Being one of the first to develop and market effective antipsychotic therapies, Lundbeck has held a strong position in the antipsychotics market since the 1950s. Lundbeck’s first antipsychotic drug was chlorprothixene, which is known under the trademark Truxal®. Lundbeck’s key products Clopixol® (zuclopenthixol) and Fluanxol® (flupenthixol) gave it a key role in the treatment of schizophrenia and other psychoses. With the development of Serdolect® (sertindole), Lundbeck was also a front-runner in the development of the latest generation of antipsychotic drugs – the so-called atypical antipsychotics.

Lundbeck currently markets seven antipsychotic drugs, and sales of these drugs accounted for 5.8% of the company’s 2002 revenue. Lundbeck expects to market Serdolect® in 2005, and has two more drug candidates in clinical development.

• Drugs in clinical development
• Launched drugs
• Major events in 2002
• What is schizophrenia?
• Emil Kraepelin
• Symptoms and course of the disease
• Life with schizophrenia
• Physiological changes in the brain
• Lundbeck's R&D activities
• Prevalence
• Diagnosis
• Existing treatments and drugs on the market

 

Drugs in clinical development

Compound	Activity	Indication	Development stage	Registration application	Expected launch
Sertindole	D2 5HT2	Schizophrenia	Post-marketing study	Â	2005
Bifeprunox	Dopamin/ Serotonin	Schizophrenia	II/III	2005	2005+
Lu 35-138	D4	Schizophrenia	I/II	2005+	2005+

 

Launched drugs

Compound	Activity	Indication	Trademark	First registration	Approved, no of countries
Melperone	Typical antipsyc.	Psychotic disorders	Buronil®, Bunil® Â	1968	14
Zuclopenthixol	Typical antipsyc.	Schizophrenia and other psychotic disorders, anxiety, restlessness and insomnia Â	Cisordinol®, Clopixol®	1982	71
Zuclopenthixol decanoate	Depot antipsyc.	Maintenance treatment of chronic psychotic disorders	Ciscordinol Depot®, Clopixol Depot®, Ciatyl-Z Depot® Â	1976	72
Zuclopenthixol acetate	Typical antipsyc.	Acute psychotic episodes, exacerbation of psychotic disorders	Cisordinol-Acutard®, Clopixol-Acutard®, Clopixol-Acuphase®, Ciatyl-Z-Acuphase® Â	1986	69
Flupentixol	Typical antipsyc.	Mild depression, schizophrenia and other psychotic disorders Â	Fluanxol®, Fluanxol Mite®, Depixol®	1965	67
Cis(Z)-flupentixol decanoate	Depot antipsyc.	Maintenance treatment of chronic psychotic disorders Â	Fluanxol Depot®, Depixol Inj.®	1970	72
Chlorprothixene	Typical antipsyc.	Schizophrenia and other psychotic disorders, anxiety and restlessness withdrawal symptoms in drug addicts	Truxal®, Truxaletten®	1959	28

On 26 June 2002, the EU Commission lifted the suspension of Serdolect® for the treatment of schizophrenia based on supplementary data submitted by Lundbeck, all substantiating the safety of Serdolect®. In connection with the lifting of the suspension, Lundbeck agreed to carry out a post-marketing study. The company expects Serdolect® to be available for general prescription and use in Europe in 2005. Lundbeck is currently in discussions with the US health authorities (FDA) to investigate whether and when it would be possible to launch Serdolect® in the US market.

In addition to being an effective drug in the treatment of schizophrenia, Serdolect® is also free of many of the side effects that normally characterise antipsychotics.

