English - Medicines for Mankind
Transcription
English - Medicines for Mankind
2361_EFPIA_brochure 10/16/06 3:56 PM Page 1 VOLUME 2 Medicines for Mankind TODAY’S RESEARCH, TOMORROW’S CURES european federation of pharmaceutical industries and associations 2361_EFPIA_brochure 10/16/06 3:56 PM Page 2 Acknowledgments This publication has been prepared by Dr. Robert Geursen. It is inspired by ABPI’s “A to Z of British Medicines Research”. We are grateful to its author Dr. Stephen Bartlett and its editor, Bill Kirkness for their permission to use this material. Special thanks go to the editing Board: Bill Kirkness and Dr. Jean-Marie Muschart (HCS), responsible for scientific and medical advice, and Marie-Claire Pickaert, coordinator. Thanks also to the members of EFPIA’s Research Directors Group, chaired by Prof. Trevor Jones, and members of the specialised groups within EFPIA: European Vaccines Manufacturers (EVM), chaired by Didier Hoch and Emerging Biopharmaceutical Enterprises (EBE), chaired by Peter Heinrich. We particularly appreciate their contribution to the sections dedicated to ongoing research and development in the different disease areas. We are also grateful to Kurt Vandenberghe, Cabinet Commissioner Busquin, and Dr. Robert Sebbag for their support to this publication. For the production of the photographs, we would like to express our appreciation to: Lander Loeckx (photography), Dr. Roland Reynaert (Groupe Médical Cinquantenaire, Brussels), Prof. José Ramet (AZ VUB, Brussels), Geert Gesquiere (Zoniën Seniorencentrum, Tervuren), Irma Janssens (Koninklijk Atheneum Tervuren), Kwikzilver & Ingrid Coppé (casting), Koen de Visscher (production). We also thank all the people in various locations who kindly consented to be photographed. For their skillful proof-reading and for their judicious input, we would like to thank Wills Hughes-Wilson and Piers Alin. And for her support in secretarial tasks, many thanks go to Fabienne Muylle. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 3 European Research Policy and the European Research Area (ERA) Philippe Busquin, Commissioner for Research Science is, and always has been, one of the biggest and most exciting adventures of the human spirit. It is the product of a creativity which must not disappear in the Europe of the 21s t century. What needs to be done to ensure it not only survives but prospers? The importance of research Research plays a central role in the implementation of public policy and is also at the heart of the policy-making process. In areas such as health and medicine, policy options and decisions must be based on solid scientific knowledge and a full and proper understanding of the economic and social aspects surrounding the problems in question. Basic research is now carried out within various institutional frameworks: universities, research institutes, companies and consortia of each. In some cases it can be translated fairly rapidly into concrete applications. This has been the case, for example, with breakthroughs in molecular biology and immunology in the field of health. It can also give rise to unexpected applications years later in fields somewhat removed from the ones they started out in. F O R M A N K I N D The European financial market has yet to discover fully the economic value of investment in knowledge. While it has now started to increase, the volume of risk capital being channelled into innovation is still limited in Europe. Investment of this type of capital in high tech sectors and in the creation of companies is much lower than in the United States. By and large, the overall climate for research in Europe needs to be improved. M E D I C I N E S The importance of investment in research Private investment by international and multinational concerns in Europe has been maintained at a high level and even increased. Because of the globalisation of the economy, together with the industrial and technological alliances and mergers and acquisitions that are mushrooming in every sector, these companies are developing research and development strategies on an international scale. For some of the private sector, research is thus increasingly at European and even world level. However, the global increase in expenditure on research and development in the private sector is less than it has been amongst its main competitors in the United States and Asia, due to the somewhat limited research effort of medium sized businesses and small enterprises. Europe would therefore be quite wrong to reduce its investment in this area. 3 2361_EFPIA_brochure 10/16/06 3:56 PM Page 4 Improving the climate for research The Treaty provides the European Union with a legal basis for measures to help support European cooperation in research and technological development. However, the principal reference framework for research activities in Europe is national. Funding of the various initiatives of European, Community or intergovernmental scientific and technological cooperation does not exceed 17% of the total public expenditure on European research. The principal instrument that has been used so far in Europe is the European Union’s Framework Programme for research. In financial terms, however, it has accounted for only about 5.4% of the total public effort and on its own it cannot improve European research effort. This fragmentation, isolation and compartmentalisation of national research efforts and systems and the disparity of regulatory and administrative mechanisms only serve to compound the impact of lower global investment in knowledge. © European Communities, 1995-2003 A sound research policy for Europe must achieve significant decompartmentalisation and better integration of Europe’s scientific and technological area, including the health and medical fields, as an indispensable condition for invigorating research in Europe. It is necessary to go beyond the current static structure of “15+1” towards a more dynamic configuration. This has to be based on a more coherent approach involving measures taken at different levels: by the Member States at national level, by the European Union with the Framework Programme and other possible instruments, and by intergovernmental cooperation organisations. Moreover, as stated at the Barcelona summit of European Heads of State and Government, investment in research must be a priority, by achieving 3% of EU GDP by the year 2010, in order to become the most competitive and dynamic knowledge-based economy in the world. The European Research Area The idea has therefore been to create a European Research Area (ERA)1 , embracing the following aspects: M E D I C I N E S F O R M A N K I N D • The networking of existing centres of excellence in Europe and creation of virtual centres through the use of new interactive communication tools 4 • The development of a common approach to the needs and means of financing large research facilities in Europe • The achievement of a more coherent implementation of national and European research activities and closer relations between the various organisations of scientific and technological cooperation in Europe • Making better use of instruments and resources to encourage investment in research and innovation: systems of indirect aid (within the Community rules on State aid), patents and risk capital 2361_EFPIA_brochure 10/16/06 3:56 PM Page 5 • The establishment of a common system of scientific and technical reference for the implementation of policies • The achievement of more abundant and more mobile human resources • The achievement of greater mobility of researchers and the introduction of a European dimension to scientific careers • Giving more prominence to the place and role of women in research • The stimulation of young people’s taste for research and careers in science • The encouragement of greater European cohesion in research based on the best experiences of knowledge transfer at regional and local levels and on the role of the regions in the European research efforts • The bringing together of the scientific communities, companies and researchers of Western and Eastern Europe • The improvement of the attractiveness of Europe for researchers from the rest of the world • The promotion of common social and ethical values in scientific and technological matters The relevance of European research to the medical sector The field of biotechnology offers enormous possibilities for new medicines for mankind. This is driven by the huge need in global healthcare for novel and innovative approaches to meet the needs of ageing populations, population subgroups and poor countries. Already there are a growing number of traditional as well as new drugs and medical services available. Developments that are expected to loom large in the near future include personalised and preventative medicinal interventions based on genetic predisposition (pharmacogenomics and pharmacogenetics). These should result in better targeted screening, diagnoses and treatments. Stem cell research and gene therapy offer the prospect of replacement tissues and organs to treat degenerative diseases and injuries resulting from stroke, neurodegenerative diseases, burns and spinal-cord injuries. The European Commission therefore intends to restore European leadership in life sciences and biotechnology. The aims are to translate knowledge into new products and services that respond to societal needs and encourage the development of new research partnerships that build on promising technologies and opportunities as a basis for future progress. The 6th Community Framework Programme for Research, Technological Development and Demonstration activities (2002-2006)2 proposes this area, “Life Sciences, Genomics and Biotechnology for Health” - in particular the application of knowledge and technologies in the field of genomics and biotechnology for health - to provide a solid platform for reinforcing R&D capacity in the health sector and help overcome existing fragmentation of research policies and efforts. Its main provisions are as follows: F O R M A N K I N D • Development of new diagnostics; to develop new tests, new tools and non-invasive methods for early diagnosis, monitoring of disease progression and the interpretation of in-vivo data so as to increase the possibilities and effectiveness of existing therapies M E D I C I N E S • Rational and accelerated development of new, safer, faster and more effective drugs including pharmacogenomic approaches, with emphasis on the use and translation of the knowledge and methods derived from genomics into concrete applications for drug design and development 5 2361_EFPIA_brochure 10/16/06 3:56 PM Page 6 • Development of new in vitro and in silico tests to replace animal experimentation, so as to develop alternatives to animal experiments, reduce the number of animals required, or reduce significantly experimental animal suffering • Development and testing of new preventative and therapeutic tools, such as somatic gene and cell therapies (in particular stem cell therapies, for example those for neurological and neuromuscular disorders) and immunotherapies • Innovative research in post-genomics, which has high potential for application, with the objective of using cutting-edge technologies in a multidisciplinary approach to address areas of research that will benefit from the developments resulting from genomics This thematic priority emphasises the importance of innovation and the integration of small and medium-sized enterprises (SMEs) in order to reach the Barcelona goal. Therefore project consortia will need to integrate all relevant competencies to address innovation related aspects, such as technology transfer, intellectual property rights, clinical trials, etc., with a view to ensuring optimal use of the generated knowledge. Research intensive and innovative SMEs play a vital role for exploiting the EU biotechnology and life sciences knowledge base and 15% of the budget of the Sixth Framework Programme is reserved for SME participation. The Commission's research programmes will develop the environment whereby science can have greatest relevance to European citizens and stimulate structural links, within the European Research Area, for a more dynamic interaction between scientists, policy-makers and society at large. Central to this, due account must be taken of ethical and societal concerns, obligations towards future generations and the rest of the world. Research carried out under the Sixth Framework Programme will therefore respect all fundamental ethical principles, including those reflected in the Charter of Fundamental Rights of the European Union and ethicists will have the means to assess continuously the societal relevance and adequacy of their analysis and evaluation. The Future of Research in Europe In order for research to have a viable future in Europe, the European Research Area (ERA) needs to be consolidated and reinvigorated3 . M E D I C I N E S F O R M A N K I N D The general lessons which can be drawn so far are as follows: 6 • As would be expected in view of the nature of the European Research Area initiative, the progress made depends directly on the degree of mobilisation of the Member States on the various topics and their level of involvement in activities relating to them • The fastest progress has been made in areas which are clearly identified and are the subject of clearly defined action at national level • It is also more difficult to make progress because policy areas other than research policy in the strict sense are involved. With regard to the mobility of researchers, for example, the real obstacles to freedom of movement are those relating to social policy (social security and pensions), tax policy, etc. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 7 • Very often, activities which are planned or in progress are linked to the EU's Framework Programme for Research and are dependent on funding from it.This trend is likely to increase further with the Sixth Framework Programme which devotes more resources to research. However, the European Research Area project cannot be seen solely in terms of these activities and must by definition create a momentum of its own within a wider framework which draws on separate initiatives All in all, the general objectives for renewal should therefore be: • to achieve a substantial increase in Member State involvement and the level of mobilisation of national activities • to increase the impact of the activities underway • to consolidate the conceptual and policy framework in which the project is being implemented New initiatives are now required to give Europe a stronger public research base and to make it much more attractive for private investment in research and innovation4. Carrying out these actions will allow the European Union to bridge the growing gap in the levels of research investment between Europe and its main trading partners – a gap which is putting at risk our long term innovation, growth and employment potential. The objective is to reach the objective set by the March 2002 Barcelona European Council, to increase the average research investment level from 1.9% of GDP today to 3% of GDP by 2010, of which 2/3 should be funded by the private sector. © European Communities, 1995-2003 F O R M A N K I N D The second set of actions aims at improving considerably public support for research. In order to increase investment in Europe, enterprises need to find here abundant and excellent teams of researchers, strong public research, well articulated with industry, and effective public financial support, including that through fiscal measures. The action plan focuses on ways to improve the career of researchers, to bring public research and industry closer together, and to develop and exploit fully the potential M E D I C I N E S An action plan to strengthen European research A first set of actions aims to support the steps taken by European countries and stakeholders, to ensure that they are mutually consistent and that they form an effective mix of policy measures. This includes a process of co-ordination with and between Member States and acceding countries. It also entails creating a number of “European Technology Platforms”, which will bring together the main stakeholders – research organisations, industry, regulators, user groups, etc. – around key technologies, in order to devise and implement a common strategy for the development, deployment and use of these technologies in Europe. An example under consideration concerns a putative European Technology Platform on medicines aimed at the faster development of new, safer medicines. This will necessarily involve all major stakeholders in the field, such as researchers, industry, clinicians, patient organisations, funding and regulatory agencies, in order to develop a European R&D strategy to speed the availability of innovative medicines and hence reduce costs, while maintaining the highest levels of drug safety and efficacy, for the benefit of European citizens. 7 2361_EFPIA_brochure 10/16/06 3:56 PM Page 8 of European and national public financial instruments. For example, the action plan asks public authorities to eliminate by 2005 the current rules and practices, attached to many public funding schemes, which prevent trans-European cooperation and technology transfer and thus reduce considerably the research and innovation opportunities available to the beneficiaries. A third set of actions addresses the necessary increase in the levels of public funding for research. Given the current economic downturn, it is all the more important to ensure that budgetary policies favour investments that will lead to higher sustainable growth in the future, among which research is a strong priority. Actions focus on encouraging and monitoring the redirection of public budgets, and on making full use of the possibilities for public support to industry offered by State aid rules and public procurement rules. For example, the action plan proposes to clarify and improve awareness of the types of public support that public authorities can use with no distortion to competition. M E D I C I N E S F O R 8 © European Communities, 1995-2003 M A N K I N D Finally, a fourth set of actions aims to improve the environment of research and technological innovation in Europe: intellectual property protection, regulation of product markets and related standards, competition rules, financial markets, the fiscal environment, and the treatment of research in companies’ management and reporting practices. For example, in order to provide adequate and necessary financing for initiatives in biotechnology, the European Investment Bank Board of Governors - the EU Ministers of Finance - at its annual meeting in June 2000, endorsed the Bank's “Innovation 2000 Initiative”, which is intended to support investments promoting areas including biotechnology as suitable targets for investment. A lending programme of e 12 to 15 billion over the three-year period beginning in June 2000 was dedicated to this purpose. The Board of Governors also decided to double the EIB's venture capital operations for small and medium sized companies to e 2 billion. In addition, in 1997, the European Commission and the European Association of Security Dealers (EASD) has set up a "Biotechnology and Finance" forum, which aims to develop links between the scientific and industrial community on the one hand and the financial community on the other, thereby promoting the development of the European biotechnology industry. The forum has identified nanobiotechnology and environmental biotechnology as key areas for investment in the future, with particular attention being paid to developing links with candidate Member Countries. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 9 The action plan also sets the objective that every student in science, engineering and business should receive at least basic training about intellectual property and technology transfer. Issues of relevance to the medical field include a proposal for a Regulation on the Community Patent, which, after review by the European Parliament, is currently being discussed in Council, as well as Directive 98/44/EC, which has now been adopted by the Parliament and the Council. This will facilitate, and make less expensive, the legal protection required for biotechnological inventions. The action plan marks the start of a process. Progress will be monitored and the Commission and Council will give further orientations in the future, if appropriate, to keep the Union on track. However, there is little time to succeed - the gap is still growing rapidly between Europe and its major trading partners. Implementation must start immediately at all levels, and it must be driven with a clear vision that what is at stake is the success or failure of Europe’s ambition to become the most vibrant place for innovation-driven growth and employment creation. –––––––––––––––––––––––––––– 1 Communication from the Commission to the Council, the European Parliament, the Economic and Social Committee and the Committee of the Regions, “Towards a European Research Area” COM 2000 (6) 2 Decision No 1513/2002/EC of the European Parliament and of the Council of 27 June 2002 concerning the sixth framework programme of the European Community for research, technological development and demonstration activities, contributing to the creation of the European Research Area and to innovation (2002 to 2006) 3 Communication from the Commission: The European Research Area: Providing New Momentum – Strengthening – Reorienting – Opening up New Perspectives, COM(2002) 565 final 4 Communication from the Commission: Investing in Research – an action plan for Europe COM(2003) 226 final M E D I C I N E S F O R M A N K I N D 9 2361_EFPIA_brochure 10/16/06 3:56 PM Page 10 MEDICINES FOR MANKIND 11 Allergy 14 Atherosclerosis 16 Attention Deficit Syndrome 18 Benign Prostatic Hyperplasia 20 Contraception 22 Glaucoma 24 Gout 26 Growth Problems 28 Haemophilia 30 Infections by Herpes Group Viruses 32 Infertility 34 Inflammatory Bowel Disease 38 Influenza 40 Kidney Disease 42 Malaria 44 Motor Neurone Disease 46 Obesity 48 Osteoarthritis 50 Pain 54 Peripheral Vascular Disease 56 Psoriasis 58 Thrombosis 62 Tuberculosis 64 Urinary Incontinence 66 Viral Hepatitis 2361_EFPIA_brochure 10/16/06 3:56 PM Page 11 Allergy What is allergy? Allergy is a hypersensitivity of the body’s immune system in response to exposure to specific substances or antigens, such as dust, pollen, saliva, animal skin, feathers, hair or urine, insect stings, components of foods, ingredients of medicines, contact with metals such as nickel, or exposure to plants such as poison ivy. The allergic reaction occurs on second contact with an antigen and can result immediately or may be delayed. In most cases, the cause of the allergy is otherwise harmless to the body. The term allergy was first coined in 1906 by the Viennese paediatrician Clemens von Pirquet (from the Greek nouns “allos” meaning altered state and “ergon” meaning reaction or reactivity). He had observed altered reactions in his patients, which he put down to the influence of external factors on the immune system. The most severe form of allergy is anaphylactic shock, which is a medical emergency. Allergy is when the body’s immune system overreacts when exposed to substances such as dust, pollen, animal hair or metals. Millions of people across Europe are affected. The pharmaceutical industry is researching the complex nature of allergy in order to develop medicines to relieve the misery it causes. Primary causes of allergies related to dust are excretions