Risk of CV Events With Anti-CGRPs in Patients With Migraine

Stephen Silberstein, MD: I watch television some nights, and I see all these people smiling and playing golf and it says, “Check for tuberculosis, cancer, diabetes.” And I said, “Oh my God.” Then I found out what the issues are. These antibodies are targeted to interact with the immune system. That’s what causes the problem. The antibody is the thing that does it. The antibodies for CGRP [calcitonin gene-related peptide] are clean. All parts of the antibodies that would interact with the immune cells or with anything else are wiped out by the magic of genetic engineering. So to remember, it’s not the antibody that causes trouble, it’s what it does for a living that causes trouble.

Stewart J. Tepper, MD: To summarize that, the previous antibodies commonly used in neurology are immunomodulating.

Stephen Silberstein, MD: Correct.

Stewart J. Tepper, MD: While the antibodies that target CGRP and its receptor do not appear to have any immune modulation characteristics.

Stephen Silberstein, MD: They have none.

Stewart J. Tepper, MD: We assume, therefore, that we will not see opportunistic infection or neoplasm further down the pike, that’s the assumption that we make with these. It’s very exciting because, it’s the prospect of using targeted antibody therapy without the potential immune consequences.

Stephen Silberstein, MD: Correct. Remember, an antibody is a tool, and the tool could be modified depending on what you want to do with it.

Andrew Blumenfeld, MD: It is important to consider what CGRP does in the body. Taking all of this into account, you explained, that it’s not part of the immune reaction, but it does have an inflammatory affect that’s involved with neurogenic inflammation and vasodilatation.

Stephen Silberstein, MD: It’s the best idea of what CGRP does in the body, it is responsible for peristalsis by activating muscles in the gut. There’s a great big deal of controversy about immune reactions, neuroinflammation, and plasma protein extravasation. The older I get, the more I read, the more confused I get. To the best of my knowledge, CGRP does not produce plasma protein extravasation directly. It can activate mass cells and other nerve modulators and perhaps produce it. It’s an argument as to how much neuroinflammation is involved in the biology of migraine, and that’s the next topic that we need to talk about. It’s still very vague, and I think I spent the last 10 weeks reading about it, and I’m more confused than ever. I just think nobody knows the answer to that question.

Stewart J. Tepper, MD: But you would agree that CGRP is the most potent endogenous vasodilator.

Stephen Silberstein, MD: Absolutely 100%. And the miracle is, when it’s blocked it makes no difference. That’s the amazing thing.

Andrew Blumenfeld, MD: That’s the amazing thing.

Stephen Silberstein, MD: Which means that there must be alternate pathways to compensate. Think about it, the body is known for its redundancy. The other point would be, if it was the only thing that mattered, why wouldn’t the antibody be 100% effective in everybody? We have to have parallel pathways in which 1 picks up where the other leaves off.

Wasn’t there some recent data by Lars Edvinsson, MD, PhD, today or yesterday, clearly showing that if you constrict or relax blood vessels, giving CGRP antibodies makes no difference, except when you’re trying to have them dilate with CGRP itself? That was nice to see that data. I think we have a lot to learn, really a lot to learn.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Yes, we definitely still have a lot to learn, especially with respect to people who have vascular disease and other risk factors for ischemia. While we have multiple mechanisms for the regulation and auto-regulation of vascular tone, particularly in the brain, we know that even in the absence of arterial narrowing or atherosclerosis, some people are more prone to vasospasm than others, and we don’t know what those mechanisms are. If they happen to be non-CGRP, and you take out some of those corollary mechanisms for vasodilation, you might be putting somebody like that at risk. But we don’t know because we haven’t really looked.

Stephen Silberstein, MD: We haven’t seen it yet, but we need to keep our eyes and ears open.

Stewart J. Tepper, MD: That’s exactly what I was going to say. At this meeting at the AAN [American Academy of Neurology] in May of 2019, a variety of randomized controlled trials and open-label extensions have all been plumbed looking at 4 monoclonal antibodies to see if there’s any signal for a vascular safety issue. So far there’s been zero signal. Now, it’s a new class of medicines and vigilance is important. It is reassuring. And the assumption is, if this does not turn out to have a vascular risk, which so far it looks really good, and I wish this table was wood so I could knock on it, it’s because the system is so redundant.