Schizophrenia translates directly from Greek Schizo = split; phrenos = mind

What is schizophrenia?
Schizophrenia is a mental disorder that is found in varying degrees, but is most often chronic. The disease typically begins in late adolescence or early adulthood and is characterised by distinct changes in the patient's way of thinking and perception of the outside world. Furthermore, the disease is characterised by short or long periods during which the patient is in an acute psychotic condition, suffering from definite hallucinations and delusions. However, there are also stable periods, during which the patient is symptom-free or experiences a significant reduction in symptoms. Even in stable periods, many patients have difficulty in establishing social contact, in completing an education programme, or in having a job. Patients with schizophrenia have difficulty in performing everyday activities such as cooking, personal hygiene and cleaning. A not insignificant proportion of the patients use intoxicants such as alcohol and cannabis. The disease is often disabling and can be very painful - first and foremost to the patient, but also to the patient's family. Furthermore, schizophrenia is a major economic burden to society, not only due to the costs of nursing and treating the patients, but also due to their reduced ability to work and the costs of social pensions and benefit schemes.

 

The German psychiatry professor Emil Kraepelin (1856-1926), who is considered to be the father of modern psychiatry, initially described the disease at the beginning of the 20th century, and the name schizophrenia was used by the Swiss psychiatrist Eugen Bleuler (1857-1939) as early as 1911.

Like depression, schizophrenia can be traced through history in sources from the Far East, Ancient Greece, and Rome, among others. Indian medics had already described schizophrenia by 1500 BC. Later, the Greek physicians, Aretaes and Soranus, wrote about the mentally ill as people who were free to walk about, availing themselves of facilities such as medicinal baths and temples along with the physically ill. Respect for the mentally ill later disappeared, and they were treated cruelly and without dignity in several cultures. For example, Roman patients were subjected to surgical procedures such as trephining, as the disease was believed to stem from poisonous gases that needed to be released. The first known hospital for the mentally ill was set up in Baghdad in 1173 BC, where the residents were treated with drugs and music.

Schizophrenia has been depicted in several movies, including "Shine" and "A Beautiful Mind", which portray pianist David Helfgott and mathematician John Nash, respectively.

Symptoms and course of disease
Schizophrenia afflicts both sexes equally, and typically starts in late adolescence, but slightly later in women than in men. Sometimes, the disease is initially misinterpreted as difficulties associated with puberty, school fatigue, effects of cannabis abuse, etc. In some cases, it is possible to identify discrete symptoms some years before the actual onset of the disease. When the disease manifests itself, it thoroughly impacts on the patient's mind and perception of the surrounding environment. Hallucinations (very often in the form of "voices" speaking about the patient in the third person) and delusions (typically persecution mania and delusions of a bizarre nature) are common symptoms. The patient's thoughts and speech often become incoherent and difficult to understand. Certain patients may become agitated and sometimes verbally or physically aggressive. These symptoms are often called positive, because they resemble normal mental functions or personality traits, albeit in an exaggerated and distorted form. In periods of pronounced positive symptoms, patients are said to be in an acute psychotic state. Medical treatment has the best impact on positive symptoms.

Negative symptoms are also frequent in patients with schizophrenia. They are called negative because they represent a lack or loss of normal mental functions or personality traits. Social interaction deficits, emotional impairment, lack of facial expression, lack of drive, and general difficulty in feeling pleasure are common negative symptoms. Although negative symptoms do not appear to be as dramatic as positive symptoms, they significantly diminish the patients' quality of life.

In recent years, attention has been drawn to the fact that many patients with schizophrenia also develop a number of disorders associated with the intellect, the so-called cognitive disorders. Symptoms include a reduced ability to concentrate, and impairment of specific memory and language functions. Actual impairment of intelligence in the common sense is usually not involved. Cognitive disorders often arise long before the onset of the first psychotic episode and can be traced back to childhood. Negative symptoms and cognitive disorders often persist even though the patient's positive symptoms have been successfully treated.

Many patients with schizophrenia also have depressive symptoms. It can be difficult to distinguish such symptoms, especially from the negative symptoms, but they are usually considered as a separate group. Suicide is far more frequent among patients with schizophrenia than among the general population. Combined with other factors (including abuse, poor social conditions), suicide contributes to increased mortality in patients with schizophrenia.

