns associated with halting the administration of a chemotherapeutic agent is that this enables the cancer to further proliferate when left untreated for several weeks. However, if the extravasation is not treated, a patient is subject to a host of other adverse conditions.

Once physicians have acknowledged the occurrence of an extravasation, the next phase involves addressing tissue damage that has already taken place. This measure primarily encompasses undertaking basic wound care measures—specifically elevating the wounded limb, absorbing excess fluids, obliterating dead space, maintaining a moist wound surface, insulating the wound, and protecting the wound from further bacteria. While many cases of extravasation eventually heal, severe incidents may require more serious measures. When the harmful fluid has spread widely, surgery may be required

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to remove the affected tissue, with a skin graft employed to repair the removed tissue. In the most severe cases, amputation of the affected limb is necessary.

While there is no gold standard to treat extravasation, some of the more traditional methods employed for treating extravasation include:

(1) Heat and cold, which are used for the following reasons:

o heat induces vasodilation, increasing drug distribution and absorption and decreasing local drug concentrations;

o cold causes vasoconstriction, localizing the extravasation and allowing time for local vascular and lymphatic systems to disperse the agent; and

o with the exception of vinca alkaloids, topical cooling seems to be more effective than topical warming in the management of cytotoxic and non-cytotoxic vesicants. In practice, the application of moist heat has lead to maceration and necrosis.

(2) Corticosteroids, which have been used to reduce inflammation in the following ways:

o as intradermal or subcutaneous injections and topically as steroid creams;

o as single treatments and in combination with other agents.

Note: Evidence suggests that corticosteroids are not helpful in the extravasation of antineoplastic agents because inflammation is not prominent in the etiology of tissues necrosis.

(3) Extravasation kits, which are currently stocked by many hospitals, contain needles, gauze tape, and syringes. Presently used antidotes for extravasation either neutralize, increase systemic absorption, or inactivate a vesicant drug. They may be given directly into the catheter or non-coring needle of the implanted port. An antidote may also be infused subcutaneously in and around the affected tissue. Antidotes are recommended by the drug manufacturers, and include:

o Phentolamine (an alpha-adrenergic blocking agent relaxing smooth vascular muscles), which has been used as an antidote to vasopressor extravasation;

o Topical glyceryl trinitrate (vasodilator), which has been used for parenteral nutrition;

o Sodium thiosulphate (direct inactivation), which has been used for mustine; and

o Dimethyl sulfoxide (an oxygen-free radical scavenger), which has been used for daunorubicin, mitomycin, and doxorubicin.

(4) Surgical excision of the extravasated area.

o Clear-cut, full-thickness skin necrosis with or without frank ulceration or intractable pain.

o Wide excision, including a margin of normal tissue ensures a satisfactory graft or flap although deep ulceration may involve tendons or nerves. Patients frequently end up with extension contractures regardless of how wound closure is achieved.

o Early surgical excision is controversial since only about one third of known vesicant extravasations will ulcerate.

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Several additional options may be employed to further eradicate the offending substance. These include:

Suction and saline washout. In some cases, this is accomplished surgically by several small incisions made around the affected area followed by removal of the fluid with a suction device.

Hyaluronidase. This method employs an enzyme that degrades hyaluronic acid (a key component of the inflammatory process), which can be found in a variety of solutions, including calcium, antibiotics, TPN, potassium, and high concentration dextrose. The enzyme is injected into the affected area through an IV, catheter, or a series of small, circular injections. Once injected, the enzyme may enhance absorption of the offending substance and ease the effects of extravasation.

Phentolamine. This substance inhibits the alpha affects of catecholamines, potentially reducing local vasoconstriction.

Snapshot of the Extravasation Market

Research has suggested that approximately one in every 1,000 chemotherapy procedures results in an extravasation. According to the National Extravasation Information Service (www.extravasation.org.uk), which has compiled statistics from 'green card reports' sent anonymously from various centers only around Great Britain, the number of reported extravasations has steadily increased over the years.

Figures 7-10 (pages 25-26) provide data from the randomly compiled ‘green card reports’ from this program since it was started, representing a span 10 years, from 1993 to 2003, where between February 1999 and May 2004, over 4,500 cards were distributed to over 140 different organizations throughout the British Isles. Figure 7 provides a snapshot of the number of extravasations reported over the ten year period, 1992-2001, serving as a basis to the data provided in Figures 8, 9, and 10 (page 26).

Figure 7 NUMBER OF REPORTED EXTRAVASATIONS

300 240 250

200 185 149 150 120

100 58 37 50 24 1 10 2 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Source: The National Extravasation Information Service 2000-2004.

Figure 8 (page 26) provides a snapshot of the 10 most commonly prescribed cytotoxic drugs that are named in the extravasation reports of the ‘green card reports’ and Figure 9 provides a snapshot of the areas of the body affected by extravasation reported in the ‘green card reports.

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Figure 8 Figure 9 TOP 10 CYTOTOXIC DRUGS NAMED IN EXTRAVASATION REPORTS AREA OF BODY AFFECTED BY EXTRAVASATION (Sample of 1200 Green Card Reports) (Sample of 1100 Green Card Reports)

Ifosfamide; 49; 450 Carboplatin; 84; 5% 400 Paclitaxel; 72; 9% 8% Vinorelbine; 34; 350 4% 300 Etoposide; 88; Vincristine; 26; 250 9% 3% 200 150 100

Epirubicin; 64; 50 7% Cisplantin; 95; 5-Fluorouracil; 0 10% 348; 36% Doxorubicin; Hand Wrist Forearm Upper Foot or CVC Not given 89; 9% joint to elbow arm leg joint Bold drugs are targeted by Topotarget.

Source: The National Extravasation Information Service 2000-2004. Source: The National Extravasation Information Service 2000-2004.

Figure 10 Worldwide, biotechnology and pharmaceutical ANTRACYCLINE VOLUME companies alike are expeditiously developing newer and more effective cancer drugs in an Antracycline - Volume effort to improve the efficacy/toxicity profile of Thousands anthracycline drugs, recognizing that these drugs 18000 16000 are likely to maintain an important position for the 14000 foreseeable future. According to IMS Health, the 12000 worldwide consumption (in units) of anthracycline 10000 drugs is still increasing, as shown in Figure 10. 8000 6000 This makes the pool of individuals that could 4000 potentially be affected by extravasation larger. 2000 0 In particular, malignant diseases being treated 1999 2000 2001 2002 2003 Year with anthracyclines that are infused as monotherapy or, more commonly, in combination regimens, can expose patients to the risk of an extravasation. Some of the most common Source: IMS Health. cancers and their respective treatments include:

breast cancer (e.g. “CEF”: cyclofosfamide+EPIRUBICIN+5-fluoruracil);

lymphoma (e.g. “CHOP”: cyclofosfamide+vincristine+DOXORUBICIN+prednisolone);

acute myeloid leukemia/AML (e.g. “ICE”: IDARUBICIN+cytarabine+etoposide); and

myeloma (e.g. “VAD”: vincristine+DOXORUBICIN+glucocoticoids).