of dust mites. Tree and grass pollens are the most common cause of hay fever (seasonal allergic rhinitis). They may also cause asthma and bronchitis. Allergies to pets often cause inflammation of the lining of the eyes (conjunctivitis) and reactions of the nose (rhinitis). Skin contact with pet-derived allergens may lead to itching and hives. Medicines like analgesics and antibiotics can cause an allergy. Allergic reactions to insect stings can be very severe, including dizziness, massive swelling of the joints, inability to breathe or speak, fainting and, in rare cases, death. Eczema, or atopic dermatitis as it is sometimes called, occurs in individuals who are sensitive to allergens in the environment which are harmless to others. In atopy, which is thought to be a hereditary condition, there is an excessive reaction by the immune system producing inflamed, irritated and sore skin. M E D I C I N E S F O R M A N K I N D 11 2361_EFPIA_brochure 10/16/06 3:56 PM Page 12 Who does allergy affect? In Europe, disorders associated with allergy affect more than 25 million people, with a steady increase in prevalence. Up to 15 per cent of all children of school age have a type of eczema, along with about eight per cent of the adult population. In identical twins, if one twin suffers from atopic eczema, the likelihood of the other twin also developing the disease is around 75 per cent. In non-identical twins, the likelihood is 30 per cent. It must be stressed, however, that eczema is a highly individual condition, which is why it is so difficult to find a “cure-all”. Present treatments: Administering increasing quantities of allergens in sensitised patients was established in the first half of the 20 t h century. “Vaccination” with different antigens has been subsequently used to desensitise patients with allergic rhinitis, conjunctivitis, asthma or insect-sting allergy. In the past 20 years, recombinant DNA technology has provided the tools for large scale production of well-defined purified allergens. Until very recently there was no clear understanding of the underlying mechanisms of action after “vaccination”. It is now widely held that the changes which lead to clinical improvement are mediated by changes in T-lymphocyte function. Common medicines used to treat allergic reactions are analgesics to reduce the pain, anticholinergic medicines and adrenaline as decongestants, and antihistamines to alleviate or stop histamine-induced inflammatory responses. Beta-agonists are widely used as bronchodilators in the treatment of asthma. In more severe cases, corticosteroids are used either topically or systemically. The shift to inhaled corticosteroids has dramatically improved their safety profile. Furthermore, patients may be treated with mast-cell stabilising agents. Treatment with theophylline plays a role in extrinsic asthma. While all of these medicines alone or in combination are effective in often providing symptomatic relief, they do not address the underlying disorder. In atopic eczema, apart from ways of minimising environmental allergens commonly found in the home, treatments include wet-wrap dressings in acute cases, emollients to maintain skin hydration as well as oral histamines and topical steroids to reduce inflammation. In severe cases, oral steroids are also prescribed. If a baby’s parents, brothers or sisters have atopic allergies, it is recommended that highly allergenic foods be avoided in the first months of life. Breast feeding has been shown to protect from or delay the development of the disease. Only recently, the introduction of topical immunomodulators applied as ointments or creams represented the first new treatment options for childhood eczema in 40 years. M E D I C I N E S F O R M A N K I N D What’s in the development pipeline? The specific receptor responsible for the physiological role of histamine was identified in the 1960s. The discovery of the H1 receptor was followed by the discoveries in the two subsequent decades of the H2 and H3 receptor. In 2000, researchers were able to demonstrate the existence of a fourth member of this receptor family. One possible role for the H4 receptor is in the histamine-induced chemotaxis of mast cells. A series of histamine H4 receptors are being investigated for potential application in the treatment of allergic disorders, including asthma. 12 New data on the role of interleukin-4 and interleukin-5 which either sustain inflammation in the tissue or are required for the generation of immunoglobulin E have led to the development of soluble interleukin-4 receptor and monoclonal antibodies against interleukin-5 and an antibody toward immunoglobulin E. Research has also led to an appreciation of the crucial role played by the Th2 subset of T-cells and their corresponding cytokines in allergic diseases. The recent introduction of leukotriene inhibitors represents the first new class of medicines for the treatment of asthma in twenty years. Another strategy is to prevent migration of effector cells, such as mast cells, eosinophilic white blood cells and Th2 cells, via chemokine receptor antagonism with suitable small molecules. The chemokine receptors CCR3, CCR4, and CCR8 are 2361_EFPIA_brochure 10/16/06 3:56 PM Page 13 preferentially expressed by these cells and therefore represent promising therapeutic targets. Antagonists can be antibodies, antisense, and protein-based inhibitors. To reduce the symptoms of perennial allergic rhinitis, research is also focusing on purine receptor P2Y2 agonists which are administered intranasally. The topical immunomodulators available so far are still restricted to use in children over two years of age. As most cases of eczema are diagnosed before the age of two, much research is undertaken regarding the safety of the compounds in infants. Also under development are ointment formulations for all stages of allergic disorders, and it is hoped to have a tablet formulation available for moderate to severe eczema in 2006. For childhood eczema (atopic dermatitis) and asthma, mycobacterium vaccaederived products are being tested in Phase 2. They are given as intradermal injections which should stimulate the immune system. The longer-term future: In allergy, the processes that lead to production of excessive allergen-specific immunoglobulin E production and the activation of effector cells are highly complex and heterogeneous. An optimal treatment strategy would permanently modify the underlying inflammatory process with long-term alleviation of symptoms. The principal challenge for approaches to block immunoglobulin E is to inhibit IgE activity without inducing mast cell degranulation. Meanwhile, non-anaphylactogenic monoclonal antibodies have been developed. New strategies for immunotherapeutic “vaccination” include methods of modifying allergen recognition by the patient’s immune system. Such techniques will include allergen modification, immunisation against allergen genes, controlled immunostimulation, and peptide immunotherapy. Non-allergen specific targets including receptor, cytokine and immunoglobulin E targets will most probably complement specific immunotherapy. (A) Scheme showing the stages through which a person may become sensitised in allergic or contact dermatitis. recruitment of various inflammatory cells into skin (C) epidermis CKs Langerhans cell cell division dermis blood vessel F O R (B) T-cells M E D I C I N E S lymph node M A N K I N D 13 2361_EFPIA_brochure 10/16/06 3:56 PM Page 14 Atherosclerosis What is atherosclerosis? Sometimes called atheroma or arteriosclerosis, this is a degeneration of the arterial wall characterised in its early stages by fatty deposits (plaques) on which blood clots can form (FIGURE 1) and later by thickening of the walls of the arteries and restricted blood flow. Plaques in the coronary artery will lead to the dysfunction of the lining of the arteries and predispose people to angina pains and heart attack, while plaques in the neck and head increases the risk of cerebrovascular disease like pre-senile dementia and stroke. Plaques may also affect the limbs and cause peripheral vascular disease. Plaques are of concern because they increase resistance to blood flow, forcing the heart to work harder, contributing to raised blood pressure and heart failure. They also reduce the delivery of oxygen to vital organs, thus precipitating serious circulation problems, and act as sites for blood clots which may detach and cause acute blockage. Plaque formation starts very early in life. Signs of it (called ‘fatty streaks’) are found even in the main arteries of three-year-olds, and 77 per cent of soldiers killed in battle at an average age of 22 had extensive plaques. So it would appear that plaques occur in all of us, but it is the degree and rate of formation that are important. Various theories exist to explain why plaques form. One theory presumes that it is a response to injury to the vessel wall by excess cholesterol, chemicals in cigarette smoke, raised blood pressure or diabetes. Certainly, a close correlation exists between these factors, age and the percentage of artery wall covered by raised plaques. M E D I C I N E S F O R M A N K I N D Who does atherosclerosis affect? The blockage of blood vessels by plaques or blood clots is a major cause of illness and death in the European Union, where cardiovascular disease accounts for around 40 per cent of deaths. 14 Present treatments: A healthy lifestyle will help control plaque formation – as will the treatment of related conditions. Cholesterol and triglyceride levels can often be controlled by dietary measures, but some people have difficulty adhering to such diets, or have an inherited tendency towards high levels of blood cholesterol, and require active therapy. The main classes of medication to control cholesterol level are bile acid sequestrants, fibrates and statins. Bile acid sequestrants have been available for almost 30 years. They work by binding to and removing bile acids from the gut during digestion. As the body synthesises more bile acids, cholesterol in the blood is consumed and a fall of 15 to 30 per cent may be achieved. However, absorption of the fat-soluble vitamins A, D, and K is also reduced as a result and circulating levels of many other medicines given at the same time can be affected, which may lead to dosage problems. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 15 Fibrates appear to act by modulating the lipid balance in the blood. Over a period of time, a five to 15 per cent reduction in cholesterol level has been demonstrated. Several are available and are used to treat at-risk patients whose raised lipid levels are resistant to diet and other medication. The most prominent class of treatments is the statins. These block a key step in cholesterol synthesis, reducing levels by 30 per cent or more. As experience with these medicines is built up, it is becoming clear that they may confer many clinically significant benefits beyond their primary indications. Recent trials suggest that these compounds may be able to reduce the risks of presenile dementia, strokes or a second heart attack. Registration still needs to be granted for these new expanded indications in cardiovascular disease. What’s in the development pipeline? Research into statins continues and several further compounds have been filed with the authorities for registration. The newer molecules have been shown in several comparative trials to produce greater reductions in low density lipoprotein or LDL-cholesterol than the currently approved medicines. Inhibitors of the enzyme acyl-CoA: cholesterol acyltransferase (ACAT) are a new type of anti-atherosclerotic therapy currently in development. They have been developed for the prevention of progression of atherosclerosis, and show a rapid reduction in triglycerides and low-density lipoprotein cholesterol. In an animal model, a combination of a statin and the new molecule has been shown to cause actual regression of atherosclerotic plaques. Trials with other ACAT inhibitors are less far advanced. Atherosclerosis is the process where fatty deposits in the arteries gradually cause them to become blocked. This leads to heart attacks, strokes, dementia and other serious conditions. Pharmaceutical research has led to medicines that reduce blood lipids (fats). These have saved the lives of millions. It is expected that further research will lead to even more effective treatments. Another molecule inhibiting cholesterol uptake from both dietary and biliary sources in the intestine was approved in the US and Europe at the end of 2002. It is the first in a new class of treatment for high cholesterol for 15 years. The new compound has yet to be filed with the authorities in a fixed combiendothelium nation with a statin as an adjunct to diet in primary hypercholesmiddle layer of artery wall terolaemia patients. This combination treatment should mean that patients will have to take fewer pills. inner layer of artery wall A new approach is a compound that prevents the splitting from LDL of a substance that is thought to trigger the inflammatory process in the early stages of plaque formation. High-density lipoprotein (HDL) is believed to protect against arteriosclerosis by removing cholesterol from the vessel walls and transporting it to the liver for elimination. The major protein component of HDL is apolipoprotein A-1. Clinical trials are in phase 2, as is a complex of a 22-amino acid peptide and lipids which mimics the biological properties of ApoA-1. Diseased artery with a plaque forming matrix monocytes attracted to and starting to stick onto unhealthy endothelium pool of fat plaque release of nitric oxide which relaxes muscle cells, dilating the artery Diagrammatic cross section of a healthy and an atherosclerotic artery F O R M A N K I N D The longer-term future: The progress in understanding of the process of atherosclerosis has stimulated the development of new agents that act directly on components of plaque other than lipids. ACAT inhibitors are one example of compounds that act directly on the sequence of events in plaque formation and the hope for the future would be to design medications that not only slow the progress of atherosclerosis, but maybe even cause its reversal. blood clot forming over a crack in the artery lining M E D I C I N E S In addition, research is exploring so-called ‘PPAR modulators’. Another new class of compound, inhibitors of microsomal triglyceride transport protein (MTP), is also being investigated in clinical trials of Phase 2. Recently, researchers reported on a series of orally active compounds with dual action to reduce both LDL and lipoprotein(a), two independent risk factors for cardiovascular disease. Another series of molecules is designed to elevate low levels of HDL which is believed to lead to the halting of the atherosclerotic process. muscle cells migrate to inner layer 15 2361_EFPIA_brochure 10/16/06 3:56 PM Page 16 Attention Deficit Syndrome What is attention deficit syndrome? Attention deficit syndrome (ADS) is the most common psychiatric disorder of childhood. It is characterised by early onset in life (studies now indicate that ADS can be diagnosed in children by the age of four) and a combination of overactive, poorly modulated behaviour and lack of concentration on tasks. It is widely thought that abnormalities in the body’s system play a crucial role in the development of ADS, but knowledge of specific causes is lacking at present. M E D I C I N E S F O R M A N K I N D ADS can affect a child’s education, development and self-esteem. Patients suffer from inattention, hyperactivity, impulsivity, underachievement in school or show behaviour problems, such as impulsive flouting of social rules. The disease is defined and diagnosed in behavioural terms. Its assessment requires evidence directly obtained from parents, caregivers and from classroom teachers regarding the core symptoms of the disorder. 16 Who does attention deficit syndrome affect? The disease is six to nine times more frequent in boys between six and 12 years of age than in girls, and affects both school-aged children and adults. In adults, the disorder seems to be equally distributed between women and men. Adults’ complications include substance abuse, high-risk and anti-social behaviour and accidents, but there are problems of diagnosis, because a clinical definition of the adult disease has not been agreed. ADS is estimated to be present in approximately 1.5 per cent of the European population, with prevalence increasing. It is not known whether this reflects a real increase in ADS or a better ability to recognise it. Evidence is increasing that genetic factors play an important role in ADS. The relatives of both boys and girls with ADS have much higher rates of the disease. In a twin study, 90 per cent of children with ADS shared it with their twin. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 17 Present treatments: Most experts and opinion leaders promote a multimodal approach to therapy for children with ADS. This includes behaviour modification, medication, psychotherapeutic and school-based approaches. Teaching children to be achievers in school is an important part of their treatment. Regarding treatment with medicines, psychostimulants have emerged as the treatment of choice for ADS as the result of controlled clinical trials. Such trials have established these medicines as effective in about 70 per cent of patients. Short-acting stimulants have a generally rapid onset of action and duration of action is about four hours. Long-acting stimulants have a slower onset of action and are used in combination with short-acting medicines. Furthermore, antidepressants with norepinephrine effects are used as independent treatment or as adjunct to stimulant medication. Tricyclic antidepressants are a common addition to treatment to improve the patient’s sleep and appetite. If depression is involved, therapy with any antidepressant is considered. Other medications used in combination with these include alpha2-blockers, to modulate emotions and behaviours that can be initiated by stimulants. Beta-blockers and low doses of certain anticonvulsive medications also can be of help. If the patient presents extreme and defiant behaviour, therapy with tranquilisers should be considered. Attention Deficit Syndrome (ADS) is the most common psychiatric disorder in children. It can seriously affect a child’s education and development. Research by the pharmaceutical industry is beginning to develop new and better medicines to improve the lives of the children and those who care for them. What’s in the development pipeline? Most recent evidence indicates that ADS has a central nervous system basis as do all normal and abnormal behaviours, thoughts and emotions. Latest research findings suggest that ADS has to do with a disorder of the right side of the brain. When applying imaging techniques in patients with ADS, it was found that the prefrontal cortex (thought to regulate the brain’s ability to inhibit responses) was less active when compared to a control group. It is also thought that areas in the centre of the brain which speed up or stop orders stemming from the prefrontal cortex may have functional deficits in ADS patients and may impair a person’s ability to control their actions, resulting in the impulsive behaviour typical of patients with ADS. The neurotransmitter dopamine is under particular scrutiny. Studies have suggested that dopamine levels are abnormal in ADS, with its effects being inhibited in the prefrontal lobes of the brain. Deficiencies of the chemical transmitter norepinephrine in the brain may also be critical in ADS. Clinical trials with a blocker of the transport system for norepinephrine are underway. Furthermore, early studies with a substance which is used to treat patients with narcolepsy suggest that it may be useful for adults and children with ADS. Also, medicines known as central anticholinesterases are being investigated for the disorder. Other findings suggest that nicotine improves ADS symptoms. Such experiences should not encourage anyone to smoke, but they show new ways of treating adult patients with smoking cessation patches. M E D I C I N E S F O R The longer-term future: Research and development of medicines to treat ADS is still at its very beginning. It was only in 1998 that ADS was agreed to be a recognised psychological condition, even though its definition has not been fully pinned down. As 60 per cent of children with ADS are still symptomatic as young adults and thus considered chronic, there is a need for new and better medicines, including formulations to improve patient compliance. M A N K I N D 17 2361_EFPIA_brochure 10/16/06 3:56 PM Page 18 Benign Prostatic Hyperplasia What is benign prostatic hyperplasia? Benign prostatic hyperplasia (BPH) is an enlargement of more than 30cc in volume of the prostate gland, constricting the urethra and making the passing of urine difficult. This increases the risk of urinary retention and of the onset of chronic prostatitis due to bacterial infection, mainly with Escherichia coli, Enterococcus faecalis and Staphylococcus epidermidis. The development of benign prostatic hyperplasia is linked to an age-related decrease in male hormones. Who does BPH affect? In Europe, BPH is the commonest cause of urination difficulties in men. Some prostate enlargement is apparent in 75 per cent of men over 50 and clinical signs may be apparent in 30 per cent of individuals in their 60s, rising to almost 100 per cent in those over 90 years of age. Bacterial prostatitis accounts for an estimated two million outpatient visits yearly. M E D I C I N E S F O R M A N K I N D Present treatments: Acute urinary retention often needs catheterisation. Under normal circumstances the catheter rests in place for some days. If this is unsuccessful, prostate surgery may be necessary. While surgical intervention may ultimately be required, useful medicines are available which provide symptomatic relief for BPH. The major class of medicines used for this purpose is the alpha-adrenoreceptor antagonists, which block receptors in the muscles that control emptying of the bladder, improving urine flow. Selective alphaadrenoreceptor blockers have a rapid onset of action and are indicated for symptomatic therapy. They are generally well tolerated, although some may cause dizziness or interfere with blood pressure control. 18 Relieving the symptoms, though, does not deal with an enlarging prostate. For this purpose, a few years ago, a first compound was introduced that inhibits type 2 of the enzyme 5-alpha-reductase. The enzyme converts testosterone – the male sex hormone – into the more potent dihydrotestosterone (DHT) which induces prostate enlargement. Inhibiting this enzyme reduces DHT formation and, as a result, shrinks the enlarged prostate gland. Six months or more of usage is, however, often necessary before its full effectiveness can be judged. In March 2003, a second compound of 5-alpha-reductase inhibitor was approved in Europe, which inhibits both types 1 and 2 of the enzyme, giving a particularly marked suppression of DHT formation. The type 2 isoenzyme is the dominant form of 5-alphareductase, type 1 accounts for 15 per cent of the concentration in the gland. Bacterial prostatitis is treated with antibiotic medicines. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 19 What’s in the development pipeline? In spring 2003, results of a large trial with a 5-alpha reductase inhibitor and alphablocker combination therapy were presented. The investigators had enrolled men at increased risk of disease progression. It could be shown that the combination was more effective than either medicine alone in relieving symptoms and reducing the risk of disease progression, such as acute urinary retention and BPH-related surgery. A further clinical trial with another combination of these two classes of medicines started in late 2003. Another alternative is offered by a plant-derived extract which is being developed in a Phase 3 trial. It has been shown that this preparation inhibits cellular proliferation and induces apoptosis (programmed cell death) in the tissue of the prostate gland, but its mechanism of action is not yet completely understood. Development of more specific alpha-adrenoreceptor blockers, which show a particularly high specificity of binding, continues and clinical research on several compounds of this class is underway. Benign Prostatic Hyperplasia (BPH) affects the prostate gland and makes it difficult for elderly men to pass urine. It is very common. Research is continuing to understand the causes of BPH and to develop medicines to help relieve this distressing condition. Further clinical research with 5-alpha-reductase inhibitors is concentrating on the prevention of prostate cancer. Enrolment of patients at risk of the disease has been started in large Phase 3 studies (with elevated prostate specific antigen levels and who are biopsy-negative within six months of inclusion). These investigations will take at least four years. The longer-term future: Further research into the biology of the prostate and its growth regulation, as well as the development of more uroselective and potent medications, are likely to bring further improvements in the treatment of benign prostatic hyperplasia – a condition that is likely to become even more common with the ‘greying’ of Europe’s male population over the next two decades. Adrenal gland Kidney Main area of prostatic glands where tumours often begin Left and right ejaculatory ducts from testes Spine Ureter Ductus deferens Turned back capsule of prostate Bladder Rectum back passage Capsule Testis Urethra Prostate gland Urethra running through prostate Male anatomy showing the location and structure of the prostate gland M A N K I N D Scrotal sac F O R Penis M E D I C I N E S Area of mucus glands 19 2361_EFPIA_brochure 10/16/06 3:56 PM Page 20 Contraception What is contraception? Contraception is the prevention of conception by physical, behavioural, or medicinal means. Which is the target group for contraception? All sexually active women between the ages of 13 and 50 share some risk of unwanted pregnancy. As the average age of marriage goes up worldwide, the period of sexual activity before marriage is increasing. Worldwide, the rate of teenage pregnancies is still unsatisfactorily high. According to the report on “World Population Monitoring” by the United Nations Population Division, in the year 2000, the percentage of all births to women under age 20 was 4.1 in Western Europe, 14.7 in Eastern Europe and 13.5 in North America. In the United States, 14 per cent of teenage pregnancies end in miscarriages and 31 per cent end in abortions. As is stated in the UN report, almost all of these teenage pregnancies are unintended. M E D I C I N E S F O R M A N K I N D The Pearl pregnancy rate is the standard rule to determine effectiveness of contraceptive methods. The index measures the number of pregnancies that occur for each contraceptive method when used by 100 women of child-bearing age for one year. Without any contraception, the Pearl index lies in the range of 85, i.e., 85 women will become pregnant during one year. Birth control pills have a Pearl index of less than 0.5. They are considered 99 per cent effective at preventing pregnancy when taken correctly. Today, about 70 million women worldwide rely on oral contraceptives. This represents some two per cent of the world’s female population. 20 Present medicinal treatments: “The pill”, of which there are three main types, is still the most effective: the progestogen-only pill, the ‘combined’ pill containing a fixed dose of an oestrogen and a progestogen (the most widely used type), and phased pills, in which there may be two or three kinds of tablet to be taken sequentially each month. While some concerns linger about the cardiovascular and cancer risks associated with their use, these risks are very low with modern contraceptives and must be balanced against the risks associated with pregnancy and the protection against ovarian and uterine cancer that contraceptives can offer. Recently, a once-weekly contraceptive patch, containing a combination of norelgestromin and ethinylestradiol, has become available in Europe. The patch delivers a constant stream of the active ingredients to the blood. It is worn for one week and replaced on the same day for three consecutive weeks while the fourth week is patchfree. Better compliance is considered to be the advantage of this new form of delivery. 2361_EFPIA_brochure 10/16/06 3:56 PM Page 21 What’s in the development pipeline? There are still advances in the field of female contraception, even though existing medications have reached a high degree of sophistication. New combined contraceptives that contain a progestogen, and a combination pill containing drospirenone have received EU authorisation. Drospirenone (a spironolactone analogue) prevents the water-retention associated with oestrogen that often causes weight gain with contraceptives. Unwanted pregnancy has serious health and social implications all around the world. The skilled research undertaken by the pharmaceutical industry has led to sophisticated medicines to prevent unwanted pregnancy. Yet research continues into contraceptive medications for women and, more recently, men. Other new approaches which are being researched are estradiol compounds. After oral administration, they are broken down by the liver into estradiol and the corresponding salt. Estradiol is the most important estrogen of the human body and could possibly replace the synthetic ethinylestradiol in oral contraceptives completely. The development of new compounds for male contraception is largely untapped. The challenge is to develop a method which is reliable and reversible, and is also acceptable to the user. An implant containing etonorgestrel has reached Phase 3 trials, combined with long-acting (three months) injections of the male sex hormone testosterone. The injection is needed because testosterone taken as a pill is immediately broken down in the liver into ineffective fragments. The compound etonorgestrel shuts down sperm production, while the testosterone is given to compensate for the lower natural levels that are produced. The longer-term future: The ultimate aim is to develop fertility control which has no influence on the body’s hormone production. In this respect, new molecules are being studied which prevent maturation of the ovum. In contrast to sexual hormones, the new compounds do not act via the feedback mechanism of the pituitary gland, but directly on the ovary and/or the uterus. New findings, such as the recent discovery of a key protein that controls sperm mobility may provide a target for the development of a male contraceptive, and increase the chances of being able to control conception safely. A major focus of research will be the post-testicular activity of sperm. Instead of influencing the production of sperm, the aim is to influence its function. In order to achieve this, researchers have had to intervene in the maturing process of sperm, which takes place inside a previously largely unexplored male organ: the epididymis. Another avenue is the fusion of the ovum and the sperm (which takes at least 24 hours) and which is still a process that is little understood and might offer a significant opportunity to prevent conception. Region/sub-region Sub-Saharan Africa 18,1 Northern Africa 9,6 South Central Asia 18,6 Other Asia 5,1 Latin America and the Caribbean M E D I C I N E S 16,5 Northern America 13,5 Eastern Europe 14,7 Other Europe 4,1 F O R Oceania 5,9 5 10 15 Percentage of all births to women under age 20, by region/sub-region 20 M A N K I N D 0 Source: United Nations Population Division, 2000. World Population Monitoring, 2000: Population, Gender and Development. 21 2361_EFPIA_brochure 10/16/06 3:56 PM Page 22 Glaucoma What is glaucoma? Glaucoma is an eye disease in which the optic nerve becomes damaged, leading to a gradual loss of peripheral vision. If untreated, this can lead to tunnel vision and blindness. The cause is raised fluid pressure in the eyeball (called intraocular pressure). The commonest form of glaucoma, primary or chronic open angle glaucoma (COAG), is especially dangerous, as there is usually no indication that anything is wrong until significant and irreversible loss of sight has occurred. M E D I C I N E S F O R M A N K I N D Fluid in the eye is constantly produced by a structure called the ciliary body. About 80 per cent escapes by flowing out through filter tubules called the trabecular meshwork into the canal of Schlemm, the remainder via the wall of the eye (FIGURE 1). Pressure rises if fluid outflow is restricted by pressure from the posterior chamber of the eye or by silting up of the filter tubules. 22 Who does glaucoma affect? Glaucoma affects about 2 per cent of the over 40s in the European Union, increasing with age to seven per cent by the age of 80. Surveys suggest that some 1.5 million people have the disorder, of whom only half have been detected. Genetic predisposition to develop the disease seems to play a role. Primary angle-closure glaucoma is known to have varying prevalence among different ethnic groups, with a particularly high incidence in Asians and Inuit in Canada. For Caucasians, there is a six times greater risk of developing the disorder, if a near relative has it. It is responsible, in whole or in part for 10 to 15 per cent of blindness in the EU. Present treatments: Most people with glaucoma require long-term treatment with medicines to reduce intraocular pressure, usually in the form of eye drops or gel. A laser operation to open 2361_EFPIA_brochure 10/16/06 3:56 PM Page 23 the drainage channels, or surgery to create a new drainage channel through the top of the eyeball may eventually be necessary, but these approaches are not suitable in all cases. Of the medicines developed to reduce intraocular pressure, the carbonic anhydrase inhibitors and the beta-blockers influence pressure by reducing the production of fluid in the eye. By contrast, the ‘miotics’ which stimulate muscarinic receptors in the ciliary muscle, causing the drainage network to relax and open, and prostaglandin analogues act to increase fluid outflow. Another class of medicines, the alpha-2 receptor agonists, acts on nerve endings and both reduces fluid production and increases outflow. What’s in the development pipeline? Recently, fixed-dose combination products with superior efficacy in reducing intraocular pressure have been approved. These include combining a carbonic anhydrase inhibitor with a beta-blocker, or a prostaglandin analogue plus a beta-blocker. Such preparations are simpler to use and it is hoped this will improve long-term compliance. Glaucoma is an eye disease in which fluid pressure in the eye damages the optic nerve. It can lead to blindness. Over the years, many medicines have been developed to reduce the fluid pressure and help take away the fear of blindness. Surgical treatment of glaucoma to create a new drainage channel (trabulectomy) has the potential to lower intraocular pressure on a long-term basis. However, it is often only temporarily successful, due to the blockage of the ducts by fibrosis through the actions of a natural substance known as transforming growth factor beta. There is a monoclonal anti-TGF beta2 antibody in Phase 3 trial to reduce the failure rate of glaucoma drainage surgery. The longer-term future: A much wider range of medicines and surgical options is now available for the treatment of glaucoma but the greatest need in healthcare terms is for increased awareness of the need for screening. Checking for ocular hypertension or open-angle glaucoma is a simple and painless procedure that can easily be done during a routine eye test and is vital for anyone over the age of 40 or with a close relative with this condition. In July 2003, researchers reported to have discovered genes related to the predisposition to primary angle glaucoma. The finding – though still preliminary – may help to pave the way for early genetic testing and diagnosis. Cornea Iris Pathway for aqueous humour Canal of Schlemm Lens Ciliary body Suspensory ligaments human eye showing the route of fluid flow in relation to the structure F O R FIGURE 1: The M E D I C I N E S Ciliary muscle M A N K I N D 23 2361_EFPIA_brochure 10/16/06 3:56 PM Page 24 Gout What is gout? Gout is the clinical manifestation of hyperuricemia (i.e., the inability of the body to sufficiently excrete uric acid) with acute arthritis and/or gouty tophi. In nearly all patients affected, the disease is caused by an isolated defect in excretion from the kidneys of uric acid. Uric acid, a member of the purine family of metabolites, is only slightly soluble in body fluids. Reduced clearance combined with purine-rich food raises blood levels of uric acid to the limit of solubility of monosodium urate so that the compound ends up precipitating in joints and the kidneys, leading to arthritis and kidney stones. Nerve ends in the inflamed area become irritated, causing extreme pain. Monosodium urate deposits tend to occur in the cooler parts of the body such as the joints of fingers and big toe, and the helix of the ear. Who does gout affect? Gout and an inherited predisposition to the disease have been recognised for centuries. Such famous people as Alexander the Great, Charlemagne, Leonardo da Vinci, Isaac Newton, Voltaire and Charles Darwin suffered from the disease. The description of signs and symptoms of gout by the English physician Thomas Sydenham holds as true today as it did in the 17t h century: “The victim goes to bed and sleeps in good health. About two o’ clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. This pain is like that of dislocation…. Then follow chills and shivers and a little fever. The pain, which was at first moderate, becomes more intense…. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room”…. M E D I C I N E S F O R M A N K I N D In central Europe, about 30 per cent of men and three per cent of women suffer from hyperuricemia. Gout rarely occurs in premenopausal women. Patients may go without clinical symptoms for many years. Depending on the duration and extent of the disorder, ten per cent of affected people will develop gout in the joints and arthritis. Acute attacks mostly occur as pain in the big toe, but they can happen at every joint. Patients suffer from chronic gout if they exhibit hyperuricemia and recurrent attacks of gout leading to joint damage, deposits of monosodium urate, kidney stones, or kidney damage. 24 Accelerated death or massive turnover of cells has also been shown to be a cause of temporary hyperuricemia, since upon death the cells’ nucleic acid and soluble purines are converted to uric acid. This is seen, for example, following cancer chemotherapy or radiation, or in psoriasis or haemolytic anaemia. But these patients rarely develop gout. Present treatments: Goals of treatment are to: (i) abort acute attacks; (ii) prevent future attacks; and (iii) treat chronic hyperuricemia. For therapy of acute gout, colchicine (an alkaloid derived from colchicum autumnale or meadow saffron), steroids or non-steroidal anti-inflam- 2361_EFPIA_brochure 10/16/06 3:56 PM Page 25 matory medicines are used. Chronic gout can be avoided by the use of uric acid lowering treatment, e.g. with uricostatic compounds (which belong to the class of xanthin oxidase inhibitors) that block the synthesis of uric acid or with uricosuric molecules which increase the excretion of uric acid via the kidney. Good compliance can be achieved with a combination in low dosage. As virtually all of the purines contained in food are converted to uric acid and excreted, patients with gout should be on a low purine diet, which means, for example, reduced consumption of meat, fish, beans and peas. Non-alcoholic fluid intake of more than 3 litres a day is desirable, in some cases alkalisation of urine with orally given sodium bicarbonate or trisodium citrate may be recommended. Consumption of alcohol should be avoided. Correctly treated patients with gout will have an undisturbed quality of life, will be able to work and have normal life expectancy. What’s in the development pipeline? As dosage of xanthine oxidase inhibitors can be up to 600 mg daily and may be given life-long, investigations are underway with new compounds of that class to reduce daily intake of medicine. Gout causes extreme pain in those affected. It is caused by crystals of uric acid settling in the joints. Its treatment is a pharmaceutical success story. Nowadays, medicines treat it so effectively that patients can have an undisturbed quality of life. In general, research into uricosuric and uricostatic compounds has now become less intensive. Since the 1950s, medicines have been developed, the biochemical basis of purine biosynthetic systems has been elucidated, and in the past several years, some causes of gout have been defined at the molecular level. For their basic research on purine metabolism, Dr. Trudy Elion and Dr. George Hitchins were awarded the Nobel Prize for medicine. Despite these accomplishments, the metabolic and genetic basis for gout in the majority of patients remains unclear. This is due in part to the lack of animal models in which the way the kidneys handle monosodium urate is identical to that in man. Further development of these techniques and of molecular genetics will continue to improve our ability to explain these abnormalities. The longer-term future: Gout can be seen as an area in which the development of new medicines over the past years has been clearly successful in improving outcomes. With the improvements now achievable with the medications currently available, the somewhat slower pace of new development can be taken as a sign of a job well done. Chronic tophaceous deposits in the tissue of both hands of a 49-year-old male patient with chronic gout. Taken from: Deutsches Ärzteblatt, Jg. 100, 44, Sauerlach/Munich. X-ray of the left hand with typical chronic joint changes M E D I C I N E S 2235; Courtesy of Prof. Ursula Gresser, F O R M A N K I N D 25 2361_EFPIA_brochure 10/16/06 3:56 PM Page 26 Growth Problems What are growth problems? Growth problems can be manifested in either growth retardation or excessive growth. However, there are many factors which may affect a child’s growth without meaning the child has a growth disorder. Causes can be environmental factors as well as hereditary factors and prolonged periods of poor health. Growth retardation or failure is mostly caused by inadequate secretion of the human growth hormone, somatotrophin. Without treatment, children with growth hormone deficiency remain small for their age and reach a final height of about 40cm below what would otherwise be expected. The deficiency may be present at birth, or it may begin at any time during infancy or childhood. Cases also include children with Turner syndrome, with chronic renal failure and Prader-Willi syndrome. M E D I C I N E S F O R M A N K I N D The hypothalamus produces growth hormone-releasing hormone (GHRH). GHRH, in turn, causes release of growth hormone by the pituitary. Most often, growth problems are the result of a failure of the pituitary gland, to produce adequate levels of growth hormone. The deficiency does not always continue into adulthood, possibly due to maturation of the structures in the brain. Children, therefore, need to be reviewed and retested once their final height has been reached. For many patients, the cause of the deficiency remains unknown. However, there are also several known causes, including a tumour of the pituitary region, the treatment of a brain tumour or cancer, a genetic disorder or a severe injury to the head. Growth hormone continues to play an important role throughout adulthood, regulating metabolism and body composition, and improving general quality of life. 26 Over-production of growth hormone leads to the clinical feature of acromegaly. The term is derived from the Greek nouns “akron” (meaning high, top, or extremity) and “mega” (meaning large), which refer to the clinical picture of the coarsening of facial features and the enlargement of the hands, feet and jaw. Acromegaly is triggered by over-secretion of growth hormone, often caused by a tumour of the pituitary gland, and leads in turn to the over-production of insulin-like growth-factor (IGF-1). Who does a growth problem affect? The prevalence of growth hormone deficiency in childhood is around three in 10,000 of the population. For the European Union, this would mean about 110,000 people. Some children with the disorder produce enough of their own growth hormone so that they may stop the treatment once growth has finished. However, some remain growth-hormone-deficient as adults and may need to continue treatment throughout their lives. Growth hormone deficiency in adults may also result from decreased production of growth hormone from the anterior pituitary gland. It usually occurs as a 2361_EFPIA_brochure 10/16/06 3:56 PM Page 27 consequence of a structural pituitary disease or peripituitary lesion, e.g., pituitary adenoma, or as a result of treatment e.g., cranial irradiation or surgery. It is estimated that the prevalence of adult-onset growth hormone deficiency is one in 10,000 of the population. Acromegaly has an incidence of four to six cases per one million inhabitants and affects around 15,000 people in Europe. European countries have started to set up national data banks to register all detected cases. The UK data bank started in 1997 and has since then collected data of some 1,600 people. Apart from the symptoms mentioned above, patients with the condition suffer from headaches, excessive sweating, soft-tissue swelling and joint disorders. Present treatments: Growth hormone was first isolated and used in treatment in 1956, and its structure was first identified in 1972. However, until the mid-1980s, the only source of growth hormone was pituitary glands extracted from human cadavers. Synthetic growth hormone was first manufactured using genetic engineering techniques in 1985. The synthetic growth hormone produced today is 100 per cent identical to the natural growth hormone produced by the body. Excessive or insufficient growth is caused by incorrect hormone levels and can have a major impact on a person’s life. Research by the pharmaceutical industry has led to synthetic hormones and other medicines which can help correct the imbalance. In turn, this helps patients lead a more normal life. In Europe, several human recombinant growth hormone preparations from different manufacturers are available for the long-term treatment of short stature of children and adults caused by a decreased or absent secretion of pituitary growth hormone. In order to improve their growth rate, children require injections daily or several times weekly over many years. Preparations for once a month application are also available. To ease application, needle-free delivery systems have been developed and received EU authorisation in June 2002. There are also compounds approved for the extended indication of treating growth disturbance in short children born small for their gestational age who fail to catch up growth by four years of age or later. Current therapies for acromegaly include surgery to remove the pituitary tumour, radiation therapy and drugs including dopamine agonists and somatostatin analogues. Since November 2002, a new class of medicines – growth hormone receptor antagonists – to treat the disorder is available in Europe. As growth hormone hypersecretion has been known to be the cause of insulin resistance, the new medicine which is applied via injections, works by blocking the effects of growth hormone and normalising IGF-1 levels. It is used in acromegaly patients who have responded inadequately to surgery or radiation or other medical therapies or for whom other therapies are not appropriate. What’s in the development pipeline? Pegylated molecules of somatotrophin have been synthesized to prolong the half-life of recombinant growth hormone in the human body. They are in clinical phase 1 trials. Research is also going on to develop further easy-to-use application systems to facilitate application for children and carers and to improve compliance. F O R M A N K I N D Gene therapy is also considered to offer new avenues for better treatment options in growth problems. M E D I C I N E S The longer-term future: Researchers aim to understand better the phenomenon of growth on the cellular and genomic levels. Special attention is paid to the IGF-1 system which signals to cells to grow, differentiate, and survive. One central player is the IGF-1 receptor. Transduction of signals through this molecule leads to multiple series of intracellular events and the activation of pathways. 