Positive and negative symptoms of schizophrenia
Positive symptoms:

• Hallucinations
• Delusions
• Agitation
• Aggression
• Abnormal behaviour
• Distorted thinking.

Negative symptoms:

• Social detachment
• Isolation
• Poor personal hygiene
• Impaired ability to express joy and sorrow
• Lack of spontaneous speech and thought.

Life with schizophrenia

Lone:
My disease started long before anyone else noticed it. I was good at hiding my inner secrets – also from myself. But I remember discovering something weird many years ago when I was taking a stroll with my second-oldest son in the pram. Suddenly, I felt like I was two persons walking side by side. They were both me. I was frightened and felt that something was wrong. But the vision disappeared again, so I repressed the experience and felt totally normal again. Like I said, I told nobody about my experience and kept it to myself.

The disease gradually progressed. But I remember feeling sad when the last of my children moved out of the house. Before then, I had started to have incoherent thoughts and feel confused, and this was something quite new. I didn't have the same pleasure in my job as I used to. One thought led to another, and I started to feel angry towards my aged mother and, later, also my ex-husband. I blamed them for my disease. My children, who were now grown-up, started to withdraw from me, because they didn't understand my anger.

I decided I didn't want to live any longer. So one night, I took an overdose of pills and two large whiskys, but they found me in time and I was admitted to the closed ward. To cut a long story short, I became one of those patients who are constantly in and out of the hospital. At one point, when I was out of hospital, I experienced being somebody else. I was the Virgin Mary and couldn't understand why the people around me wouldn't believe me.

Left picture:
The blue area in the brain indicates reduced activity in the frontal lobe of the brain. The red area indicates excess dopamine activity in the underlying brain structures.

Pictures on the right:

1. Synapse (contact site between two nerve cells) with normal dopamine activity.
2. Synapse with increased dopamine activity in a schizophrenic patient. 
3. Synapse with increased dopamine activity, in which an antipsychotic has been administered that binds to and blocks the dopamine receptors. The goal is to reduce the excess activity to a normal level.

Physiological changes in the brain
The causes of schizophrenia are unknown, but genetic and environmental components are likely to be involved. Several genes have recently been identified as risk factors for schizophrenia. Factors that can cause schizophrenia are believed to include early mental impacts, environmental factors, stressful events, and difficult family relations. In addition, it has been demonstrated that disturbances at certain embryonic stages (for example virus infection and malnutrition), and certain birth complications (for example lack of oxygen) can increase the risk of developing schizophrenia later in life.

Neurochemical abnormalities seem to play an important role in schizophrenia, and research has focussed on neurotransmitters, especially increased activity in the basic dopamine system, disturbances in the functions of other neurotransmitters (serotonin, neuropeptides and excitatory amino acids such as glutamic acid), and enzymes. In addition to these abnormalities, structural and developmental disorders in the anatomy and physiology of the cerebral cortex are believed to contribute to the progression of the disease.

Some of the cognitive disorders are believed to be linked with hypofrontality – the inability to activate neurones in the frontal cerebral cortex in connection with solving intellectual tasks.

Lundbeck's R&D activities
Lundbeck conducts a number of research projects and preclinical projects specialising in schizophrenia.

Lundbeck has two drug candidates in clinical development: Bifeprunox in phase II and Lu 35-138 in phase I.

Bifeprunox is a potent partial dopamine D2 receptor agonist and serotonin 5-HT1A agonist that is expected to treat both the positive and negative symptoms of schizophrenia. Bifeprunox has been in-licensed from the Belgium firm Solvay Pharmaceuticals B.V., and Lundbeck holds the rights to market the product outside the USA, Canada, Mexico, and Japan. A phase IIb trial is currently underway to establish the optimum dose. Lundbeck plans to commence phase III trials in 2003.

Lu 35-138, developed by Lundbeck in-house, also belongs to the class of atypical antipsychotics. The product has a unique profile and primarily affects dopamine D4 receptors. Lundbeck expects to initiate efficacy trials in patients in 2003.

