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Beating the system

New treatment regiments and more experimental research are showing promise in PD

The Parkinson's disease (PD) market looks set to grow over the next seven years, reaching $2.37bn in 2013, according to Datamonitor. This represents a 39 per cent increase from 2006 levels. Combinations, reformulations and indication expansions are expected to be major drivers behind this growth. Datamonitor predicts that three of the new and soon-to-be-launched drugs, will be key: GlaxoSmithKlineís (GSKís) Requip-Modutab, Novartis/Orion's Stalevo and UCB-Schwartz's Neupro.

PD is one of the most common disorders of the nervous system and is caused by a degeneration of dopamine-containing neurons in the brain, leading to dopamine depletion. The main features of the disease are tremor, muscle stiffness, slower movements and postural instability, but PD is also associated with a number of non-motor symptoms such as depression and sleep disturbance.

Levodopa
There is no single drug of choice in the initial pharmacotherapy of early PD; dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, may be used to relieve symptoms. Levodopa remains the gold-standard treatment and nearly all patients will take it eventually - often in combination with other agents - but after a few years of therapy with levodopa the response to the drug is complicated by the onset of motor fluctuations and periods of "off' time - when the effects of medication wear off and PD symptoms return. For this reason, initiation of levodopa is often delayed.

Drivers for growth
There has been increasing interest in the use of continuous dopaminergic stimulation (CDS), which aims to reduce motor complications and improve the quality of life for patients with PD. Most PD treatments cause dopamine receptors to be stimulated in a pulsatile manner and it is thought that this stimulation causes changes in neuronal firing, leading to the development of motor complications. Therefore, treatments that provide a more continuous stimulation of receptors and mimic normal physiological dopamine can improve symptom control and reduce motor complications in patients with PD.

Requip-Modutab
Requip-Modutab is the new prolonged-release formulation of dopamine agonist ropinirole, which has been developed by GSK in conjunction with SkyePharma PLC. Datamonitor anticipates that it will be the key brand behind the growth - and become the leading PD brand in 2011. Ropinirole prolonged-release tablets will be the first and only once-daily nonergot oral dopamine agonist available as a treatment for PD with a simplified "uptitration regimen' - to enable the correct dose concentration to be established for each patient.

The demonstration of clinical efficacy for the prolonged-release formulation is based on the results of two phase III, randomised, double-blind studies - Studies 168 and 169, collectively known as EASE-PD. Ropinirole prolonged-release tablets are as effective as ropinirole 3x-daily tablets as monotherapy in early PD. The prolonged-release tablet is also clinically and statistically superior to placebo as adjunct therapy in advanced-stage PD patients, who were not optimally controlled on levodopa, improving the quantity and quality of 'on' time during the day.

Requip-Modutab has now been launched in France, Estonia, Latvia, Slovenia, Slovakia and Switzerland. GSK expects the treatment will launch in 20 countries by the end of 2008.

Neupro
The recently launched Neupro daily transdermal patch, from UCB-Schwartz, is also designed to provide consistent and continuous delivery, over 24 hours, of a new dopamine agonist - rotigotine. The patch, which is changed once daily, can offer an alternative to conventional oral therapies and may be of benefit in patients with difficulties swallowing, delayed gastric emptying and resorption of PD medication.

Neupro is indicated for the treatment of the signs and symptoms of early-stage idiopathic PD as monotherapy or in combination with levodopa - through to late stages when fluctuations occur. It has been shown to be more effective than placebo but less effective than high-dose ropinirole at reducing symptoms in patients with early-stage PD. A multicentre, double-blind, randomised, controlled trial, compared the efficacy and safety of the rotigotine transdermal patch with ropinirole and placebo. A 20 per cent improvement was seen in 52 per cent of patients receiving rotigotine, 70 per cent receiving ropinirole and 30 per cent receiving placebo.

Stalevo
Stavelo from Novartis and Orion Pharma, is a novel form of levodopa therapy as it also contains the catechol-O-methyl transferase (COMT) inhibitor, entacapone. The enzyme COMT breaks down levodopa before it reaches the brain. The idea is that the increased availability of levodopa may lead to smoother and steadier levels of dopamine in the brain, providing better symptom control.

The QUEST-AP (QUality of Life Evaluation of STalevo Asia Pacific), which involved 184 early phase PD patients with no or minimal, non-disabling motor fluctuations, found Stalevo significantly improves quality of life compared to traditional levodopa therapy. The treatment effect of Stalevo was part­icularly significant for emotional wellbeing, communication, social relationship and stigma. Earlier this year Orion announced the results of the phase III FIRST-STEP study involving 423 patients with early stage PD. The study compared Stalevo with standard levodopa therapy, with the primary endpoint of change from baseline in combined UPDRS (United Parkinson's Disease Rating Scale) part II and III scores measuring activities of daily living and motor function. The study found that improvement with Stalevo was statistically significant (p <0.05).

Azilect
Azilect (rasagiline), from Teva and Lundbeck, is another new product in the market that is continuing to gain interest. Azilect is a novel, potent, second-generation, selective, irreversible MAO-B inhibitor that blocks the breakdown of dopamine; it also has the benefit of being a once-daily medication. Data reveals that 1 mg Azilect once daily is efficacious both as first-line adjunct treatment to levodopa in patients with moderate PD with mild fluctuations, as well as in addition to concomitant therapies in patients with more advanced PD. Unlike the older MAO-B inhibitor selegiline, rasagiline is not converted into amphetamine metabolites.