27 2361_EFPIA_brochure 10/16/06 3:57 PM Page 28 Haemophilia What is haemophilia? Haemophilia is an inherited disorder of blood clotting. The bleeding of individuals with haemophilia is prolonged due to a defect or a deficiency of clotting factors normally present in the blood. Haemophilia A, which is the most common form and affects about 80 per cent of haemophiliacs, is caused by the deficiency of Factor VIII. Haemophilia B is due to a lack of Factor IX. Haemophilia varies in severity and this variability is related to the amount of clotting factor present in the blood. The more severe the disorder is, the earlier in life the signs of abnormal bruising or bleeding are observed. Minor trauma can result in extensive tissue bleeding. Apart from bruising, haemorrhages into joints are the most common feature of the disease. Bleeding into muscles is also common and may occur after injury or spontaneously. If such haemorrhages are improperly managed, they will result in crippling musculoskeletal deformities. M E D I C I N E S F O R M A N K I N D Who does haemophilia affect? As the genetic codes of Factors VIII and IX are both located on the human X chromosome which also determines the gender of an individual, haemophilia A and B almost exclusively affects males. Haemophilia occurs in about one in 5,000 male births and is found in all populations. This means that 400 boys with haemophilia are born in Europe each year. Altogether, there are more than 22,000 European patients with haemophilia A and B. Women who carry the gene normally have no bleeding problems. Spontaneous mutation in the Factor VIII and Factor IX gene continue to add new patients and carriers of the genetic defect. 28 Present treatments: Haemophilia is a life-long condition for which, at present, there is no cure. However, with the development of comprehensive care and the provision of preparations containing clotting factors, it is possible for people with even severe forms of haemophilia (Factor VIII or Factor IX levels less than one per cent of the average value of the unaffected population) to control bleeding and live near normal lives. Treatment must be given as soon as possible after the onset of a bleeding episode. Factor concentrates are also being used prophylactically on a planned regular basis to prevent recurrent haemorrhage, e.g., before physiotherapy and other exercise programmes. Today, the transfusion of Factor VIII concentrates is done under medical supervision at a hospital or haemophilia centre, at home by parents to treat their child or by patients themselves. In January 2004, the European Commission approved a plasmaderived Factor IX concentrate, for continuous intravenous infusion, which will help patients maintain a minimum and predictable level of Factor IX. Factor concentrates are either produced from the plasma in blood donations, or synthetically by recombinant genetic engineering of cells that produce Factor VIII or Factor IX. For haemophilia A, the treatment of choice is viral attenuated or recombinant 2361_EFPIA_brochure 10/16/06 3:57 PM Page 29 Factor VIII concentrate. The products fall into three categories: (i) recombinant products; (ii) monoclonal antibody purified plasma products; and (iii) intermediate- and high-purity plasma Factor VIII products, which are also used to treat a rare bleeding disorder called von Willebrand Disease. For haemophilia B, the treatment of choice is a highly purified viral inactivated Factor IX concentrate. In the early 1980s, transmission of infectious particles through the preparations was a major problem. Since then, a series of inactivation procedures, such as heating and ultra-filtration, has been introduced into the manufacturing process and has dramatically lessened the risk of transmitting infectious diseases, such as hepatitis B and human immunodeficiency virus. Nowadays, this risk has become very small. Between 20 and 30 per cent of severely affected haemophilia A patients and about three to five per cent of the Haemophilia B patients develop inhibitors against Factor VIII or Factor IX, respectively. This is due to the reaction of the patient’s immune system which recognizes the given clotting factors as foreign substances and forms inhibitory antibodies against them. Such inhibitors complicate the treatment of bleeding episodes. Several treatment methods are available by which, in most patients with inhibitors, resistance to therapy can be overcome. In such cases, specialized haemophilia centres are consulted. Haemophilia is an inherited disorder where the blood does not clot properly. Only men are affected. Once a crippling or even fatal condition, the pharmaceutical industry has introduced preparations to control bleeding and allow many patients to lead near normal lives. In mild (Factor VIII level between six and 50 per cent) or moderate (Factor VIII level between one and five per cent) forms of haemophilia A, the synthetic vasopressin analogue DDAVP can be used in the form of a highly concentrated nasal spray, which acts by releasing Factor VIII stores. Antifibrinolytic agents may also be prescribed. They slow the natural breakdown of blood clots and are particularly useful in mouth and tooth socket bleeding. Newly diagnosed haemophiliacs should be vaccinated against hepatitis A and B. What’s in the development pipeline? The worldwide total demand for Factor VIII lies between 250 and 500 grammes of protein every year. The highest priority of research is being devoted to the development of a non-plasma source for the manufacturing process of Factor VIII and Factor IX preparations. New preparation methods in cell cultures of gene-modified yeasts and bacteria are being investigated. Research also concentrates on new treatment avenues for hemophilia patients with inhibitors. Objectives are either to develop tolerance or to influence the person’s immune system. Through this intensive and cooperative effort eventually will come the knowledge needed to treat this problem more effectively, and, most importantly, to prevent it altogether. M E D I C I N E S F O R M A N K I N D The longer-term future: The ultimate research goal of haemophilia therapy is to become totally independent of blood donations. For a haemophiliac, gene therapy would allow continuous synthesis of a normal protein to correct the deficiency in vivo. The resultant protein synthesis would be comparable to a cure. A variety of approaches for transferring genes for Factors VIII and IX are being investigated. No single technique has emerged as superior, but considerable progress has been made in factor expression, which has led to considerations of clinical trial development for both factors. Within the last years, newly-found vectors, i.e., gene-ferries, have provided sufficiently encouraging results to allow contemplation of clinical trials in humans. 29 2361_EFPIA_brochure 10/16/06 3:57 PM Page 30 Infections by Herpes Group Viruses What are herpes infections? There are eight known human herpes viruses, classified into three groups. Cold sores, which affect the majority of us, are caused by Herpes simplex (HSV) Type-1 (FIGURE 1); genital herpes, one of the most common sexually transmitted diseases, is usually the result of infection by HSV-2 (although some cases are due to HSV-1), and chicken pox and shingles are manifestations of Varicella zoster infection. Apart from the fact that their genomes consist of double-stranded DNA or deoxyribonucleic acid, the group of herpes viruses shares the property that, following primary infection, they persist in one or more body cells (nerve cells in the case of HSV-1, -2 and -3) in a dormant form and may be reactivated, either spontaneously or when the immune system is depressed, possibly with more severe consequences than during the primary infection. Herpes viruses of the gamma type have been implicated in the development of various cancers. M E D I C I N E S F O R M A N K I N D Who does herpes affect? Most human beings are exposed to HSV-1 and those who have a sore often become carriers and have recurrences. Cold sores are usually trivial, but in people undergoing immunosuppressive therapy, or who have cancer or AIDS, they can be life-threatening. Similarly, in a new-born baby, infection arising from a vaginal sore can be very serious. Of newborns who survive neonatal herpes, 50 per cent have prolonged, permanent neurological consequences. Until vaccines against varicella became available, chicken pox was a common childhood infection and shingles, frequent in older people, is often accompanied by severe, long-lasting neuropathic pain. In kidney transplant patients, infection with cytomegalovirus can result in rejection of the graft. Immunosuppressive treatment due to chemotherapy or transplantation can cause chicken pox to develop into an overwhelming general infection with a fatal outcome. 30 Present treatments: While latent, herpes virus is concealed inside cells where it is invisible to the immune system. In cold sores, these are cells of nerves in the head and neck, while in genital herpes the virus lodges in the nerves in the lower spine. Varicella zoster, which causes chicken pox, hides in clusters of nerves alongside the spine. Medical treatment deals with the symptoms, but does not eradicate the latent virus infection. Milder outbreaks of oral or genital herpes are often treated with non-prescription topical preparations, but more serious or frequently recurring cases require systemic medication. Available anti-herpes preparations include a series of nucleoside analogues and work by blocking replication of the viral DNA, preventing the formation of infectious parti- 2361_EFPIA_brochure 10/16/06 3:57 PM Page 31 The Human Herpes Viruses and the Diseases they Cause Type Common name Disease associated with virus HHV-1 Alpha Herpes simplex, type 1 Cold sores HHV-2 Alpha Herpes simplex, type 2 Genital sores HHV-3 Alpha Varicella zoster (VZV) Chicken pox, shingles HHV-4 Gamma Epstein-Barr (EBV) Infectious mononucleosis, Burkitt’s lymphoma HHV-5 Beta Cytomegalovirus (CMV) Retinitis, pneumonia (immunocompromised) HHV-6 Beta Human herpes virus 6 Roseola infantum HHV-7 Beta Human herpes virus 7 Not known HHV-8 Gamma Human herpes virus 8 Infections by herpes viruses cause a lot of misery – including cold sores, genital herpes, chicken pox and shingles. While there have been extraordinary advances in medicines, research continues into vaccines and other ways to combat these common viruses. Kaposi’s sarcoma (immunocompromised) cles. There are tablets and a topical preparation, also available is an infusion form for use in serious systemic infections. Three DNA polymerase inhibitors are used for the treatment of cytomegalovirus infections in AIDS and immunocompromised patients. The drawbacks of all of these anti-herpes preparations are the regularity with which they have to be applied, and the fact that they do not eliminate the latent virus. What’s in the development pipeline? The growing frequency of sexually transmitted diseases has increased the need for effective prevention of HSV infections, and this is where most current development work is focused. One of the mentioned antivirals has recently received approval to prevent transmission of HSV infections among heterosexual, monogamous couples. There is research going on to evaluate a vaccine for the prevention of genital herpes infections, and also the development of a prophylactic vaccine is continuing. Another research group has isolated a lipopeptide from a marine fungus that appears to be at least as effective as the existing DNA nucleoside analogues in inhibiting HSV-1 and HSV-2, and this compound is now being developed for testing in the clinic. The longer-term future: Removal of the virus from inside nerves remains the ultimate goal for new treatments in herpes virus infections, but is still tantalisingly out of reach. Meanwhile, more effective prevention and the development of less toxic antiviral compounds that can increase symptom-free periods would seem to be more realistic goals. FIGURE 1: Electron-microscopic picture of Herpes simplex (HSV) Type-1 M E D I C I N E S F O R M A N K I N D 31 2361_EFPIA_brochure 10/16/06 3:57 PM Page 32 Infertility What is infertility? Infertility is defined as ‘the incapacity of a couple to achieve conception or to bring a pregnancy to term after a year or more of unprotected intercourse’. Who does infertility affect? Any number of factors can cause infertility, as more than ten per cent of couples worldwide know all too well from their own experience. In Europe, one in six couples faces infertility problems at some point in their lives. Exclusively female or male problems account for 35 per cent each, 25 per cent are due to problems in both partners and five per cent remain unexplained. Advances in the area of infertility treatment now mean that around half of these couples can be successfully treated. Present treatments: The yield of biotechnological research over the past ten years has resulted in a complete range of fertility medicines for each stage of the female reproductive cycle, from ovulation through to early pregnancy. M E D I C I N E S F O R M A N K I N D Today, recombinant human medicines are used in different settings, e.g., when there is a hormonal defect that inhibits ovulation. If low levels of natural hormone are produced, a woman may be prescribed an oestrogen antagonist for several days in each monthly cycle. This stimulates the pituitary gland to release gonadotrophin, which stimulates ovulation. If this fails or is inappropriate, the individual will be given recombinant follicle stimulating hormone (rFSH) and recombinant human chorionic gonadotrophin (rhCG). These mimic the natural hormonal cycle and prepare the woman for ovulation and implantation if the egg is fertilised. 32 Where infertility has other causes than ovulation failure, such as tubal dysfunction, endometriosis, anti-sperm antibodies or low sperm counts or motility, couples may be offered outside the body or in vitro fertilisation (IVF), also termed assisted reproductive techniques or ART. An oestrogen antagonist and rhCG are used to induce ovarian hyperstimulation, oocytes (eggs) are removed and fertilised in vitro and the resulting embryos re-implanted (FIGURE 1). Success rates lie in the order of magnitude of 25 per cent. Another disorder which can cause infertility is hyperprolactinaemia, a disease state that suppresses ovulation because of excess levels of the hormone prolactin. If this is the case, the woman will be treated with a prolactin inhibitor. Male infertility may be due to erectile dysfunction, low sperm production or defects in sperm motility or maturation. Impaired testicular function or hypogonadism results in a lower concentration of testosterone in the blood, which leads to diminished sexual 2361_EFPIA_brochure 10/16/06 3:57 PM Page 33 function, lethargy and reduced bone mass. Transdermal testosterone therapies are available to increase low hormone levels in the blood. A new preparation containing a slow-releasing depot formulation of an androgen has improved treatment, as it can be administered by just four injections a year. Erectile dysfunction is common in later life and is often due to physical causes such as progressive atherosclerosis or venous leaks, although it may also be related to medication use. The introduction of an oral phosphodiesterase-5 inhibitor has improved prospects for treating erectile dysfunction, although it is not effective in all cases. Low sperm production may be improved by the use of rFSH. Hospital and institute-based research efforts in Europe have made valuable contributions to infertility treatment, for example, IVF was pioneered in the UK, France and Germany. What’s in the development pipeline? Research continues into improvements in assisted reproduction technology and fertility treatment. Thus, approval has been received for recombinant forms of human luteinising hormone (LH) and human chorionic gonadotrophin (CG). There is an emerging belief that combined treatment with rFSH together with rLH may offer therapeutic advantages, including increased pregnancy rates in some group of patients. “Chimerical” gonadotrophins, possessing both FSH and LH activities in a single protein molecule, are being developed. Such compounds which have recently entered the pre-clinical phase of development may be potent activators of the human FSH and LH receptors. Infertility means that couples cannot have children. There are many possible causes of infertility. However, intensive research by the pharmaceutical industry continues to increase the chances of family happiness for thousands of couples. Recombinant leukaemia inhibitory factor (rLIF) is in Phase 2 trial for treatment of embryo implantation failure, as well as a microencapsulated form of rFSH. LIF is a protein believed to be important to the process of attachment of the embryo to the inner lining of the uterus. Recently, a gonadotrophin-releasing hormone antagonist has been launched for use in ART, which reduces the number of injections that must be given during ovarian stimulation. About ten per cent of all pregnancies end prematurely. Reducing uterine activity during pre-term labour could improve the outcome. An approach would be to switch off premature uterine contractions. Research in this area focuses on oxytocin receptor and prostaglandin receptor antagonists. New compounds for erectile dysfunction and related problems have received EU registration. Two further oral phosphodiesterase-5 inhibitors have been shown to be effective in older men, as well as in those with diabetes – both groups that are likely to have an increased rate of impaired erectile function. Lastly, research is ongoing to explore the usefulness of a selective 5HT1A receptor agonist in counteracting the loss of libido seen in some patients taking antidepressants. M E D I C I N E S The longer-term future: Prospects for successful treatment of infertility continue to improve and new findings, such as the discovery of a key protein that controls sperm motility, may provide better understanding of the various causes that can lead to infertility in couples. F O R M A N K I N D 33 2361_EFPIA_brochure 10/16/06 3:57 PM Page 34 Inflammatory Bowel Disease What is inflammatory bowel disease? There are two major forms of inflammatory bowel disease (IBD): ulcerative colitis and Crohn’s disease. Key differences between them are shown in the table, although it may not always be possible to distinguish them with certainty. The main feature of IBD is inflammation of the lining of the intestine, leading to ulceration, pain, diarrhoea (bloody in ulcerative colitis) and bowel obstruction (in Crohn’s disease). Both diseases typically have an unpredictable relapsing/remitting chronic course, with the risk of anaemia, malnutrition, difficulty in maintaining body salt balance and an enhanced risk of developing bowel cancer. ULCERATIVE COLITIS CROHN’S DISEASE Parts affected Large intestine and rectum only Any part of the digestive tract from the mouth to the rectum Areas inflamed Only the lining of the intestine is inflamed All layers of the digestive tract may be inflamed M E D I C I N E S F O R M A N K I N D Key differences between ulcerative colitis and Crohn’s disease 34 It is now generally believed that IBD is caused when three main factors interact inappropriately, possibly in association with dietary elements: (i) our individual genes; (ii) the immune system; and (iii) the bacteria living in the gut. The genes suspected so far are scattered on different chromosomes, notably 3, 5, 6, 7, 12 and 16. In 2001, a 2361_EFPIA_brochure 10/16/06 3:57 PM Page 35 mutation in a gene known as NOD2 on chromosome 16 has been found to markedly increase susceptibility to Crohn’s disease, but not to ulcerative colitis. A protein product of this gene is involved in the recognition by cells in the gut of a bacterial membrane component called lipopolysaccharide, and an inappropriate immune response to gut bacteria, with migration of inflammatory leukocytes into the epithelium, has been suggested as a causative mechanism in Crohn’s disease. Mycobacterium paratuberculosis, which may be found in cow’s milk and is known to cause a similar disease in sheep and cattle, has been suggested as a likely pathogen. If this disease model were verified, it would be a striking parallel to the causation of stomach ulcers by Helicobacter pylori. Inflammatory Bowel Disease affects the intestine and causes great pain and discomfort. Whilst modern treatments help make life tolerable, there is a lot of research into advances that will help millions lead a more normal life. Who gets ulcerative colitis and Crohn’s disease? Ulcerative colitis affects some 500,000 people in the EU and 30,000 new cases are diagnosed each year. About 250,000 people suffer from Crohn’s disease, with around 18,000 new cases per year. Because of under-recording, European health experts presume that the true number of people suffering from IBD in the EU may be nearer to one million. The age of onset of both diseases peaks between the ages of 15 and 3035 and men and women are equally affected. Present treatments: Management of the acute phase of IBD commonly involves symptomatic relief with antidiarrhoeal medicines, nutritional support and the use of anti-inflammatory steroids, which induce complete or partial remission in about 80 per cent of cases. In severe cases, immunosuppressive medication may be necessary. Once the acute symptoms have been controlled, remission is usually maintained through the use of 5amino-salicylate derivatives. All are approved for use in ulcerative colitis, but only one compound is indicated for Crohn’s disease as well. Salicylates work by inhibition of 5lipoxygenase and various hormones which induce inflammation (cytokines), and may also be used for acute treatment in mild to moderate ulcerative colitis, but tend to be less effective than steroids. Where disease is confined to the rectum and Mesentery lower part of the colon, the medication may be administered in the form