Data from two MS pilot trials: Rolipram a miss, Minocycline & Copaxone a possible hit

Two MS treatment pilot studies recently released their results -- one had a positive outcome (well, positive enough) but the other did not turn out as well. The first one was a phase II combination trial of minocycline plus Copaxone in 44 people with relapsing-remitting MS. Minocycline is an antibiotic that also has immunomodulating properties; for instance, it can inhibit the expression of MMP-9 and thus strengthen the blood-brain barrier. In this trial, half the participants received Copaxone plus minocycline while the other half received Copaxone plus a placebo. Four dropped out due to adverse events (two in each group), so 40 subjects finished the 9 month treatment phase. Adverse effects were mild and moderate and the most common were injection site reactions, headache and nausea. Infections and gastrointestinal problems were more common in subjects receiving placebo than minocycline.

Although none of the clinical outcomes reached statistical significance, the minocycline group did have a greater reduction in enhancing lesions, new and enlarging T2 lesions, and total T2 lesion burden. There were fewer relapses in the minocycline group as well. The minocycline group had a higher number of enhancing lesions at baseline, so regression to the mean may have played a role in the results. However, the authors conclude that the the trends were consistently in favor of combination therapy, and minocycline is well-tolerated, safe, and inexpensive, so therefore further trials with larger numbers would be justified.

The other trial was a phase I/II study of the antidepressant rolipram in subjects with relapsing-remitting or secondary progressive MS. Rolipram is a member of class of drugs (PDE-4 inhibitors) that also have immunomodulatory properties, affecting functions such as immune cell activation and release of factors called cytokines. Preliminary studies in the mouse model EAE produced positive results, and additional evidence suggested a neuroprotective effect, so a group of scientists at the NIH decided to do a small trial (6 subjects) to select a dose and then a slightly larger trial (up to 20 subjects) to assess the safety, tolerability and potential efficacy of rolipram.

Unfortunately, after enrollment and dosing (eight months) of only eight subjects (6 phase I, 2 phase II), the trial was called off because 6 of the subjects had an increase in the number or volume of Gd-enhancing lesions. No clinical deterioration was observed, however. Analysis of blood samples from these subjects showed that the drug inhibited immune cell proliferation and also reduced numbers of CD4+ T cells and monocytes. These findings did not shed much light on why the MRI outcomes were so disappointing, but the authors said that perhaps regulatory populations of immune cells were adversely affected by the drug.