Topotect for Extravasation

Topotect (dexazoxane) is TopoTarget’s Phase III antidote for patients who experience chemotherapy- induced necrosis. Representing the Company’s first internally developed drug, Topotect has shown profound CI activity, exhibiting high protection efficacy against extravasation-induced necrosis in several studies.

Preclinical and clinical trials of the drug have demonstrated that prompt administration of Topotect in both animals and humans has prevented necrosis and eliminated the need for surgery, although it was necessary to administer the drug within six hours after the accident. In particular, the first trial was initiated in the second quarter of 2001 at all 17 cancer centers in Denmark. The second trial was initiated in the second and third quarters of 2002 at 19 centers in The Netherlands, Italy, and Germany. Patient

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enrollment was completed for the first trial, with patient enrollment sufficient for an interim analysis with data sufficient to apply for a Marketing Application in the U.S. and the European Union.

TopoTarget obtained European Medicines Evaluation Agency (EMEA) orphan drug designation for extravasation in 2002 and is discussing with the EMEA the protocol for a pan-European registration; a similar designation was granted in the U.S. in 2004. The Company plans to use partnering agreements to distribute the drug in other locations, including the U.S.

We note that dexazoxane is already on the U.S. market for the indication of cardiotoxcity under the name Zinecard®, and is sold by Pfizer; Cardioxane® sold by Chiron (CHIR-NASDAQ) is on the market in five European countries (France, Italy, Austria, Denmark, and Ireland). Zinecard® is used to prevent and/or reduce the risk of heart side effects of doxorubicin, an anti-cancer medication.

Since there is currently no approved treatment besides surgery for extravasation and dexazoxane is already approved (as patient numbers are very few), Swedish and Danish regulatory authorities have indicated that they do not require a control arm for the trial. Therefore, clinical trials are open-label and non-randomized, where the accumulation of sufficient well-documented cases may help to provide evidence for approval.

Proof of Principle (Journal of Clinical Figure 11 Figure 12 Oncology) TREATMENT OF THORACIC TREATMENT OF PERIPHERAL EXTRAVASATION WITH EXTRAVASATION WITH Figures 11 and 12 provide snapshots TOPOTECT TOPOTECT of the first two patients treated with Topotect. Figure 11 is a case of successful intervention with Topotect, where a Dutch patient with thoracic extravasation is administered the antidote Topotect. The picture shows the patient after seven days and again after 49 days. Figure 12 illustrates an arm that was extravasated, where the sample was sent to a pathologist to evaluate whether there was florescence. The Upper photograph: Day 1. 11 of pathologist thus determined whether Lower photograph: No sequelae or not anthracycline—using the Upper photograph: Day 7. florescence method—was present. If Lower photograph: Source: TopoTarget A/S. anthracycline was present, No sequelae at day 49 extravasation took place. The top arm Source: S.W. Langer et al.: represents a pale arm, where ”Dexrazoxane in anthracycline circulation was momentarily stopped extravasation” J. Clin. Oncol. 2000; 18 (16): 3064. and the patient was biopsied. The outer circle is what was intended to be removed by surgery. The patient was administered Topotect and is shown in the bottom at day 45, with no evidence of any problems other than some scaring due to the biopsy procedure with no surgery necessary.

Phase II/III data (TT01)

TopoTarget has completed a Phase II/III (TT01) trial involving 18 patients and has an ongoing Phase II/III (TT02) trial involving 19 patients with promising interim data. These trials are to determine Topotect’s efficacy for protection against tissue damage caused by accidental extravasation. Endpoints are prevention of surgical intervention following extravasation of an anthracycline drug and the prevention of necrosis.

Since dexazoxane has already been approved for cardiac protection (Zinecard®), a wealth of toxicology and pharmocodynamic information is available regarding human trials. This has allowed TopoTarget to

Executive Informational Overview Page 27

fast-track Topotect through clinical studies, thus reducing the risk of product failure and enhancing the Company’s chances of finding a new indication for the drug.

Over the course of the trials, 32 patients with anthracycline extravasations (confirmed by fluorescence- positive biopsies) have been treated. Extravasation is determined by the presence of swelling, and/or redness, and/or pain at the site where the anthracycline leakage is suspected to have occurred. To date, only one of the 32 patients tested required an operation, when the individual received the chemotherapy and the nurse had left the room due to an emergency. Consequently, this patient’s forearm was filled with anthracycline and was given Topotect for three days. However, by day four the patient began to blister and consequently required surgery.

Topotect Kit

Figure 13 Due to the urgency of treatment in extravasation injuries, TopoTarget has developed a Topotect emergency kit (Figure THE EXTRAVASATION EMERGENCY KIT 13) to be retained by oncology departments who employ cytotoxic agents that may cause extravasation. The kit contains the medication required for the treatment course, along with safe handling devices, detailed instructions for use, a demarcation pen, a caliper, and a camera (for insurance purposes). The kit will have a maximum shelf life of two years with a color-coding system employed to ensure that the product has not expired.

Potential Use of Topotect Kit

There are approximately 9,000 oncology hospitals and centers worldwide, of which 2,800 are in the European Union Source: TopoTarget A/S. and 2,300 in North America. One such center may contain just one oncology ward, or it may contain several. TopoTarget’s goal is to get its Topotect antidote into each center, believing that chemotherapy should not be administered without the antidote nearby and ready to use if needed, similar to the way a fire extinguisher sits idle until the unlikely need for its use.

Based on the incidence of extravasations and the shelf life of the formulation, which is two years, TopoTarget estimates an average hospital or center to maintain an average stock of two emergency kits at all times. This number could vary from 1-8 kits, depending on the internal organization of the hospital, (with most having two kits). Hospitals can then replace the kits as they are either used or reach their shelf-life limit.

Sales and Marketing Approach

Table 11 TopoTarget seeks to establish the Topotect TopoTarget A/S emergency kit as an essential KEY AUDIENCE FOR TOPOTECT item for chemotherapy units oncologists and oncology societies (e.g. European School of Oncology) worldwide. The Company hematologists and hematology societies currently has Orphan Drug pediatric oncologists (hematologists) designation for the product in oncology nurses (oncology & hematology) and respective societies the U.S. and European Union, hospital pharmacists and expects to sell the product in Europe by the Source: TopoTarget A/S. second quarter 2005 through its internal sales force of approximately a dozen people. Specifically, this sales effort is expected to target oncology units that use cytotoxic agents. Additionally, the Company expects to apply for a Japanese Orphan Drug designation near term.

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Specifically, the customer base for Topotect upon marketing and pricing approval comprise the audience described in Table 11 (page 28). This audience is expected to be reached and served by the chosen promotional instruments, including TopoTarget’s own specialty sales force supplemented by a contract sales force in the introductory phase.

Potential Market

Based on the lack of current efficacious extravasation treatments and the potential for market expansion, TopoTarget estimates that the market for its Topotect kit could be very lucrative. Several additional factors may also stoke market-wide expansion for this niche market in the future, including:

increasing use of adjuvant treatment, specifically for breast cancer with anthracycline;

use of a rescue kit, as shown on page 28;

pressures to avoid malpractice suits from patients; and

changes in medical practice since currently many patients are catheterized to reduce risk of extravasation. This procedure, however, has significant disadvantages and there is existing evidence that hospitals will stop using permanent central catheters once they have an effective antidote.

