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Targeting CGRP for the Prevention of Episodic Migraine



Peter Salgo, MD: Let’s take a look at some of the data for the prevention of episodic migraines. And I want to start by looking at the human monoclonal antibody treatment, or mAb treatments, to block the calcitonin gene-related peptide, or the CGRP. So, let’s talk about some biology first. What’s the mechanism of action and the rationale for targeting CGRP for migraines?

Stephen Silberstein, MD: It’s actually several observations. 1) People measured CGRP in the bloodstream, and they found it went up during a migraine attack, it went down either after a triptan or when the migraine attack went away. 2) If you infuse CGRP in the patients with migraine, it can bring on a migraine attack. That’s the biological basis of CGRP in migraine. And a number of years ago, people developed small-molecule CGRP antagonists, which were effective. So we knew that the basis was there [and] the principle [was] there, but the problem we had with some of the older drugs was the problem with the way they were designed and toxicity.

Peter Salgo, MD: Is there a difference then? Because I know that we can either attack the ligand or the attack the receptor at which the ligand is working, and there are drugs that do 1 or the other. Is there a difference then biologically? Is 1 preferred versus the other?

Stephen Silberstein, MD: At this point in time, we don’t know. But I think it’s also important to realize that there are 2 CGRP receptors, and the antibody goes to [only] 1 of them. It’s called the canonical CGRP receptor. The second receptor for CGRP is called the amylin 1 [AMY1] receptor. In contrast, the antibody to the CGRP prevents it from going to both receptors.

Peter Salgo, MD: One is, I don’t know the actual numbers. As you say, we don’t really know yet. But let us assume for the sake of argument, fifty-fifty. If you give the receptor antagonist, 50% still go unblocked.

Stephen Silberstein, MD: To the different receptor, but we really do not understand yet what is the purpose of the amylin receptor in pain. We do know that there is a drug that goes to the amylin receptor that’s given to diabetics with insulin to delay gastric emptying, so that they don’t get a sudden increase in glucose. But we do not understand what the brain amylin receptor does.

Peter Salgo, MD: Every time you think you’ve reached the last receptor, there’s another receptor.

Stephen Silberstein, MD: That is correct.

Peter Salgo, MD: Complicated. Job security for receptor research, isn’t it?

Stephen Silberstein, MD: That’s exactly correct.

Peter Salgo, MD: If you want to discuss a drug, then you’ve got to discuss its safety, and you have to discuss patient factors for these drugs. Let’s start with patient factors. First, what patient factors do you consider for a CGRPR [CGRP receptor] antagonist?

Stephen Silberstein, MD: I would say for all the drugs in this class, you have to [determine]—if it’s a woman— if she’s attempting to get pregnant. And the reason I say that is if you give an antibody, it might take 5 months to get out of the system, and we have no idea yet what the effects of the antibody [are] on a growing baby.

Peter Salgo, MD: OK, so that’s a big lookout.

Stephen Silberstein, MD: Correct.

Peter Salgo, MD: All right.

Stephen Silberstein, MD: And the same with nursing. If you’re nursing, for the first month of nursing, the antibody can be transmitted across the stomach into the baby. After that, that disappears.

Peter Salgo, MD: Tell me about the STRIVE study?

Stephen Silberstein, MD: One of the biggest questions in the entire antibody field is, “Are they safe?” And originally when they were made, we were concerned because CGRP is a vasodilator, and the antibodies stop that. So the STRIVE study looks at the long-term outcome of people, and now it’s up to 5 years, looking for heart disease, hypertension, [and] anything that can be related to vasoconstriction. Nothing has shown up. There is no evidence yet, that taking 1 of these antibodies long term is detrimental to your cardiovascular health.

Peter Salgo, MD: The long-term data that you’re talking about [are] 5 years.

Stephen Silberstein, MD: Yes.

Peter Salgo, MD: It’s now getting to be non—this is a medical phrase I hate—noninsignificant.

Stephen Silberstein, MD: That is correct.

Peter Salgo, MD: That is to say, “It’s significantly long.”

Stephen Silberstein, MD: At this point in time, we have absolutely no evidence there’s a risk to taking these drugs.

Peter Salgo, MD: From a clinical standpoint, what does that mean?

Stephen Silberstein, MD: What it means is that physicians can now be more comfortable using these drugs long term. We had no idea at the beginning how safe they would be long term. But as the studies extend, and we have a 5-year life, it gives us more confidence in the safety of these drugs.

Peter Salgo, MD: Now there’s another study out there, the LIBERTY study. I think there’s a growth business of people inventing the names of these studies.

Stephen Silberstein, MD: Yes.

Peter Salgo, MD: Acronyms are us, incorporated.

Stephen Silberstein, MD: Another question [has] always been raised in migraine studies, and most of the trials prohibited people from failing many drugs in the trial. If you failed 2, 3, or 4 different drugs, does that means that nothing will be useful for you? And I think what the LIBERTY study tried to do is take failures of other drugs and see if they still failed. And the fundamental issue is the following. The results were a little bit worse, but the placebo response rate was way down. Because the people kept failing, their expectations went down, and what we really showed is it had the same benefit over placebo than people who had never failed another drug.

Peter Salgo, MD: Yeah, but the LIBERTY study was with these receptor drugs, is that right?

Stephen Silberstein, MD: That is correct.

Peter Salgo, MD: And these are people who had failed nonreceptor drugs?

Stephen Silberstein, MD: Well, let’s stop a second. All the previous medications we’ve had for the treatment of migraines were not physiological or scientifically based. They were found out by accident, in other words for migraines, after being taken. So it’s like we talked about earlier: beta-blockers, antidepressants. People got a beta-blocker for angina, their migraines went way, but they have nothing to do with the receptor. And as you just simply pointed out, drugs that work by an entirely different mechanism are still effective when other things don’t work.

Peter Salgo, MD: OK, so this was taking another class of drugs and trying it in people who’d failed previous classes of drugs.

Stephen Silberstein, MD: That is absolutely correct.

Peter Salgo, MD: And in that group, who were, I’m assuming, called almost intractable, there wasn’t an effective treatment to demonstrate it in many of them.

Stephen Silberstein, MD: That is correct.

Peter Salgo, MD: That’s the LIBERTY study.

Stephen Silberstein, MD: [And] they did as well as they did as if they hadn’t failed other drugs.

Peter Salgo, MD: So what’s the implication clinically?

Stephen Silberstein, MD: The implication clinically is 2-fold. One, the best people to put in a clinical trial now are drug failures, because they get better statistical separation from placebo. And 2, just because a person failed a drug, doesn’t mean that they’re not going to fail a drug with a new mechanism of action.

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