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Next generation

Treatments aimed at preventing the loss of dopaminergic function are entering the pipeline

A large starship in spaceParkinson's disease (PD) is a progressive motor disorder, characterised by slow movement (bradykinesia), tremor and a stooped posture, as well as neurological and emotional disturbances. PD is caused by the loss of dopamine-producing neurons in the brain, primarily in the substantia nigra – a midbrain structure named for the presence of melanin in the dopamine-producing cells. The death of neurons in the substantia nigra results in disruption of signalling in the basal ganglia, a group of nuclei that plays a key role in the regulation of motor function, as well as mood and cognition.

As loss of dopaminergic neurons is the primary cause of PD, many treatments have been targeted at increasing dopaminergic activity. The first line therapy for PD is levodopa, the immediate precursor of dopamine. Supplementation with levodopa increases the amount of dopamine produced in the substantia nigra, allowing dopaminergic signalling to be maintained as the number of dopaminergic neurons declines. However, as the enzyme responsible for converting levodopa to dopamine, DOPA decarboxylase, is found in both the peripheral and central nervous systems, only a small fraction of the supplemental levodopa reaches the substantia nigra, and dopamine-related peripheral adverse events are common. To counter this, levodopa is commonly administered with peripheral DOPA decarboxylase inhibitors such as carbidopa.

However, one of the main problems with levodopa treatment is the need for dopamine producing neurons to convert the levodopa to dopamine; as PD progresses, more dopaminergic neurons die, reducing the efficacy of levodopa. In patients with advanced PD, patients receiving levodopa can also experience on-off symptoms (remission [on] and return [off] of motor symptoms due to fluctuations in drug levels and efficacy during the day) and dyskinesias (involuntary movements). Hence, drugs that act to inhibit the degradation or reuptake of dopamine, stimulate dopamine receptors or mitigate the effects of the dopamine deficiency by acting on other targets present attractive opportunities for the treatment of PD.

Monoamine oxidase B inhibitors
Monoamine oxidase B (MAOB) is an enzyme responsible for metabolising biogenic amines, particularly dopamine. Inhibition of MAOB prolongs the activity of dopamine in the synapse, thus reducing the symptoms of PD. Rasagiline (Teva Pharmaceutical Industries) and selegiline have both been launched for the treatment of PD. Safinamide (Merck Serono) is an MAOB inhibitor currently in phase III trials as an adjunctive therapy for the treatment of PD. However, safinamide also acts as a glutamate release inhibitor, as well as a sodium and calcium channel blocker.

In a study of patients with early-stage PD receiving a dopamine agonist, safinamide 50-100 mg/day was associated with significant improvement in Unified PD Rating Scale parts II and III scores at 24 weeks (primary endpoint), and was generally well tolerated at dosages of 50-100 mg/day and 100-200 mg/day. In another study in patients with advanced PD, both safinamide 50 and 100 mg/day met the primary endpoint of improvement in ON time compared with placebo. Evaluation of safinamide is ongoing.

Dopamine agonists
Dopamine agonists have also proved to be a successful treatment strategy for PD, with an instant-release formulation of pramipexole (Mirapex, Mirapexin, Sifrol; Boehringer Ingelheim) and rotigotine (Neupro; UCB) currently among the marketed treatments for PD.

Pramipexole is a non-ergot dopamine agonist with activity at the dopamine D2, D3 and D4 receptors. While the instant-release formulation of pramipexole has been approved since 1997, an extended-release formulation was approved in the EU in October 2009, and an NDA is currently under review by the US FDA.

Solvay Pharmaceuticals is currently developing pardoprunox, a partial dopamine D2 and D3 agonist and full serotonin 1A agonist in phase III trials for the treatment of early-stage and advanced PD. Though full results are not yet available, pardoprunox appears to have some efficacy in advanced PD.

Axxonis Pharma is developing lisuride, a dopamine D2 and serotonin 1A receptor agonist, and an antagonist of serotonin 2A, 2B and 2C receptors.

