Significance of Understanding MOAs When Treating MS

Fred D. Lublin, MD: While we’re on the topic of targets, Suhayl, tell us what you think, in terms of an understanding of the mechanism of action [MOA] and how important that is in choosing a therapy.

Suhayl S. Dhib-Jalbut, MD: Let me just start by saying that we don’t really fully understand the mechanism of action of the drugs we have for MS [multiple sclerosis]. We have some understanding but not complete understanding to guide us in choosing therapy. But when I think about mechanisms, I think of the drugs in 4 categories: Those that are immune modulatory, meaning they don’t kill cells but they change their immune profile and inflammatory profile; I think of the immunosuppressive drugs that deplete cells—T cells, B cells, or both; I think of drugs that interfere with trafficking and migration to the nervous system; and finally, those that are potentially neuroprotective, although we don’t really have solid evidence for that with the existing drugs.

In terms of choosing therapy, I think understanding the MOA has certain applications at the present time—practical application in the clinic. The best example would be in the case of NMO [neuromyelitis optica], where we think that the antibody is involved in the pathogenesis. And because of that, it would make perfect sense to use a B-cell depleting agent rather than a pan-depleting agent. That’s one example where I think mechanism of action can help you choose a therapy for a particular condition.

However, I think understanding the MOA has more implications on safety, particularly if we think of biomarkers that can predict complications of treatment. A perfect example would be the case of natalizumab and PML [progressive multifocal leukoencephalopathy], where we don’t treat patients who are JC virus-positive. Another situation would be pregnancy. Understanding a mechanism of action will help you decide on the safest drug during pregnancy. We have data on a fair number of drugs being safe or unsafe during pregnancy.

Finally, I think mechanism of action is important in choosing drugs based on comorbidities that patients might have. Just as an example, if somebody has cardiac disease, you want to avoid drugs that can affect the heart rate or heart function. In thyroid disease, you want to avoid drugs that can result in autoimmune thyroiditis. Those comorbidities and understanding the mechanism of action of the drug and its adverse effects can help you select the appropriate treatment for the right patients.

Fred D. Lublin, MD: Other thoughts on mechanism of action?

Clyde E. Markowitz, MD: I couldn’t agree more.

Fred D. Lublin, MD: I particularly like natalizumab in people who have concomitant inflammatory bowel disease, for example. On the other hand, I might avoid fingolimod in diabetics because they’re more likely to get macular edema. And hypertension occurs with a couple of the agents, and such. So I think that it’s not the first consideration, but I think MOA fits in there, especially with the comorbidities. The other is pregnancy, which is a much longer conversation but one that we discuss with every patient since almost all of them are in reproductive years, and the timing and such, which will take us to another evening’s discussion just on pregnancy. Yes, Clyde?

Clyde E. Markowitz, MD: Another thing is the notion of sequencing. With a mechanism of a particular drug that’s going to necessarily deplete a population of cells, maybe you have another drug that’s going to have an effect on trafficking. And if there are no cells around to affect trafficking, you’ve wasted your time, or just the opposite may be true. So knowing what the drug does is very important, and knowing where you’re going to go after that is key.

Suhayl S. Dhib-Jalbut, MD: Absolutely. I think it will be more important when we start combining drugs. Ideally, if you’re entertaining combination therapy, you want to use drugs that have different mechanisms of action. That’s why understanding mechanisms are important, although I should say that a fair number of these drugs have overlapping mechanisms of action. But there are differences that could be enough to rationalize combining certain drugs.