Additional Indication for Topotect: Cardioprotection (CP)

Despite the availability of newer compounds, anthracyclines are still a mainstay in the treatment of some of the most common tumor types, such as breast cancer. Metastatic breast cancer typically requires long- term treatment and possible sequential use of several different agents. Anthracyclines are still a potentially valuable option in these patients. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types.

Two major pharmaceutical companies, Pfizer and Chiron, currently hold marketing authorizations for dexrazoxane for cardiotoxicity in certain countries in the European Union, U.S., and the Far East. While these companies do not actively market the drug, as its sales are very small for such large companies to focus their efforts upon, TopoTarget retains the option to commercially pursue regulatory approval and subsequently tap business with its own compound, Topotect for this indication.

According to IMS Health, Inc., worldwide sales of the two competitors products in 2003 amounted to USD $19.4 million, with the U.S., France, and Italy commanding the major market shares with $8.6 million, $6.4 million, and $2.2 million, respectively. The cardioprotection indication, therefore, could offer a secondary business opportunity for TopoTarget beyond that of extravasation.

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Brain Metastases

Brain tumors may either be primary, such as glioblastomas, or secondary, where it is a metastasis from a primary cancer that is not located in the brain. More than 90% of all malignant brain tumors are metastatic. The two most common cancers that eventually spread to the brain are lung and breast cancer. These cancers spread to the brain via the blood in up to 60% of cases of SLCL and in 20% of breast cancer patients. These metastatic tumors are difficult to treat and may cause a serious impairment or loss of function. Additionally, these cancers are usually lethal. In SLCL, up to 60% of patients will develop brain metastases, while the proportion is 20% in breast cancer patients

Symptoms

The brain is responsible for a multiplicity of key functions. It orchestrates behavior, movement, feeling, and sensation while controlling life-sustaining functions such as breathing and heartbeat. Since the brain is involved in so many core aspects of human life, brain metastases cause a wide array of serious complications, resulting in damage to key areas of the brain and causing impairment of function. These symptoms are primarily triggered by increased pressure within the skull from the growing tumor, which blocks the flow of cerebrospinal fluid.

Consequently, some of the common symptoms of brain tumors include:

Headaches. As the growing tumor exerts pressure on pain-sensitive areas on the brain, patients often experience recurring headaches that can last several minutes to several hours. As the tumor grows, the intensity of the headaches typically increases.

Nausea and vomiting. These symptoms often accompany headaches.

Seizures. Brain tumors can often disrupt the normal flow of electricity through the brain cells, causing seizures marked by convulsions, loss of consciousness, or loss of bladder control.

Vision or hearing problems. Increased pressure within the brain can also decrease blood flow to the optic nerve, causing blurred vision, double vision, or partial visual loss. Tumors growing near sensory nerves can interfere with hearing or vision, often yielding ringing or buzzing sounds, abnormal eye movements, and partial loss of vision or hearing.

Behavioral or cognitive symptoms. When tumors occur in the brain’s cerebral hemispheres, many behavioral symptoms can result, which can cause a change in personality, communication, thinking, and behavior. Affected individuals may suffer from slurred speech, psychotic episodes, and changes in personality.

Motor problems. Brain tumors may affect areas of the brain responsible for bodily movement, yielding weakness, paralysis, lack of coordination, or trouble with walking. Individuals may also experience loss of equilibrium, which can cause dizziness or difficulty with balance.

Treatment

While secondary brain metastases are incurable and very difficult to treat, there are several methods that can potentially relieve symptoms, improve function, and enhance comfort. The common treatments for brain metastases include:

Surgery. Surgery may be used for metastatic brain tumors when there is a single, localized lesion. If the tumor is located in a desirable area, it may be completely removed. For deep tumors that have infiltrated the brain tissue, surgeons may remove significant mass of the tumor to reduce its size. Surgery is also employed to reduce intracranial pressure and relieve symptoms, with the goal of halting the spread of the initial tumor.

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Radiation. Radiation therapy employs beams of energy to kill tumor cells and is usually initiated after a surgical procedure. The therapy, which occurs over a six-week period, is given in relatively uniform doses and is especially useful for tumors that are large or have infiltrated into surrounding tissue. When used to treat brain tumors, radiation poses several immediate threats to the patient and may cause irreversible damage to surrounding tissue. As a result, doctors may choose a modified form of radiation therapy by changing the dosage schedule and amount of radiation.

Chemotherapy. In addition to surgery and radiation, chemotherapy is often used to prevent the division of cancer cells and halt the spread of brain metastases. Chemotherapy yields a broad array of side effects and has experienced limited success in eradicating brain metastases. Additional drugs may be used to address certain side effects such as:

o Corticosteroids, to reduce swelling of the brain;

o Osmotic diuretics, to reduce swelling of the brain;

o Anti-convulsants, to reduce seizures; and

o Antacids or antihistamines, to control stress ulcers.

Catalytic Inhibitors (CI) to Enhance Chemotherapy. DNA topoisomerase II is an essential enzyme in the cell’s nucleus and is the target of a number of important anti-cancer drugs. These drugs, which act by creating DNA breaks in topoisomerase II drug complexes, are known as topoisomerase II poisons. While effective in a variety of cancers, they often have difficulty achieving their full potential due to toxic effects on the body.

In contrast to topoisomerase II, CIs act at stages of the enzyme’s functional circuit where DNA breaks do not occur. Importantly, CIs can act as antagonists to poisons, stabilizing topoisomerase II in a form that is inaccessible to the poison. Consequently, CIs can effectively protect cells and tissues against the poison, and allow existing cancer chemotherapies to be used either at an increased dose (to overcome resistant or recalcitrant tumors) or with reduced side effects.

The following sections provide an overview of TopoTarget’s proprietary CI and its utility in fighting brain metastases in combination with an existing chemotherapeutic agent.

Topotect for Brain Metastases

One of the primary reasons conventional cancer therapeutics experience difficulty in treating brain metastases is the blood brain barrier, which is an assembly of membranes protecting the brain from various substances in the blood. Since the blood brain barrier is known to restrict cytotoxic treatments from reaching the brain, etoposide, a chemotherapeutic treatment for SCLC, is unable to deliver a sufficiently high degree of therapy to the brain. Therefore, cancer cells that are localized in the brain remain protected from chemotherapy and, due to the toxic effects of chemotherapy, the dose level cannot be raised to adapt. This significantly increases an individual’s risk of contracting secondary brain metastases following SCLC.

TopoTarget has demonstrated that Topotect does not pass the blood brain barrier. This pharmacokinetic difference can be used to direct a cytotoxic effect to the brain using high doses of chemotherapy while reducing the body’s systemic toxicity. The prophylactic use of a combination of Topotect and etoposide can potentially deliver higher levels of cytotoxic therapy to the brain than simply etoposide alone. Since normal brain tissue has low levels of topoisomerase II, there should be little toxic effect on the brain tissue, enabling for the tumor to be more adequately treated.

