Lessons from linomide

The clinical1 and MRI2 analyses from the phase III study of linomide (roquinimex) in this issue of Neurology demonstrate that large clinical trials have value beyond the obvious goal of establishing clinical efficacy. Preclinical observations showed that linomide had immunomodulatory effects, suggesting it might be beneficial for MS. It prevented or ameliorated experimental allergic encephalomyelitis (EAE), an animal model of MS. In phase I and II clinical trials, linomide appeared safe and reduced MS activity detected by MRI. When the phase III trial of linomide was initiated in 1996, hopes were high that it would become one of the first treatments to slow progression of MS. Instead, linomide had unexpected, unacceptable toxicity (myocardial infarction), prompting the abrupt discontinuation of linomide studies before efficacy could be assessed.

Were large numbers of patients inappropriately exposed to an inadequately tested agent? No. Previous trials in over 700 patients treated with linomide showed that up to 2% experienced pleuritis or pericarditis. These occurred predominantly in patients with acute myeloid leukemia, however, suggesting that many of these events were related to the underlying disease rather than the linomide treatment itself. Myocardial infarctions had not occurred in previous animal studies or clinical trials up to 6 months long. The potential risks of linomide treatment appeared to be acceptable for a …