of suppositories or enemas. Serosa IBD is a disorder in which inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha), interferon gamma and interleukin-1 are overproduced. These can result in local tissue damage. If they could be controlled, the disease itself might be controlled or eliminated. Several research groups have recognised the potential this provides and the most popular target in recent years for intervention has been TNF-alpha. Since 1999, anti-TNF-alpha products have been available in Europe for the maintenance treatment of severe active and fistulising Crohn’s disease. Intestinal villi Longitudinal and circular muscle layers Lumen Mucosa Submucosa Thin muscle layer (muscularis mucosa) Plica (circular fold) Lymphoid tissue Villus muscularis mucosa Submucosa Serosa M A N K I N D Longitudinal muscle F O R Circular muscle M E D I C I N E S In severe IBD that does not respond to medicines, surgical removal of the diseased segment of the intestine may be necessary. About 75 per cent of people with Crohn’s eventually need surgery, compared to only about 20 per cent in ulcerative colitis. Surgical removal of large sections of the intestine can result in short bowel syndrome – a serious and potentially life-threatening condition. Since December 2003, a recombinant somatotropin product has been approved for use in this indication. Diagrammatic cross section of the human small intestine 35 2361_EFPIA_brochure 10/16/06 3:57 PM Page 36 What’s in the development pipeline? Further anti-TNF alpha products are being tested in Phase 3 clinical trials in Crohn’s disease, to show that the compounds may allow withdrawal of steroids in disease remission, while a second trial is examining use in acute disease. Researchers also have a pegylated monoclonal antibody directed against the same antigen in Phase 3 trials. This is expected to be administered through a once-monthly subcutaneous injection, rather than an intravenous infusion. Other approaches include another antiTNF alpha molecule that has completed Phase 2 trial, investigations with a recombinant TNF binding protein in Phase 2 trial in Crohn’s disease, and the development of an inhibitor of the enzyme that produces TNF alpha. Interferon beta-1a is in Phase 2 trials in ulcerative colitis. Haematopoietic growth factor for white blood cells is being investigated in Phase 3 trials in Crohn’s. Alpha4 -integrins are important in the adhesion of leukocytes to blood vessel walls and their subsequent migration into underlying tissue, such as the tissue of the gut, where they can contribute to the inflammatory response seen in IBD. Investigations are carried out on a humanised monoclonal antibody that inhibits alpha4 -integrin. Clinical results obtained in people with Crohn’s showed a marked decrease in disease activity, but results of further clinical trials must be awaited. Detailed structure of a villus showing the rich provision of blood vessels, nerves, and lymph ducts in the underlying lamina propria Steroid derivatives also continue to be developed for IBD. Here, research focuses on an oral steroid which is active locally in the gut but produces only low blood levels, which should reduce the incidence of side-effects. Another research group uses a colonic drug delivery system (enema formulation) to release a corticosteroid locally in the intestine, with the same objective of reducing systemic side-effects. Brush border Microvilli Nerve fibre Epithelial cell Capillary Intestinal gland (crypt) Small artery Small vein Lamina propria M E D I C I N E S F O R M A N K I N D Artery 36 Nerve fibre Epidermal growth factor (EGF) enemas may provide another new avenue for ulcerative colitis. Enema rather than oral formulation is necessary as the protein would be broken down in the upper gastrointestinal tract. Research suggests that EGF might exert its beneficial effect by facilitating the repair of damaged intestinal cells, and thereby stopping antigens from irritating the lining of the colon. A number of other pathways and mechanisms probably play a part in IBD and are being exploited as potential targets for new types of medicines. One is the CD 40 pathway that is involved in both antibody responses and in the processes of cell-tocell contact that occurs in the inflamed bowel. New antibodies are being investigated that block this pathway. Assessment is also carried out on small molecules that mimic an enzyme found in inflammation that is involved in trapping reactive forms of oxygen. Vein Lymph duct Muscularis mucosa The longer-term future: Several more approaches to IBD are in development. One is treatment with antigamma interferon antibody in Crohn’s disease. The cell adhesion molecule ICAM-1, a glycoprotein cell recognition 2361_EFPIA_brochure 10/16/06 3:57 PM Page 37 molecule involved in inflammatory response is the target of an antisense inhibitor that has already shown clinical benefit in a Phase 2 trial in active ulcerative colitis. Meanwhile, an enema formulation of the antisense product is available. PPAR gamma, a nuclear receptor of great interest in diabetes research, can inhibit tissue injury associated with immune activation, and hence may be a future target in IBD, as may the transcription factor Nuclear Factor-B. In view of the large number of molecules involved in the disease process, in both ulcerative colitis and Crohn’s disease, there is no shortage of future medicine development targets and substantial research efforts can be expected to continue. Many of the symptoms of IBD are disabling in their own right, so medicines that can help control these help make life more tolerable. M E D I C I N E S F O R M A N K I N D 37 2361_EFPIA_brochure 10/16/06 3:57 PM Page 38 Influenza What is influenza? The influenza virus (FIGURE 1) causes potentially serious infections affecting the nasal passages, throat, larynx and lungs and periodically causes epidemics or even pandemics (world-wide epidemics). It belongs to the group of orthomyxoviruses which is characterised by an envelope and a viral genome composed of segments of single stranded RNA. Influenza or flu is transmitted when an infected person coughs, sneezes, or speaks and sends microscopic drops loaded with influenza virus into the air, and other people inhale these. The usual influenza or flu season in the northern hemisphere occurs from November to April. M E D I C I N E S F O R M A N K I N D The surface of an influenza virus particle carries haemagglutinin molecules, which enable it to adhere to cells in the respiratory tract of human beings, and the enzyme neuraminidase, which is involved in the release of new virus particles. Today, we know of 15 different types of haemagglutinin molecules and nine different types of neuraminidase. The possible combinations in the make up of these macromolecules lead to different influenza families of type A, B or C and a multitude of strains. Due to rapid mutation of the viral surface molecules and hence the changing of prevalent strains, a new vaccine is needed each year. To allow for enough time for the manufacturing of some 300 million doses in Europe, each year in early summer, the composition of the new vaccine is determined according to surveillance data collected by a world-wide network of virologists under the guidance of the World Health Organization. 38 Who does influenza affect? Anyone can get influenza. Most people who get the flu will recover in one to two weeks, but some will develop life-threatening complications. People aged 65 years and older, people of any age with chronic medical conditions (such as asthma or congestive heart failure), and very young children are particularly susceptible to the complications that can follow. These people are known as “high risk” and should be immunised. Furthermore, a person can have influenza more than once. It has been estimated that 120 million people get influenza every year in the USA, Europe and Japan. Every ten years or so, a highly contagious and virulent influenza virus strain appears and results in a worldwide epidemic, called a pandemic. The last two pandemics occurred in 1957 and 1968, when more than five million people died. Over 20 million people are estimated to have died worldwide during the great influenza pandemic of 1918/19. It has been cited as the most devastating epidemic in recorded world history. 2361_EFPIA_brochure 10/16/06 3:57 PM Page 39 Present treatments: Over-the-counter medicines such as aspirin and decongestants only provide relief from symptoms and have no effect on reducing the transmission of the virus to others. The best way to prevent infection with influenza virus is to be vaccinated each autumn, before the start of the influenza season. Once influenza has set in, over-the-counter medicines provide symptomatic relief and reduce fever, but there are no medicines that cure influenza. Antiviral medicines are other therapies that can be used to help prevent and treat influenza. Compounds belonging to the group of cyclic amines are available for the prophylaxis and treatment of flu. They are mainly used in immunocompromised patients or other high risk people, as the benefits are somewhat modest for general use. Cyclic amines are only active against Type A flu viruses, which account for 65 per cent of outbreaks. An inhaled neuraminidase inhibitor has been approved more recently for treatment of symptomatic influenza Types A and B. Studies have shown that treatment with the compound shortens the period of symptoms by approximately one day. As it is inhaled, it is not generally recommended for use in persons with underlying lung disease. There is another anti-viral compound which is administered orally. This medicine is approved both for prevention and treatment of influenza Types A and B. Influenza is caused by a virus. It affects millions every year – and it can be fatal. The development of vaccines has played a major part in protecting people but as there are changes in virulence continuing research is essential to find new ways of combating this menace. What’s in the development pipeline? Prevention of influenza depends on the rapid production of vaccines tailored to the specific strain at the first signs of an epidemic. Thus, each vaccine is, in effect, a new product each year. In addition, preparedness regarding a future pandemic remains a permanent challenge in terms of research, development and production. New types of vaccine are also being explored. There is an intranasal live attenuated vaccine in Phase 3 trial. It contains influenza virus rendered unable to cause the disease and may make future vaccinations easier and more acceptable to people who wish to avoid injections. Other research groups are studying a proteosomal influenza vaccine. This type of vaccine consists of a small part of the influenza virus genetic code. Inserting this material into a few cells of the body leads to synthesis of a part of the virus, which in turn stimulates the body to produce high levels of protective antibody. There are also efforts to develop new manufacturing processes by cell culture to complement those that are conventionally produced on hen’s eggs. The longer-term future: Scientists are looking for new medicines to prevent or treat influenza. Long-acting neuraminidase inhibitor products which are expected to be active in a once-weekly dosing regimen are still at the preclinical stage. Another avenue which is being studied is the application of immunoglobulin fusion proteins that act on a receptor molecule found on the surface of activated white blood cells or T-cells. This approach is thought to be able to attenuate the immune response of the human body to the viral infection and to avoid the impaired lung inflammatory process. M E D I C I N E S The public would no doubt welcome effective treatments for the flu. Whether these will ever be able to stop the infection in its tracks once it has started is unclear, but certainly a treatment that could prevent a fatal outcome to influenza in elderly, at-risk patients would be of genuine clinical value if, as some experts believe, another pandemic is always just around the corner. FIGURE 1: Electron-microscopic picture of the influenza virus F O R M A N K I N D 39 2361_EFPIA_brochure 10/16/06 3:57 PM Page 40 Kidney Disease What is kidney disease? Kidney disease has many causes and takes many forms, but any condition leading to restricted blood flow through the kidney can result in damage to its tissue. Some medicines may also be toxic to the kidney. Acute kidney failure is a sudden decline in the function of the organ, leading to an increase in concentrations of urea, creatinine and other substances that the kidney normally eliminates from the body. Often reversible and self-limiting, uncorrected acute kidney failure can be fatal. Chronic kidney failure results in a significant reduction in a range of important functions of the kidney. Its major causes include diabetes, hypertension, long-lasting inflammation and scarring (pyelo- and glomerulonephritis) after bacterial infection. Urinary obstruction and inherited disorders such as polycystic kidney disease are less common causes of chronic kidney failure. M E D I C I N E S F O R M A N K I N D Who does kidney failure affect? It is estimated that around 200,000 people are receiving treatment for kidney disease in the EU; 50 per cent of them have had a kidney transplant and are receiving anti-rejection treatment, while many of the rest are being given regular dialysis, of whom about half undergo peritoneal dialysis and the remainder haemodialysis. Haemodialysis to purify the blood in kidney failure is usually carried out three times a week and is normally performed in hospital; peritoneal dialysis can often be done by the patient at home. There were 10,644 kidney transplants performed in the European Union in 2001, with over 50,000 people on the waiting-lists. Impaired kidney function is more common in the elderly and may be undetected in its earlier stages. 40 Present treatments: In acute kidney failure, salt balance has to be maintained and the remaining function sustained with diuretics and vasodilators to allow the damaged kidney time to recover. Established acute kidney failure requires close monitoring to deal with emerging electrolyte balance issues, including excess potassium and increasing tissue acidity. Patients should also be monitored for possible infection and problems of nutrition. Dialysis may be necessary, but can be stopped when kidney function has recovered. In chronic kidney failure, many patients will have high blood pressure and should be treated appropriately. A low protein diet is used to help control urea levels, and anaemia will be treated by regular injections of erythropoietin every second day. Recently, a longer-acting variant of erythropoietin has been approved which can be given once a week. Chronic kidney failure will also lead to secondary hyperparathyroidism with problems of maintaining blood levels of phosphorus, calcium. parathyroid hormone, and cal- 2361_EFPIA_brochure 10/16/06 3:57 PM Page 41 cium-phosphorus product. To avoid defective bone formation, phosphate binders are given to reduce phosphate absorption in conjunction with vitamin D sterols which may raise blood calcium and phosphorus levels. An oral calcimimetic compound has been available since March 2004 for the treatment of secondary hyperparathyroidism. The medicine increases the sensitivity of calcium receptors on the parathyroid gland to calcium levels in the blood, thus reducing levels of parathyroid hormone, phosphorus, calcium and calcium-phosphorus product. Regular dialysis or transplantation are used to treat end-stage disease, which is otherwise fatal. Transplantation has been greatly aided by medicines which suppress the body’s own immune system to avoid rejection. The anti-hypertensive ACE inhibitors have been shown to be able to slow the progress of kidney disease associated with diabetes and hypertension and many are authorised for this purpose. Kidney disease can lead to patients needing either dialysis or even a transplant. Research by pharmaceutical companies has resulted in many medicines to help prevent kidney damage and make transplants safer. What’s in the development pipeline? Several new medicines for kidney transplantation are in clinical development or have recently been introduced. They include monoclonal antibody products, which block the IL-2 receptor involved in kidney rejection and a new myriocin analogue, which is being widely tested in Phase 3 trials. ACE inhibitors have been shown to slow progression of kidney disease and now another class of anti-hypertensive medicines, the angiotensin 2 receptor antagonists (ARBs), has been shown to be similarly effective in recent major trials. This class of new medicines was found to be effective in lowering microalbuminaemia - a sign of early-phase kidney disease and for prevention Position of progression of kidney disease in diabetes. Projects at an earlier stage include trials of immunosuppressive agents in the autoimmune kidney disease lupus nephritis and the study of an adenosine A1 receptor antagonist in kidney disease. An endothelin receptor antagonist is also being explored for acute kidney failure. The longer-term future: The kidney is a complex, vital and sensitive organ. Taking about one quarter of the heart’s output of blood at rest, it is intimately connected with the health of the cardiovascular system. As has been seen with ACE inhibitors and ARBs, medicines that normalise the working of the heart may also have beneficial effects on the kidney. The prevention of other underlying causes of kidney disease, like polycystic renal disease, is also under study; here, one approach is the use of antisense oligonucleotides which target the c-myc oncogene. New patients Greece Germany Luxembourg Czech Republic Italy Portugal Spain Belgium Austria France Sweden Denmark United Kingdom Bulgaria Netherlands Norway Hungary Switzerland Ireland Finland Poland Iceland Romania 173 163 155 143 131 126 121 116 115 112 99 98 87 84 82 80 77 75 69 68 44 33 26 European Dialysis and Transplant Association F O R New dialysis patients in various European countries (1995, per million population) M E D I C I N E S Kidney disease represents a significant burden on the health care budget of every European country. For example, the annual cost of haemodialysis is approximately e 30,000 per patient and the initial cost for transplantation is similar. It is thus highly desirable, from an economic as well as a humanitarian point of view, to develop ways of preventing the occurrence and progression of kidney disease and to diagnose it early. Given the level of research to provide new medicines in this area, the prospects for treating kidney disease should improve over time, easing pressure on transplantation and expensive endstage care such as dialysis. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Country M A N K I N D 41 2361_EFPIA_brochure 10/16/06 3:57 PM Page 42 Malaria M E D I C I N E S F O R M A N K I N D What is malaria? Malaria is a parasitic infectious disease. It is transmitted through the bite of bloodsucking anopheles mosquitoes, which infects the victim with one of the four plasmodium species causing the disease, of which plasmodium falciparum is the most lethal. The name of the disease stems from the Italian nouns “mala” and “aria” which means “bad air”. Malaria has been known for thousands of years. Analysis of archaeological remains in a cemetery in southern Italy, using the latest DNA techniques, has established the existence of a particular virulent form of malaria in about 450 AD, lending weight to the hypothesis that a widespread outbreak of the disease contributed to the fall of the Roman Empire. The first effective quinine-based treatment for malaria was given to Europeans as early as in the beginning of the 17t h century. 42 During the first half of the 20 t h century, malaria was an important health problem in all regions of the world, including much of Europe and North America. In the late 1950s, it was believed that malaria could be completely eradicated. Through a combination of social and economic developments, prompt and effective treatment, and mosquito control, mainly the spraying of the inside of houses with DDT, it was eliminated from Europe, North America, Australia and much of the Middle East by 1970. A decline in funding, insect resistance to insecticides and environmental concerns related to DDT led to the malaria eradication campaign being abandoned in 1972. The disease has been rebounding ever since. It is now reappearing in some countries that had previously eliminated it. Who does malaria affect? Between 300 and 500 million new cases occur each year and more than one million people – mainly children under five living in sub-Saharan Africa – die from it. Malaria is prevalent in the least developed countries, but more than 12,000 cases were reported among European travellers in 1999 and climatic changes could also increase its reach. 2361_EFPIA_brochure 10/16/06 3:57 PM Page 43 Present treatments: Molecular derivatives of quinine, such as chloroquine, primaquine, mefloquine or amodiaquine, and other antiprotozoal medicines have been used for decades in the prevention and treatment of malaria, but many countries are reporting high levels of resistance to these classes of compounds. Health authorities have, as a result, moved to recommend the combination of sulphadoxine-pyrimethamine (which consists of a sulphonamide and a blocker of the parasite’s enzyme dihydrofolic acid reductase) as first-line treatment, but resistance to this is also spreading. The World Health Organisation has recently been urging developing countries to tackle rising resistance to antimalarial medicines; particularly with the use of artemisininebased combination therapies. The principal structure of artemisinine has been found in the Chinese mugwort (artemisia annua). For centuries, extracts from this plant had been used in Chinese medicine to lower fever. Artemisinine-based combinations consist of two different medicines, e.g., artesunate plus mefloquine or dihydroartemisinin plus piperaquine, which both work in different ways, so it seems unlikely that the malaria parasite would evolve to resist these combinations. The main interventions to reduce the burden of malaria in Africa, where 90 per cent of morbidity and mortality are concentrated are: (i) preventing parasite-carrying anopheles mosquitoes from infecting humans either by spraying insecticides or by using insecticide-treated bed nets complemented by indoor residual spraying, killing the larvae, and environmental management; (ii) provision of prompt treatment in or near the home; (iii) providing intermittent preventive therapy, i.e. anti-malarial medications to symptom-free pregnant women in high-transmission areas to protect both expectant mother and newborn; (iv) supporting and improving forecasting, mapping areas at risk and giving technical help for prevention of and response to malaria outbreaks. Malaria is an infectious disease spread by mosquitoes. More than one million people a year die of it. Many agents have been developed to fight malaria. But since parasites develop resistance to available medicines, new research is needed. This is a challenge being enthusiastically met by the pharmaceutical industry. What’s in the development pipeline? New combination treatments of antibiotics and chloroquine are being tested in large Phase 2 clinical trials. Encouraging earlier data has shown that the combination with a macrolide compound is three times more effective than chloroquine alone. For children aged one to four years, a new malaria vaccine has been developed. At the moment, this project is in Phase 2 trials. New findings that the artemisinine compounds work by blocking the enzyme ATP6 of the parasite have opened another avenue to look for further key molecules which may interfere with the enzyme system of the plasmodium species. Electron-microscopic picture of plasmodium sp. F O R M A N K I N D According to the latest reports, the parasite, when entering red blood cells in its merozoïte form, uses so-called Gs receptors. These belong to the group of beta-adrenergic receptors, which can be inactivated by beta-blockers. If this approach was feasible, it would overcome the problem of resistance, as it would interfere with a structural element of the human body and not of the parasite. M E D I C I N E S The longer-term future: Recent research has shown that infection of the cells of the liver, or hepatocytes, is the first step for plasmodium in establishing a malaria infection. The parasite, in its sporozoïte phase, moves through the organ damaging liver cells, which in turn produce hepatocyte growth factor (HGF). This makes other cells in the liver susceptible to plasmodium infection. The research finding may also explain why malaria can be more severe in patients with hepatitis B, who produce more HGF than normal. HGF and its receptor may be two new potential targets for innovative treatment strategies. 