Scrip's Complete Guide to Gene Therapy

Scrip's Complete Guide to Gene Therapy

CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
GLOSSARY AND ABBREVIATIONS
CHAPTER 1 INTRODUCTION
1.1 Why gene therapy?
1.2 Technical issues
1.3 Progress to date
1.4 Reasons for optimism

CHAPTER 2 TECHNOLOGIES AND TECHNIQUES
2.1 Introduction
2.2 Vectors
2.3 Target tissues
2.4 Expression
2.5 The ex vivo versus in vivo approach
2.6 Viral vectors
2.6.1 Retroviral vectors
2.6.2 Adenoviral vectors
2.6.3 Vaccinia vectors
2.6.4 Herpes simplex virus vectors
2.6.5 Adeno-associated viral vectors
2.6.6 Lentiviral vectors
2.6.7 Choice of viral vector
2.6.8 Future prospects for viral vectors
2.7 Non-viral methods of gene transfer
2.7.1 Liposomes
2.7.2 Naked DNA
2.7.3 The 'gene gun'
2.7.4 Electroporation
2.8 The ideal vector
2.9 Future developments

CHAPTER 3 CANCER
3.1 Cancer-causing genes
3.1.1 Oncogenes
3.1.2 Tumour suppressor genes
3.2 Forms of cancer
3.2.1 Brain cancer
3.2.2 Breast cancer
3.2.3 Cervical cancer
3.2.4 Colorectal cancer
3.2.5 Haematopoietic malignancies
3.2.6 Head and neck cancer
3.2.7 Hepatocellular carcinoma
3.2.8 Lung cancer
3.2.9 Melanoma
3.2.10 Ovarian cancer
3.2.11 Prostate cancer
3.2.12 Renal-cell carcinoma
3.3 Gene therapy of cancer
3.4 Gene therapy strategies
3.4.1 Replacement of tumour suppressor genes
3.4.2 Chemoprotection
3.4.3 Suicide gene therapy
3.4.4 Antisense
3.4.5 Immunotherapy
3.4.6 Non-specific immunotherapy
3.4.7 Specific immunotherapy
3.4.8 Anti-idiotype DNA vaccines
3.4.9 Chimaeric T-cell receptors
3.4.10 Anti-angiogenesis
3.4.11 Hypoxia-specific anti-cancer therapy
3.5 Company developments
3.5.1 Introgen/RPR
3.5.2 Novartis
3.5.3 Cell Genesys
3.5.4 Vical
3.5.5 Genetix
3.5.6 Transgène
3.5.7 Schering-Plough/Canji
3.5.8 Targeted Genetics
3.6 Clinical realities

CHAPTER 4 GENETIC DISEASES
4.1 Types of monogenic disease
4.2 NIH protocols
4.3 Cystic fibrosis
4.4 Muscular dystrophy
4.5 Haemophilia
4.6 Sickle-cell anaemia/beta-thalassaemia
4.7 Severe combined immunodeficiency/adenosine deaminase deficiency
4.8 Chronic granulomatous disease
4.9 Gaucher's disease
4.10 Phenylketonuria
4.11 Growth hormone deficiency
4.12 Storage diseases
4.13 Other monogenic diseases

CHAPTER 5 HIV AND AIDS
5.1 The structure and life cycle of HIV
5.2 The course of HIV infection
5.3 Gene therapy in the treatment of AIDS
5.4 Gene therapy - theoretical approaches
5.5 Anti-HIV gene therapy studies
5.5.1 The first reported study
5.5.2 Cell Genesys
5.5.3 Novartis
5.5.4 Theratechnologies
5.5.5 Aastrom
5.5.6 Ribozyme Pharmaceuticals
5.5.7 Chiron
5.5.8 Avigen
5.5.9 Oxford BioMedica
5.5.10 Targeted Genetics
5.5.11 Vical

CHAPTER 6 CARDIOVASCULAR AND OTHER DISEASES
6.1 Cardiovascular diseases
6.1.1 Coronary artery disease
6.1.2 Peripheral vascular disease
6.1.3 Hypercholesterolaemia
6.1.4 Congestive heart failure
6.1.5 Prevention of restenosis
6.1.6 Enhanced thrombolysis
6.1.7 Hypertension
6.1.8 Other cardiovascular disorders
6.1.9 Other developments in cardiovascular gene therapy
6.2 Neurological disorders
6.2.1 Parkinson's disease
6.2.2 Alzheimer's disease
6.2.3 Motor neuron disease
6.2.4 Stroke
6.2.5 Epilepsy
6.3 Other diseases
6.3.1 Asthma
6.3.2 Diabetes
6.3.3 Rheumatoid arthritis
6.3.4 Obesity
6.3.5 Erythropoietin
6.3.6 Future developments

