CGRP Receptor Antagonists for Migraine Prevention: What's New

Andrew N. Wilner, MD; David W. Dodick, MD


August 19, 2022

This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I'm Dr Andrew Wilner, reporting virtually from the American Academy of Neurology meeting. I'm here today with Dr David Dodick to speak about his presentation regarding a new migraine treatment.

Dr Dodick is a professor emeritus of neurology from the Mayo Clinic and current chair of the Atria Academy of Science and Medicine. I had the pleasure of passing Dr Dodick in the hall a few years ago when I worked at the Mayo Clinic as a locum tenens neurologist. Dr Dodick, it's a pleasure to see you again.

David W. Dodick, MD: It's great to see you, Dr Wilner. Thank you for having me.

Abstract at AAN

Wilner: I'm pretty excited to learn. I culled the abstracts to find an interesting one, and somehow yours popped up because it concerns these calcitonin gene-related peptide (CGRP) inhibitors that I'm reading more and more about. Tell us about your abstract and what you did.

Dodick: Sure, Dr Wilner. The abstract focuses on mean monthly migraine days, acute medication use days, and migraine-specific quality of life in individuals who were enrolled in an atogepant prevention trial. We did a post hoc analysis.

When we look at prevention trials in migraine, the primary endpoint is generally a reduction in mean monthly migraine days. Comparing baseline, 1 month before starting treatment, patients are usually on treatment for 3 or maybe 6 months; then we look at the mean monthly reduction in migraine days during whatever primary endpoint time period we've identified compared with baseline. In this particular case, we're looking at weeks 9 through 12, so the third month compared with the baseline month.

In addition to that, in prevention trials, we also look at the responder rate, so the proportion of patients who have at least a 50% reduction in mean monthly migraine days. Mean monthly migraine day reduction is the primary endpoint. The secondary endpoint is usually the responder rate.

Here, we wanted to look at the responders and the nonresponders and get a little more granular to identify the magnitude of the response in those who do respond and the magnitude of the nonresponse in those who didn't respond. This was a typical prevention trial with atogepant, which is an oral CGRP receptor antagonist. It's a small molecule that is different from the CGRP monoclonal antibodies, which are biologics that are injected once a month or once every 3 months.

To be enrolled, patients had episodic migraine, so four to 14 migraine headache days per month, and again, they had to have a history of migraines for at least a year. We're looking at weeks 9 through 12. The actual primary endpoint in this trial was the overall 3-month reduction, so what was the mean monthly reduction over the 3 months during the trial?

Here, we're looking at that third month because when we start a preventive treatment, we know that there's a cumulative benefit over time. Patients look better at month 3 than they do at month 2 than they do at month 1. Most prevention trials do look at that third month. I wanted to take a look at that third month and look at the magnitude of the response in those who actually responded.

We found that 71% of people on 60 mg of atogepant had achieved a greater than 50% reduction in mean monthly migraine days during that third month. That's quite a substantial responder rate. Typically, when we look at other oral preventive treatments, we're looking at somewhere between 45% and 55% of those who respond having a greater than 50% reduction at weeks 9 through 12.

I know I'm comparing across trials, but I'm just trying to put this in a bit of context here. In those who responded to treatment, their mean monthly migraine days went from 7.7 days of migraine at baseline per month down to 0.6 at weeks 9 through 12 — so, 7.7 to 0.6. That's a substantial difference.

Treatment Naive vs Failed Prior Therapy

Wilner: I was curious if there was any requirement to get into the trial that you had already tried other preventive medicines, or could they be on other preventive medicines? Was this was an add-on trial, or were these patients who were not taking anything else?

Dodick: That's a good question. Typically, in these trials, we tend to exclude people who are treatment failures, if you will — those in whom more than two previous preventive treatments have failed. Although it varies from trial to trial whether patients can be on a preventive medication, in this trial, patients could be on a preventive medication so long as that medication was stable and hadn't had a recent change in the dose. Does that answer your question?

Wilner: Yes, it does. It's a little different than epilepsy trials, where two medicines have to fail for patients to get in. In your case, it's the opposite. That's very interesting.

Dodick: In this particular case, and in most migraine trials, actually, you can be treatment naive — you can never have had a prior preventive medication — or you could have had up to two [failed medications]. It's interesting because when we look at some of the biologic prevention studies, among those in whom have two to four medications have failed, the separation from placebo is even greater. The more medications that have failed, the greater the effect size, if you will, because I guess expectation of a patient in whom medications have already failed is going to be lower, so the placebo response is lower.

In most prevention trials, as more medicines fail, the magnitude of the response may be somewhat attenuated or blunted, but the effect size or the ability to separate from placebo is actually greater.

