Therapeutic approaches to multiple sclerosis: an update on failed, interrupted, or inconclusive trials of neuroprotective and alternative treatment strategies.

Currently approved multiple sclerosis (MS) therapeutics have a mainly anti-inflammatory mode of action. However, a number of promising clinical trials have been initiated that either focus on neuroprotection or follow completely different treatment strategies. So far, all of these clinical trials have failed to show efficacy or had to be halted prematurely because of unexpected adverse events. Some others show results that are of unknown significance with regard to a reliable assessment of true efficacy versus safety. For example, trials addressing the highly promising sodium channel blockers are under close observation because of potential adverse effects after drug withdrawal. Previously failed therapeutic approaches in MS have indicated that there are discrepancies between the theoretical expectations and practical outcomes of different compounds. Learning from these failures helps to optimize future study designs and to reduce 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 the design of future studies. In order to maintain clarity, this review focuses on neuroprotective and various other treatment strategies. Clinical trials addressing anti-inflammatory research strategies are presented elsewhere.