CHAPTER 7 THE POTENTIAL MARKET FOR GENE THERAPY
7.1 Market overview
7.1.1 The value of the market
7.1.2 First products to reach the market
7.1.3 Geographical breakdown
7.1.4 Market estimates
7.2 Cancer
7.2.1 Brain cancer
7.2.2 Breast cancer
7.2.3 Cervical cancer
7.2.4 Colorectal cancer and liver metastases
7.2.5 Head and neck cancer
7.2.6 Hepatocellular cancer
7.2.7 Lung cancer
7.2.8 Malignant melanoma
7.2.9 Ovarian cancer
7.2.10 Prostate cancer
7.2.11 Renal-cell carcinoma
7.3 Genetic diseases
7.3.1 Severe combined immunodeficiency/adenosine deaminase deficiency
7.3.2 Cystic fibrosis
7.3.3 Muscular dystrophy
7.3.4 Haemophilia A
7.3.5 Sickle-cell anaemia/beta-thalassaemia
7.3.6 Gaucher's disease
7.4 AIDS
7.5 Cardiovascular disease
7.5.1 Coronary artery disease
7.5.2 Prevention of restenosis
7.5.3 Peripheral vascular disease
7.5.4 Congestive heart failure
7.6 Neurological disorders
7.6.1 Parkinson's disease
7.6.2 Alzheimer's disease
7.6.3 Motor neuron disease
7.6.4 Stroke

CHAPTER 8 THE LEGAL/REGULATORY ENVIRONMENT
8.1 Patents
8.1.1 The patenting of gene therapy
8.1.2 Key patents
8.1.3 In vivo patents
8.2 The regulation of gene therapy
8.2.1 Gene therapy trials
8.2.2 The US
8.2.3 Europe
8.2.4 Japan
8.2.5 Regulatory approval
8.3 Ethical issues

CHAPTER 9 STRATEGIC ISSUES
9.1 Structure of the industry
9.1.1 Dedicated gene therapy companies
9.1.2 Cell therapy companies
9.1.3 Biotechnology companies
9.1.4 Pharmaceutical companies
9.2 The US versus Europe
9.3 A multi-component product
9.4 Disease targets
9.5 Forms of gene therapy
9.5.1 The ex vivo approach
9.5.2 The in vivo approach
9.6 Risks and rewards

CHAPTER 10 COMPANY PROFILES
10.1 Avigen
10.2 Cell Genesys
10.3 Chiron
10.4 GeneMedicine
10.5 GenVec
10.6 Introgen
10.7 IntroGene
10.8 Megabios
10.9 Novartis
10.10 Oxford BioMedica
10.11 Rhône-Poulenc Rorer
10.12 Schering-Plough
10.13 Targeted Genetics
10.14 Transgène
10.15 Transkaryotic Therapies
10.16 Vical

CHAPTER 11 DIRECTORY OF COMPANIES, RESEARCH INSTITUTES AND ORGANISATIONS
11.1 Companies
11.2 Research institutes
11.3 Organisations