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Preclinical Studies

Figure 14 Preclinical studies have shown that TopoTarget A/S Topotect protects against etoposide- induced lethality in mice and allows a 3.6- PROTECTION BY TOPOTECT AGAINST ETOPOSIDE IN fold dose escalation of etoposide. HEALTHY MOUSE MODEL

An important milestone was achieved 12 when mouse brain tumor models with high-dose etoposide given in combination 10 Topotect 250mg/kg with Topotect provided a significant increase in survival time compared with 8 Etoposide 90mg/kg normal etoposide doses without 6 Topotect. Consistent with the protective Etoposide 90mg/kg +Topotect role of CI’s, Topotect was shown to 50mg/kg 4 protect bone marrow cells from etoposide, resulting in a reduced fall of 2 leukocyte and neutrophil granulocyte counts. 0 1 5 9 13 17 21 25 29 33 37 41 45 49 53 Figure 14 illustrates healthy mice being treated with a very high dose of Source: TopoTarget SA. etoposide, which kills 10 out of 11 mice. This is compared to Topotect at a very low dose, where 50 mg was able to protect the mice from this fatality. The healthy mice show that etoposide is being blocked.

Phase I/II

TopoTarget is now conducting two Phase I/II trials. One trial (TT10) seeks to establish the optimal dose of Topotect in combination with etoposide for the treatment of malignant disease in CNS. Two oncology centers in Denmark are participating in the trial, which was initiated in the third quarter 2002.

The TT10 trial endpoints are:

To establish the optimal dose of Topotect for protection against side effects of etoposide;

To evaluate the level of protection of the combination treatment;

To evaluate the response rate of the combination treatment for patients with malignant CNS; and

To evaluate the tolerance and toxicity of Topotect used in this combination.

This trial includes a cohort of six recruited patients at three defined dose levels of Topotect. Once this trial has identified a clearly optimal dosing regime, TopoTarget is expected to commence work on planning a pivotal Phase III trial to test the clinical efficacy of the approach in preventing brain metastases following SCLC. TopoTarget’s strategy is to pursue an orphan drug designation for the use of this approach for the palliative treatment of brain metastases once they have occurred. Should this trial be completed in 2004, it would allow for immediate Phase III trials to commence. In 2004 TopoTarget, in collaboration with Raffa, a CRO started an Israel Phase I/II trial TT11.

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The TT11 trial endpoints are:

Primary Objective

To determine the safety and toxicity profile of the combination of Figure 15 etoposide and Topotect TopoTarget A/S TOPOTECT PHASE I/II To determine the best protective dose of Topotect at the maximum tolerated dose of etoposide using the following 3-step method:

(1) Part I: At a protective dose of Topotect of 25 mg/m2, determine the MTD25 of etoposide.

(2) Part II: At the MTD25 of etoposide, determine the best protective dose (BPD) of Topotect.

(3) Part III: At the BPD of Topotect, determine the maximum tolerated dose of etoposide (MTDBPD).

Secondary Objectives

To assess the antineoplastic effect of the etoposide/Topotect 6 doses of 1000mg/m2 (dexrazoxane) combination in patients with brain metastases. Topotect + 1000 mg/m2 etoposide Figure 15 illustrates a Computed Tomography (CT) scan of a patient’s brain undergoing palliative treatment of brain metastases with Topotect-enabled high dose chemotherapy. The top section is multiple metastases before treatment, showing a large metastasis seen as a white halo of infused x-ray content. After seven weeks of treatment, where the patient was administered six doses of 1000 mg/m2 of Topotect with high dose etoposide, the halo has disappeared; only the dark scar remains. The patient survived for 17 months, versus an expected 1.5 months.

Histone Deacetylase (HDAC) Inhibitors for Multiple Indications

A growing body of research highlights the role of HDAC in regulating gene expression, particularly the expression of cancer-related genes. HDAC inhibitors represent a new class of mechanism-based anti- cancer therapeutics that target HDAC enzymes, and have been shown Source: TopoTarget A/S. to: (1) arrest growth of cancer cells (including drug resistant subtypes); (2) induce apoptosis, or programmed cell death; (3) promote differentiation; (4) inhibit angiogenesis; and (5) sensitize cancer cells to overcome drug resistance phenotype when used in combination with other anti-cancer agents. HDAC inhibitors are believed to play a role in a wide range of solid and hematologic malignancies.

Recent efforts in the field of oncology have been focused on the research and development of HDAC inhibitors to regulate the cell cycle and treat a variety of cancers. These drugs attempt to inhibit HDAC, thus inducing genes associated with cell cycle arrest, including tumor suppressor genes that inhibit angiogenesis and block tumor growth in vivo.

TopoTarget has established a broad base of knowledge in the development of HDAC drugs by employing its understanding of HDAC biology and biochemistry to identify a series of proprietary and novel families of HDAC antagonists that may possess improved properties over existing compounds. These compounds have demonstrated striking effects on tumor progression by substantially delaying the growth of tumor xenografts derived from common human cancers, such as ovarian and colon. TopoTarget’s HDAC research initiatives have resulted in a broad library of proprietary HDAC inhibitors, lead by PXD101, the

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Company’s Phase I anti-cancer therapeutic. Additionally, more than 120 compounds out of an 800 compound library have been identified as HDAC inhibitors making up six patent families.

PXD101

PXD101 is one of the most advanced HDAC inhibitors in clinical development and has been shown in preclinical studies to have a favorable therapeutic window based on its targeted activity on cancer cells versus normal cells. PXD101 has the potential to treat a wide range of solid and hematologic malignancies either as a monotherapy or in combination with other active anti-cancer agents. Additionally, PXD101 is part of a new generation of cancer therapeutics that attempts to regulate chromatin and control gene expression. The compound has shown the ability to inhibit proliferation and induce apoptosis in a range of human tumor cells. Striking anti-tumor activity has been observed in animal models in both xenograft and leukemic mouse models and no evidence of cross-resistance to conventional anti-cancer drugs has been observed.

TopoTarget believes that PXD101 may gain clinical use as a single agent while combination studies with existing cancer drugs are currently underway to further clarify the drug’s clinical application. TopoTarget expects to employ the drug to target a variety of cancer indications, including multiple myelomas, lymphomas, SCLC, and prostate cancer. An extensive preclinical toxicology and pharmacological regulatory study has demonstrated that PXD101 is well tolerated. The compound has been synthesized in bulk and formulated for intravenous clinical administration using a proprietary formulation. Specifically, in multiple myelomas, PXD101 has demonstrated to be very potent in all multiple myeloma cell lines tested at the National University Hospital in Denmark. The Scandinavian Myeloma Group trial of 50 patients is expected to commence November 2004.

Phase I

An initial multi-center Phase I trial of PXD101 is nearing completion at The Royal Marsden Hospital (London and Surrey, UK) and the Beatson Oncology Centre (Glasgow, Scotland). A total of 24-36 patients with advanced solid tumors were enrolled in this study in order to evaluate the safety, pharmacokinetic, and pharmacodynamic response to PXD101. The drug is administered by the intravenous route in cycles of one dose per day for five days interspersed with a 14-day non-treatment period.

