Lundbeck's goal is to build a portfolio of drugs to treat Alzheimer's disease. In 2002, Lundbeck launched Ebixa® (memantine), which was in-licensed from the German company Merz. Furthermore, Lundbeck and the Danish company Pharmexa are working together to develop a new treatment for Alzheimer's disease.

• Most significant events in 2002
• What is Alzheimer's disease?
• Alois Alzheimer
• The three stages of the disease
• Life as an Alzheimer's patient
• Physiological changes in the brain
• Lundbeck's R&D activities
• Prevalence
• Diagnosis
• Existing treatments
• Ebixa®
• Drugs in the market

Drugs in clinical development    Â
 Compound	 Activity	 Indication	 Development stage	Registration applicationÂ	Expected launch
 Memantine	 NMDA-antagonist	 Mild to moderate Alzheimer's	 III	  2004	2005
Launched drugs    Â
 Compound	 Activity	Indication	Trademark	First registration	Approved, no of countries
Memantine	NMDA-antagonist	Moderately severe to severe Alzheimer's	Ebixa®	2002	21
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In 2002, Lundbeck launched Ebixa® for the treatment of Alzheimer's disease in 10 countries. Ebixa® is Lundbeck's first major in-licensed product to be launched on all Lundbeck's markets. Ebixa® is a new type of drug for the treatment of Alzheimer's disease. It is the first approved drug for the treatment of late stage Alzheimer's disease (moderate to severe). Ebixa® fulfills unmet needs for these patients, for whom no other approved treatment is currently available.

Together with business partner Merz, Lundbeck has initiated several clinical trials to investigate the efficacy of Ebixa® on mild to moderate Alzheimer’s disease. Lundbeck expects to complete these studies in 2003, and to file an application with the authorities to extend the indication in 2005.

Alzheimer's is a progressive disease affecting middle-aged and elderly people.
The initial signs are frequent forgetfulness, changes in personality and confusion. Patients subsequently lose the ability to perform everyday activities; disorientation, delusion and language problems set in, and at some point, they fail to recognise their loved ones. The disease ultimately progresses to death, following a period in an almost vegetative state, during which the patient loses the ability to communicate, eat and drink.

There is no cure for the disease. It manifests itself through cognitive symptoms (loss of memory and failure to learn new things), and emotional symptoms (anxiety and depression). Some patients also have psychotic symptoms such as delusions and hallucinations

Alois Alzheimer (1864-1915) was a German neuropathologist and neuroscientist. He initially described the form of dementia that carries his name in 1906-1907 in Munich, when he examined the brain of a diseased woman who had suffered from memory loss, confusion and hallucinations. He found that the woman’s cerebral cortex was thinner than usual and demonstrated quite extraordinary cell changes in the brain’s grey matter.

Subsequent studies have confirmed that these changes are characteristic of the disease that has been named after him. Today, the diagnosis is made primarily on the basis of a thorough medical history, as was the case when Dr Alzheimer made his discovery, although the diagnosis is now accompanied by a neuropsychological examination and brain scan. Alzheimer himself died of heart failure in 1915 at the age of 51.

The three stages of Alzheimer’s disease are mild, moderate and severe. The stages tend to overlap, because at the same time, some symptoms can be mild while others can be moderate or severe. Disease progression differs from patient to patient. Many patients develop the disease in old age and do not progress through all the stages before dying of other causes.

The mild stage can last from two to four years. Patients experience problems in learning new things, suffer from loss of recent memories, and may have great difficulty in using correct terminology and grammar. Patients are often aware of their situation and can take part in planning the treatment, but they also have a greater risk of becoming depressed.

The moderate stage can last up to ten years, during which the patient’s mental and physical condition gradually deteriorates. The patient loses touch with his past, can no longer use the telephone or a coffee machine, and requires assistance in getting dressed. The patient no longer recognises his spouse and children, and cannot go out unaccompanied. As the disease progresses, confusion, anxiety and distrust set in.