43 2361_EFPIA_brochure 10/16/06 3:58 PM Page 44 Motor Neurone Disease M E D I C I N E S F O R M A N K I N D What is motor neurone disease? Motor neurone disease (MND) is a fatal progressive neurodegenerative disease that attacks specialised nerve cells in the spinal cord and the brain, called motor neurones, which control the movement of voluntary muscles. MND is also known as Lou Gehrig’s disease, maladie de Charcot and amyotrophic lateral sclerosis. Lou Gehrig was an American baseball celebrity who died of the disease. Dr. Jean-Martin Charcot, a French neurologist, described MND in 1869. He was the first to link symptoms of the disease to a group of nerves specifically affected – the motor neurones that originate in the spinal cord. “Amyotrophic” refers to the loss of muscle mass; “lateral” refers to the nerve tracks that run down both sides of the spinal cord, where many of the neurones affected by MND are found; “sclerosis” refers to the scar tissue that remains after disintegration of the nerves has occurred. 44 Motor neurones reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. When motor neurones die, the ability of the brain to initiate and control muscle movement is lost. Patients are initially prompted to seek medical advice because of a persistent muscle twitch, muscle fatigue, or even muscle wasting. This usually starts in the hands or lower legs, often accompanied by cramps. As MND progresses, patients lose the ability to dress and feed themselves, sit up, walk, or even speak. The bodily functions that remain intact until or near death are the control of urination and bowel movements, sexual function, eye movement, and intellect. Generally, patients survive three to five years after diagnosis. Death usually occurs due to respiratory failure. Who does motor neurone disease affect? Although it can affect anyone, MND is most prevalent in the age range of 40 to 70 years and about 20 per cent more common in men than in women. The cause of the disease is still unclear. About 10 per cent of MND cases are inherited. Of those, 2361_EFPIA_brochure 10/16/06 3:58 PM Page 45 20 per cent are caused by mutations in a gene on chromosome 21 called SOD1. Over 60 mutations or structural defects of the SOD (super oxide dismutase) enzyme have been found which alter the enzyme’s ability to protect against damage to motor neurones. About 90 per cent of all cases in the general population are sporadic and have no known cause. MND occurs throughout the world with no racial, ethnic or socioeconomic boundaries. Also, MND is not contagious. With an incidence of two per 100,000 people, it is estimated that about 10,000 cases are diagnosed in Europe each year. As many as 50,000 Europeans have the disease at any given time. Present treatments: Present treatment of MND is aimed at symptomatic relief, prevention of complications and maintenance of optimal function and optimal quality of life. Most of this, in the later stages, requires nursing management of a patient who is alert but functionally quadriplegic with intact sensory function, bedridden and aware he or she is going to die. The first treatment to alter the course of MND has been available since 1995. The antiglutamatergic medicine appears to prolong the life of persons with MND and more recent studies suggest that the compound also slows the progress of the disease, allowing the patients more time in the higher functioning states. Recently, a catalytic antioxidant compound which destroys oxygen-derived free radicals has received orphan drug status to treat patients with MND. MND is a progressive disease of the nerves in the spinal cord and brain. As it progresses it leaves patients unable to move but mentally alert. Research is continuing to discover the cause and to find medicines that can improve the lives of patients with this devastating disease. What’s in the development pipeline? There are findings that transgenic mice with MND live longer when treated with a tetracycline antibiotic or the dietary supplement creatine. Researchers have been showing that the antibiotic stops a cell “suicide” (neuronal apoptosis) programme. Apoptosis includes the activation of nitric oxide and caspase enzyme. Both processes are believed to be involved in the pathology of MND. Other scientists have demonstrated that the antibiotic has a better effect when combined with a calcium channel blocker and an anti-glutamate medicine. Therefore, different combination therapies are underway to explore their effectiveness in patients with MND. An inhibitor of neuronal GAPDH-dependent programmed cell death is in Phase 3 trials. Also, clinical investigations with an anti-oestrogen medicine and a COX-2 inhibitor have been started. The longer-term future: It has been shown in mice that insertion of the gene for glial-derived neurotrophic factor, or GDNF, slows the progression of MND in mice. The same holds for the genes that encode for the glutamate transport protein. Inserting extra genes for the protein may be an approach to cleaning up the nervous system chemical glutamate from the area around nerve cells. Excess glutamate is thought to be a factor in MND. F O R M A N K I N D All these findings have yielded important knowledge on the cell death mechanisms of motor neurones in MND. M E D I C I N E S Additionally, laboratory research has revealed that genetic flaws in a cell supply line cause a human disease similar to MND. The finding suggests that blockade of the supply line that is required for transporting nutrients and growth factors within nerve cells could be a pivotal event leading to the disease. Motor neurones are distinct from other neurones in the body because of the remarkable lengths of their extensions or axons, which can extend up to a metre. Thus motor neurons are especially dependent on active axonal transport from the cell body to the neuromuscular junction and vice versa. Researchers have found that outward transport requires motor proteins known as kinesins, while inward transport is based on the motor protein dynein and its activator dynactin. Molecular deviations of these proteins may open new avenues to understand and treat MND in the future. 45 2361_EFPIA_brochure 10/16/06 3:58 PM Page 46 Obesity What is obesity? Obesity is defined as an excessive amount of body fat, rather than just excessive weight, and is a potentially serious health problem. Some individuals are obese because of an underlying medical condition, many more because of a sedentary lifestyle and high food intake in combination with a genetic predisposition of obesity. Someone is considered to be obese when their body mass index (BMI, defined as body weight in kg divided by the square of their height in m) exceeds 30. Such people have a markedly higher chance of death compared with someone of the same age and normal weight, owing to the link between obesity and diabetes, hypertension, atherosclerosis, gall bladder disease, osteoarthritis and some cancers. Obese women have 12 times the risk of developing type 2 diabetes compared to women who are not overweight and more than 85 per cent of patients diagnosed with type 2 diabetes are obese. Apart from the risk of disease, obesity leads to poor physical functioning and reduced quality of life. Symptoms of chronic low back pain are clearly related to massive overweight, and there are obvious economic and individual connotations. Obese people have far more work days lost through illness than people with normal body weight. M E D I C I N E S F O R M A N K I N D Who does obesity affect? Generating statistical figures on obesity prevalence in Europe is somewhat difficult, as these tend to be based on self-reporting data which are conducted each year in some, but not all, member states. Only a few countries measure both height and weight. During the last 20 years, the prevalence of obesity has risen tremendously in the EU. In the Netherlands, the numbers have doubled, and data from Denmark, Sweden, and Norway show a similar pattern. The prevalence of obesity in most European countries is high (15-25 per cent in women; 10-20 per cent in men) and growing in most countries. 46 In Eastern Europe, the prevalence of obesity in women is even higher, in the area of 30 to 40 per cent. In conclusion, obesity constitutes an important health hazard throughout Europe. It is becoming a major problem as increased affluence coincides with middle age and exercise tends to fall away. Also worrying is the increasing prevalence of obesity among children. In many European countries, the most rapid growth in obesity is seen in children at the age of six. Within countries there is a great variation in the prevalence of obesity between different sub-populations. In addition to social class, ethnicity also plays a role: compared to Central European children, children of immigrant parents have twice the prevalence of obesity. Present treatments: Despite the widespread nature of the problem, only two medications are currently approved in the EU for the treatment of obesity. One of these is a lipase inhibitor 2361_EFPIA_brochure 10/16/06 3:58 PM Page 47 which, taken in combination with a fat-controlled diet, acts within the stomach and small intestine to prevent breakdown and absorption of dietary fats. In clinical trials, 20 per cent of patients taking the compound lost 10 per cent or more of their body weight over two years, compared with just eight per cent of patients taking a placebo. The other obesity treatment currently available is a centrally acting serotonin – and noradrenaline – reuptake inhibitor, and is also used in combination with a controlled diet. The medicine brings about weight loss by enhancing feelings of fullness and by raising the metabolic rate. Maximal weight loss in clinical trials typically occurred in the first six months of treatment, after which the molecule given once a day was effective in helping maintain reduced weight for up to 18 months, whereas people on placebo rapidly regained lost weight. What’s in the development pipeline? Several of the medicines in development for obesity act centrally in the brain. One of the currently most advanced research programmes concentrates on an inhibitor of the central cannabinoid receptors, which is thought to reduce sensations of hunger. Another molecule, also applied to prevent epileptic seizures has been shown to cause significant weight loss over six months or more of treatment. Both these compounds are currently in Phase 3 trials. A further compound, a selective antagonist of dopamine D-1 and D-5 receptors, has reached Phase 2 trial. Another lipase inhibitor is also in Phase 2b trial. Obesity is when someone has too much body fat. It can lead to serious health problems such as diabetes and raised blood pressure. More and more people are suffering from it. Despite this there are currently only two medicines available to treat obesity. However, there are several others being researched by the pharmaceutical industry. The longer-term future: Feelings of hunger and fullness are regulated by peptide hormones secreted by the gut, acting on the brain. One of these, cholecystokinine (CCK), dispels the feeling of hunger, and there is a compound in Phase 1 trial that acts at CCKA receptors. Also, a naturally occurring gut peptide, PYY336, which signals the brain to stop feeling hungry after a meal, could be a new treatment for obesity. An exploratory investigation has shown that intravenous infusion of the peptide led to remarkable reduction in calorie intake. 25 20 Another natural anorectic could be a fatty acid, oleylethanolamide (OEA), which in an animal model reduced hunger, promoted weight loss and decreased blood levels of cholesterol and triglycerides. The action of OEA is dependent on its binding to the receptor PPAR-alpha, which might become a target for the development of a novel therapy. An alternative long-term approach is to develop medicines that raise the metabolic rate and burn off excess calories. Two of these are under investigation and are both in Phase 1 trials. 10 5 Jap an Ko (200 r No ea (2 1) Sw rwa 001 itse y (1 ) rlan 99 8) d Ita (1997 l Fra y (20 ) nce 00 ) ( Au st 2000 ) S ria Ne wede (1999 the n( 20 ) rla De nds ( 01) nm 2 ark 001) Irel (20 an 0 Fin d (19 0) lan 99 Pol d (20 ) an 01 Pol d (19 ) a 9 Bel nd (1 6) giu 99 Ice m (2 6) lan 001 d ) Spa (200 Cze Port in (20 2) uga ch 0 1 Rep l (1 ) 99 ub 9) Slo C lic vak anad (199 Rep a (2 8) Ne 0 u w Z blic 01) ( eal a 19 Hu nd ( 98) 1 n Au gary 997) Un ited stra (20 0 Kin lia ( gdo 199 0) m ( 9) a 2 Un ited Mexic 001) Sta o (2 a 0 tes (19 00) 99 )a 0% Obesity rates among the adult population, latest year available M A N K I N D Notes: Obesity rates are defined as the percentage of the population with a Body Mass Index (BMI) over 30. (a) For Australia, UK and US, figures are based on health examinations, rather than self-reported information. F O R Although there are now a significant number of compounds under investigation for use in weight reduction, the approach of the registration authorities is likely to remain cautious and directed towards patients whose obesity places them at genuine medical risk, rather than at those for whom weight loss is primarily a cosmetic consideration. 15 M E D I C I N E S According to recent research reports, newly discovered mutations of the melanocortin 4 receptor (MC4R) gene are implicated in obesity from overeating, making MC4R a candidate gene for the control of eating behaviour. Several investigators are exploring the MC4R as target for anti-obesity medicines. 30 Source: OECD Health Data 2003 47 2361_EFPIA_brochure 10/16/06 3:58 PM Page 48 Osteoarthritis What is osteoarthritis? Osteoarthritis (OA) is the term used for a family of conditions involving the degeneration of cartilage and proliferation of new bone and connective tissue, causing visible bumps and ridges around the joints in late stage cases. OA can affect most joints, including the spine, but the disease is more common in the knees, hips, feet and hands. Nodal OA, affecting the finger joints and which occurs predominantly in middle-aged women, is clinically distinct from, for example, OA of the knees, which is often related to obesity and shows a more even sex distribution. Symptoms depend on the part of the body affected, but include pain, stiffness and loss of function. Pain can become severe in the later stages of OA. M E D I C I N E S F O R M A N K I N D Who does OA affect? By the age of 65, 80 per cent of people have evidence of OA in X-rays, although only about 25 per cent have symptoms. Recent estimates have put the number of people suffering from OA in the European Union at almost 15 million, but this may be an underestimate. 48 Present treatments: Treatments for OA today are solely concerned with managing symptoms such as pain. Exercises to build muscle are useful in people who are still active, simple analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for pain control, and corticosteroid injections into the joint can help in acute states. In addition, various preparations are available for injection to improve the elasto-viscous properties of the synovial fluid in the joints, but this does not alter the course of the disease. NSAIDs inhibit an enzyme called cyclo-oxygenase (COX), blocking the formation of inflammatory prostaglandins (PGs). COX exists in two forms: COX-1 and COX-2. Prostaglandins produced by COX-2 are inflammatory and damage the gut, producing gastric ulcers and bleeding, but those from COX-1 have a protective effect. Of the 2361_EFPIA_brochure 10/16/06 3:58 PM Page 49 older NSAIDs, some inhibit COX-2 preferentially but are not entirely selective. In general, they have a lower risk of gastric ulcer formation than NSAIDS that preferentially inhibit COX-1. Several truly COX-2 selective NSAIDS have been available in Europe for some years. They should be given preferably to patients with a risk of developing stomach ulcers and other complications with older NSAIDs. What’s in the development pipeline? Additional selective inhibitors of COX-2 are being studied for use in OA. These are second generation compounds with more specific pharmacological profiles. Of particular interest will be injectable formulations, in the form of pro-drugs of existing COX-2 molecules. Another type of NSAID, which is currently in Phase 3 trials and has been shown to inhibit not only cyclo-oxygenase, but also the enzyme 5-lipoxygenase which produces leukotrienes that cause pain and inflammation. The substance controls pain and inhibits platelet aggregation and has been found to be of value in rheumatoid arthritis as well as in OA. The possibility of modifying disease progress is being investigated in a Phase 3 study that uses a bisphosphonate compound. Microscopic fractures of bone at the joint surface have been suggested as a possible underlying cause of OA and bone cysts and sclerosis are seen in advanced stages of the disease. As bisphosphonates have been shown to prevent bone remodelling in osteoporosis, there is hope that it might slow disease progress in OA too. Osteoarthritis causes pain and stiffness of the joints. Over the years, many medicines have been developed which offer pain relief to patients and help them stay mobile and independent. By understanding the disease process, there is the promise of even better medicines to come. The longer-term future: Medicines that modify disease progress must be the long-term goal for research in OA. There is research underway to find inhibitors of aggrecanase, an enzyme that breaks down aggrecan, a major component of healthy cartilage. This programme is still at an early pre-clinical stage. Other investigations are directed towards the discovery of inhibitors of matrix metalloproteinase enzymes which are also involved in the breakdown of joint membranes in arthritic diseases. Finally, the food supplement glucosamine sulphate, a molecule involved in the natural production of cartilage, has been shown to have some effect in controlling mild to moderate pain in people with OA of the knee. However, it is not at present clear that this substance will be developed for formal regulatory approval. M E D I C I N E S F O R M A N K I N D 49 2361_EFPIA_brochure 10/16/06 3:58 PM Page 50 Pain What is pain? From the earliest times, mankind has been stalked by the spectre of pain and there is much evidence from early civilisations of the struggle to provide pain relief. Over the millennia, pain has been variously attributed to demons, evil humours or dead spirits, or seen as a punishment for wickedness – in fact, the word “pain” derives from the Latin word “poena”, for punishment. Under normal circumstances, acute pain is a defence mechanism – a warning to the body that something is going wrong or that there is a risk of injury. Rare individuals born without a sense of pain usually have short lives and many injuries, because they have no warning mechanism. Chronic pain, however, serves no such purpose. Chronic pain may result from direct tissue injury and inflammation (e.g., arthritic musculoskeletal pain), from disease-related damage, or from the nervous system itself (neuropathic pain for example, in diseases such as diabetes). M E D I C I N E S F O R M A N K I N D Who does pain affect? Nearly two-thirds of adults in the EU experience back pain at some time in their lives and 35 million people a year consult their GP because of it. Furthermore, chronic pain is a common feature of the later stages of diseases such as osteoarthritis, rheumatoid arthritis, osteoporosis, diabetes and cancer, and can lead to major disability; little surprise that pain has been called the “silent epidemic”. 