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Therapeutic Approaches to Multiple Sclerosis

An Update on Failed, Interrupted, or Inconclusive Trials of Immunomodulatory Treatment Strategies

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Abstract

Multiple sclerosis (MS) continues to be a therapeutic challenge, and much effort is being made to develop new and more effective immune therapies. Particularly in the past decade, neuroimmunologic research has delivered new and highly effective therapeutic options, as seen in the growing number of immunotherapeutic agents and biologics in development. However, numerous promising clinical trials have failed to show efficacy or have had to be halted prematurely because of unexpected adverse events. Some others have shown results that are of unknown significance with regard to a reliable assessment of true efficacy versus safety. For example, studies of the highly innovative monoclonal antibodies that selectively target immunologic effector molecules have not only revealed the impressive efficacy of such treatments, they have also raised serious concerns about the safety profiles of these antibodies. These results add a new dimension to the estimation of risk-benefit ratios regarding acute or long-term adverse effects.

Therapeutic approaches that have previously failed in MS have indicated that there are discrepancies between theoretical expectations and practical outcomes of different compounds. Learning from these defeats helps to optimize future study designs and to reduce the risks to patients. This review summarizes trials on MS treatments since 2001 that failed or were interrupted, attempts to analyze the underlying reasons for failure, and discusses the implications for our current view of MS pathogenesis, clinical practice, and design of future studies. In order to maintain clarity, this review focuses on anti-inflammatory therapies and does not include studies on already approved and effective disease-modifying therapies, albeit used in distinct administration routes or under different paradigms. Neuroprotective and alternative treatment strategies are presented elsewhere.

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Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors declare the following: Jochen C. Ulzheimer has received consulting fees, honoraria for lecturing, and travel expenses from Biogen Idec Inc., Merck Serono S.A., Sanofi-Aventis S.A., and Novartis S.A. Stefan Bittner has received travel expenses for attending meetings from Merck Serono and Bayer Schering. Christoph Kleinschnitz has received honoraria for lectures from Biogen Idec, Bayer Schering, Teva, Merck Serono, and Novartis. Bernd C. Kieseier has received honoraria for lectures from Biogen Idec, Bayer Schering, Teva, Merck Serono, and Novartis. Sven G. Meuth has received honoraria for lectures from Biogen Idec, Bayer Schering, Teva, Merck Serono, and Novartis. Heinz Wiendl has received honoraria for lectures from Biogen Idec, Bayer Schering, Teva, Merck Serono, and Novartis.

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Authors and Affiliations

  1. Department of Neurology, University of Wuerzburg, Wuerzburg, Germany

    Jochen C. Ulzheimer, Sven G. Meuth, Stefan Bittner & Christoph Kleinschnitz

  2. Clinic of Neurology, Caritas Hospital Bad Mergentheim, Bad Mergentheim, Germany

    Jochen C. Ulzheimer

  3. Department of Neurology — Inflammatory Disorders of the Nervous System and Neurooncology, University of Muenster, Domagkstr. 13, 48149, Muenster, Germany

    Sven G. Meuth &  Heinz Wiendl

  4. Department of Neurology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

    Bernd C. Kieseier

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  1. Jochen C. Ulzheimer
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Correspondence to Heinz Wiendl.

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Ulzheimer, J.C., Meuth, S.G., Bittner, S. et al. Therapeutic Approaches to Multiple Sclerosis. BioDrugs 24, 249–274 (2010). https://doi.org/10.2165/11537160-000000000-00000

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