The severe stage can last from one to three years. The patient can no longer look after himself or live a normal life, take care of personal hygiene, or eat or drink. At a certain point, the patient will be permanently confined to bed, requiring 24-hour care. The patient finally dies, often from pneumonia or general debility.

Frank:
Memory is something we all take for granted. But think what it would be like if you had to learn everything over again every day: washing, getting dressed, making breakfast. We are gradually deprived of our daily activities. We cannot slow it down, and the doctors are unable to help us.

You often hear of people who have "photographic memory". But why is it that you hear so little about "us Alzheimer’s" who have great difficulty in performing even the simplest things? We want people to know about our predicament of failing memory.

I have come to terms with the fact that we only have a limited time in which we can express the things we want to say. So I advise all healthy people not to disregard any problems of failing memory or learning difficulties. Don’t think that you’re probably just getting older or that you are "stressed these days", and don’t ever say like I did: "It’ll pass, it is always the other guy who gets the disease".

I am grateful that my disease was diagnosed at an early stage. I have learned a lot: don’t postpone until tomorrow what you can to today, or it may be too late. Doing things while you still can will bring you happiness, the best medicine of all.

The picture on the left shows the brain of an Alzheimer patient. There is loss of brain tissue and wide furrows. The picture on the top right shows a synapse (contact site between two nerve cells), with one nerve cell transmitting impulses to the other. On the bottom right both nerve cells are about to perish, and there is a reduced amount of signal compound.

One of the theories for the cause of Alzheimer's disease is that excessive levels of glutamate, which transmits signals between nerve cells, is present in the brain. These signals are crucial for memory and learning.

The unnaturally high level of glutamate causes constant activation of the NMDA receptors – stressing and ultimately destroying the nerve cells. Another result of this activation is that normal signals sent between nerve cells are lost in the interference from the NMDA receptors. There is a degradation of nerve cells and accumulation of protein-rich material between the cells. At the same time, the amount of other neurotransmitters in the brain (including acetylcholine) is reduced, leading to a deterioration of cognitive function. The psychiatric and behavioural disorders afflicting Alzheimer’s patients may be rooted in the same cause.

Not all the mechanisms causing the disease and its progression are known, but accumulation of the protein called beta-amyloid in the so-called plaques, and of tau protein in the cells, has a toxic effect on the cells, which subsequently die.

Lundbeck's R&D activities
The cause of Alzheimer's disease remains to be discovered, but there is much to indicate that progression of the disease can be slowed down or even stopped, if drugs are developed that prevent the formation of amyloid plaques or the neurodegeneration that occurs in connection with the disease.

Lundbeck and Pharmexa, a Danish biotech company, have signed an agreement for research in, and development of, a therapy for Alzheimer's disease. The collaboration concerns the use of the AutoVac technology on a specific protein target in the central nervous system. The agreement was signed in April 2000. It gives Lundbeck an exclusive global license to use the AutoVac technology on this protein target.

Proof of concept of this technology was demonstrated in preclinical trials in 2002.

Age (years)	Point prevalence (%)
60-64Â	1.0
65-69Â	1.2
70-74Â	4.1
75-79Â	5.7
80-84Â	13.0
85-89Â	21.6
90-94Â	32.2

Prevalence
It is estimated that roughly 37 million people around the world will suffer from some form of dementia by 2025. Alzheimer's disease is the most common form of dementia, and the most extensive European epidemiological study – The Rotterdam Study – shows that 72% of all patients with dementia suffer from Alzheimer’s disease.

Alzheimer's disease is an age-related disease. This means that the estimates available today underestimate the number of Alzheimer patients in the future, since they will live longer. The number of individuals above the age of 60 is expected to double over the next 25 years – most notably in the developing countries.

In 2001, there were about 1.2 billion people aged 60 or above. In the seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, the UK, and the USA), approximately 42% of the population are aged 60 or above.