Agreement with NCI

The NCI and TopoTarget signed a Letter of Intent in May 2004 to enter into a Cooperative Research and Development Agreement (CRADA) to conduct the preclinical and clinical development of PXD101. The agreement will involve the determination of the most appropriate anti-cancer agents for use in combination with PXD101. Additionally, the NCI and TopoTarget will collaborate on the identification of anti-cancer drug candidates from TopoTarget’s library of HDAC inhibitors. Both TopoTarget and the NCI’s Division of Cancer Treatment and Diagnosis (DCTD) will provide preclinical development resource and drug screening capabilities. The DCTD will contribute expertise in designing, implementing, and monitoring Phase I and Phase II clinical trials through its intramural and extramural clinical trials network. The NCI is expected to also assist TopoTarget in obtaining the necessary regulatory approval by the U.S. FDA for PXD101.

Agreement with Curagen

Given that PXD101 may play a role in both solid and hematological malignancies, in addition to the ongoing Phase I trial in patients with advanced solid tumors, CuraGen Corporation and TopoTarget announced on June 3, 2004 a license, collaboration, and commercialization agreement on a small molecule inhibitor program targeting HDAC in oncology, with a plan to initiate a new Phase I trial of PXD101 in patients with hematological malignancies.

Under the agreement, the two companies are expected to work together to identify additional clinical candidates from TopoTarget’s extensive proprietary HDAC inhibitor library that act selectively against HDAC sub-units. CuraGen’s expertise in systems biology, genomics, and bioinformatics are expected to

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provide important guidance on identifying and stratifying responsive cancers to treat with PXD101 and sub-unit selective HDAC inhibitors.

Financial terms of this agreement include TopoTarget retaining European rights and expected to receive: (1) a USD$5 million equity investment; (2) USD$5 million in license fees; (3) up to USD$10 million within the next 12 months in milestones and research support; (4) USD$4 million of research support over the subsequent 24 months; and (5) up to USD$27 million in additional milestone payments based on successful development, regulatory approval, and commercialization of PXD101. For each additional product that enters the collaboration that is successfully developed and commercialized, TopoTarget will receive from CuraGen a USD$1 million take-up fee and up to USD$30 million in milestone payments. TopoTarget will also receive royalties from CuraGen based on sales of PXD101 and additional products commercialized under the collaboration for sales in territories outside of Europe.

CuraGen is expected to receive reciprocal royalties from TopoTarget based on sales of PXD101 and additional products in Europe. CuraGen is to meet the global clinical development costs of PXD101 and additional products, including European development in TopoTarget territories. TopoTarget has the option to fund a portion of the global clinical development costs in exchange for higher royalties.

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Early Stage Development

HDAC Inhibitor Library

TopoTarget has a large panel of cancer cell lines for compound profiling, which can to help identify the most suitable target cancers for a given drug. Additionally, the use of drug combinations is a widely used practice in cancer therapy, hence identifying the most effective combinations at an early stage can be pivotal in the design of clinical trials. Furthermore, TopoTarget has animal facilities and employs a veterinarian on its staff. It has established and validated an array of tumor models on which compounds can be tested for efficacy and toxicity.

In particular, TopoTarget has evaluated five distinct classes of HDAC inhibitor compounds through absorption, distribution, metabolism, and excretion (ADME) profiling, activity in tumor progression assays, and sub-unit specificity. This program is operating with the goal of identifying compounds with distinct pharmacokinetic properties, including oral bioavailability, prolonged half-life, and collective activity with different HDAC sub-units. TopoTarget believes that this program could yield a new generation of cancer therapeutics, combined with efficacious compounds to treat additional, non-cancer indications. This strategy includes the preclinical compounds described below.

HDACi Non-Oncology

TopoTarget is also using its extensive HDAC inhibitor library to discover a variety of HDAC inhibitors for non-oncology indications. The Company is expected to leverage this segment of its business as an out- licensing opportunity, specifically focused on:

Psoriasis. TopoTarget has proprietary HDAC compounds that exhibit profound anti-proliferative effects on human keratinocytes, epidermal cells that play a key role in the development of psoriasis;

Restenosis. TopoTarget is involved in a collaboration to evaluate the potential of HDAC inhibitors in cardiovascular disease and in-stent restenosis after Percutaneous Transluminal Coronary Angioplasty (PTCA). TopoTarget has found that HDAC inhibitors are active in human vascular smooth muscle cells and endothelial cells, two key targets involved in the pathology of restenosis; and

Parasitic disease. TopoTarget has found that HDAC enzymes are evolutionary conserved, being present in parasitic genomes, including the malaria parasite, plasmodium. In collaboration with the World Health Organization (WHO), TopoTarget is identifying HDAC inhibitors that are specific for parasitic HDACs for diseases of worldwide importance.

Non-catalytic Inhibitors

TopoTarget is in collaboration with Professor Brian Hasinoff from the University of Manitoba to develop dexrazoxane analogues without catalytic inhibition of topoisomerase II, but with retained ability to protect against myocardial damage caused by the free radical effects of anthracyclines. A lead compound has been identified and animal studies are planned.

HSP90

HSP90 is a newly established and validated target for anti-cancer therapy. HSP90 has been found to be primarily drug sensitive in malignant cells due to mutations in the enzyme. Experimental HSP90 drugs, such as 17-AAG and 17-DMAG, are in the clinic but have experienced problems with liver toxicity. Using the published crystal structure of HSP90, its experience with topoisomerase II ATPase which resembles that of HSP90, as well as an arrangement with Inhibox Ltd (a molecular modeling company), TopoTarget believes that it can design and test efficient HSP90 inhibitors for targeted treatment. Synthesis of candidate drug has begun in TopoTarget’s contract research facility in Riga, Latvia.

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E2F

E2F is a cell cycle protein that activates the genes responsible for cell cycle division and has been identified as a therapeutic target for cancer. TopoTarget has identified various strategies to control E2F as a means to halt the proliferation of cancer. Based on its intellectual property position for E2F, TopoTarget believes the best approach for its E2F program could be to develop collaborations to further development.

DUBS

De-ubiquinating systems (DUBS) are a potential angiogenesis target in cancer therapy. TopoTarget owns IP in the field, derived from a collaboration with Professor Rene Bernards at the Netherlands Cancer Institute. A particularly promising DUBS, VDU1, which inhibits the angiogenesis signal HIF-1α, is being cloned and expressed for compound screening.

In-licensed

Endovion

TopoTarget entered into a collaboration with NeuroSearch on August 12, 2004 to develop the NeuroSearch compound Endovion (NS3728), an orally active chloride channel blocker for the treatment of cancer. Endovion blocks a certain subtype of chloride ion channels important for cell division, cell migration, and the formation of new blood vessels (angiogenesis).

Endovion has shown efficacy in preclinical cancer models and has completed Phase I clinical trials in 92 subjects. TopoTarget aims to commence additional preclinical assessment in order to design the Phase II clinical studies. Under the terms of the agreement, TopoTarget will fund future preclinical and clinical development and the two companies will share any future revenues from the product. Financial details were not disclosed.

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Potential Milestones Within Next 12-24 Months

TopoTarget has set forth a series of milestones, which it has targeted to achieve over the next 12-24 months. These include:

Secure a Topotect supply source

Out-license the U.S. marketing rights of Topotect for extravasation

Obtain regulatory approval for Topotect for extravasation in Europe and commence marketing in Europe

Obtain publication of successful European trial results in a reputable medical journal in the U.S.

