Next to Alzheimer's disease, Parkinson's disease is the most common neurodegenerative disorder.

Lundbeck's goal is to develop drugs to treat, delay, and if possible, stop the progression of Parkinson's disease. Through its own research and strategic alliances, Lundbeck has built a development portfolio encompassing two drug candidates for Parkinson's disease. These drug candidates are currently in phase II and III clinical trials, respectively.

• Drugs in clinical development
• Most significant events in 2002
• What is Parkinson's disease
• James Parkinson
• The stages of the disease
• Life as a Parkinson patient
• 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
Rasagiline	MAO-B	Parkinson's disease	III	2003	2005
CEP-1347	Kinase inhibitor	Parkinson's disease	II & III	2006+	2006+

In 2002, Lundbeck started its largest-ever phase II/III clinical trial in collaboration with Cephalon, Inc., a US-based biotech company. The objective is to determine whether the drug candidate CEP-1347 is effective in delaying the disability due to the progression of Parkinson's disease. Patients are enrolled into the study over a two-year period, and each patient will receive placebo or CEP-1347. Approximately 800 patients will be enrolled in the study, which will be conducted in co-operation with physicians and hospitals in the USA and Canada. If CEP-1347 proves to be a safe and effective drug that can delay the progression of Parkinson's disease, it is expected to revolutionise the treatment of the disease. Today, existing drugs only treat the symptoms of the disease

What is Parkinson's disease?
Parkinson's disease is a progressive neurological disease caused by lack of the neurotransmitter dopamine.

Parkinson's disease is one of several motor system disorders. Parkinson's and related disorders are the result of the loss of dopamine-producing brain cells in the patient, primarily in the so-called black substance, substantia nigra. Dopamine is one of several chemical neurotransmitters responsible for transmitting signals within the brain. Loss of dopamine results in loss of normal nerve cell activity, leaving patients unable to direct or control their movement in a normal manner.

The primary symptoms of Parkinson's are tremors in hands, arms, legs, and head; muscle rigidity that leaves the body immovable and the face expressionless; slowness of movement; and impaired balance and coordination. Patients may also have difficulty walking, talking, or completing simple tasks. The disease is both chronic and progressive. There are a few cases of inherited Parkinson's disease. Early symptoms can be subtle and difficult to diagnose.

James Parkinson (1755-1824) was an English physician. Towards the end of the 18th century, he played an important role as a social reformer, voicing his opinions on war, poverty, civil disobedience and other social aspects. However, his name is primarily associated with the disease he described in 1817 in

"An Essay on the Shaking Palsy", in which he mapped the symptoms, claiming that the disease emanates from the nervous system. It was not until many years later that the disorder was named "Parkinson's disease". The disease is described in historic sources dating as far back as 1000 BC. Indian Vedic literature and the Greek physician Hippocrates (ca. 460-377 BC) both described disorders that are a direct match to the
disease we now refer to as Parkinson's disease.

The stages of the disease
The characteristic motor and facial expressions that are typical of Parkinson patients appear gradually. Patients often develop a mask-like expression, and movements get fewer and slower. As the disease progresses, inhibited and rigid movements may leave the patient unable to take care of himself. In the late stages of the disease, the patient's condition has deteriorated strongly, often confining him to a chair or the bed. Other symptoms include depression and dementia.

Life as a Parkinson patient

Svend:
Let me start at the very beginning: about a year before I was diagnosed with Parkinson's disease, which is a chronic and slowly progressing disease, I had discovered a few symptoms. It started as a slight quivering and trembling in my left hand, but over the next year or so the symptoms increased, spreading to my arms and shoulders and my left leg. At first, I put it down to stress and ignored the symptoms, although I wondered why only one side of my body was affected.

I was also afraid of what really caused the symptoms, but left it at that. One day, about a year after I had first noticed the symptoms, I read an article in a magazine. Reading it made me frightened, for now I knew: I had Parkinson's disease. I tried to ignore it but realised that I had to visit the doctor. I made an appointment to see a neurologist and went there about a month later. It took him three minutes to make the diagnosis, and he subsequently referred me to another neurologist, who was conducting a study and was looking for volunteers. I was given a leaflet about the disease, describing the course I was to anticipate.

I read the leaflet on my way home in the car, and it made me feel bad. The disease was described as being quite severe, and the back pages described the auxiliary equipment available when the disease progresses to the stage where patients can no longer function. Two things came out of being diagnosed with the disease: the first was clarity – now I knew what was wrong with me, so at least I could do something about it. The second thing was that the diagnosis changed my outlook for the future. Reading about how my physical state would develop once the disease progresses gave me a new and frightening perspective. As I have almost never been ill and have always been full of energy, this diagnosis really shook me up. It was as if a rug had been pulled out from under me.