Although only 1% of the total population in the Western world suffers from Alzheimer's disease, the prevalence rises to about 5% for people aged 65-74 and to 20% for those aged 80 or above. Alzheimer's disease is the fourth-most frequent cause of death of those above the age of 65 in the Western industrialised countries. Eighteen million people in the world suffer from dementia.

Alzheimer's disease affected an estimated three million people in 2001 in the five major European pharmaceutical markets (France, Germany, Italy, Spain, and the UK). Of these patients, 47% are estimated to suffer from mild Alzheimer's, 29% are in the moderate stage, while 24% have severe Alzheimer'’s. Many patients with the mild form are incorrectly diagnosed or are not diagnosed at all. Only about 60% of European patients with Alzheimer's are correctly diagnosed. Of those patients diagnosed, 20% suffer from mild Alzheimer's, 40% from the moderate form, and 40% from the severe form of the disease.

Many patients are never diagnosed with dementia, because people around them believe that they are showing symptoms of normal aging.  Although Alzheimer's disease is the most common cause of dementia, other possible causes must be ruled out. It is important to the patient and relatives that the correct diagnosis is made at an early stage.

The disease may affect anyone and strikes unpredictably. The risk increases with age and is slightly higher for women than men. New research results indicate that factors that increase the risk of thrombosis, e.g., excessive blood pressure, smoking, obesity and diabetes, also increase the risk of Alzheimer's disease.

Existing treatments
Drugs available on the market today only treat the symptoms of Alzheimer's disease. Thus, there is a large unmet therapeutic need. This has encouraged several pharmaceutical companies to initiate Alzheimer's research projects. The goal is to develop new drugs that can delay or even stop progression of the disease. However, only few drug candidates have been tested for therapeutic efficacy in large numbers of patients, and none have yet completed phase II studies.

The oldest Alzheimer's drugs increase the level of the neurotransmitter acetylcholine in the brain by inhibiting the breakdown of acetylcholine in the brain (acetylcholinesterase inhibitors). The reduced levels of acetylcholine in patients with Alzheimer's is especially correlated with the cognitive symptoms, but also with some of the psychotic symptoms.

• donepezil (Aricept®) 
• rivastigmine (Exelon®) 
• galantamine (Reminyl®).

None of these drugs will cure Alzheimer's or stop the disease from progressing. They are approved for the treatment of mild to moderate Alzheimer's disease, but not for the severe form.

Some patients treated with acetyl-cholinesterase inhibitors will experience an improvement or a stabilisation of symptoms for various lengths of time. In other patients, the symptoms continue to deteriorate at a constant pace. The most common side-effects are gastrointestinal, e.g., diarrhoea, nausea, loss of appetite, and weight loss; sleep problems and fatigue can also occur. The side-effects are often of a temporary nature, but some patients have to terminate treatment due to side-effects.

Ebixa®
Lundbeck’s anti-Alzheimer's drug, Ebixa®, inhibits the abnormal activation of the NMDA receptors but maintains their normal activation, which is required for memory. Thus, Ebixa® restores the normal signalling mediated by the neurotransmitter glutamate, thereby maintaining the mechanisms that support memory and learning processes.

Ebixa® is the first drug for the treatment of moderate to severe Alzheimer’s disease.

Drugs in the market
The market for anti-Alzheimer's drugs is dominated by Aricept® from Pfizer, which accounted for approximately 77% of global sales in 2001. Exelon® from Novartis, Cognex® from Horizon and Reminyl® from Shire, Janssen and Sanochemia accounted for a small part of sales of anti-Alzheimer's drugs in 2001.

Brand name	Active ingredient	Marketing corporation(s)	Sales 2001 worldwide (mUSD)	Growth in %
Aricept®                     Â	donepezil	Eisai	923	26
Exelon®	rivastigmine	Novartis	228	119
Reminyl®	galantamine	Johnson & Johnson	45	--