Andrew N. Wilner, MD; Jeremy S. Chataway, PhD


January 10, 2013

Editor's Note:
While onsite at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Lyon, France, Andrew N. Wilner, MD, spoke with Jeremy Chataway, PhD, Honorary Senior Lecturer and Consultant Neurologist at University College Hospitals in London, England about a new study looking at simvastatin therapy in secondary progressive multiple sclerosis (SPMS).

Dr. Wilner: Dr. Chataway, today you did a presentation[1] regarding the use of simvastatin in SPMS. Previous research has shown that simvastatin does not appear to work in relapsing-remitting multiple sclerosis (RRMS). Is that correct?

Dr. Chataway: Early work in 2004[2] showed that there was an effect in a small group of 30 people with RRMS, and there was encouragement that it would become a treatment. However, subsequent larger-sized trials with both simvastatin and atorvastatin did not ultimately back up that effect in RRMS. We decided to look at a different phase of MS -- secondary progressive disease.

Dr. Wilner: Let’s get back to the beginning. Why would a statin that’s normally prescribed for hyperlipidemia in people with cardiovascular disease be used in MS?

Dr. Chataway: If you look at the enzymatic pathways, statins inhibit HMG coenzyme reductase, which of course lowers cholesterol. But apart from that, there are many other chemical pathways that are controlled by this enzyme, including those involving small immune regulatory molecules. It's been very well studied in animals that blocking that enzyme, apart from lowering cholesterol, has the capability to modulate immune function. For example, it could alter T-cell function; it could alter the innate immunity; it could affect leukocyte migration. There are many mechanisms by which blocking this enzyme, in a non-cholesterol-lowering way, could have an effect in an immune-mediated disease. Even in the progressive phase of the disease, there's still inflammatory activity going on as well as a possible neuroprotective effect.

Dr. Wilner: Why did you choose simvastatin among all of the possible statin choices?

Dr. Chataway: This again comes back to the 2004 study, which I read and enjoyed, and which used a high, 80-mg dose of simvastatin. I based my work on what they did. It seemed to be tolerated, it seemed to have an effect, and that was the drug that I chose.

My study was a phase 2 study of 140 patients with SPMS who were randomly assigned 1:1 to placebo or active drug over a 2-year period.

Dr. Wilner: And what was the result?

Dr. Chataway: The primary outcome we're looking at is brain atrophy. All of our brains shrink a little as we age. But in SPMS, the brain shrinks a little bit more, by about 0.6% per year. And that can be measured by advanced MR volumetric measures and measured very accurately. That was our primary measure -- to see if we could reduce the rate of brain atrophy. And over this 2-year period, indeed, that was found to be the case over the dummy drug (placebo). It reduced brain atrophy roughly from about 0.6% to about 0.3%. More exactly, by 43%.

The consensus in the MS community is that brain atrophy correlates with disability. If you can slow brain atrophy in the progressive phase, you have a biological marker, which ultimately should have a clinical impact.

Dr. Wilner: Now if, as you say, all of us are subject to progressive brain atrophy over time, should all of us take simvastatin?

Dr. Chataway: That's an interesting idea, but our rate without MS is about 0.1% per year, so it's a lower rate. It would be speculative to say that we should all be on simvastatin, outside of its cardiovascular protective properties. And, of course, one must be careful. Simvastatin is a drug. This was high-dose simvastatin. It was actually well tolerated in this trial, but there have been well-publicized side effects of simvastatin that occur less frequently but can be very severe: kidney failure, liver failure, muscle weakness. So I wouldn't recommend that everyone should be on a statin.

Dr. Wilner: What's next in your research with simvastatin?

Dr. Chataway: I think these results are very encouraging, both in terms of the primary outcome but also in terms of a small but statistically significant improvement in 2 secondary outcomes: a doctor-measured scale and a patient-reported scale of MS outcome. This was unexpected but, again, encouraging. I think the primary outcome results and those 2 secondary outcomes, plus its safety profile, which was very good, would say that this drug should go forward into a large phase 3 trial -- a purely clinical measurement, probably over a longer time period, in a larger group of patients to generalize these results in SPMS.

Dr. Wilner: It might be worth mentioning that simvastatin is a generic statin, and consequently your study was not pharmaceutically sponsored. Who would sponsor the phase 3 trial?

Dr. Chataway: As you say, this was a non-pharma-sponsored study. It was investigator led and charity funded, by 3 separate charities. Who would sponsor it? I think it would have to come from the global MS movements.

Dr. Wilner: Thank you very much for sharing the results of your exciting research with Medscape.