PARKINSON’S DISEASE

What is Parkinson’s disease?

Parkinson's disease is a progressive, degenerative brain disorder, characterised by a loss of specialised nerve cells in parts of the brain called the substantia nigra and locus coeruleus and their connections. These cells contain the chemical messenger dopamine and become greatly depleted in advanced Parkinson's disease (Figure 1). Dopamine is involved in many functions, including the control of movement and co-ordination - in other words, Parkinson's is a dopamine deficiency disease.

The onset of Parkinson's disease is gradual. Common symptoms are slowness in initiating movement, muscular rigidity - which may lead to a loss of facial expression - and shaking (in about 70 per cent). More debilitating symptoms such as speech and swallowing difficulties, depression and constipation may emerge later. The rate of progression varies from 3-30 years and not all people develop the more severe symptoms.

Who does Parkinson's disease affect and what does it cost?

About 120,000 people in Britain are estimated to have Parkinson's disease and about 10,000 new cases are diagnosed annually. It most commonly affects those aged 50 or over and becomes more common with age, but younger people can also develop the disease. A study in 1998 found that the average cost of care for somebody with Parkinson's disease was nearly £6,000 per year. NHS costs accounted for 38 per cent of this cost, social care costs for 34 per cent and medication costs 24 per cent in those aged under 65. Costs increased dramatically with increasing disease severity, from an average of £2,971 a year in early disease to £18,358 a year at the most advanced stage.

Present treatments and shortcomings

Dopamine does not pass from blood into the brain and so cannot be given directly. Instead, a chemical called L-dopa is used, which does enter the brain and is converted there into dopamine (Figure 2). This transformation is brought about by the enzyme dopa decarboxylase (DDC), which is also present in tissues outside the brain. Formation of dopamine in the general circulation leads to troublesome side-effects such as involuntary jerky movements (dyskinesia), and L-dopa is therefore given in combination with a DDC inhibitor (benserazide or carbidopa) that does not cross the blood/brain barrier. Such combinations form the mainstay of initial treatment and are available from Roche (Madopar) and Bristol-Myers Squibb (Sinemet) and as an intestinally administered gel formulation (Duodopa, Solvay).

Dopamine is broken down by the enzymes monoamine oxidase-B (MAO-B), and catechol-O-methyl transferase (COMT). Blocking these enzymes therefore provides a way of enhancing the action of dopamine in the brain. The MAO-B inhibitors selegiline (Eldepryl, Orion) and rasagiline (Azilect, Teva) and the COMT inhibitors entacapone (Comtess, Orion) and tolcapone (Tasmar, Valeant) are used for this purpose, often in combination with L-dopa. A triple combination of L-dopa, carbidopa (a DDC inhibitor) and entacapone is also available (Stalevo, Novartis).

Unfortunately, in most people, L-dopa loses its effect within 5-10 years, as well as causing fluctuations in motor ability and jerky movements (dyskinesias), and alternative strategies are then needed. One is to use compounds that mimic dopamine and stimulate its receptor (dopamine agonists). Bromocriptine (Parlodel, Novartis) and pergolide (Celance, Lilly) act in this way. Other more specific dopamine agonists are also available; these are ropinirole (Requip) from GlaxoSmithKline, cabergoline (Cabaser, Pfizer), pramipexole (Mirapexin, Boehringer Ingelheim) and rotigotine (Neupro, Schwarz), the latter being applied as a skin patch.

What's in the development pipeline?

While L-dopa is not likely to be displaced soon from its central role, research continues into ways of improving current medical treatment. Novartis has the acetylcholinesterase inhibitor rivastigmine (Exelon), the first medicine to treat dementia in Parkinson's disease, and Eisai has donepezil (Aricept) in Phase 3 trial for this purpose. GlaxoSmithKline is developing an extended release formulation of its dopamine agonist ropinirole. In a recent trial, adding this medicine to standard therapy delayed the return of symptoms as medication wears off (so-called 'off time') by an average of more than two hours a day.

At Phase 3, Merck Serono has a new MAO-B inhibitor (safinamide) which is also an inhibitor of dopamine reuptake. Preliminary results indicate that it improves motor symptoms, but it has also shown an effect in improving cognition. Eisai is studying an agent (E-2007) that is directed to a type of glutamate receptor. Kyowa Hakko also has a new agent in Phase 3 trial (KW-6002, istradefylline) to reduce motor symptoms and this represents a completely different approach from current medicines. Other companies trying this approach are Vernalis (V2006) and Schering- Plough (SCH-63390), but these compounds are still in Phase 2.

Solvay also has a new oral agent (SLV308) in Phase 3 trial. This combines dopamine activity with effects on the neurotransmitters noradrenaline and serotonin that may help with common symptoms such as depression and anxiety. A survey has shown that 80 per cent of people with Parkinson's disease also experience depression, although nearly half did not discuss such symptoms with their doctor.

A number of other new approaches are being explored in Phase 2 trials. Acadia Pharmaceuticals has ACP-103, which is being investigated for treating the L-dopa-induced tremors and hallucinations that may develop with prolonged use. Faust Pharmaceuticals has a compound (FP0011) that acts on glutamate receptors and protects nerves. Juvantia Pharma has JP-1730 (fipamezole) for treating dyskinesias, and sanofi-aventis has SR 57667.

Parkinson's disease has been seen as one of the key areas in which gene therapy might be of benefit. Progress has, however, been slow and such projects are still at a relatively early stage. Oxford Biomedica is working on a lentivirus vector system (ProSavin) to introduce the genes necessary for dopamine production into brain cells. Ceregene has started phase 1 trials with an adeno-associated virus vector (AAV) delivery system containing the neurturin gene, which makes a protein that aids survival of dopamine-producing cells. Avigen is also using an AAV vector system in its AV201 project to deliver the gene for the enzyme dopa decarboxylase into the brain. Lastly, Neurologix has announced positive interim results in a Phase 1 trial of its agent NLX-P101 that uses the AAV vector to introduce a gene for the enzyme glutamate decarboxylase. This enzyme produces the major inhibitory neurotransmitter in the brain, gamma-amino-butyric acid (GABA). Patients treated in this way showed an improvement in motor function one year after treatment, indicating that this approach may be of value in those with advanced Parkinson's disease.

FOR FURTHER INFORMATION CONTACT:

THE PARKINSON’S DISEASE SOCIETY
215 Vauxhall Bridge Road
London, SW1V 1EJ
Phone: 0808 800 0303 (Helpline)
Website: www.parkinsons.org.uk