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Neurology Today:
doi: 10.1097/01.NT.0000446548.20819.57
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A Statin Is Found to Ameliorate Late-Stage Disability in MS: Experts Call for Phase 3 Trial

Valeo, Tom

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ARTICLE IN BRIEF

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Researchers reported that, in a double-blind trial, patients with secondary progressive multiple sclerosis who took simvastatin showed a 43 percent reduction in the annualized rate of brain atrophy compared with the placebo group.

Simvastatin (Zocor), one of the most widely prescribed statins, appears to slow brain shrinkage in patients with secondary progressive multiple sclerosis (MS). Since brain shrinkage is the most reliable marker of worsening disease, the findings, if they hold up, could make simvastatin the first treatment capable of affecting the late-stage disability that eventually affects about 65 percent of MS patients.

“At the moment, we don't have anything that can stop patients from becoming more disabled once MS reaches the progressive phase,” said co-author Richard Nicholas, MD, of the Faculty of Medicine at Imperial College London, in a statement released prior to the publication of the study in the March 19 online edition of The Lancet. “This is a promising finding, particularly as statins are already cheap and widely used. We need to do a bigger study with more patients, possibly starting in the earlier phase of the disease, to fully establish how effective it is.”

The two-year, double-blinded, controlled trial involved 140 patients, ages 18 to 65, with secondary progressive MS. They were randomly assigned to receive either 80 mg of simvastatin or a placebo. Those on simvastatin showed a 43 percent reduction in the annualized rate of brain atrophy compared with the placebo group (-0.254 percent per year, p=0.003). Despite the high dose — the Food and Drug Administration warns against starting patients on 80 mg of simvastatin because of the risk of muscle damage — there were no differences in serious adverse effects between the two groups.

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EXPERTS COMMENT

Multiple sclerosis experts hailed the results as a major development in the treatment of secondary progressive MS. Reducing brain shrinkage “is a big deal,” said Richard M. Ransohoff, MD, director of the Neuroinflammation Research Center at the Cleveland Clinic Lerner Research Institute, staff neurologist at the Cleveland Clinic's Mellen Center for MS Treatment and Research, and professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

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“In the life history of a disease, the single most important moment is when you first find a treatment that makes a difference. Until then you don't have confidence about how to proceed. If this result holds up and is extended, this may be the first glimmer of hope for progressive MS.”

[Dr. Ransohoff is the editor of a new open-access, online only journal associated with the flagship AAN journal Neurology, Neurology: Neuroinflammation and Neuroimmunology that will launch April 25.]

Timothy Vollmer, MD, FAAN, lead author of a 2004 study also published in The Lancet that found a 41- to 44-percent reduction of gadolinium-enhanced lesions in MS patients taking 80 mg of simvastatin, said the reduction in brain atrophy points to the first effective treatment of a disorder currently considered intractable.

“Preventing brain atrophy is the single most important therapeutic goal because it has the strongest predictive value for ultimate disability,” said Dr. Vollmer, professor and director of clinical research at the University of Colorado School of Medicine. “Preserving brain volume, theoretically, should correlate with better long-term outcomes in terms of disability, and that's very exciting. So this report in The Lancet is very important because statins may provide a strategy for maximizing life-long brain health in our patients.”

Scott S. Zamvil, MD, PhD, FAAN, who was the lead author of a 2002 paper in Nature that found atorvastatin capable of preventing or reversing chronic and relapsing paralysis in the experimental autoimmune encephalomyelitis mouse model of MS, found The Lancet paper encouraging because it provides strong evidence that statins are in fact effective at treating MS.

“These data are incredibly provocative and exciting,” said Dr. Zamvil, professor of neurology at the University of California, San Francisco. “This should lead to a phase 3 trial that tests the effect of simvastatin on disease progression and disability. When you have a positive result like this, you take it forward.”

Since statins are known to have anti-inflammatory effects, especially on endothelial cells that line arteries, several researchers followed up on Dr. Zamvil's 2002 Nature paper, but the results have been inconsistent and sometimes contradictory.

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A 2002 Neurology paper found that three statins — lovastatin, simvastatin, and mevastatin — were effective immunomodulators, with simvastatin the most potent. However, the statins “also exhibited some proinflammatory effects,” the authors reported.

While Dr. Vollmer and his colleagues reported a dramatic decline in gadolinium-enhanced lesions in MS patients on 80 mg of simvastatin in their 2004 paper in The Lancet, the patients showed no clinical improvement.

A 2008 study in Neurology concluded that adding atorvastatin to MS patients on interferon beta-1a actually increased gadolinium-enhancing T2 lesions on MRI in 10 out of 17 subjects, compared with one out of nine on placebo.

However, a study led by Dr. Ransohoff and Richard A. Rudick, MD, FAAN, and published in Neurology in 2009, concluded the opposite — that “statin therapy does not appear to affect clinical effects of IM [intramuscular] interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.”

