Improving levodopa-based complications to advance Parkinson's Disease therapies

The pharmaceutical market for the treatment of neurodegenerative disorders will grow by an unprecedented amount over the next ten years. The aging of the baby-boom generation, combined with new and improved treatments for neurodegenerative disorders such as Alzheimer's and Parkinson's disease will lead to an expansion of the multi-billion neurodegenerative market.

Parkinson's disease, a chronic and progressive neurological condition, affects approximately 1.5 million people in the alone. While its cause is unknown, the symptoms of Parkinson's disease are primarily the result of degeneration of dopaminergic neurons, in the substantia nigra, a part of the brain that controls and modulates movement. Symptoms include limbs that tremble; slowness of movement; stiffness and rigidity of limbs and gait or balance problems. As the disease progresses, these symptoms usually increase and impact a person's ability to work and function. Replacing dopamine through the administration of dopamine itself is an ineffective replacement therapy due to its inability to cross the blood-brain barrier (BBB). The gold-standard therapy for Parkinson's disease is therefore levodopa which is converted to dopamine after entering the brain.

The effectiveness of levodopa has been limited by its extensive peripheral metaboli. When administered orally less than 1% of the levodopa dose crosses the BBB. The majority (approximately 70%) is peripherally metabolized by dopa decarboxylase (DDC) to form dopamine, resulting in adverse effects such as nausea and orthostatic hypotension. An additional 10% of systemic levodopa is O-methylated by catechol O-methyltransferase (COMT) to form 3-O-methyldopa, which although not associated with adverse effects, conveys no antiparkinsonian benefit.

In addition to the adverse effects of levodopa, its efficacy can be limited in some patients. Approximately 15% of parkinsonian patients have atypical parkinsoni and do not respond to this agent. Even in responsive patients continued usage leads to decreased levodopa efficacy and consequently the motor complications of Parkinson's disease appear prior to the next scheduled levodopa administration. Consequently after 2 to 5 years of treatment, as many as 50% of patients begin to experience fluctuations in their response to levodopa (on-off effect). The duration of improvement after each dose of drug shortens ("wearing off") and patients can experience swings from intense akinesia as the symptoms of Parkinson's return to dyskinesia, an involuntary movement that can accompany peak doses of levodopa. During the first few years of levodopa therapy patient response is ooth and extended, with a low incidence of dyskinesias. Striatal dopaminergic activity resulting from levodopa administration is likewise ooth and prolonged. As the disease progresses however, patient response to levodopa becomes shorter in duration and is associated with an increased risk of dyskinesias.

Strategies that flatten the pharmacokinetic profile of levodopa prolonging the exposure to levodopa and reducing peak concentrations have attracted conderable attention. Improved efficacy and reduced adverse effects which have been achieved as a result have driven and will continue to drive the therapeutic market for Parkinson's disease.

Studies have shown that the continuous administration of levodopa or dopamine agonists by injection conveys substantial clinical benefits. This is not a practical long-term treatment option and therefore daily doses can be fractionated or alternatively sustained-release drug formulation can be used.

As an alternative inhibition of enzymes responsible for the removal of levodopa has also been shown to be an effective approach. Carbidopa inhibits dopa decarboxylase thus reducing decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metaboli of levodopa within the central nervous system. Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa (the combination product is known as Sinemet or Atamet) increases the dose of levodopa dose that crosses the BBB from 1 to 5-10%. This ooths the levels of levodopa within the brain and furthermore it reduces the adverse side effects arising from high levels of systemic dopamine.

Although the adverse effects of levodopa therapy can be improved following the co-administration of carbidopa dyskinesia remains a problem and other full and partial dopamine agonists are often prescribed instead of levodopa/carbidopa or as an adjunct. Bromocriptine (see today's DailyUpdates for information on the genericization of this agent), pergolide, and more recently Requip (GSK, ropinirole) and Mirapex (pramipexole, Boehringer Ingelheim) are all agonists that can be given alone or with levodopa and may be used in the early stages of the disease or started later to lengthen the duration of response to levodopa in patients experiencing wearing off or on-off effects. The increasingly important role of these and other dopamine agonists is driving Parkinson's disease drug revenues which grew an impressive 17% across the seven major markets to reach $1.7 billion in 2003. However, several patent expiries and product launches are set to send the market through a period of change.

A newer approach to optimizing the pharmacokinetics of levodopa involves the use of catechol-O-methyltransferase inhibitors. Catechol O-methyltransferase metabolises levodopa, particularly so in the presence of a dopa decarboxylase inhibitor. Blocking this enzyme by, for example, Entacapone (Comtan), inhibits peripheral catechol O-methyltransferase (COMT) metaboli of levodopa, increasing and oothing the central bioavailability of levodopa. Entacapone thus provides more constant dopaminergic stimulation that has been shown to result in improved control of levodopa-associated motor fluctuations. Comtan was approved world-wide between 1998 and 1999 as an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose 'wearing-off'. With a growth rate of 33.5% between 2002-03, the catechol-O-methyltransferase inhibitor class has witnessed the greatest year-on-year revenue growth. Stalevo is a single pill treatment incorporating levodopa, carbidopa and Entacapone which was approved in 2003 and which will ensure the continued strong growth of this class.

Although the development of Entacapone and carbidopa have improved the pharmacological profile of levodopa marketed therapies for Parkinson's disease still exclusively work by treating disease symptoms. However, several compounds in development have demonstrated 'neuroprotective' properties and have the potential to revolutionize the market. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) conducted a systematic assesent of candidate pharmacological agents with putative neuroprotective properties. Twelve agents have been selected as potential candidates for upcoming clinical trials and novel disease modifying treatments of Parkinson's disease will hopeful soon emerge.

For further reading click here or for a complete listing of relevant reports click here

Source: LeadDiscovery editorial September, 29^th