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AAN REPORT 4: Cholesterol drugs for MS and switching therapies

American Academy of Neurology highlights

A high-profile study presented at this year’s AAN meeting is the MS-STAT trial, which looked at whether a high dose of Zocor (simvastatin), a drug used to lower cholesterol, was beneficial in people with secondary-progressive MS (Chataway and colleagues. AAN 2013; abstract PL02.001).

In the phase II study, people with SPMS either received an 80-mg dose of Zocor (a high dose) or a placebo. The endpoint they looked at was brain atrophy (shrinkage), which may reflect neurodegeneration. (The usual trial endpoints, such as relapse rates and MRI lesions, reflect inflammatory activity so they weren’t the main interest.)  At the end of the study, the average rate of brain atrophy was 43% lower in the Zocor group compared to the placebo group.

In SPMS, the inflammation seen in MS becomes less important and neurodegeneration becomes more prominent. So drugs used in relapsing-remitting MS, which act primarily on inflammation, have little impact in SPMS. Over the past decade, numerous laboratory studies have found that the statin drugs (which include Lipitor and Crestor) not only lower cholesterol but also have anti-inflammatory effects (Youssef and colleagues. Nature 2002;420:78-84). More importantly to SPMS, it’s been suggested that these drugs may also promote repair mechanisms in the brain (Paintlia and colleagues. FASEB J 2005;19:1407-1421).

While the MS-STAT results are promising and may lead to larger studies, they should be viewed in a larger context. There was a great deal of enthusiasm for statin therapy following the results of an initial small trial in relapsing-remitting MS (Vollmer and colleagues. Lancet 2004;363:1607-1608). But a subsequent study suggested that combining a statin with an interferon-beta might worsen RRMS (Birnbaum and colleagues. Neurology 2008;71:1390-1395). The larger studies that followed showed mixed results. Some found that statins were beneficial (Paul and colleagues. PLoS One 2008;3:e1928; Lanzillo and colleagues. Mult Scler 2010;16:450-454). But two meta-analyses of treatment trials found that taking statins provided no added benefit in RRMS (Bhardwaj and colleagues. Am J Health Syst Pharm 2012;69:1494-1499; Wang and colleagues. Cochrane Database Syst Rev 2011 Dec 7;(12):CD008386). The largest study to date, called SIMCOMBIN, found no benefit when Zocor was added to Avonex (Sorensen and colleagues. Lancet Neurol 2011;10:691-701).

On the more negative side, a laboratory study suggested that statins may inhibit remyelination (Miron and colleagues. Am J Pathol 2009;174:1880-1890), and a recent study suggested that statins may actually interfere with the action of interferons (Feng and colleagues. Arch Neurol 2012;69:1303-1309). The story of statins may be different in SPMS. But larger studies will be needed to clarify if there’s a role for these drugs in MS.

Another area of interest at this year’s AAN meetings was studies looking at whether Gilenya is an option for people who can no longer continue taking Tysabri. Tysabri is highly effective and has helped many people with MS. However, there is an increasing risk of developing PML (progressive multifocal leukoencephalopathy), an often fatal brain infection, if Tysabri is continued for longer than two years, or if the person shows exposure to the JC virus. But stopping Tysabri can be a problem because many will experience relapses and worsening disease activity. The FIRST study looked at people who switched to Gilenya after being on Tysabri (Comi and colleagues. AAN 2013; abstract P07.103). In the first month after starting Gilenya, those previously treated with Tysabri for 3-6 months were three times more likely to have a relapse compared to people initially on no therapy. However, this relapse activity soon died down and only 2-4% continued to have relapses within four months of the switch.

Similarly, the ENIGM study in France found that two-thirds of people had a relapse after stopping Tysabri (Cohen and colleagues. AAN 2013; abstract S41.002). After switching to Gilenya, one-third continued to have relapses. This may have been due to how long they were off treatment (the washout period) before starting the second therapy. More study is needed to determine the best way of stopping Tysabri, what their best and safest treatment options are, and when is the optimal time to start another drug in those who can no longer continue taking Tysabri.

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