Several unmet needs still exist in the treatment of schizophrenia. Lundbeck's research is aimed at the development of drugs that offer an enhanced effect on both positive and negative symptoms, fewer side-effects, and an impact on the cognitive processes that also characterise the disease.

Age (years)	Point prevalence (%)
All	  0.5

Prevalence
The antipsychotic market comprises drugs for the treatment of different types of psychotic disorders, including schizophrenia. Some 9.6 million people suffer from a disease in this category in the seven major pharmaceutical markets alone (France, Germany, Italy, Japan, Spain, the UK and the USA); a large proportion of these patients suffer from schizophrenia.

Schizophrenia most often occurs in late adolescence or early adulthood, and men and women are equally affected. However, studies indicate that women develop the disease at an older age than men. Up to 1% of the world's population will, at some point in their life, be affected by schizophrenia, while approximately 0.5% will be afflicted by the disease at any given time.
The USA and Europe have relatively high diagnosis rates for schizophrenia, with about 80% of all schizophrenics receiving the correct diagnosis. In Japan, the diagnosis rate is 75%.

Diagnosis
There are many symptoms of schizophrenia, and all can be features of other mental disorders. It is the duration, nature, and pattern of mental symptoms that form the basis of the diagnosis. In order to be diagnosed with schizophrenia, one or two of the most important symptoms must have been present for at least one month. Certain symptoms specifically indicate a diagnosis of schizophrenia: these include auditory hallucinations in the form of voices referring to the patient in the third person. To diagnose the disease, the physician must also rule out the possibility that the symptoms are rooted in other mental illnesses. The American Psychiatric Association and the WHO have each issued a set of diagnostic guidelines for schizophrenia. The two sets of guidelines are almost, but not entirely, identical.

The latest generation of antipsychotic drugs are the so-called atypical antipsychotics, which accounted for 88% of the global antipsychotic market in 2001. Growth in atypical antipsychotics was 35% in 2001, while the market for the early antipsychotics declined by 10% in 2001.

The early antipsychotic drugs were introduced in the 1950s and 1960s. At the time, these drugs represented major progress over the therapies previously offered to patients with schizophrenia and other psychoses. Although these drugs proved effective against the positive symptoms, they were less effective in treating negative symptoms. Moreover, treatments with these drugs induced so-called extra pyramidal symptoms (EPS), which are motor side effects, such as slow movements and tremors. The atypical antipsychotic drugs, introduced in the 1990s, are characterised by being just as effective in the treatment of the positive symptoms as typical medications, without causing EPS. The atypical antipsychotic drugs are also effective against the negative symptoms, but there is still no convincing effect.

The best selling drugs are Zyprexa® (olanzapine) from Eli Lilly, Risperdal® (risperidone) from Johnson & Johnson, Seroquel® (quetiapine) from AstraZeneca, Leponex® (clozapine) from Novartis, and Zeldox® (ziprasidone) from Pfizer. In recent years, Zyprexa® and Risperdal® have had particularly good growth in the antipsychotic market.

At 30 June 2002, Zyprexa® was the best selling brand followed by Risperdal® both in the USA and Europe.

 

Brand name	Active ingredient	Marketing corporation	Sales 2001 worldwide (mUSD)	Growth in %
Zyprexa®                     Â	olanzapine	Eli Lilly	3226	35
Risperdal®                   Â	risperidone	Johnson & Johnson	2110	23
Seroquel®                    Â	quetiapine	AstraZeneca	793	82
Leponex®                    Â	clozapine	Novartis	322	-1
Zeldox®                      Â	ziprasidone	Pfizer	137	>999
Solian®                      Â	amisulpride	Sanofi-Synthelabo	89	18
Haldol®                      Â	haloperidol	Johnson & Johnson	73	-15
Tiapridal®                   Â	tiapride	Sanofi-Synthelabo	63	-