Current and Future Disease-Modifying Therapies in Multiple Sclerosis

Abstract and Introduction

Abstract

The development of disease-modifying therapies (DMT) in multiple sclerosis (MS) has rapidly evolved over the last few years and continues to do so. Prior to the United States Food and Drug Administration approval of the immunomodulatory agent, interferon-β1b in 1993, no other drug had been shown to alter the course of the disease in a controlled study of MS. At present, there are five licenced disease-modifying agents in MS – interferon-β1b, interferon-β1a, glatiramer acetate, natalizumab and mitoxantrone. All have shown significant therapeutic efficacy in large controlled trials. However, current therapies are only partially effective and are not free from adverse effects. Moreover, available DMTs are overwhelmingly biased in favour of those with relapsing-remitting disease. Effective treatment for progressive MS is severely limited, with only interferon-β1b and mitoxantrone having licenced use in secondary progressive, but not primary progressive disease. Monoclonal antibodies, such as natalizumab selectively target immune pathways involved in the pathogenic process of MS. Alemtuzumab, daclizumab and rituximab are other notable monoclonal antibodies currently undergoing phase II and III trials in MS. Alemtuzumab has so far shown promising therapeutic benefit in relapsing disease, although immunological adverse effects have been a problem. Oral therapies have the benefit of improved tolerability and patient compliance compared with current parenteral treatments. Cladribine and fingolimod (FTY720) have shown encouraging results in their phase III clinical trials. It is also worth noting the evidence for starting DMT in patients with clinically isolated syndrome, whereby early treatment has shown to delay the onset of clinically definite MS in separate phase III studies.

Introduction

Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). The multifocal nature of the disease manifests clinically as a range of sensorimotor, cerebellar, visual, sphincteric, cognitive, and neuropsychiatric symptoms. Most patients present with a relapsing and remitting course, which is characterised by recurring attacks of acute neurological deficits or exacerbations of existing deficits (relapses) followed gradually by partial or full recovery (remission). Although the clinical course may vary considerably between individuals, secondary progression eventually occurs in the majority, characterised by irreversible, progressive disability.^[1] The immune pathogenesis of MS is thought to be heterogenous, with recent studies showing the involvement of distinct subsets of T-cells,^[2] and the crucial role of B cells and antibodies.^[3] The exact aetiology is unknown, although it is likely to stem from the loss of immune regulation, leading to the breakdown of immune tolerance, influenced by genetic susceptibility. Focal CNS inflammation, demyelination, axonal loss and eventual neuronal death are typical features although pathologically there is heterogeneity.

Multiple sclerosis is a challenging disease to treat, not least because of its significant heterogeneity and unpredictable clinical course. Traditional immunosuppressants such as cyclophosphamide and azathioprine have been used in MS for some time, showing a variable degree of benefit.^[4–6] However, the risk of serious infections amongst other significant side effects, and the emergence of new immunomodulatory drugs, has limited their use.

Immunomodulatory agents, which became available from the early 1990s, aim to prevent relapses, minimise disability and may reduce disability progression (particularly relapse-related disability) without significant immunosuppressive effects. The immunomodulatory agents interferon (IFN)-β1a, 1b and glatiramer acetate are first-line therapy in MS. For more severe disease, second-line therapy consisting of the monoclonal antibody natalizumab and cytotoxic agent mitoxantrone are used.

Increasingly, new and novel therapeutic agents are being trialled in MS centres worldwide. These include monoclonal antibodies and oral agents for relapsing and progressive forms of the disease. In this non-systematic review, we outline the existing disease-modifying agents; briefly discuss the promising new drugs currently in development and look at the current evidence for disease-modifying therapies (DMT) in early MS.

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