50 Present treatments: Modern management of chronic pain seeks to eliminate pain completely where possible and to establish a treatment schedule consistent with the minimum use of medication that prevents it recurring, rather than allowing it to return and then re-treating active pain. There are three distinct elements in pain: (i) detection by receptors; (ii) transmission by the nerves, and (iii) the perception/interpretation by the brain. Accordingly, the wide range of medicines that are used in pain management act at a variety of sites in the human body. Some act in the peripheral tissues at the site of damage. Others act in the spinal cord, while yet others act in the brain. Therapy often needs to be individualised, but pain management generally follows the three-step ‘analgesic ladder’ established by the World Health Organisation in 1990. This entails first using non-opioid analgesics or non-steroidal anti-inflammatory drugs (NSAIDs). If this proves inadequate, a weak opioid is added or substituted. In addition, steroids, local anaesthetics, anti-emetics or tranquillisers may be given to increase the effectiveness of these analgesics. Lastly, in severe, intractable pain, strong opioids are used. These include transdermal patches of opioids and slow release morphine, which give a more even and prolonged effect than some injected 2361_EFPIA_brochure 10/16/06 3:58 PM Page 51 or oral treatments. Despite these alternatives, many people suffer from intractable chronic pain or neuropathic pain that is difficult to control, or experience breakthrough pain as the effect of their medicine wears off. What’s in the development pipeline? Medicines research into pain is very specialised and many analgesics are already available, but there are a considerable number of companies actively working in this area. The sensation of pain is complex (FIGURE 1) and this gives considerable scope for developing medicines that act by new mechanisms, or on different parts of the nervous system. One example of such a mechanism involves exploration of the ability of adenosine to modulate pain perception. Several research groups have shown that the adenosine A1 receptor, known to be important in nerve transmission, is involved in neurogenic pain, and adenosine itself (which occurs naturally in the body) has analgesic properties. Several modulators of this receptor are in Phase 2 trials for effectiveness in treating neuropathic pain. Other agents under development act on nerve pathways involving glutamate. Another principle to treat neuropathic and chronic pain is to act on neuronal receptors responding to the neurotransmitter acetylcholine. Pain is the body’s most important defence mechanism. It also results from disease. A lot of specialised research is under way to develop new pain killers and to improve those that we already have. The prospects for people in pain should significantly improve in years to come. While not involving a new mechanism, NSAIDs with a lower incidence of side-effects are also being studied. Registration has been recently received and some applications are still pending for a group of second generation COX-2 inhibitors. Research is also underway with an unusual COX-2 inhibitor that delivers nitric oxide to sites of inflammation. Nitric oxide is known to have relaxing actions on capillary walls that result in reduced inflammation. A synthetic version of a peptide found naturally in snail venom, which blocks N-type calcium channels, has shown interesting results in Phase 3 clinical trials for treatment of severe chronic neuropathic pain. The medicine is applied by using a subcutaneous pump. An application for regulatory approval in the EU was filed in May 2003. Limbic system Cortex Thalamus Cerebellum Midbrain Pons Brain stem M A N K I N D FIGURE 1: The human brain in cross section, showing many of the structures concerned with pain processing and perception. F O R Medulla M E D I C I N E S Hypothalamus 51 2361_EFPIA_brochure 10/16/06 3:58 PM Page 52 Taking a different approach, investigators have three projects in progress to develop pain-relieving preparations based on cannabinoids. Delivered as a spray, one (tetrahydrocannabinol) is being tested in cancer pain (phase 3 trials), while another (a tetrahydrocannabinol: cannabidiol combination) is under study in pain from spinal cord injury and in neurogenic pain at the Phase 3 stage. New types and formulations of opioids are also being developed. The efficacy of an opioid transdermal patch, currently approved for cancer-related pain, is being studied in a Phase 3 trial in chronic back pain. The patch delivers the medicine over 72 hours. Another research group is developing the new synthetic opiate fumarate for moderate to severe pain, which is in Phase 3 trial. Meanwhile, scientists are further investigating the action of morphine itself, with a sustained release form (Phase 2 in postoperative pain), and the metabolite morphine-6-glucuronide, which has fewer unwanted effects than the parent compound (also in Phase 2 for relief of pain after hip replacement). The longer-term future: There is much research devoted to pain relief and the complex mechanisms of pain perception are becoming better understood. With the parallel search both for more effective pain control and a reduction in side effects, the prospects for medical control of chronic pain especially should be significantly improved within a few years. By molecular cloning and the use of specialised pain models, several research groups have identified specific ion channels, receptors and neurotransmitters that may be involved in pain. On the basis of such studies, it has been shown that a family of sodium channels is specific to neurons and central pain regulation. Other research targets are calcium ion channels which may be of interest to treat neuropathic pain. The cloning of neurotransmitter receptors has already opened new avenues. Dorsal root ganglion Dorsal root Spinal cord Inhibitory commissural interneuron Sensory neurons from skin Excitatory commissural interneuron Stimulus Ventral root Motor neuron to flexor muscle M E D I C I N E S F O R M A N K I N D Motor neuron to extensor muscle 52 Motor neuron to flexor muscle Flexor muscle stimulated Extensor muscle inhibited Nerve and spinal cord connections involved in the response to a painful stimulus such as a pin-prick. The sensory nerve enters the dorsal root and passes its messages via interneurons to the motor neurons that leave through the ventral root to produce a reflex muscle response 2361_EFPIA_brochure 10/16/06 3:58 PM Page 53 There is great interest in the structure and function of the NDMA receptor, a particular part of which is thought to be involved in the maintenance of chronic pain. Yet another receptor target is called the vanilloid (VR1) receptor. VR1 is a non-selective cation channel expressed on the peripheral and central terminals of some types of neurons. It is thought to be a key integrator of pain signals in the nervous system. It has also been shown that capsaicin (the hot component of chilli peppers) binds to it. Also, research is targeting bradykinin (a peptide that can strongly enlarge small blood vessels) as it is considered to be involved in peripheral tissues where it augments pain caused by tissue damage and inflammation. Another naturally occurring protein, artemin, could represent an effective new approach to treating neuropathic pain, as its receptor is only found on sensory neurones. Another long-term approach to pain control may be through the use of monoclonal antibodies which can be designed to bind with great selectivity to ion channels, membrane receptors or neurotransmitters. M E D I C I N E S F O R M A N K I N D 53 2361_EFPIA_brochure 10/16/06 3:58 PM Page 54 Peripheral Vascular Disease M E D I C I N E S F O R M A N K I N D What is peripheral vascular disease? Peripheral vascular disease (PVD), also known as peripheral arterial occlusive disease (PAOD), is atherosclerosis of the lower extremities that restricts or obstructs blood flow to the legs and feet. Its characteristic symptom, intermittent claudication (IC), is a pain in the leg that develops on walking and subsides on resting. This pain has the same cause (inadequate blood-borne oxygen and nutrient supply to muscle because of atherosclerosis) as the pain of angina pectoris in people with cardiovascular disease. Patients with IC typically have a 2-3 times higher mortality due to heart attack or stroke than healthy people of the same age. 54 IC may be progressive, limiting independent living and eventually leading to critical restricted blood flow in the limb that demands emergency treatment, such as thrombolytic treatment or angioplasty to open or widen the blocked artery, vascular surgery to replace a section of blocked artery, or even amputation. Raised blood triglyceride levels, smoking and diabetes are all important risk factors for disease progression. Diabetic patients having angiograms for PVD are five times more likely to have an amputation than non-diabetic patients and in another study, smokers had an amputation rate eleven times that of non-smokers. Nevertheless, an amputation will be necessary in the lifetime of only two to four per cent of those with IC and, in the majority of patients, the disease runs a relatively benign course that can be treated medically. Who does peripheral vascular disease affect? PVD is unusual below the age of 50, but prevalence rises with increasing age. In a survey of men and women aged 55-74 in the UK, the overall prevalence of IC was 4.5 per cent. However, the number of people with symptomless PVD is much greater: almost two-thirds of people in this age range. 2361_EFPIA_brochure 10/16/06 3:58 PM Page 55 Present treatments: Non-emergency treatment for PVD has two aspects: managing the symptoms that degrade quality of life and addressing the risk factors of the underlying atherosclerotic process. Aggressive treatment of lifestyle factors (e.g., smoking cessation, weight loss) and intervention to manage concomitant diabetes and reduce hypertension and elevated lipids is essential to prevent disease progression. Relatively few medications have been authorised specifically for symptomatic treatment of IC. Vasodilating medicines are given to reduce peripheral vascular resistance to blood flow. The commonly used vasodilators improve the flow properties of blood, lowering blood viscosity and increasing red blood cell flexibility. Another compound enhances muscle utilisation of glucose and oxygen, making better use of the available blood supply. The improvements in pain-free walking distance achieved with these medications is usually modest (40-50 per cent) but can be crucial at home where walking distances can be covered without pain. In physically active patients, a regime of exercise training should accompany medicines therapy and may sometimes be more effective. Peripheral Vascular Disease (PVD) restricts or stops blood flow to the legs. People with PVD cannot walk far without pain. New medicines to treat it are being studied. The research should bring welcome relief to patients whose lives are limited with PVD. What’s in the development pipeline? The development of new medications for IC has suffered setbacks in the past, with new compounds showing only limited improvement in pain-free walking distance (the main indicator of efficacy). However, there is a new 5HT2A receptor antagonist currently in Phase 3 trial in the EU. 5HT2A receptors are involved in platelet aggregation and the relaxation of smooth muscle, so this anti-platelet therapy may both reduce eventual formation of blood clots and relax arteries, improving blood flow. Research is also progressing with an anti-platelet compound in Phase 3 trials. Two plaque-formation inhibitors are also under study in PVD, a lipid-lowering agent and a new ACAT inhibitor, both in Phase 3. The longer-term future: PVD is an area that may see the application of gene therapy, with several separate initiatives already underway to use this technique to promote angiogenesis, the growth of new blood vessels that may bypass an obstructed artery. Phase 1 and 2 studies are under way to test whether these therapeutic approaches hold promise. Such medicines would act locally in muscle cells to produce an angiogenesis-promoting protein that is not secreted into the bloodstream. In Europe, the first clinical studies have started with a vector that inserts the gene for fibroblast growth factor 4 (FGF-4), an angiogenic protein. Another principle is to develop placental growth factor (PIGF) as a possible treatment for ischaemic disease based on preclinical results that it has a targeted effect at the site of ischaemia. In the USA, Phase 2 clinical trials have begun with a hepatic growth factor (HGF) genetic medicine which induces blood vessel regeneration. M A N K I N D Narrowing or blockage of a major artery in the leg is the cause of intermittent claudication. F O R Build up of deposits of fat in the wall of the artery M E D I C I N E S While this gene therapy approach does not cure the blockage that causes symptoms, it may provide a relatively simple way of improving functional status (pain-free walking) that would bring a welcome relief in patients whose lives are limited by peripheral vascular disease. 55 2361_EFPIA_brochure 10/16/06 3:58 PM Page 56 Psoriasis What is psoriasis? Psoriasis is a chronic inflammatory skin disorder, often with relapses and remissions, characterised by red disc-like raised lesions with dry, silvery scaling, most frequently on the elbows, knees or scalp. These build up because the rate of cell (keratinocyte) division of psoriasis skin is much higher than normal. Most cases are mild, but a few can be widespread and disfiguring. Psoriasis is not contagious. Its cause is still not M E D I C I N E S F O R M A N K I N D known. Until the 1980s, the disease was thought to be caused by cells dividing at an abnormally high rate. However, as scientists began to perceive psoriasis as an immunological condition, research has focused on the role of inflammatory messenger compounds (cytokines) in the condition’s progress, on the role of T-lymphocytes (white blood cells), and on genetic factors. In November 2003, research groups in Europe and the USA independently reported on the implication of three genes on human chromosome 17 and of the regulatory gene RUNX 1 in psoriasis. While the disease is not curable, treatment can bring periods of remission and improve both appearance and mood. 56 Who does psoriasis affect? In Europe, it is estimated that plaque psoriasis has a prevalence of about 0.8 per cent. This means that the disease affects about 3.7 million Europeans, with about 2.4 million people considered to have moderate to severe disease. Psoriasis usually occurs in young adults (15-40 years, with mean age of onset 33), with men and women equally likely to be affected. Present treatments: Mild to moderate skin plaques are traditionally treated with topical formulations containing either dithranol or coal tar and colloidal sulphur. Ointments containing Vita- 2361_EFPIA_brochure 10/16/06 3:58 PM Page 57 min D derivatives or a Vitamin A derivative are also used to treat chronic plaques. Steroids applied to the skin are also frequent first-line treatments, but inflammation may recur when they are stopped. Also available is a combination cream containing both a Vitamin D derivative and a steroid. Antibacterial and antifungal solutions may be useful in preventing infection of the inflamed skin. Exposure to certain wavelengths of UV light while simultaneously taking psoralen and a vitamin A derivative (retinoid) can be beneficial in some cases. In severe psoriasis, immunosuppressive medicines are effective. None of the many treatments for psoriasis has been really satisfactory. Many topical preparations are messy and slow-acting (four to six weeks); and none eradicate the condition: relapse is inevitable. An orally given retinoid persists in the body for a long time and can cause birth defects, so women of child-bearing age are warned not to become pregnant for two years after a course of this type of treatment. With new understandings of the disease’s action has come a new generation of products that offer the first new approaches in 40 years. Close to becoming available in Europe is a human fusion protein, which has been already approved in the USA. This protein, given by injection, consists of two different parts. By its dual function, the fusion protein inhibits so-called memory-effector T-lymphocytes, which are thought to play a key role in psoriasis. Effector T-lymphocytes are also targeted by an injectable anti-CD11a monoclonal antibody that is currently in late stage of clinical investigations in the US. In September 2003, the US FDA’s dermatologic and ophthalmic drugs advisory committee unanimously recommended approval of this new medicine. Both products are intended for use in moderate to severe psoriasis and appear to have similar efficacy, with about 35 per cent of patients achieving a reduction in symptom score of 75 per cent or more. Psoriasis is an inflammation of the skin. It is not contagious but heavy forms of it make sufferers’ lives a misery. Over the years, the pharmaceutical industry has discovered many medicines to treat it. Current research is likely to result in even better therapies in the future. Finally, several new compounds are under trial that are directed against the inflammatory mediator tumour necrosis factor alpha (TNF-a). One anti-TNF-a monoclonal antibody has already been approved for the condition in the USA and the EU. Several other anti-TNF-a monoclonal antibodies have reached the Phase 3 stage. All of these compounds acting on TNF-a are being mainly developed in the USA. What’s in the development pipeline? The range of biological treatments for psoriasis is set to expand. New treatments under development include an anti-IL-2 monoclonal antibody. Already approved for transplant rejection, this is being tested in Phase 3 trials to see whether it can prolong the disease-free period after an initial response to immunosuppressive treatment with a calcineurin inhibitor. The cytokine IL-8, a potent keratinocyte growth factor and greatly raised in psoriasis, is the target of a specific monoclonal antibody in Phase 3 trials in the US. Another monoclonal antibody in Phase 2 trials in both the USA and Europe is directed against the CD2 antigen found on activated T-lymphocytes in psoriasis. IL-18 binding protein, a human recombinant molecule directed against the mediator of inflammation interleukin-18, has recently moved into Phase 2 clinical investigation. An analogue compound of the calcineurin inhibitor cyclosporine is also in clinical trial Phase 2. F O R A psoriatic plaque before and after 2, 4 and 8 weeks treatment with a topical retinoid, showing a good response. M E D I C I N E S M A N K I N D The longer-term future: Although psoriasis is still not well understood, the new biological compounds under development all focus on molecules that are known to be involved in its progress and are more specific in their actions than older medicines such as steroids, immunosuppressants, vitamins and coal tar. There is, therefore, good hope of treatments that give better control of symptoms with fewer troublesome side-effects and greater convenience in use. 57 2361_EFPIA_brochure 10/16/06 3:58 PM Page 58 Thrombosis M E D I C I N E S F O R M A N K I N D What is thrombosis? Thrombosis occurs when a clot inside a blood vessel restricts or blocks blood flow. Maintaining the liquid state of the blood depends on complex interactions between blood cells, the endothelial cells lining the blood vessels and substances in the blood itself. These promote coagulation when required, but prevent it at other times. For example, injury, exposure to air and to collagen fibres at the site of damage initiates the clotting process. Collagen is a fibrous protein and a major component of cartilage, bone and connective tissue. Blood platelets become sticky and collect together and a network of fibrin fibres forms which binds the clot together, stopping bleeding. 58 In some disease states, this balance fails and clots develop inside arteries. This may result in a heart attack or stroke. If a clot forms in a vein deep in the tissues, there is a risk that part of it may detach and travel to the heart, lungs or brain where it can cause an obstruction (a thromboembolism), with serious consequences. Clot formation after major operations that involve collagen, such as hip replacement or knee surgery or through prolonged immobility, such as bed-rest while in intensive care or during long-distance air travel, (deep vein thrombosis, DVT), can put life at risk. A clot in a superficial vein may give rise to inflammation, known as phlebitis, but carries less risk of detachment and, with rest, normally settles down quickly. Clot and plaque formation are both made more likely by risk factors such as smoking, high cholesterol, high blood pressure and diabetes. Who does thrombosis affect? About ten million people die each year world wide from stroke and heart attack, making it one of the biggest killers on earth. Research suggests that one in 12 white EU citizens carry a gene mutation making inherited thrombosis more likely – a significant 2361_EFPIA_brochure 10/16/06 3:58 PM Page 59 target for prophylaxis, if effective medication can be developed. In patients undergoing surgical knee replacement without medical prophylaxis, DVT events have been found in up to 85 per cent of all cases. Thrombosis occurs when a clot inside a blood vessel restricts or blocks blood flow. It can lead to heart attacks or strokes. Major research by pharmaceutical companies has developed medicines to dissolve clots or to stop them forming. These have saved many lives. Present treatments: From a medical point of view, there are two separate, though overlapping, issues. The first is the prevention of blood clots. This may be a temporary requirement after an operation or accident, or it may be part of long-term management after a first heart attack or other circulatory episode. The second is the removal or reduction of clots once they have formed. These situations present different challenges and require different medicines. Thrombosis prevention involves the use of either anti-platelet agents, or anti-coagulants that inhibit components of the cascade that produces the fibrin tangles in clots. The best-known anti-platelet medicine is aspirin, which decreases platelet stickiness and markedly reduces the risk of a heart attack or stroke in those who have already had one, or who have unstable angina. Other compounds with a different molecular structure but similar action are also used for this purpose, possibly in combination with aspirin. A more recently introduced oral anti-platelet medicine blocks the ADP-receptor on platelets and prevents clumping. The molecule has shown a protective effect in addition to that provided by aspirin and other medicines such as ACE inhibitors and cholesterollowering statins and, like these, is indicated for long-term protection. Also effective in the long-term prevention of recurrent venous thromboembolism are derivatives of coumarin that work as vitamin K antagonists and Thickening at junction prevent the biosynthesis of clotting factors in the liver. A low dose regimen of such medicines has been shown to give a high reducFat deposits in tion in risk of DVT recurrence. fibrous plaque Early fatty streak Heparin and low-molecular weight (LMW) heparin derivatives are the main agents used for short-term prevention of blood clotting in the hours immediately following a myocardial infarction or stroke and during operations such as angioplasty. Also used for this purpose are the recently introduced inhibitors of the glycoprotein 2b/3a receptor that is involved in platelet aggregation. Also available are a cyclic heptapeptide, a tyrosine derivative and a monoclonal antibody, which are normally given under specialist care by intravenous injection, in addition to aspirin and heparin or LMW heparin derivatives. Thrombus made of fibrin and platelets Embolus breaking free Vessel narrowing Bleeding within vessel wall Calcification Inflammation and necrosis Embolus blocking side branch Wandering embolus Thickening and ‘hardened’ wall of artery M A N K I N D Stages in the development of atherosclerotic plaque and the formation of emboli F O R Ulceration of inner wall M E D I C I N E S Plaque The treatment of clots that have already formed is mainly with so-called ‘clot-busting’ medications such as the enzyme streptokinase, or the more specific recombinant forms of the naturally occurring tissue plasminogen activator (TPA). These medicines transform the naturally occurring molecule plasminogen in the blood into plasmin, an enzyme which splits fibrin tangles and dis- 59 2361_EFPIA_brochure 10/16/06 3:58 PM Page 60 solves existing clots. Plasminogen activators must all be given intravenously under expert supervision and within three to six hours of suspected infarction if they are to be of benefit. Low molecular weight heparins are also indicated for the treatment of clots in pulmonary embolism and deep vein thrombosis. They are given by subcutaneous injection. Bleeding and depressed platelet counts are side-effects associated with heparins and careful monitoring may be required to avoid overdosing. What’s in the development pipeline? The new medicines in development are mainly anti-coagulants. One group is directed at inhibiting activated Factor X and another at inhibiting thrombin. Only recently, a synthetic pentasaccharide Factor X a inhibitor was registered in the EU in a variety of indications. The same scientific partners have another pentasaccharide in Phase 3 trials for DVT prophylaxis. Other research groups are also working on Factor X a inhibitors. A monoclonal antibody against Factor VIII for thromboembolism is still in preclinical development. The most advanced compound in the category of new thrombin inhibitors is in Phase 3 trials for the prevention and treatment of venous thromboembolism and for postinfarct prevention. Two further new thrombin inhibitors are being studied in the early clinical phase. The advantage of this new class of medicines is their fixed oral dose. Other approaches are an antagonist of ADP-binding