Then a 2011 study in Lancet Neurology “found no beneficial effect of simvastatin as an add-on therapy for MS patients on interferon beta-1a.”

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THE MECHANISM BEHIND THE EFFECT

The evidence published in The Lancet that simvastatin reduces brain atrophy added some welcome clarity to the issue. However, the mechanism behind this effect remains a source of debate.

The anti-inflammatory action of statins, which may seem like the obvious mechanism, may not be in effect here, according to Dr. Vollmer.

“My sense is that statins may be working in the brain at the level of the astrocyte,” he said. “There's evolving data that astrocytes are being activated as a result of the inflammation that characterizes MS, and they produce toxic intermediates, including nitric oxide and tumor necrosis factor, which can then lead to toxic effects on oligodendrocytes and neurons that affect mitochondrial function and energy production.”

Statins do not affect the adaptive immune system in people who take them to lower their cholesterol, and the same is probably true for MS patients, according to Dr. Vollmer.

“I think that's likely to be the same in MS — statins act on pro-inflammatory signaling processes that upregulate various toxic intermediates that can then lead to tissue damage.”

Dr. Zamvil and colleagues recently published a paper in the Journal of Neuroinflammation that concluded the therapeutic effect of atorvastatin in a mouse model of MS may be due to the ability of the drug to inhibit the proliferation of proinflammatory encephalitogenic T cells, and not the induction of anti-inflammatory Th2 cells.

“We see a more potent effect in vivo from blocking lymphocyte proliferation than we do from immune modulation,” he said. “It may be that statins inhibit lymphocytes and certain other cells from dividing. It's difficult to say that it's one effect or another — that it's due to its antiproliferative effects, its immunomodulatory effects, or a composite.”

Dr. Zamvil and his colleagues hope to begin tests next year in humans using atorvastatin, the same drug given to mice.

The authors of The Lancet paper say their results support testing simvastatin in a phase 3 trial, but Dr. Vollmer believes valuable data could be extracted immediately from the medical records of MS patients already on statins to lower their cholesterol. “We probably could do some quick cross-sectional comparisons of those patients through large databases to see if there's any hint of toxicity,” he said.

Investigators might want to review diffusion-weighted imaging and spectroscopy of patients on statins for cardiovascular reasons to look for white matter differences compared with patients not on statins, Dr. Vollmer said.

He also would like to see a trial investigate whether people already on anti-inflammatory therapy such as natalizumab, rituximab, and fingolimod would preserve more brain volume by also taking statins. “That would be a very exciting study to do,” he said. “The statin story is telling us some important things.”

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FROM THE AAN: A NEW OPEN ACCESS JOURNAL ON NEUROIMMUNOLOGY & NEUROINFLAMMATION

Richard M. Ransohoff, MD, is the editor of a new open-access, online only journal associated with the flagship AAN journal Neurology®. The newest addition, Neurology®Neuroimmunology & Neuronflammation, will launch April 25; an iPad app will be available shortly thereafter. The journal is aimed at both clinicians and scientists, and will provide both basic and translational studies; case reports; and clinical observations. There has been an explosion of research on the effects of neuroinflammation and neuroimmunology on both diseases of aging and neurodevelopment, Dr. Ransohoff said in a podcast interview. The new journal will embrace the best science of both emerging fields.To learn more about the new journal, dubbed Neurology N2, visit http://bit.ly/1dAcOXH. Listen to Dr. Ransohoff's podcast interview here: http://bit.ly/1h33yGn.

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LINK UP FOR MORE INFORMATION:

•. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): A randomized, placebo-controlled, phase 2 trial. Lancet. 2014; E-pub 2014 Mar. 19.

•. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004; 363:(9421):1607–1608.

•. Youssef S, Stüve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002; 20:(6911):78–84.

•. Birnbaum G, Cree B, Altafullah I, et al. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology. 2008; 71:(18):1390.

•. Rudick RA, Pace A, Rani MR, Hyde R, Panzara M, Appachi S, Shrock J, Maurer SL, Calabresi PA, Confavreux C, Galetta SL, Lublin FD, Radue EW, Ransohoff RM. Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a. Neurology. 2009; 72:(23):1989–1993.

•. Sorensen PS, Lycke J, Erälinna JP, et al. for the SIMCOMBIN study investigators. Simvastatin as add-on therapy to interferonβ-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): A placebo-controlled randomized phase 4 trial. Lancet Neurol. 2011; 10:(8):691.

•. Weber MS, Prod'homme T, Youssef S, et al. Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin. J Neuroinflam. 2014; 11:29.

•. Ibudilast clinical trial: http://1.usa.gov/1fst2NO

•. Barkhof F1, Hulst HE, Drulovic J, et al. for the MN166–001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant. Neurology. 2010; 74:(13):1033–1040.

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