MS clinical trials: Lessons from recent failures

Despite the emergence of several immunotherapeutic agents which appear to alter the natural history of multiple sclerosis (MS), many drugs continue to undergo unsuccessful therapeutic trials. It is possible, however, to draw useful information from trials with apparently negative results. Three examples are considered here. Lenercept appeared to worsen MS as measured by number of exacerbations, pointing to a flaw in the rationale for its expected beneficial effect. That the worsening did not correlate with MRI lesion load was also surprising, hinting at a caveat in the use of this surrogate endpoint. Linomide was unexpectedly linked to an increased incidence of myocardial infarction in the active treatment groups, emphasizing the importance of carefully monitored and designed phase III trials for the detection of rare but dangerous side-effects. Sulphasalazine initially appeared to reduce relapse rate in a fashion similar to beta interferon, but the improvement disappeared in the second half of the trial, highlighting the importance of long-term follow-up in establishing efficacy in chronic diseases such as MS.