File NDA for Topotect for extravasation in the U.S.

Obtain regulatory approval for extravasation in non-European/non-U.S. territories

In-license European marketing rights to late-stage niche cancer product, which is either on or close to the market

Enter into co-development and/or marketing agreement for brain metastases with large pharmaceutical company and/or biotechnology company

Enter into out-license agreement for the psoriasis indication of HDAC and/or E2F

Enter Phase II for PXD101 in myeloma, T-cell lymphoma, and ovarian cancer

Enter Phase II for Endovion

.

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Historical Financial Results

Tables 12, 13, and 14 provide a snapshot of TopoTarget’s key historical financial statements, including its Statement of Operations, Balance Sheet, and Cash Flow Statement, all converted from DKK to USD at the respective exchange rate.

Table 12 TopoTarget A/S STATEMENT OF OPERATIONS, USD (DKK converted to USD at respective exchange rate) 2001 2002 2003 Dec. 31, 2001 Dec. 31, 2002 Dec. 31, 2003 1 DKK = 0.119719 1 DKK = 0.141143 1 DKK = 0.169062 Revenues — 157 — Research and development costs (1,073) (4,415) (7,784) General and administrative expenses (442) (1,601) (2,711)

Operating profit (loss) (1,515) (5,859) (10,496)

Financial income 97 199 139 Financial expenses (16) (32) (230)

Profit (loss) before tax (1,434) (5,693) (10,586)

Tax — 326 —

Net profit (loss) (1,434) (5,366) (10,586)

Source: TopoTarget A/S.

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Table 13 TopoTarget A/S BALANCE SHEET, USD (DKK converted to USD at respective exchange rate) 2001 2002 2003 Dec. 31, 2001 Dec. 31, 2002 Dec. 31, 2003 1 DKK = 0.119719 1 DKK = 0.141143 1 DKK = 0.169062

Assets Total non-current assets 197 6,657 7,444 Receivables 65 643 497 Cash and cash equivalents 1,925 8,095 1,469

Total Assets 2,187 15,395 9,409

Liabilities and shareholders' equity

Shareholders' equity 1,939 14,782 7,111 Non-current liabilities 42 35 1,362 Total current liabilities 206 578 937 Total liabilities 248 613 2,298

Total liabilities and shareholders' equity 2,187 15,395 9,409

Source: TopoTarget A/S.

Table 14 TopoTarget A/S CASH FLOW STATEMENT, USD (DKK converted to USD at respective exchange rate) 2001 2002 2003 Dec. 31, 2001 Dec. 31, 2002 Dec. 31, 2003 1 DKK = 0.119719 1 DKK = 0.141143 1 DKK = 0.169062

Cash flow from operations (1,397) (4,725) (9,029)

Cash flow from investing activities (159) (6,391) (591)

Cash flow from financing activities 2,657 16,941 1,393

Cash and cash equivalent at the end of the 1,925 8,095 1,469 period

Source: TopoTarget A/S.

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Table 15 TopoTarget A/S OTHER FINANCIAL DATA (2) 2001 2002 (1) 2003 Dec. 31, 2001 Dec. 31, 2002 Dec. 31, 2003

Number of fully paid shares in issue as of 500,000 1,180,787 1,180,787 period end

Weighted average number of shares in issue 449,863 902,313 1,180,787 for the period

Cash flow from opertaions per share (3) (25.95) (37.10) (45.23)

Equity Ratio (5) 0.89 0.96 0.76

Average number of employees (full-time 7 35 39 equivalents)

Notes: (1) Prolifix Ltd., now TopoTarget UK Ltd. was acquired. (2) Stated in accordance with the recommendations of the Danish Association of Financial Analysts. (3) Calculated on the basis of the weighted average number of Shares registered and outstanding during the relevant period. (4) Basic and diluted profit/(loss) per Share and cash flow from operations per Share have been calculated on the basis of the weighted average number of Shares registered and outstanding during the relevant period.

(5) Calculated as shareholders’ equity and reserves at end of period divided by the total assets at end of period.

Source: TopoTarget A/S.

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Risks

Any investment in shares of TopoTarget A/S Common Stock involves a high degree of risk. Prior to subscribing to the shares, investors should carefully examine this entire memorandum and give particular consideration to the general risks attendant to speculative investments generally and the other special operating and investment risks set forth below.

No Public Market for the Stock

There is no public market for TopoTarget’s securities. As a result, the purchasers of the Common Shares may not be able to liquidate their investment readily, if at all.

Competition

The biopharmaceutical industry is very competitive. TopoTarget competes with other companies that develop products to treat the same diseases. Many of these companies have considerably greater resources than TopoTarget and there is no guarantee that the products developed by other companies will not cause TopoTarget’s products and technologies to become less competitive. Competition within the extravasation market includes more traditional methods listed on pages 23-25. Additionally, TopoTarget has recognized the following products as potential competition to its HDAC and E2F business segments:

HDAC

Nihon Schering—MS-275 (Phase II). This is a weakly potent compound from Nihon Schering (formerly Mitsui). It is currently in Phase II trials for colon and lung cancer in Japan. In animal models, the dose limiting toxicity was of the bone marrow.

Aton Pharma—SAHA (Phase II). Suberanilohydroxamic acid (SAHA) was given to a limited number of cancer patients by I.V. infusion in a Phase I trial. The drug measurably affected the pharmacodynamic markers and dose escalation studies were performed. The drug has entered Phase II trials, being given both I.V. and orally.

Fujisawa (FJSPF.PK)—FR-901228 (Phase II). This cyclic peptide underwent Phase I trials by Fujisawa in collaboration with the NCI. Responses were seen in patients with T-cell lymphoma and a Phase II trial of the drug for this indication is underway.

Aton Pharma—Pyroxamide (Phase I). This compound is chemically similar to SAHA, and has entered Phase I trials run by Aton Pharma; findings have not been released.

Novartis—LAQ824 (Phase I). This hydroxmate HDAC inhibitor has recently entered Phase I trials for cancer; findings have not been released.

Methylgene—Small molecules/antisense (Discovery). This company has filed a number of patent applications covering small molecule HDAC inhibitors and HDAC antisense. However, none of these have entered clinical trials.

Shionogi—Oxamflatin (Discovery). This is a hydroxamate with a sulphonamide linker that blocks HDAC activity. Oxamflatin has been reported to inhibit cell proliferation and reverse transformation. No clinical trials have been initiated.

E2F

Dana-Farber—Gene therapy (Discovery). A recombinant adenovirus vector is being investigated, which acts selectively on tumor cells by targeting E2F. The planned therapeutic indication is glioma.

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Osaka University—Decoys (Discovery). Oligonucleotide decoys that bind to E2F have been investigated for therapy of restenosis and cancer. Although they exhibited some activity in a rat restenosis model, they were ineffective in mouse tumor models run by Fujisawa.

Novartis—E2F: Cyclin A antagonists (Discovery). A combinatorial library of spirolactams has been synthesised as antagonists of the interaction between E2F-1 and cyclin A. No data on cell-based activity are available.