Physiological changes in the brain
A characteristic of Parkinson's disease is the pathological loss of dopamine-producing nerve cells, primarily found in the substantia nigra of the brain. The loss of these neurones substantially reduces the amount of dopamine in the brain, leading to changes in the basal ganglia (striatum) and consequent motor disruptions. This process causes the most important symptoms of Parkinson's disease: tremors, slow movements, stiffness and impaired balance.

The basal ganglia are found deep within the brain, and along with the motor cortex and the cerebellum they help to control our movements. Parkinson patients suffer from a loss of the impulses that activate the basal ganglia, the dopaminergic pathways from the substantia nigra.

The cross-section at the bottom right illustrates the reduced amount of dopamine in Parkinson's disease.

Lundbeck's R&D activities
Over the last five years, Lundbeck has conducted research with the aim of developing drugs for the treatment of Parkinson's disease. Lundbeck currently has two drug candidates in clinical development and runs a number of Parkinson research projects.

Rasagiline, in-licensed from Teva Pharmaceuticals in Israel, is a selective MAO-B inhibitor with a positive effect on symptoms in patients with Parkinson's in the early stages of the disease. Initial phase III clinical trials have documented that rasagiline is well-tolerated and effective for the treatment of Parkinson's disease. Ongoing phase III trials are expected to be completed during the first half of 2003.
 
Lundbeck expects to file an application for registration of rasagiline in 2003 and to launch the product in 2004. In Europe, Lundbeck will launch rasagiline in collaboration with Teva, while Teva holds the rights in the rest of the world, including the USA. The launch of rasagiline is expected to create a platform for Lundbeck's sales organisation in the field of Parkinson's disease, providing Lundbeck's sales teams with in-depth knowledge of the market ahead of the launch of Lundbeck's other drug candidate, CEP-1347.
 
Whereas all other registered anti-Parkinson's drugs only offer symptomatic relief, CEP-1347 is a disease-modifying drug that is expected to slow down, and possibly stop, disease progression. Thus, if CEP-1347 proves to be a safe and effective drug, it is expected to revolutionise the treatment of Parkinson's disease.

CEP-1347 is a potent inhibitor of members of the mixed-lineage kinase (MLK) family. MLK family members are key participants in the activation of c-Jun N-terminal kinase (JNK), which is thought to underlie neuronal dysfunction and subsequent death.
Research at Cephalon and Lundbeck has shown that CEP-1347 enhances the survival of nerve cells that produce dopamine. Additionally, animal models of Parkinson's disease have shown that CEP-1347 protects precisely those dopamine-producing neurones whose destruction causes Parkinson's disease.

Lundbeck and Cephalon, Inc. are developing CEP-1347 jointly, and a large phase II/III clinical trial of patients with early-stage Parkinson's disease was initiated in 2002.

Lundbeck holds exclusive commercial rights to market CEP-1347 in Europe, South America, Australia, South Africa and several other countries, while Cephalon holds the rights to the US market. Kyowa Hakko Kogyo Co., Ltd. is Cephalon's partner in the commercialisation of CEP-1347 in the rest of the world.

Prevalence
Parkinson's disease affects men and women equally, and an estimated four million people worldwide suffer from the disease. The disease typically occurs at a late age, affecting approx. 1% of the population over the age of 65. In the USA, Japan, and the five major European markets (France, Germany, Italy, Spain and the UK), about 2.7 million people suffer from Parkinson's. Of this group, 85% are over 65 years of age.

Age (years)	Point prevalence (%)
65+	1.0

 

Diagnosis
An estimated 70% of patients with Parkinson's are believed to have been correctly diagnosed. Given the rising proportion of elderly people in society, the number of people with Parkinson's is expected to grow by 2% per annum until 2006 in the USA, Japan, and in the five major European markets.

The current market for anti-Parkinson's drugs is characterised by a large number of drugs that all only offer symptomatic treatment. Many of these are generic drugs.

Levodopa drugs are the most commonly used drugs. These drugs are converted to the missing compound dopamine in the brain. Levodopa is particularly effective in patients with mild to moderate Parkinson's, but unfortunately it causes severe long-term side effects in the form of involuntary movements, on-off syndromes, and hallucinations in late stages of the disease.

As a result, current Parkinson's treatments are often initiated with a dopamine agonist – a drug that acts directly on the dopamine receptor, replacing the lost dopamine. Dopamine agonists do not seem to cause side effects as severe as those with the levodopa drugs. However, the agonists are not as effective, so most patients are treated with levodopa drugs at some point during treatment.

Another group of drugs, catechol-o-methyl transferase inhibitors, reduce the conversion of levodopa at peripheral sites and are used in advanced-stage patients with Parkinson's to stabilise the levodopa level. In addition, another MAO-B inhibitor is available in the market that lowers dopamine breakdown in the brain.

So, even though levodopa has been called one of medicine's great successes and remains the principal treatment option for Parkinson's disease, the therapy only offers efficacy for a few years. Thus, there is still a major need for developing new drugs.