Alternatives to current disease-modifying treatment in MS: what do we need and what can we expect in the future?

Disease-modifying treatments (DMTs) for multiple sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, magnetic resonance imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies. However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue. Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease. Available treatments address systemic immune dysfunction, blood-brain barrier permeability and the inflammatory process in the central nervous system. Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive immunosuppression with cytostatic agents or even autologous stem cell transplantation. However, new approaches are being developed. Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS. Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease. These treatments include humanised monoclonal antibodies such as the anti-VLA-4 antibody natalizumab, inhibitors of intracellular activation, signalling pathways and T-cell proliferation, and oral immunomodulators such as sirolimus, teriflunomide or statins. There remains, however, an urgent need for treatments that protect against demyelination and axonal loss, or promote remyelination/regeneration. Due to the chronicity of MS, the therapeutic window for neuroprotective agents is wider than that following stroke or acute spinal cord injury, and may therefore allow the use of some drugs that have proven disappointing in other situations. Novel potential neuroprotective agents such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and ion-channel blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.