REFERENCES

LIST OF TABLES
Table 2.1 Comparison of viral vector systems
Table 2.2 Vector systems in use or under consideration for gene therapy
Table 3.1 Examples of oncogenes involved in human cancers
Table 3.2 Examples of tumour suppressor genes involved in human cancers
Table 3.3 Breakdown of gene therapy protocols by type of cancer
Table 3.4 Gene therapy strategies being studied in cancer patients
Table 3.5 Gene therapy products currently undergoing clinical development for the treatment of cancer
Table 4.1 Monogenic diseases being studied in US gene therapy protocols
Table 4.2 Companies and research organisations involved in the development of gene therapy approaches to CF
Table 4.3 Gene therapy products undergoing development for the treatment of monogenic diseases (excluding CF)
Table 5.1 Gene therapy products undergoing development for the treatment of AIDS
Table 6.1 Gene therapy products currently undergoing development for the treatment of cardiovascular diseases
Table 6.2 Targets for neuronal gene therapy
Table 6.3 Gene therapy products currently undergoing development for the treatment of 'other' diseases (excluding cardiovascular disease)
Table 7.1 Incidence of some of the major cancers, US, Europe and Japan
Table 7.2 Mortality of some of the major cancers, US and Europe
Table 7.3 Market estimates for anti-cancer gene therapies
Table 7.4 Market estimates for gene therapies for genetic diseases
Table 9.1 Biotechnology companies with a significant gene therapy commitment (includes established biotech companies plus dedicated gene therapy companies)
Table 9.2 Gene therapy activities of the pharmaceutical majors
Table 10.1 Avigen's financial results ($ thousands), third quarter ended 31 March
Table 10.2 Avigen's financial results ($ thousands), year ended 30 June
Table 10.3 Cell Genesys' financial results ($ thousands), first quarter ended 31 March
Table 10.4 Cell Genesys' financial results ($ thousands), year ended 31 December
Table 10.5 Chiron's financial results ($ thousands), first quarter ended 31 March
Table 10.6 Chiron's financial results ($ thousands), year ended 31 December
Table 10.7 GeneMedicine's financial results ($ thousands), first quarter ended 31 March
Table 10.8 GeneMedicine's financial results ($ thousands), year ended 31 December
Table 10.9 Megabios' financial results ($ thousands), third quarter ended 31 March
Table 10.10 Megabios' financial results ($ thousands), year ended 30 June
Table 10.11 Novartis' financial results (SwFr million), first quarter ended 31 March
Table 10.12 Novartis' financial results (SwFr million), year ended 31 December
Table 10.13 Oxford BioMedica's financial results (£)
Table 10.14 RPR's financial results ($ millions), year ended 31 December
Table 10.15 Partners in the RPR Gencell network
Table 10.16 Schering-Plough's financial results ($ million), first quarter ended 31 March
Table 10.17 Schering-Plough's financial results ($ thousands), year ended 31 December
Table 10.18 Targeted Genetics' financial results ($ thousands), first quarter ended 31 March
Table 10.19 Targeted Genetics' financial results ($ thousands), year ended 31 December
Table 10.20 Transgène's financial results (Fr thousands), first quarter ended 31 March
Table 10.21 Transgène's financial results (Fr thousands), year ended 31 December
Table 10.22 Transkaryotic Therapies' financial results ($ thousands), first quarter ended 31 March
Table 10.23 Transkaryotic Therapies' financial results ($ thousands), year ended 31 December
Table 10.24 Vical's financial results ($ thousands), first quarter ended 31 March
Table 10.25 Vical's financial results ($ thousands), year ended 31 December

LIST OF FIGURES
Figure 1.1 Gene therapy - technical risk versus commercial risk
Figure 2.1 Different vectors used in gene therapy
Figure 5.1 The structure of HIV
Figure 5.2 The life cycle of HIV
Figure 5.3 The intracellular infectious cycle of HIV with emphasis on different points during infection at which genetic antivirals can be applied

EXECUTIVE SUMMARY
It is now eight years since the first human gene transfer study was performed. In the intervening years, close to 300 gene therapy clinical trials involving over 2,000 patients have been initiated - and yet not a single gene therapy product has succeeded in reaching the market. The indications are that this is all about to change, with several gene therapy products now in the final stages of clinical development and a first launch scheduled for possibly as early as 2000. Given the compelling scientific rationale for gene therapy, it is likely to result in major therapeutic advances being made in a number of areas (once the technology proves successful) including cancer, acquired immune deficiency syndrome (AIDS), cardiovascular and neurological conditions, as well as the 'single gene' disorders for which it was originally intended.

The purpose of this report is to provide an up-to-date overview of the gene therapy field, particularly in terms of commercial developments to date and prospects for the future. It is intended as a follow-on to Scrip's first report on gene therapy: The Current Status and Future Potential of Gene Therapy (BS741, 1995). However, whereas the previous report focused on the technical aspects, this report tends to focus more on the commercial issues. Thus, for each of the main therapeutic areas in which gene therapy is being applied, a summary is given of the companies involved and the stages of development for their various products.

The report is organised in such a way as to take the reader through the basics of gene therapy technology and the main therapeutic areas in which it can be applied. Following this introduction, an analysis of the potential markets for gene therapy products, the legal/regulatory environment and the strategic issues faced by companies involved in the field is provided.

An introduction to the subject of gene therapy is given in Chapter 1. This provides a definition as to exactly what is meant by the term 'gene therapy' and reviews the various ways in which the technology can be used in the treatment of disease. It also seeks to explain why this technology is so special, particularly in terms of the characteristics that set it apart from other therapeutic modalities. An outline is provided of the key technical issues that still have to be resolved for gene therapy to fulfil its full potential, together with a review of the progress that has been made to date. Several reasons for optimism about the future of gene therapy are also presented.

Chapter 2 reviews the key technologies that have transformed this technology from scientific theory into a medical reality. A large part of the chapter is devoted to a review of the various gene transfer (vector) systems used in gene therapy - both viral and non-viral - and their relative merits and failings. The characteristics of 'the ideal vector' are analysed and key areas of research for the future are reviewed.

Chapters 3-6 look at the main therapeutic areas in which gene therapy has been applied. The first area, cancer (reviewed in Chapter 3), is the indication being most widely investigated in current protocols; it is also probably the most complex area of gene therapy research. The genetic basis of cancer is explained, and the cancers most amenable to treatment by gene therapy are reviewed. The various gene therapy strategies which can be used to treat cancer are described, ranging from replacement of tumour suppressor genes, chemoprotection and suicide gene therapy, through to immunotherapy, deoxyribonucleic acid (DNA) vaccines and anti-angiogenesis. Brief summaries are also given of the activities of the main companies involved in the field. Finally, an assessment is made of the realistic possibilities that can be expected for anti-cancer gene therapy.

