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Multiple targets

There is a need for novel, more convenient drugs in multiple sclerosis

A targetIt is estimated that more than two and a half million people worldwide have multiple sclerosis (MS), an inflammatory disease resulting in damage to the protective myelin sheath which surrounds nerve fibres of the central nervous system (CNS). Myelin acts as electrical insulation to the nerves, allowing rapid conduction of sensory and motor signals.

Damage to the myelin disrupts the nerve's ability to transmit this information and is responsible for a wide range of symptoms, including blurred vision, weak limbs, tingling sensations, unsteadiness and fatigue. The precise aetiology of MS is unknown though several theories exist. The most favoured is that the body's T-cells attack and destroy the myelin of the CNS in an autoimmune response. It is not known what triggers the immune system to attack the myelin but it is likely to be attributable to multiple factors.

Current treatments
Six MS disease-modifying drugs have been launched in the US and Europe since 1993: Avonex, Betaseron, Rebif, Copaxone, Novantrone and Tysabri. Despite the significant number of established drugs there remains a market for further innovation. All of the approved drugs are administered by injection, which can be inconvenient and uncomfortable - particularly as most available treatments require frequent doses. Another issue is that five out of the six current treatments are indicated for relapsing remitting MS only. Treatment options for the remaining types of MS - primary progressive, secondary progressive and progressive relapsing - are extremely limited. Data from Thomson Pharma shows that numerous companies are rising to the challenge to develop novel and more convenient therapies.

Late-stage oral drugs
One solution would be to develop an oral drug formulation so that patients did not have to self-inject or travel to receive treatment. Teva, in collaboration with Merck Serono, is developing an oral formulation of cladribine (Mylinax) which inhibits adenosine deaminase (ADA) - an enzyme with an important role in immune function. Adenosine oral cladribine is currently in phase III trials and launch is planned for 2009. The drug was granted fast track status by the FDA in the US for relapsing MS in 2006.

Teva, in collaboration with Active Biotech, is also developing laquinimod (SAIK-MS) - an oral, selective autoimmune suppressant currently in phase III trials. Data from a phase IIb trial showed treatment with laquinimod for 36 weeks significantly decreases inflammatory disease activity and substantially reduces the number of clinical relapses. Further data have shown once-daily dosing of laquinimod significantly reduces disease activity detected by MRI - by 38 per cent - and is well tolerated by the patient. There was a trend towards a reduction in annual relapse rate, an increase in the number of relapse-free patients and in time to first relapse.

A capsule formulation of fingolimod (FTY-720), a sphingosine-1-phosphate (S1P) agonist, is being developed by Novartis and Mitsubishi Tanabe - S1P is an important cellular metabolite. In 2005, six month trial data showed fingolimod could reduce both relapse rate and the number of brain lesions detected by MRI, and resulted in a longer time to first relapse. Data from the same trial, at 12 months, showed relapse rate decreased by 50 per cent and more than 80 per cent of subjects who took the drug for 12 months were free of MRI-defined active inflammatory lesions. Phase III trials began in Europe and the US in 2006.

Sanofi-aventis is also contributing to the development of an oral treatment with teriflunomide which inhibits dihydroorotate dehydrogenase - an enzyme in pyrimidine metabolism - and tyrosine kinase - an enzyme involved in phosphorylation. By February 2004, teriflunomide had shown significant efficacy in human trials. The drug is currently still in phase II trials but filings for teriflunomide as a monotherapy are expected in 2012.

BG-12 (BG-00012; Panaclar) is under development by Biogen Idec, following its acquisition of Fumapharm. A European phase II trial reached its primary endpoint of a statistically significant reduction in the total number of gadolinium-enhanced brain lesions, leading to the initiation of a worldwide phase III trial at the beginning of last year. Gadolinium is a chemical compound given during MRI scans that highlights areas of inflammation. Active lesions indicate that there has been a breakdown of the blood-brain barrier.

Therapeutic vaccines
A therapeutic vaccine to help people who already have MS would represent a significant step forward. Apitope Technology is developing ATX-MS-1467, a vaccine containing soluble synthetic peptide tolerogens - antigens which can induce immunological tolerance - derived from myelin basic protein. The company recently reported extremely promising results from a phase I/IIa trial in six patients. The vaccine was safe and well-tolerated and reduced myelin basic protein-induced T-cell proliferation by up to 40 per cent following one month of treatment, without affecting normal immune responses. Additionally, one patient showed an improvement in the gadolinium-enhanced MRI scan indicating a reduction in neuroinflammation. The company plans to initiate a phase IIb trial by the fourth quarter of 2008 and is seeking a partner or licensee for phase III development.

