Simvastatin as a disease modifying immunoregulatory candidate treatment of Parkinson's disease
SummaryParkinson's disease drug revenues grew an impressive 17% across the seven major markets to reach $1.7 billion in 2003. Despite the commercial success associated with this therapy area, currently available treatments focus on levodopa which replaces the loss of striatal dopamine, the hall mark of Parkinson's disease, rather than targeting disease progression. The efficacy of levodopa eventually declines in most patients and new therapies with disease modifying activity are urgently required. A gr
Parkinson's disease is a chronic and progressive neurological condition that affects approximately 1.5 million people in the US 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. The gold-standard therapy for Parkinson's disease is levodopa which is converted to dopamine after entering the brain. Despite the growth of generic levodopa products, Parkinson's disease drug revenues grew an impressive 17% across the seven major markets to reach $1.7 billion in 2003 (see Parkinson's Disease - Increased Focus on Earlier Treatment and Managing Levodopa Complications Will Drive Market Growth ).
The effectiveness of levodopa is limited by its extensive peripheral metabolism. 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 parkinsonism and do not respond to this agent. Even in responsive patients A further problem associated with levodopa emerges after 2 to 5 years of treatment, when 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.
Strategies that flatten the pharmacokinetic profile of levodopa prolonging the exposure to levodopa and reducing peak concentrations have therefore attracted considerable attention. Hence Carbidopa, a DDC inhibitor, and Entacapone (Comtan), a COMT inhibitor have been developed. 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. The development of neuroprotective agents that slow the gradual loss of dopamine neurons represents an alternate approach that is attracting much attention (for a general insight into neurodegenerative disease treatments and markets see World Neurodegeneratives Disease Markets, 2005-2009).
Inflammation is accepted as a contributor to the etiology of Parkinson's disease and it has been suggested that increased levels of cytokines induce the expression of iNOS in glial cells thus producing neurotoxicity. Anti-inflammatory agents may offer a novel approach to the treatment of Parkinson's disease.
Statins were originally developed for the treatment of hypercholesterolemia an effect resulting from their ability to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase thereby lowering circulating cholesterol concentrations. The value in 2004 of the world market for anti-cholesterol drugs was worth over $25 billion, making this drug class the most successful therapeutic area in the world. Statins dominate the market taking over 90% of the market, worth an estimated $22 billion. Statins not only dominate the anti-cholesterol market but also the world market for any drug class. The statin, Lipitor (Atorvastatin) is the best selling drug in the world (see our feature The Cardiovascular Report). Major changes in drug indications for the statins may extend market revenues even further.
The mechanisms through which the statins exert their anti-inflammatory activity remain to be fully elucidated however recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma, leading to repression of MHC II-mediated T-cell activation. More recently statins have been reported to inhibit the expression of specific cell surface receptors on leukocytes preventing their adhesion to vessel walls and the expression of several proinflammatory cytokines. The statins have already been shown to limit disease in experimental models of arthritis, multiple sclerosis and lupus. In the Brain Res study highlighted here, Dr Michael Selley from Angiogen Pharmaceuticals evaluated the possibility that statins may also be a potential new therapy for the treatment of Parkinson’s disease. Simvastatin and lovastatin may be particularly useful readily penetrating the blood–brain barrier and the efficacy of simvastatin was therefore evaluated in the MPTP mouse model of Parkinson’s disease.
MPTP is selectively toxic to the cells in the substantia nigra, and is capable of producing virtually all the signs and symptoms of Parkinson's disease. Like Parkinson’s disease, MPTP is also characterized by the infiltration of CD4+ and CD8+ T-cells in the substantia nigra, the up-regulation of MHC class I and class II antigens on microglia, and increased IL-1 production in the striatum. The Brain Res study demonstrated that simvastatin is able to completely reverse the loss of striatal dopamine activity and that this effect paralleled a reduction of TNF-alpha levels. Furthermore the production of nitrosylated free radicals, an effect thought to contribute directly to neuronal cell death, was also reversed by simvastatin.
This study therefore clearly demonstrates in an established model that simvastatin may have therapeutic activity in Parkinson's disease. Unlike current dopamine replacement therapies simvastatin targets the etiology of disease preventing striatal dopamine depletion. This appears to be related to simvastatin's anti-inflammatory activity and cellular studies suggested that this activity involved a decrease in the release of inflammatory mediators from microglia.
Angiogen Pharmaceuticals is focused on the development and commercialization of new therapies in inflammation, neurological disease and cancer. In particular the company's corporate strategy involves discovering new therapeutic uses for marketed drugs. There are several advantages to a drug discovery program based on new therapeutic uses. Firstly, the development program for the marketed indication will have investigated the compounds toxicity and established its tolerability. This makes it is possible to proceed directly to clinical trials once the efficacy of the compound has been established in animal models. Secondly, the costs and risks involved in the drug development process are greatly reduced. Thirdly, it is possible to establish a partnership with the manufacturer for further development and commercialization. Simvastatin exemplifies this approach. This statin is an established therapeutic agent which has been in use since 1991 and because the safety and tolerability of this therapeutic is well established it is hoped that the clinical evaluation of simvastatin will be able to proceed rapidly in Parkinson's disease patients.
A US provisional patent application has been filed for the use of simvastatin in the treatment of Parkinson's disease and companies interested in licensing this technology are invited to contact Dr Michael Selley at Angiogen Pharmaceuticals