Chapter 4 is devoted to the diseases for which gene therapy was originally intended, namely monogenic or single gene disorders - that is, those classical inherited diseases whose cause can be linked directly to a genetic defect. In all, some 4,000 human diseases are known or suspected to arise from defects in single genes. Many of these are comparatively rare, but as a group, they contribute significantly to the chronic disease burden and cause an immense deal of suffering. Cystic fibrosis (CF) is the most widely researched of these monogenic disorders with some 18 companies identified as involved in the development of gene therapy approaches to the disease.

An overview of gene therapy approaches to the treatment of human immunodeficiency virus (HIV)/AIDS is provided in Chapter 5. After cancer, the next largest group of gene therapy clinical studies (about 10%) relates to AIDS. (In theory, a number of chronic infectious diseases are potential candidates for gene therapy approaches but, so far, HIV infection has received the greatest attention.) The reasons why HIV/AIDS presents a more complex target are analysed and various theoretical approaches to attacking HIV infection are reviewed. Brief summaries are also given of company activities in the field.

In recent years, gene therapy has found application in a number of 'other' disease areas and these are discussed in Chapter 6. The use of gene therapy to stimulate the growth of new blood vessels (therapeutic angiogenesis) represents one of the more novel applications of this technology, and yet it is the area which has produced some of the most compelling clinical evidence to date in support of the technique. In addition to cardiovascular disease, the chapter also considers other therapeutic areas in which gene therapy may have potential, including the treatment of neurological disorders (such as Parkinson's and Alzheimer's disease, motor neuron disease and epilepsy), asthma, diabetes and rheumatoid arthritis. As new gene functions are identified, further opportunities are likely to become apparent.

The potential market for gene therapy is examined in Chapter 7. Given that a gene therapy product has yet to be launched, it is difficult to put a meaningful figure on the total value of the market; estimates put forward by various sources are analysed in terms of their likelihood of being achieved. Projections are given as to when the first products are likely to reach the market and what these are likely to be. In-depth analyses are then provided of potential markets for gene therapy products on an indication-by-indication basis.

Chapter 8 covers the legal/regulatory environment in which gene therapy operates and looks at three main areas: patents, the regulatory system and ethical issues. The key gene therapy patents issued to date are examined, together with the disputes which some of these have already provoked. With over 75% of gene therapy clinical trials being conducted in the US, this is the main focus for review of the regulation of gene therapy; brief overviews are also provided of the regulatory systems in Europe and Japan. Ethical issues are discussed primarily in terms of public perceptions of gene therapy.

The strategic issues faced by companies operating in the field are discussed in Chapter 9. The development of the industry is reviewed and the various approaches to gene therapy taken by different companies are examined. (The gene therapy activities of the main companies - including the involvement of the pharmaceutical majors - are summarised in table form.) The risks attached to the development of a gene therapy product are analysed, together with the rewards to be gained when a product finally reaches the market.

Finally, Chapter 10 provides profiles of some of the leading companies in this area. Of the 16 companies profiled, 12 are dedicated gene therapy companies, three are pharmaceutical companies and one is a biotechnology company. For each company, up-to-date financial information is given, together with details of major gene therapy research projects and collaborations with other companies and research institutes.

A variety of information resources were used in preparing the report. At PJB Publications, the two main sources used were Scrip World Pharmaceutical News and Pharmaprojects; other Scrip reports on specialised subjects such as AIDS were also consulted (details of which are outlined in the references section). Additional technical background information was obtained from a review of the current literature. Several analysts' reports were consulted. In addition, all companies in the field were contacted for information on their gene therapy activities.

Scrip's Complete Guide to Gene Therapy

This new, fully updated report is essential for everyone currently involved or interested in gene therapy. It provides an overview of the current status of gene therapy, concentrating particularly on therapeutic applications and commercial issues. It also closely examines potential markets and projects future product sales.

Scrip's Complete Guide to Gene Therapy will enable you to: identify which applications offer the greatest investment potential; assess which products are likely to reach the market first; understand the main technical hurdles restricting the development of gene therapy and access invaluable competitor information.

The following areas are reviewed: AIDS, Alzheimer's disease, angiogenesis, asthma, cancer, cardiovascular disease, cystic fibrosis, epilepsy, monogenic disorders, Parkinson's disease and rheumatoid arthritis.

PUBLISHED: JULY 1998
REF: BS969E
PAGES: 205
PRICE: £445/$940/¥107,000