Government Regulation

TopoTarget is subject to substantial regulation by the FDA and other federal and state regulatory agencies. FDA regulations require the Company to obtain either a 501(k) clearance or pre-marketing approval prior to marketing its products in the United States. The Company is also subject to foreign regulations and is dependent upon the receipt of various types of approvals from certain foreign government agencies prior to the sale of products in those countries. The clearance and approval process from both FDA and foreign regulatory authorities can be costly, time consuming, and uncertain. In addition, the Company is required to obtain FDA approval before exporting a product. There can be no assurance that the Company will receive these clearances or that it will have sufficient resources to commence or complete the regulatory approval process. Delays in obtaining such clearances or PMAs would have a material adverse effect on the Company, while changes in existing requirements could also have a material adverse effect on the Company.

Patents and Technologies

The Company’s strategic approach is to build a portfolio that provides broad protection of technology, as well as a tiered patent claim structure to provide specific composition of matter, disease indication, and manufacturing claims. The Company’s policy is to file patent applications in all major markets in the world. TopoTarget’s patent portfolio includes 48 issued U.S. patents and 35 pending U.S. patent applications. TopoTarget has also established substantial foreign patent protection for its lead drug candidates. There is no guarantee that the Company will obtain patents in the other countries in which patent applications have been or will be filed, or that it will develop other patentable products or processes.

Reliance on Strategic Partnerships

TopoTarget is dependent on partners for the commercial development of its products. The Company does not currently have, nor does it expect to have in the near future, sufficient financial resources and personnel to develop and market its products on its own. Accordingly, the Company expects to continue to depend on large pharmaceutical companies and/or other such organizations for revenues from sales of products, research sponsorship, and distribution of its products.

The process of establishing partnerships is difficult and time consuming. Discussions with potential partners may not lead to the establishment of new partnerships on favorable terms, if at all. If new partnerships are successfully established, the partnerships may never result in the successful development of product candidates or the generation of significant revenue. Management of relationships with these partners would require significant time and effort from its management team; coordination of its research with the research priorities of its corporation partners; effective allocation of resources to multiple projects; and an ability to attract and retain key management, scientific, and other personnel.

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Recent Events

11/09/2004—Entered into a two-year collaboration with Inhibox Limited to use Inhibox’s ultra-high throughput virtual screening technology for anti-cancer lead identification.

10/18/2004—Announced that the United States Patent Office has granted the Company a key patent relating to the administration of topo II inhibitors such as Topotect (ICRF-187) for preventing severe tissue damage in cancer patients following accidental extravasation of topoisomerase II poisons (e.g. anthracyclines). Related patents are already granted in Europe, Australia, and New Zealand.

08/24/2004—Announced that its licensing partner, CuraGen Corporation, had signed a Clinical Trials Agreement (CTA) with the Division of Cancer Treatment and Diagnosis (DCTD) at the National Cancer Institute (NCI) for PXD101, a histone deacetylase (HDAC) inhibitor currently in Phase I clinical trials. Under the agreement, the NCI will sponsor several clinical trials evaluating the activity of PXD101, either alone or in combination with other anti-cancer therapies, for the treatment of solid and hematologic cancers.

08/12/2004—Announced that it had entered into a collaboration with NeuroSearch (NEUR.CO) to develop the NeuroSearch compound Endovion (NS3728), an orally active chloride channel blocker for the treatment of cancer. Endovion blocks a certain subtype of chloride ion channels important for cell division, cell migration, and the formation of new blood vessels (angiogenesis). Endovion has shown efficacy in preclinical cancer models. The compound has completed Phase I clinical trials in 92 subjects. TopoTarget aims to commence additional preclinical assessment in order to design the Phase II clinical studies. Under the terms of the agreement, TopoTarget will fund future preclinical and clinical development and the two companies will share any future revenues from the product. Financial details were not disclosed.

06/03/2004—TopoTarget A/S and CuraGen Corporation announced a license, collaboration, and commercialization agreement on a small molecule inhibitor program targeting HDAC in oncology. The most advanced product, PXD101, is a novel HDAC inhibitor currently in Phase I clinical trial in advanced cancer patients and due to enter Phase II clinical trials in patients with hematological malignancies.

05/03/2004—Announced an imminent collaboration with the NCI for the development of a series of HDAC inhibitors from its proprietary library to combat hematological disorders. Under the CRADA, the two organizations will pursue the preclinical and clinical development of PXD101, TopoTarget’s proprietary HDAC inhibitor.

10/20/2003—Announced the appointment of Hans Christian Hollander, formerly head of international sales and marketing at the Danish Government–owned enterprise Statens Serum Institute (SS), as sales and marketing director.

10/13/2003—Announced that it had initiated a Phase I clinical study of PXD101, proprietary HDAC inhibitor, in patients with advanced cancers. The two-center trial is being carried out by investigators at the Royal Mardsen Hospital (London and Surrey, UK) and the Western Infirmary (Glasgow, Scotland). The Phase I trial will evaluate intravenous administration of PXD101 in 24-36 patients. In addition to standard clinical evaluations of safety and efficacy, clinicians will monitor pharmacokinetics and pharmacodynamic responses.

09/25/2003—Announced that it had received the Copenhagen enterprise Award 2003, which is awarded in connection with the Copenhagen Business Council’s annual conference. The Award recognizes TopoTarget’s development of Topotect, a new enzyme inhibitor, which relieves serious side effects associated with chemotherapy. The developmental work has involved a close collaboration between both private and public parties.

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Glossary of Lesser-Known Terms

Accelerators—Also called oncogenes, accelerators are genes that once played a normal role in the cell, but have been altered by mutations. Accelerators are believed to contribute to tumor growth.

Adjuvant Chemotherapy—A cancer therapy primarily employed after the tumor has been removed and there is little evidence of cancer present, but a risk of recurrence remains. This approach also assists in reducing the chances of proliferation if a tumor does develop and is useful in killing any cancer cells that may have spread to other parts of the body.

Alkylating Agents—Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning.

Angiogenesis—Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor.

Antacids—Drugs that counter or neutralize acidity within the stomach.

Anthracycline—A member of a family of antibiotic chemotherapy drugs, which attempt to inhibit cell division by disrupting the structure of DNA. These drugs are also known to cause extravasation when improperly administered intravenously.

Anti-Angiogenesis—Drugs that halt the process of developing 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.

Antibiotics—A substance that kills bacteria within the body.

Anti-convulsants—A group of pharmaceuticals used to prevent the occurrence of epileptic seizures.

Antidote—A substance that counteracts the effects of a poison.

Anti-Metabolites—Anti-cancer drugs, which are chemically similar to purine and pyrimidine and are the building blocks of DNA. By masquerading as these substances, anti-metabolites inhibit them from being incorporated into DNA during the S phase of the cell cycle, which halts normal development and division.

Antineoplastic Agents—Agents inhibiting or preventing growth of neoplasms, checking the maturation and proliferation of malignant cells.

Apoptosis—The physiological process necessary for the elimination of superfluous, diseased, or damaged cells and the formation of new cells. Also called programmed cell death.