Lisuride is currently awaiting approval for PD in the European Union. Two formulations of lisuride have been developed – a transdermal patch, intended for the treatment of early PD, and a continuous subcutaneous infusion for the treatment of advanced PD. Results from the CALIPSO study indicate that SC lisuride is effective in these patients.

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Non-dopaminergic treatments
The majority of approved treatments for PD acts directly on dopamine signalling, however, several therapies with more novel mechanisms of action are in development. Kyowa Hakko has developed istradefylline, an adenosine A2 receptor antagonist, which has completed phase III trials in the US, Europe and Japan, with an NDA submitted to the US FDA in April 2007. However, the FDA issued a non-approvable letter in February 2008, requesting an overall summary of non-clinical mineralisation findings, and follow-up data as part of phase IV evaluation commitments. Following discussions with the FDA, development in the US and Europe has been suspended while Kyowa Hakko Kirin awaits the results of a phase II trial of istradefylline in Japan. The study demonstrated the efficacy of istradefylline compared with placebo, and Kyowa Hakko Kirin then decided to continue domestic development of the agent with a phase III trial in Japan.

Merck & Co is currently developing preladenant, also an adenosine A2 receptor antagonist, which is in phase II trials as adjunctive treatment for Parkinson's disease. Preladenant was granted fast track status for PD in the US in mid 2003. A dose-finding phase II study evaluating the efficacy and safety of preladenant as adjunctive therapy in 253 patients with moderate-to-severe PD experiencing motor fluctuations and dyskinesia was completed in late 2008.

The trial met its primary endpoint, with preladenant being significantly more effective than placebo in reducing the time spent in the off state. Preladenant was safe and well tolerated. A phase III clinical trial programme for preladenant is currently being planned.

Another strategy being investigated for the treatment of PD is adjunctive therapies aimed at improving the efficacy of levodopa, mainly by reducing levodopa-induced dyskinesias, or decreasing the amount of time patients experience wearing-off. Biovail Corporation and Santhera Pharmaceuticals are developing fipamezole, an α-2 adrenergic receptor antagonist, for the treatment of dyskinesia and wearing-off symptoms in patients with advanced Parkinson's disease. Fipamezole received fast track status for this indication in the US in November 2002. Fipamezole appeared effective in the phase II FJORD study, with a slightly greater improvement from baseline than placebo in Levodopa-Induced Dyskinesia Scale scores (primary endpoint) following 28 days of treatment. Fipamezole was not associated with any significant worsening of other Parkinson's disease symptoms.

While drugs to treat Parkinson's disease have largely focused on symptomatic therapies, treatments aimed at preventing the loss of dopaminergic function have also begun to enter the pipeline. Merck & Co and Ono Pharmaceutical are currently evaluating arundic acid (Arocyte, Cereact) for the treatment of Parkinson's disease and other neurodegenerative disorders. Arundic acid is an astrocyte-modulating agent intended to provide neuroprotection against neuronal damage by decreasing levels of reactive nitrogen and oxygen species, as well as inhibiting the expression of cyclo-oxygenase 2 (COX2) and inducible nitric oxide synthase (also known as nitric oxide synthase type II). The efficacy of this treatment remains to be seen, with the compound currently in phase II trials in Japan.

Unfortunately, neuroprotective treatment of Parkinson's disease is still in its infancy, with some nascent treatments already appearing to be ineffective. Mitoquinone, a targeted version of ubidecarenone, was assessed in a phase II trial by Antipodean Pharmaceuticals. While the drug was well tolerated, it did not appear to have any significant effect on disease progression in Parkinson's disease. Researchers believe that this lack of efficacy may have been due to the large number of impaired cells in Parkinson's disease; these cells may have had limited or no ability to regenerate and, therefore, could not benefit from the antioxidant properties of mitoquinone.

The Author
Pipeline was written by Bernard Kerr of Adis International - Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight and Clinical Trials Insight.
For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email:

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10th March 2010


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