BHT-3009, a myelin basic protein-encoding plasmid and cytokine-encoding plasmid DNA vaccine, is under development by Bayhill Therapeutics. Subjects with high anti-myelin basic protein antibodies in their cerebrospinal fluid (CSF) have shown a statistically significant reduction in gadolinium-enhanced lesions following treatment. Additionally, a statistically significant reduction in several CSF myelin-specific auto-antibodies was achieved in all patients treated with BHT-3009. An end of phase II meeting with the FDA is being planned.

Orchestra Therapeutics is developing NeuroVaxa combination vaccine comprising three T-cell receptor peptides - BV5S2, BV6S5 and BV13S1. The vaccine stimulates the T-cell regulator FOXP3 and increases regulatory T-cell activity to help control the pathogenic T-cells that have the potential to attack myelin. A phase II trial in central and eastern Europe began in March 2007.

Tovaxin is a T-cell therapeutic vaccine currently being investigated by Opexa Pharmaceuticals in a phase IIb study. It uses attenuated myelin-reactive T-cells (MRTCs) derived from the patient's peripheral blood to induce an immune response. MRTCs are thought to have a key role in multiple sclerosis pathogenesis. By September 2007, more than 60 per cent of the total 750 vaccine doses had been administered and no safety issues had been reported. Opexa is currently seeking a licensee for the programme.

Novel drug targets
As there are thought to be multiple causes of MS, none of which has yet been determined, the number of targets available for drug development is vast. Drugs with different actions would be welcomed as the cause and progression of the disease may differ dramatically between patients.

Sphingosine-1-phosphate agonists
BAF-312 is an oral S1P agonist under development by Novartis that has completed a US phase I safety trial in healthy volunteers. Ono Pharmaceuticals is also developing ONO-4641, a tablet formulation of an S1P agonist. A phase I trial of the drug was initiated in the US last year. A series of S1P agonists is under investigation by Merck. One compound has demonstrated superior efficacy to fingolimod in experimental allergic encephalomyelitis (EAE) - an animal model of brain inflammation.

Potassium channel blockers
Bionomics, under licence from the Walter and Eliza Hall Institute of Medical Research (WEHI), is investigating a series of Kv1.3 potassium channel blockers derived from khellinone, a product isolated from Ammi visnaga - a plant related to carrots, celery and hemlock. The Kv1.3 channel is one of two potassium channels, expressed by T lymphocytes, that are involved in proliferation and cytokine secretion - processes that are part of the immune response.

Preclinical studies have found that treatment with one compound, BNC-245, dose-dependently inhibits the proliferation of myelin basic protein. The drug has also lowered the severity of EAE in rats in a comparable manner to dexamethasone. BNC-245 is well tolerated and has demonstrated no associated adverse events. Clinical trials are being prepared.

Airmid's Kv1.3 potassium channel blockers are derivatives of naturally occurring components of venom from the sea anemone Stichodactyla helianthus. A lead compound, ShK-186, has been shown to inhibit the chronic phase of chronic relapsing EAE and has a good safety profile.

Other companies investigating Kv1.3 potassium channel blockers include 4SC, Merck and Co and Actelion - in collaboration with Roche.

Future opportunities
There is a gap in the market for novel, more convenient drug formulations for MS. Little research is being carried out into inhaled formulations, although Merck Serono, under licence from Syntonix, is investigating an inhaled interferon beta (IFNbeta) fusion protein. IFNbeta is a cytokine with antiviral, antiproliferative and immunomodulating activity. Preclinical studies of a once-weekly formulation appear to be ongoing.

Despite the rapid increase of research into MS over the past two decades there is plenty of room for further development. The elusive nature of the causes of MS greatly increases the range of potential targets for the development of new treatments. With inadequate treatment options for secondary progressive, primary progressive and progressive relapsing MS, the market is still open to the development of innovative therapies as well as novel formulations.

The Author
Hannah Fisher
is an editor of content integrity at the drug information department of Thomson Scientific. This article is based on information from the database at www.thomson-pharma.com

30th May 2008

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