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Double or quits!

Companies are working against the clock to be the first to get an oral MS drug to market

Multiple sclerosis (MS) is a chronic neurodegenerative disorder of the central nervous system (CNS), resulting from immune-mediated demyelination of the myelin sheath that insulates neuronal processes.

Several cell types have been implicated in the development of MS, but mainly they include autoreactive T-cells (CD4+ or CD8+) and B-cells.

Around 80 per cent of patients suffer with relapsing-remitting MS and current treatments are only available for relapsing, not early, forms of MS.

In 2004, combined sales of products approved for the treatment of MS exceeded $3bn, and there are a large number of pharma companies engaged in active research and development of novel and improved therapies.

Experts predict that an oral MS drug has definite blockbuster potential, and that the introduction of oral therapies will double the current market for MS treatments, reaching $6bn by 2012.

Approved treatments
In the US and the EU, there are currently four products approved for the treatment of MS. Avonex (Biogen Idec) and Rebif (Serono) are recombinant human inter-feron B-1a products; administration is via subcutaneous (SC) injection once- and thrice-weekly, respectively.

Both products are indicated for use in relapsing forms of MS. However, Avonex can also be used for a single neurological event indicative of demyelination, if MRI results are consistent with MS.

Betaferon (Schering AG) is a recombinant form of interferon B-1b, also indicated for relapsing forms of MS, and administered subcutaneously, every other day.

Interferons have a range of immune cell-related effects, including reduced proliferation of T-cells, decreased antigen presentation and reduced transport of immune cells into the CNS.

Teva's Copaxone (glatiramer acetate) is a synthetic compound, composed of four amino acids that make up myelin basic protein, an antigen that experts suspect to be involved in the induction of auto-immunity in MS.

The drug, administered daily via SC injection, binds human leukocyte antigen (HLA) class II on antigen-presenting cells in the lymph nodes, blocking the activation of myelin-reactive T-cells, or rendering them anergic. In addition, glatiramer acetate induces drug-specific and anti-inflammatory Th2 helper cells, which cross the blood-brain barrier and enter the CNS.

Also approved in the US is Novantrone (mitoxantrone; Serono), for the treatment of worsening relapsing-remitting MS, and progressive-relapsing or secondary progressive MS. Administered by intra-venous infusion four times yearly, the drug is potentially cardiotoxic, and the lifetime limit is 8-12 doses.

Overall response rates to the current drugs for MS are relatively low; hence, there is a market for the development of products with greater efficacy.

Natalizumab
One of the most advanced of the potential new treatments for MS is natalizumab (Tysabri; Biogen Idec, Elan). The drug is a humanised monoclonal antibody that binds to the a4-subunit of a4B1 and a4B7 integrins that are expressed on the surface of leukocytes, inhibiting the a4-mediated adhesion of leukocytes to key receptors, thereby reducing inflammation.

The robust efficacy of natalizumab has been demonstrated in the two largest phase III trials ever conducted in MS: the pivotal Safety and Efficacy of Natalizumab in Combination with Interferon -1a in Patients with Relapsing-Remitting MS (SENTINEL), and the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) trials.

However, development of this product for the treatment of MS was halted after two documented cases of progressive multifocal leukoencephalopathy (PML) - a rare and severe demyelinating disease caused by infection with a human polyoma virus - in patients receiving the drug as part of the SENTINEL trial.

No new cases of PML have emerged in additional MS studies, including the AFFIRM trial, and dosing suspension was lifted by the Food and Drug Administration (FDA) in February 2006.

Two-year data from the AFFIRM and SENTINEL trials revealed that natalizumab produced statistically significant reductions in the risk of disability progression and decreased the annualised relapse rate, with fewer new or enlarging MRI lesions, compared with placebo and interferon -1a monotherapy, respectively.

Treatment with interferon B-1a, B-b, or glatiramer acetate, is associated with a reduction in the annualised relapse rate of about one third. In the AFFIRM and SENTINEL studies, the annualised relapse rates after treatment with natalizumab fell by 68 per cent and 55 per cent, respectively. The FDA is due to make a decision on natalizumab by the end of June 2006.

Oral alternatives
The development of an oral therapy for the treatment of MS will provide a welcome alternative to regular injections.

Several oral therapies are in late-stage clinical development for the treatment of MS. Fingolimod (FTY720; Novartis), a sphingosine-1-phosphate receptor agonist, is in phase III clinical development. It significantly reduces both rates of relapse and the number of active lesions.

A dihydroorotate dehydrogenase inhibitor, teriflunomide (sanofi-aventis), is also in phase III clinical development, and phase II studies showed reductions in the mean number of lesions to a greater extent than placebo.

Oral cladribine (IVAX Corporation, Serono) is undergoing phase III clinical investigation; in previous studies, the drug produced significant effects on some gadolinium-enhancing MRI lesions.

An oral, enteric-coated tablet formulation of glatiramer acetate was evaluated in phase III clinical trials, but having failed to produce significant results, development has since been discontinued.

Other compounds in phase II trials for oral MS therapies include laquinimod (Teva), BG 12 (Biogen Idec), pirfenidone (Schering AG), temsirolimus (Wyeth), xaliproden (sanofi-aventis), ibudilast (MediciNova) and interferon (Pepgen).

Oral formulations of very late antigen 4 integrin antagonists, the same class as natalizumab, are also being developed. T 0047 (GSK) and CDP 323 (UCB) are in phase II and I development, respectively.

The author
Pipeline is written by Ben Richardson of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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