Blood Brain Barrier—An assembly of membranes protecting the brain from various substances in the blood.

Brain Metastases—Cancer that spreads from its original tumor to the brain.

Brakes—Genes that assist in the suppression of tumor growth. Also called suppressor genes.

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.

Cardiotoxicity—Toxicity that affects the heart.

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Catecholamines—Nitrogen-containing chemical compounds that act as neurotransmitters or hormones.

Cerebrospinal Fluid—A fluid surrounding the brain and spinal cord continuously produced and absorbed.

Chemotherapy—Treatment with cytotoxic anti-cancer drugs.

Chromatin—A protein responsible for the formation of chromosomes, containing DNA, RNA, and various proteins.

Chromosomes—Structures within a cell nucleus that carry genetic information that determines the sex and characteristics an organism inherits from its parents.

Colorectal Cancer—Cancer of the colon and rectum in which a malignant tumor appears on the inner wall of the large intestine.

Combination Therapy—A cancer treatment strategy that employs a variety of different chemotherapeutic agents simultaneously. Since each drug differs in mechanism and side effects, this approach may minimize the possibility of the patient developing a resistance to the therapy.

Combined Modality Chemotherapy—A cancer treatment strategy that combines the use of chemotherapeutic drugs with additional cancer treatments, such as radiation or surgery.

Corticosteroids—A group of synthetic hormones used in the treatment of some leukemias and for the suppression of graft rejection and graft-versus-host disease following bone marrow transplants.

Cytotoxic—Cell-killing.

Deoxyribonucleic Acid (DNA)—The genetic material of all living organisms (except for RNA-carrying viruses, such as HIV). DNA is a double-stranded, helical molecular chain found within each cell. DNA contains the information necessary for cells to produce proteins, which enable cells to reproduce and carry out their functions.

Doxorubicin—An antibiotic used as an anti-cancer drug.

E2F—A cell cycle protein, which activates the genes responsible for cell cycle division and has been identified as a therapeutic target for cancer.

Endothelial cells—Main type of cell found on the inside lining of blood vessels, lymph vessels, and heart.

Etiology—Study of the causes of diseases.

Etoposide—A well-established chemotherapeutic agent that has demonstrated high efficacy in combination therapy with Topotect.

Extravasation—A severe form of tissue damage resulting from an adverse reaction to chemotherapy. Extravasation occurs when the cytotoxic poisons from chemotherapeutic medications escape from the vein at the injection site, inducing proliferative tissue necrosis that can be life-threatening.

Glioblastomas—A primary malignant tumor originating in the brain.

Histone Deacetylase (HDAC)—Enzymes that work in conjunction with cell cycle proteins like E2F and p53 to modify a histone substrate, affecting their regulatory activity and potentially contributing to the spread of malignant tumors.

Immunotherapeutics—See monoclonal antibodies.

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In Vivo—Within a living organism.

Keratinocytes—Epidermal cells that synthesize keratin. Keratinocytes also play a key role in the development of psoriasis.

Leukocyte—Any of the small, colorless cells in the blood, lymph, and tissues, which are important to the body’s defense against infection.

Maceration—The act of softening a tissue by soaking it, especially in acids.

Malaria—An infectious parasitic disease transmitted by the Anopheles mosquito or by a contaminated needle. Symptoms of this often deadly disease include headache, vomiting, diarrhea, muscle aches, cough, and in severe cases, even kidney and liver failure or coma.

Malignant Lymphoma—A group of cancerous tumors of unknown cause, characterized by painless, progressive enlargement of the lymphoid tissue.

Melanoma—A malignant tumor that develops from melanocytes, which are melanin-producing cells in the skin.

Metastases—The spread of cancer from one part of the body to another. Cells in metastatic (secondary) tumors may not be antigenically similar to those in the original (primary) tumor.

Metastasize—The action of metastasis.

Micrometastasis—The spread of undetectable cancer cells.

Mitosis—Division of a body cell into two daughter cells, each of which possess the same chromosome as the parent cell.

Monoclonal Antibodies—Identical antibodies produced in large amounts in a laboratory.

Multiple Myeloma—A malignancy of the plasma cells that affects multiple sites within the bone marrow and secretes all or part of a monoclonal antibody.

Necrosis—Death of tissues, cells, or an organ in the body. This happens when not enough blood is supplied to the tissue, whether from injury, radiation, or chemicals. Once necrosis occurs, it is not reversible.

Neutrophil—A type of white blood cell filled with tiny sacks of enzymes that assist the cell in killing and digesting microorganisms that it has engulfed through phagocytosis.

Non-Hodgkin Lymphoma—Malignant tumors of the lymphatic system consisting of several subtypes of lymphatic cancer.

Orphan Drug Designation—Describes a rare disease that affects fewer than 200,000 people, or a common disease that has been ignored because it is less prominent in the U.S., compared with developing nations. According to the NIH, there are approximately 6,000 of these diseases.

Osmolarity—The concentration of osmotically active particles in a solution.

Osmotic Diuretics—Drugs that promote the elimination of water and electrolytes through urination. Osmotic diuretics are also used to inhibit brain swelling.

Ovarian Cancer—A malignant tumor on the ovaries. While the condition is fairly uncommon, it poses a remarkably high death rate, representing the fifth leading cause of cancer death in women and the leading cause of death from gynecologic malignancies.

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Plant Alkaloids—Anti-cancer drugs that are derived from plants. These drugs work by blocking cell division and preventing microtubules, which are vital for cell division, from being synthesized. This action prevents cell division from occurring.

Plasmodium—Parasite responsible for malaria.

Prostate cancer—A malignant tumor containing cells from the prostate gland.

Psoriasis—A chronic skin disease marked by scaling and inflammation of the epidermis.

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-bem 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 radiolabeled monoclonal antibody that circulates throughout the body. This method is also called radiotherapy.

Restenosis—The re-narrowing of the coronary artery following an angioplasty.

Retinoblastoma (RB)—A suppressor gene that halts the proliferation of cells.

Small Cell Lung Cancer (SCLC)—A form of lung cancer in which the cells appear small and round when viewed under a microscope.

Taxanes—Chemotherapeutic agents that inhibit cancer cell growth by stopping cell division.

Topoisomerase poisons—Drugs that interfere with the catalytic cycle of topisomerases at a step where the DNA is cleaved are called topoisomerase poisons.

Topoisomerases—A unique group of enzymes that untangle chromosomal DNA. Topoisomerases cut gaps in one strand of double-stranded DNA, pass through the other strand through the gap, and subsequently reseal the break.

Vasoconstriction—A narrowing of the blood vessels resulting from a contraction of the muscular wall of the vessels.

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Jeffrey J. Kraws or 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 TopoTarget A/S, (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 USD$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 TopoTarget A/S’s press releases and other publicly disclosed documents. The content of this report with respect to TopoTarget A/S has been compiled primarily from information available to the public released by TopoTarget A/S. TopoTarget A/S 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 TopoTarget A/S 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 TopoTarget A/S, the reader is directed to the Company's website at www.TopoTarget.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 TopoTarget A/S, and its public filings, as well as free copies of this report can be obtained in either a paper or electronic format by calling 011-45 39 17 83 90.

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