In development
There are a number of PD drugs now in development, some still at very early stages, but three stand out as showing particular promise: Vernalis' V1512, Merck Serono's safinamide and Eisai's E2007 (perampanel). V1512 is a new, patented formulation of levodopa now just entering phase III development. V1512 is designed to address some of the drawbacks inherent in older levodopa preparations. V1512 is an effervescent formulation of the more soluble form of levodopa, levodopa methyl ester, in combination with the decarboxylase inhibitor, carbidopa.

The clinical efficacy and safety of V1512 has been established in 18 clinical studies, including two European phase II clinical studies and a proof-of-concept study, which have shown evidence of a significantly more rapid onset of action and improved mobility. The trials have also demonstrated a more reliable drug response in comparison with conventional levodopa preparations.

Safinamide - an alpha-aminoamide derivative that is orally administered - represents a new type of therapy. Studies suggest that safinamide may combine the inhibition of dopamine re-uptake and MAO-B and also inhibit glutamate release. Data from a six-month randomised, double blind, placebo-controlled trial, presented at the American Academy of Neurology 59th Annual Meeting in 2007, demonstrated that the addition of safinamide to a stable dose of a single dopamine agonist in patients with early stage PD resulted in a statistically significant improvement in motor symptoms, as measured by the UPDRS part III motor score. Treatment with safinamide at the dose of 50 to 100 mg once daily over a 24-week period also resulted in a significant improvement of UPDRS Part II activities of daily living score, compared with dopamine agonist monotherapy.

E2007 is a new chemical entity with a novel mechanism of action of selectively antagonising AMPA-type glutamate receptors. Eisai is conducting three phase III studies (301, 302 and 309). Currently available analysis did not show a significant difference in the reduction in 'off' time when the drug was compared with placebo. However, E2007 was well tolerated and no significant safety issues were observed. Preclinical results showed that E2007 prolonged both levodopaís duration of action and the time Parkinsonian symptoms were improved, while improving the dyskinesia caused by levodopa. Eisai file E2007 for approval in the US and Europe in Q1 2009.

In recent years adenosine A2A antagonists have emerged as a possible new PD treatment. Vernalis, for example, is developing a selective adenosine A2A receptor antagonist, V2006. This new class of drugs target adenosine A2A receptors, which are expressed selectively in the basal ganglia. Adenosine is a neuro­transmitter involved in motor co-ordination and movement control. These new agents could help to restore motor function without the adverse effects associated with existing therapies.

Stem cells
It is hoped that stem cells may be able to replace diseased or dead cells in patients with PD. However the Parkinson's Disease Society (PDS) in the UK warns that although there is potential for embryonic stem cells to form appropriate nerve cells to alleviate Parkinson's, tumour formation remains a problem. Research into preventing tumours is still at an early stage.

Gene therapy
Gene therapy is showing some initial promise. The US company Ceregene has released promising follow-up results from a 12-patient phase 1 clinical trial of CERE-120. The trial showed that CERE-120 was safe and well tolerated, and the results suggest a sustained improvement in the motor symptoms of PD up to 24 months post treatment when compared to baseline data. CERE-120 uses the adeno-associated virus type 2 vector to deliver the gene for neural growth factor neurturin, into the brain. CERE-120 is injected directly into the striatum - the region of the brain that contains lower amounts of dopamine in PD patients. Once integrated into the cell's genome, neurones in the striatum produce increased amounts of the neural growth factor. This is thought to help protect and restore the dopamine-containing neurones from degeneration.

Oxford Biomedica, a spin-out company from Oxford University, has begun a phase I/II clinical trial of gene-based therapy ProSavin in patients with mid-to late-stage PD who are not responding to levodopa. Injected into the striatum, ProSavin delivers the genes for three enzymes that are required to make dopamine: tyrosine hydroxylase, GTP-cyclohydrolase 1 and aromatic amino acid decarboxylase.

US-based Neurologix has also announced that the FDA has granted a fast-track designation for its gene therapy, NLX-P101. NLX-P101 uses an adeno-associated virus to carry the glutamic acid decarboxylase (GAD) gene into the neurones of the subthalamic nucleus - the part of the brain that is over-stimulated in people with PD.

Surgery
The subthalamic nucleus (STN) is now well established for deep brain stimulation (DBS); its goal is to improve motor function in advanced PD. It has recently been suggested that it could be safe and effective to target the pedunculopontine nucleus (PPN); this has a role in postural stability and gait. In a small study, six patients underwent bilateral implantation of DBS electrodes in the STN and PPN. The study found that the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities.

Looking ahead
Continuous dopermingeric stimulation therapy that works as monotherapy, delaying initiation of levodopa and those that help to reduce the 'off' times associated with levodopa will make the biggest impact in the intermediate term. In the longer term, neuroprotection, neurorescue and, of course, stem cell therapy would all represent major leaps forward in the treatment of this disease.

Nicola O'Connell is a freelance medical writer based in London

1st May 2008

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