English - Medicines for Mankind

Transcription

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.
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
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.
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 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.
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
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
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.
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
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
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 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.
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.
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.
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.
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
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.
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 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.
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.
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.
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
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
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
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.
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.
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.
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 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
industry.
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
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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
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.
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
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.
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
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).
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.
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.
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.
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

English - Medicines for Mankind

Transcription

Similar documents

PDF ??жатын