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Health See other Health Articles Title: Recycled Meds and New Approaches in Multiple Sclerosis Andrew N. Wilner, MD: This is Dr. Andrew Wilner, reporting from the 65th Annual Meeting of the American Academy of Neurology (AAN) in San Diego, California. Today it's my pleasure to greet Dr. Lawrence Steinman, immunologist and Professor of Neurology and Neurological Sciences, Pediatrics, and Genetics at Stanford University in California. Dr. Steinman received the prestigious Charcot Award in 2011 and later published his ideas in Multiple Sclerosis. [1] Dr. Steinman has also cofounded several immunology-related companies. Dr. Steinman, thanks for joining us. Lawrence Steinman, MD: Thanks for inviting me. Dr. Wilner: We are here today at the AAN meeting, where there are 2400 posters and presentations. Which is the most important from your point of view in terms of advances in multiple sclerosis (MS)? Dr. Steinman: It is great to see how many of the posters and presentations were about MS, because MS is only part of the general field of neurology. One aspect of MS that is very encouraging is that for some forms of the disease, we have multiple choices of therapies that really provide benefit. Having said that, there are other aspects of the disease, certain forms of MS, for which we don't have anything to offer at the present time. We have multiple drugs for the form of disease that we call "relapsing-remitting," which probably involves inflammation in the brain and allows us to intervene in many ways with immune-related drugs. That's very encouraging, but there are also vast components of the disease that we call "secondary progressive," in people who have passed through the relapsing-remitting stage and have an insidious downhill course. For those patients, we have little to offer right now, but there were some encouraging posters and presentations for that disease. There is an even rarer segment of MS, involving only a small percentage of patients, that we call "primary progressive." They never go through the relapsing-remitting phase. There are some encouraging prospects for developing treatments for them, but today we have nothing that is approved. Recycling Drugs for MS Dr. Wilner: It takes many years and hundreds of millions of dollars to develop a new drug for any disease. I understand that you have been looking at repurposing some drugs that are already approved for MS. Can you tell us about that? Dr. Steinman: This effort was based in part on the success of the drug BG-12, a component of the Krebs cycle that we all studied in medical school, and which had astonishing results. BG-12 reduced relapses by approximately 50%, had a very big effect on MRI activity, and reduced disability. So I thought to myself -- and others are thinking similar thoughts -- what if other drugs that affect common pathways would have a big effect on MS? Dr. Wilner: BG-12 is dimethyl fumarate, and its approval is still pending, although we expect a verdict from the US Food and Drug Administration any day. Dr. Steinman: That's right. They had 2 successful phase 3 trials. Dimethyl fumarate is composed of 2 fumarate molecules with a little methyl bridge. Don't ask me to recite the Krebs cycle, but fumarate is an important part of it. How could this drug that affects the central pathway of intermediary metabolism have such a profound effect not only on relapsing-remitting MS but also in treating psoriasis, a totally different disease? Dr. Wilner: Perhaps psoriasis is also immunologically based? Dr. Steinman: Yes. The idea is that there might be other drugs that are commonly used for other indications and that have a reasonably good safety profiles. Take a drug such as the common antihypertensive agent lisinopril. We give it to experimental animals that have the model disease that resembles MS, and the paralysis goes away after several doses. We learn from studying these animals that various inflammatory pathways are suppressed. So, we have a very strong biochemical foundation for thinking that if we attempt this in humans, we might see benefit that would rival what has been reported for dimethyl fumarate. You said that it takes many years and a hundred million dollars or so to test a new drug, and there isn't a lot of profit to be made by repurposing drugs that have been around for a long time. So, what needs to be done in the field is to find a way of rapidly testing to see whether a given drug has a big effect. We might miss drugs that could potentially work that have a small effect or take a long time to work, but one of the most exciting paths forward would be to develop clinical trials that rapidly assess -- over a period of a few months -- whether the drug has a benefit, using imaging and clinical techniques. We might find a big difference from using such drugs as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for new indications. In past years people have attempted to use statins, which work in animal models, without much success. We just have to keep trying. Steinman: The other thing, when you design these trials, is that you can't take away therapy that is of proven benefit. We are looking for something additive. When we turn to oncology, most of the successful oncologic therapies target more than 1 of the pathways involved in malignancy. The idea would be to take one of these repurposed drugs and hope that it adds benefit by affecting a different pathway than a drug that is of proven benefit. One of the topics at this meeting was a very big trial conducted by Fred Lublin at Mount Sinai, called the CombiRx trial,[2] in which they looked to see whether giving 2 of the most popular drugs for relapsing-remitting MS -- glatiramer and beta-interferon -- together would have a bigger effect than giving 1 drug at a time. This trial was supported by the National Institutes of Health, and the drugs were supplied by the manufacturers. After spending all that money, in 7 years we came to the conclusion that there is no additive effect. We need more attempts like this, but we have to do them more rapidly and more efficiently. Dr. Wilner: It was an important study, however, because the results were not intuitive. Although both drugs are immunologic, they work differently. One might reasonably conclude they would be additive, and yet it turns out in practice that they are not. Dr. Steinman: That's right. Probing more deeply reveals a very interesting issue. Beta-interferon is a drug that has such a complicated mechanism of action that 50 years after its discovery, we are still wondering (although we know its receptors and signaling pathway) how and why and in whom it works. The same can be said for glatiramer. Dr. Wilner: You are saying that we also need to emphasize our efforts in basic research so that we understand better what we are doing. Dr. Steinman: That's right, but there are a lot of good people out there pursuing that basic science. Post Comment Private Reply Ignore Thread Top • Page Up • Full Thread • Page Down • Bottom/Latest Begin Trace Mode for Comment # 1.
#1. To: Tatarewicz (#0)
Good stuff - thank you!
There are no replies to Comment # 1. End Trace Mode for Comment # 1.
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