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Disease-Modifying Agents for Multiple Sclerosis

Recent Advances and Future Prospects

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Currently, six medications are approved for immunmodulatory and immunosuppressive treatment of the relapsing disease course and secondary-progressive MS. In the first part of this review, the pathogenesis of MS and its current treatment options are discussed.

During the last decade, our understanding of autoimmunity and the pathogenesis of MS has advanced substantially. This has led to the development of a number of compounds, several of which are currently undergoing clinical testing in phase II and III studies. While current treatment options are only available for parenteral administration, several oral compounds are now in clinical trials, including the immunosuppressive agents cladribine and laquinimod. A novel mode of action has been described for fingolimod, another orally available agent, which inhibits egress of activated lymphocytes from draining lymph nodes. Dimethylfumarate exhibits immunomodulatory as well as immunosuppressive activity when given orally. All of these compounds have successfully shown efficacy, at least in regards to the surrogate marker contrast-enhancing lesions on magnetic resonance imaging.

Another class of agents that is highlighted in this review are biological agents, namely monoclonal antibodies (mAb) and recombinant fusion proteins. The humanized mAb daclizumab inhibits T-lymphocyte activation via blockade of the interleukin-2 receptor. Alemtuzumab and rituximab deplete leukocytes and B cells, respectively; the fusion protein atacicept inhibits specific B-cell growth factors resulting in reductions in B-cells and plasma cells. These compounds are currently being tested in phase II and III studies in patients with relapsing MS.

The concept of neuro-protection and -regeneration has not advanced to a level where specific compounds have entered clinical testing. However, several agents approved for conditions other than MS are highlighted. Finally, with the advent of these highly potent novel therapies, rare, but potentially serious adverse effects have been noted, namely infections and malignancies. These are critically reviewed and put into perspective.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

Dr Menge was a postdoctoral fellow of the National MS Society and was supported by grants from the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University, the German MS Society. Dr Stüve was supported by a Start-up Grant from the Dallas VA Research Corporation, a New Investigator Award from VISN 17, Department of Veteran’s Affairs, a Merit Review Award from the Department of Veteran’s Affairs, Research Grants from National Multiple Sclerosis Society (NMSS; RG3427A8/T, and RG2969B7/T), and a grant from the Viragh Foundation. Dr Hemmer was supported by the Deutsche Forschungsgemeinschaft (He2386/4-2, 7-1), the Gemeinnützige Hertie-Stiftung, and the MS Society Chapter of Düsseldorf.

Dr Hemmer has received honoraria from Roche, Amgen, Novartis and Biogen Idec, and research grants from Teva-Aventis, Bayer, Merck-Serono and Biogen Idec. Dr Zamvil has received honoraria from Teva Neuroscience, Biogen Idec and Genentech, and research grants from the National Institutes of Health, National Multiple Sclerosis Society and the Maisin Foundation and Dana Foundation. Dr Khan has received honoraria and research grants from Teva, Biogen Idec, Bayer, Serono and Genentech. Dr Hartung has received fees for consultancies and speaking at symposium from Bayer, Biogen Idec, BioMS, BayerSchering, Merck-Serono, Sanofi/Teva/Aventis, Novartis and Genzyme with approval of the CEO of the University of Düsseldorf hospital and the Dean of the Heinrich-Heine University, Düsseldorf. Dr Hartung’s department has received unrestricted grants for research projects from BayerSchering, Biogen Idec, Merck-Serono, and Teva with approval of the CEO of the University of Düsseldorf hospital and the Dean of the Heinrich-Heine University, Düsseldorf. Dr Stüve has received honoraria from or acted as a consultant to Teva Neuroscience, Merck-Serono, Novartis, Genetech and Biogen Idec. Drs Menge, Weber, Kieseier, von Büdingen, Warnke and Boster have no conflicts of interest that are directly relevant to the contents of this review.

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Authors and Affiliations

  1. Department of Neurology, Heinrich Heine-University, Düsseldorf, Germany

    Til Menge, Bernd C. Kieseier, Clemens Warnke & Hans-Peter Hartung

  2. Department of Neurology, Klinikum rechts der Isar, Technical University, München, Germany

    Martin S. Weber & Bernhard Hemmer

  3. Department of Neurology, University of California, San Francisco, California, USA

    Martin S. Weber & Scott S. Zamvil

  4. Department of Neurology, University of Zürich, Zürich, Switzerland

    Hans-Christian von Büdingen

  5. Department of Neurology, The Ohio State University, Columbus, Ohio, USA

    Aaron Boster

  6. Department of Neurology, The Multiple Sclerosis Clinical Research Center, Wayne State University School of Medicine, Detroit, Michigan, USA

    Omar Khan

  7. Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Road, Dallas, Texas, 75216, USA

    Olaf Stüve

  8. Department of Neurology, University of Texas Southwestern Medical Centre at Dallas, Dallas, Texas, USA

    Olaf Stüve

  9. Department of Immunology, University of Texas Southwestern Medical Centre at Dallas, Dallas, Texas, USA

    Olaf Stüve

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  1. Til Menge
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Correspondence to Olaf Stüve.

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Menge, T., Weber, M.S., Hemmer, B. et al. Disease-Modifying Agents for Multiple Sclerosis. Drugs 68, 2445–2468 (2008). https://doi.org/10.2165/0003495-200868170-00004

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