to platelets in Phase 3 trial. At the pre-clinical stage, researchers are investigating a compound that inhibits plasminogen activator inhibitor (PAI-1), and another group to start clinical trials in acute myocardial infarction with a dual thrombolytic and anti-thrombotic agent. For the thrombolytic treatment of acute myocardial infarction, a pegylated recombinant staphylokinase variant is in Phase 2 clinical trial. Another new approach under review is microplasmin, a LMW form of natural plasminogen. This compound has completed Phase 1 for the treatment of ischaemic stroke, peripheral arterial occlusive disease and bleeding into the vitreous of the eye. MEDICAL MANAGEMENT OF BLOOD CLOTTING M E D I C I N E S F O R M A N K I N D PREVENTION OF BLOOD CLOTS THROMBOLYSIS-REMOVAL OF CLOTS Post-operative prevention Long-term prevention in patients pre-disposed to thrombosis “Clot-busting” medicines (Heparin, LMW heparins and other compounds which inhibit platelet aggregation) (Aspirin and other compounds which inhibit platelet aggregation) (Streptokinase, recombinant tissue plasminogen activators, also LMW heparins) Medical strategies for preventing and managing blood clots 60 2361_EFPIA_brochure 10/16/06 3:58 PM Page 61 The longer-term future: Thrombosis is still an area of major research and development effort, as existing therapies have significant drawbacks. Doctors still have to walk the tightrope of anticoagulant dosing until an antithrombotic therapy has been found that specifically targets life-threatening thrombi. Advances are being made, although these have tended to be incremental. Biotechnology is enabling the design of new medicines that are very precisely targeted at specific steps in the formation or breaking down of blood clots and there is hope that this will result in a clinically significant improvement in outcome in the various hitherto life-threatening manifestations of thrombosis. Scalp Skull Cerebral arteries in brain Fluid filled space between skull & brain BRAIN Basilar artery in brain Artery to face and nose Internal carotid artery Vertebral bones in the neck Vertebral artery Bifurcation of the carotid, one of the commonest sites of plaque formation First rib Right common carotid artery Aorta from the heart Diagram showing the main vessels supplying blood to the brain M E D I C I N E S F O R M A N K I N D 61 2361_EFPIA_brochure 10/16/06 3:58 PM Page 62 Tuberculosis What is tuberculosis? Tuberculosis is a bacterial infectious disease caused by mycobacterium tuberculosis. It is characterised by formation of granulomas. Primarily, the disease affects the lungs. Signs and symptoms include a cough for more than 3 weeks, chest pain, tiredness and fatigue, night sweats, coughing up blood and weight loss. Tuberculosis is transmitted when an infected person coughs, spits or sneezes and sends microscopic droplets loaded with the bacteria into the air, and other people inhale these. Body fluids of patients, like saliva, blood and urine can also be a source of infection. Tuberculosis thrives in conditions of poverty and overcrowding. A person with active tuberculosis can infect an average of 15 people a year. Not everybody who is infected falls ill. One in three of the global population – about two billion people – have latent tuberculosis infection, but only about ten per cent of them will go on to develop the disease. In patients with a weakened immune system, the disease may generalise and lead to abscesses in multiple organs, including the brain and the skeletal system. M E D I C I N E S F O R M A N K I N D Who does tuberculosis affect? Every year, about eight million people contract tuberculosis and two million die from it. The World Health Organisation estimated recently that, between 2000 and 2020, nearly one billion people will be newly infected, 200 million will get sick and 35 million will die from tuberculosis. This is largely due to the spread of HIV in Africa and to the economic difficulties affecting the newly independent states of Eastern Europe and Central Asia. Approximately 80 per cent of all tuberculosis cases are found in 22 “high burden” countries with the largest number of cases in Africa and southeast Asia. 62 Present treatments: Until approximately 50 years ago, there were no medicines to treat tuberculosis. Since the 1950s, appearance of new therapies of different types allowed tuberculosis epidemics to be brought rapidly under control. One of the difficulties of treatment is that tuberculosis bacteria have become resistant to medicines, though there is less danger of this when two or four medications are given together. Some bacterial strains are resistant to a single medicine or even a combination of them. Multi-drug-resistance is caused by inconsistent or partial treatment, when patients do not take their medicines regularly for the required period. Multi-drug-resistant tuberculosis takes at least 18 to 24 months of treatment and has a poor chance of cure. Another problem with tuberculosis treatments is that they are lengthy and complicated. To cure tuberculosis, a four-drug combination – isoniazid, rifampicin, pyrazinamide and ethambutol – preferably in one tablet, given over 6- to 9-month treatment periods is advised. The therapy must be given under strict supervision, since patient compliance is crucial for the success of the treatment. 2361_EFPIA_brochure 10/16/06 3:58 PM Page 63 Multi-drug-resistant cases may also be treated with rifapentin, a substance which was introduced in 1998. The strategy recommended by the World Health Organisation (WHO) for the detection and cure of TB is known as DOTS (Directly Observed Treatment Short-course). DOT (Directly Observed Therapy) is a system of monitoring compliance of TB patients and their treatment regimens. The entire system is underpinned by trained volunteers, but also involves many health workers at health care facilities. WHO aims to detect 70 per cent of new infectious TB cases and to cure 85 per cent of those detected. Six countries achieved these targets in 1998 and all 22 of the high burden countries had adopted DOTS. Currently, 43 per cent of the global population has access to DOTS, double the amount reported in 1995. In the same year, 21 per cent of estimated TB patients received treatment under DOTS, also double the amount reported in 1995. Other interventions include BCG (Bacille Calmette-Guerin) vaccination of newborns or young people to prevent tuberculosis. Although BCG is efficacious against serious forms of the disease in children, protection is variable in adults. Tuberculosis is an infectious bacterial disease that affects the lungs and/or other organs. Until 50 years ago there were no treatments for it. Nowadays there are many medicines but further research is required to overcome resistance and to eradicate this centuries old scourge. What’s in the development pipeline? A number of new candidate vaccines for tuberculosis have been tested in preclinical studies, under an EU project involving public and private research organisations and pharmaceutical companies. The project, called the TB Vaccine Cluster, was set up under the fifth research framework programme 1998-2002, and has allocated e 15 million to vaccine research. TBVac has established a joint academic-industrial consortium capable of taking TB vaccine candidates from the laboratory bench to Phase 1 trials. It involves 38 leading European research groups from 12 countries, including two large pharmaceutical companies. In addition, the EU is supporting complementary vaccine projects, two of which are looking at the possibilities of intranasal or oral vaccination as an alternative to injection. In the USA, a Phase 1 trial has been started in January 2004 to test a recombinant vaccine containing two proteins of mycobacterium tuberculosis. Only recently, a new lead substance based on the natural product, thiolactomycin, has been found. This compound has shown activity against TB both in vitro and in vivo and efforts have begun to develop a compound with improved potency, although it will probably be several years before these compounds enter development. Also in preclinical studies is a nitroimidazopyran-containing agent which acts against mycobacterium tuberculosis and has bactericidal activity comparable to isoniazid. It also appears to be active against non-replicating organisms, suggesting it might be a potent sterilising agent capable of significantly shortening TB treatment time. Research is also underway to look into new disease models. Scientists have developed a goldfish model of tuberculosis, which they hope to use to design an attenuated live mycobacterium tuberculosis vaccine. Goldfish play host to mycobacterium marinum, a species closely related to mycobacterium tuberculosis. The pathology of mycobacterium marinum infection in the model parallels that of human TB infection, with giant cell and granuloma formation. F O R M A N K I N D It is projected by the scientific community that at least one new medicine against tuberculosis will be registered by 2010 and available in high-burden areas by 2012. To achieve this, five new medicines against the disease will need to have completed preclinical trials by 2005. M E D I C I N E S The longer-term future: Much of the future scientific work will depend on improving knowledge of the genome of mycobacterium tuberculosis. This is still at an early stage. What are especially needed are new medicines that work in latent tuberculosis and will markedly reduce the treatment time frame. Microscopic picture of Mycobacterium tuberculosis 63 2361_EFPIA_brochure 10/16/06 3:58 PM Page 64 Urinary Incontinence What is urinary incontinence? Incontinence is an inability to control the bladder, resulting in involuntary leakage of urine. Common forms are stress incontinence (leakage on coughing, laughing, physical exertion), due to increased abdominal pressure, and urge incontinence, as a result of spasm. The latter is the most responsive to medication. The mechanisms controlling normal urination are complex, involving the brain, nervous system and various muscles in the bladder itself. Treatment for incontinence should address any organic cause of loss of control where possible. Who does incontinence affect? In Europe, more than 16 per cent of men and women aged 40 or older experience symptoms of overactive bladder, giving a total of 25 million people. Patients usually complain about several episodes of incontinence in the last month, and having to get up twice or more during the night to urinate (nocturia). The proportion of people affected by incontinence episodes, an increased rate of urinations per day and a decreased average volume of urine passed per urination increases with age. Cerebrovascular disease (stroke, dementia), impaired mobility and multiple medications are associated with incontinence in the elderly and it is the most common triggering factor for an elderly person being admitted to residential care. M E D I C I N E S F O R M A N K I N D Incontinence remains a taboo topic and it is estimated that only 10-20 per cent of people with an unstable or overactive bladder receive any kind of treatment; only one fifth of those are on medication. 64 Present treatments: To date, treatment options have been limited. Teaching muscle control and retraining of the bladder (pelvic floor exercises) helps some of those affected. In addition, medicines acting on the bladder may be helpful. Several medicines, called anti-cholinergic compounds, work on the contractile muscle of the bladder (the detrusor muscle) to reduce spasms by selectively blocking muscarinic receptors of the M3 subtype. In addition, there is a different type of anti-cholinergic medication, which acts selectively on muscarinic receptors regulating bladder relaxation (M2 receptors). What’s in the development pipeline? Several further M3 receptor-specific compounds are in late stage clinical trials to treat overactive bladder (both urge and frequency incontinence). In March 2003, a clear patch applied twice weekly was authorised in the EU and provides an alternative to existing oral medicines. The product is said to have a lower anti-cholinergic side effect profile. Such unwanted effects, including dry mouth, blurred vision and constipation, are common reasons for treatment discontinuation with older anti-cholinergic products. As the elderly make up a large part of the patient population for urinary incon- 2361_EFPIA_brochure 10/16/06 3:58 PM Page 65 tinence, an improved side-effect profile would be beneficial for patients taking multiple medicines. While medicines to treat overactive bladder are now intensively researched, there are no medications approved for the other common form of incontinence, stress incontinence. Therefore, researchers are exploring a compound which acts in the central nervous system by inhibiting reuptake of serotonin and norepinephrine in nerves involved in controlling bladder function. Also in development is a compound which is believed to be an inhibitor of C-fibre nerves with an original mechanism of action to treat incontinence. The longer-term future: There would seem to be limited scope for improving clinical results by developing more specific muscarinic receptor blockers which act on the muscle itself; instead, progress is likely to come from investigating alternative mechanisms of action. Compounds interacting with neurokinin (NK) receptors are exciting most interest at present. The furthest advanced compound with this mode of action, which targets NK-1 receptors in the central nervous system, is in Phase 2 trial. The advantage of this approach is that the medicine works on the nerves controlling the urination process and does not inhibit the functioning of the detrusor muscle itself, which should reduce the risk of urinary retention. Urinary incontinence is the involuntary leakage of urine. The embarrassment of this condition means that many people don’t receive treatment. Research-based companies are developing promising medicines to help improve the lives of incontinence sufferers. Other neurokinin antagonists are under development either in Phase 1 trial or still in the preclinical stage. Approaches being explored include inhibitors of central nervous system alpha1-adrenoceptors in preclinical development for stress incontinence, and a potassium channel opener, in Phase 2 trial for overactive bladder. The modulation of potassium channels of small and intermediate conductance of nerves affecting the bladder muscle may be such a promising pathway. So far, molecules with this profile have shown promise by increasing the time between urination and the amount of urine in the bladder. Other research is being devoted to temporarily restricting urine production, allowing patients “to turn it off” for a certain period, so that people can attend meeting or go to the cinema. Ureter Detrusor smooth muscle Inner mucous membrane Peritoneal coat Trigone Prostate gland Pelvic floor striated muscle F O R M A N K I N D Anatomy of the bladder (male). Contraction of the detrusor muscle expels urine from the bladder; the urethral sphincter muscle squeezes tight to prevent flow. M E D I C I N E S External urethral sphincter 65 2361_EFPIA_brochure 10/16/06 3:59 PM Page 66 Viral Hepatitis What is viral hepatitis? Viral hepatitis is an infection of the liver caused by one of several viruses. Three such viruses cause significant disease: Hepatitis A (HAV), transmitted by contaminated water, food or smear infection, is generally an acute disease that is only occasionally fatal, but hepatitis B (HBV) and hepatitis C (HCV), both transmitted through blood and body fluids, can lead to chronic infections that are a serious health problem. Vaccines are available for the prevention of hepatitis A and B, but so far not for hepatitis C. Who does hepatitis affect? Throughout Europe, there is a considerable underestimate of the true incidence of hepatitis A, as many cases especially in young children (more than 70 per cent) show no symptoms. Contrary to these findings, more than 75 per cent of patients infected with HBV or HCV are in the age range 15-44. More than 400 million people around the world have hepatitis B and approximately 170 million people suffer from hepatitis C. Adults infected by HBV mostly develop an acute infection and subsequently recover, but about 10 per cent develop chronic infection, which can progress to cirrhosis or to hepatoma, a form of liver cancer. The poorest prognosis of the disease goes along with genetic mutations to the core promoter and/or pre-core region of the virus genome. This occurs 10-20 years after the onset of the infection and is characterised by loss of the HBe antigen. HBeAG-negative chronic hepatitis B – also known as “variant” or “pre-core mutant” disease – has so far been less responsive to therapy and progresses faster towards cirrhosis. In the past ten years, there has been a dramatic increase in the prevalence of this form of disease. It is estimated that in southern Europe HBeAG-negative HBV infections account for 80 per cent of cases. M E D I C I N E S F O R M A N K I N D Persistent infection with HCV is the main cause of liver transplantations in Europe. The number of those chronically infected with HBV or HCV in Europe is not accurately known, but is estimated at three per 10,000 of the population, with a somewhat higher prevalence of HCV in Southern Europe. Altogether, this would be equivalent to 12 million people. 66 Present treatments: The main therapy for both chronic HBV and HCV infections has been treatment with conventional recombinant alpha-interferon. Combining this with an antiviral drug has been shown to be more effective than monotherapy in chronic HCV infection. With the arrival of long-acting, pegylated interferon alfa-2a, which is given once weekly, the treatment of chronic hepatitis B looks set for significant changes. In October 2003, results of clinical trials in patients with the most difficult to treat form of the disease – HBeAg-negative chronic hepatitis B – have been encouraging, with respect to defined treatment duration and resistance development. More applications for approvals are expected in 2004. To reduce the viral load in HBV, monotherapy with nucleotide analogues is an alternative to interferon treatment; about a quarter of patients become virus-free within one year. Unfortunately, therapy resistance develops in around 40 per cent of cases after two 2361_EFPIA_brochure 10/16/06 3:59 PM Page 67 years. In March 2003, a new nucleotide analogue compound was approved in the EU. The product also works by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the human body. The molecule has been authorised for the treatment of adults suffering from stable HBV infection with evidence of active viral replication, persistently elevated serum alanine aminotransferase levels and histological evidence of active liver disease. What’s in the development pipeline? There are Phase 3 trials in progress to extend the use of nucleotide analogues in HBV to children in the age range 2-16 who may have contracted the disease as a result of transmission from their mother. Another antiviral blocking HBV DNA polymerase is in Phase 3 trial for the treatment of patients with chronic HBV who do not respond to other nucleotide analogues. Development of interferons continues, with international trials of pegylated alpha-interferon and beta-interferon in chronic HCV. Patients treated with a combination of pegylated interferon plus nucleoside analogue without achieving undetectable serum levels of HCV RNA may benefit from the accompanying therapy with a newly found inosine monophosphate dehydrogenase inhibitor which is in phase 2 clinical trials. Another protease inhibitor for HCV is in preparation with targeted delivery to the liver. An orally given caspase enzyme inhibitor is in Phase 2 clinical trial. Caspase enzymes have been shown to mediate apoptosis (programmed cell death) and to be implicated in liver diseases. The approach might thus be valuable also for patients with fatty liver disease or hepato-biliary disease. Viral hepatitis is an infection of the liver by one of several viruses. If it becomes a chronic illness it may lead to cancer or liver failure. The pharmaceutical industry is exploring many ways to find new medicines and vaccines to tackle this serious worldwide health problem. Two interesting projects are underway in the vaccine area: the first is a DNA-based vaccine for the prevention of HBV. It is believed that vaccinating with DNA coding for HBV antigens will be an efficient alternative to the more usual vaccines that employ recombinant protein and may induce cellular as well as antibody-based immunity. The second project is a therapeutic vaccine, which is intended for treatment of chronic HBV. Marketing approval has been received in Europe for the combined HAV +HBV vaccine and for two infant combination vaccines that include HBV along with other childhood vaccines. Two DNA vaccines encoding genetically modified proteins from the surface of HCV have just entered Phase 1 clinical trials. They are supposed to elicit an immune response to prevent infection with HCV. The longer-term future: Some approaches at an early stage of exploration include the pre-clinical development of an inhibitor of a key HCV enzyme called helicase. In addition, there is exploration of an antisense compound that may inhibit viral replication; this is undergoing early clinical investigation in the United States for chronic HCV infection. Electron-microscopic picture of Hepatitis A F O R Electron-microscopic picture of Hepatitis B M A N K I N D In January 2004, a joint-development agreement was announced, which will see two research groups expanding their HCV cooperation and working to develop a therapeutic vaccine. Development of an effective and affordable vaccine against HCV is highly desirable. Like HIV, the virus is known to undergo continual rapid mutation and, so far, the development of a therapeutic vaccine remains a challenging project. M E D I C I N E S Research also pursues the development of new thiophene-2-carboxylic acid derivatives to inhibit the HCV-NS5B protein. This is the primary catalytic enzyme of the HCV replicase complex, an RNA-dependent RNA polymerase which is believed to be responsible for the genome replication of HCV. Recent research findings on how HCV is hiding itself from the human immune system may open new avenues for medical treatment of persistent infection: Apparently, the virus uses a protease called NS3/4A to neutralize human enzyme interferon-regulatory-factor 3 (IRF-3) which under physiological conditions would orchestrate the spectrum of countermeasures of the human body against viral infections. 67 2361_EFPIA_brochure 10/16/06 3:59 PM Page 68 © Geursen Consulting Heiligenbergstrasse 3 D – 69121 Heidelberg Germany Tel.: + 49 6221 5860 570 Fax: + 49 6221 5860 571 e-mail: [email protected] Editor: Robert G. Geursen, MD, PhD Prepared for the European Federation of Pharmaceutical Industries and Associations (EFPIA) Inspired by “A to Z of British Medicines Research” with autorisation of ABPI. Photo credits: ABPI, Allergan, AstraZeneca, Aventis, EFPIA-Lander Loeckx and Roche Design: Megaluna, Brussels (Belgium) Print: Arte-Print, Brussels (Belgium) The Medicines for Mankind publication is made available on condition that no part of the publication (including photographs) may be reproduced or abstracted without prior agreement with the European Federation of Pharmaceutical Industries and Associations (EFPIA). Under no circumstance can any of the material (including photographs) included in this publication be used in promotional material. May 2004