Wilner: Are there any other oral CGRP antagonists like this drug?

Dodick: There is. There's a drug called rimegepant, which is the only oral CGRP receptor antagonist that is approved both for the acute treatment of migraine at 75 mg and the preventive treatment of migraine at 75 mg taken every other day. There are two oral CGRP receptor antagonists: one used every day and one used every other day.

Injectable vs Oral?

Wilner: I don't know if there are enough data to be fair to ask you to answer, but the ones I've been reading about are mostly injectable, and now there's an oral. Would there be any reason to take an injectable if there's an oral?

Dodick: Usually, it's a personal reason and sometimes there may be a medical reason. As I said earlier, the injectable CGRP antagonists are monoclonal antibodies. They're large, 150-kDa molecules. They're peptides, so you really can't take them orally because they're too large and they'd be metabolized by peptidases and enzymes in the stomach, so they have to be injected. They have a long half-life that is, on average, about 28 days or a month. That's why they're usually injected subcutaneously once a month.

The benefit of having an antibody is that you don't have to take a pill every day or a pill every other day. You take an injection once a month or with some of these antibodies, you can take an intravenous (IV) infusion once every 3 months, and one of the subcutaneous antibodies you can take every 3 months at a higher dosage. It's ease of use, perhaps. You don't have to take a pill every day or every other day.

The downside, of course, is that it does have a long half-life. Let's say you're a young woman of childbearing age and you plan to have a family. You have to be off a drug, as you know, for at least five half-lives before you become pregnant or before you conceive. If you're planning a pregnancy or planning conception and you're on an antibody, you have to be off that antibody for 5 months before you try to conceive.

With these small molecules, they're small; they can be taken orally. They're not peptides; they're drugs. The half-life is somewhere between 6 and 12 hours. If you needed to stop the medicine, the medicine is out of your out of your system, so to speak, in a much shorter period of time, and within a week, certainly.

Wilner: Now, as a clinical neurologist myself who is not a headache specialist, I still treat many patients in my clinic with migraine.

Dodick: Yes.

What to Choose and What Is Covered

Wilner: There are many different classes of prophylactic medications. You look for reasons to try this one, like topiramate for weight loss or a beta-blocker if they have hypertension. Where does this new class fit in? Is it at the top of the list? The bottom of the list? Obviously, you're going to individualize, but how should I visualize this?

Dodick: It's a great question. My answer to that question is that the decision has been somewhat taken out of your hands, because if you're individualizing treatment and you felt for whatever reason that atogepant, rimegepant, or one of the monoclonal antibodies should be first choice for that patient, it just so happens that it can't be first choice. Insurance carriers will not reimburse or cover one of these new medicines unless a patient has failed at least two prior preventive medications in the United States today.

If a patient who's naive to preventive treatment comes into your office and has disabling migraine — let's say they have eight migraine days per month, which is clearly an indication for prevention — you must try one of the older oral preventive medications, or you could try a device or non-pharmacotherapy. If you want to start a drug therapy, you really can't start an antibody or one of these new CGRP receptor antagonists until at least two have failed. Once two have failed, if you feel, for example, that the patient is a good candidate for one of these CGRP antagonists, then by all means [use it].

Wilner: There is a roadblock that's not medical. I guess we'll just leave it at that for now. If all of the medications were free, would you have any preference as to where to start?

Dodick: Well, let me answer that by saying, do I think there's a role for the older preventive medicines? The answer to that is yes. You alluded to some of the reasons why I might start an oral preventive [agent]. For a patient who needs weight loss or who might have epilepsy, for example, topiramate may be a very reasonable choice. For someone who needs to sleep better or has a very lean body mass index who may have a bit of depression, then perhaps a tricyclic may be indicated in that patient.

Having said that, what mental health expert actually starts a tricyclic as a first-line therapy for depression? The problem with some of these medicines is that the adverse events in people with migraine occur at much lower dosages. The dosage of with topiramate at which a patient with epilepsy might experience adverse events may be very different from that in migraine. You try to get a twofer, right? You try to start a medicine because of its antidepressant effect. You start it, but you can't get them up beyond 25-30 mg. That's simply not enough to have an antidepressant effect.

My inclination is to try to optimize the treatment of the disease that you're treating, and if you feel comfortable, optimize the treatment of some of the other comorbidities with different medicines or with different lifestyle or behavioral modifications.

Let me come back to your question: Do I think there's a role, if money were taken off the table and cost was not an issue, where I would start a CGRP monoclonal antibody or a CGRP receptor antagonist first-line? Absolutely. Without doubt, 100%.

The reason I say that is we have enough long-term experience. Now, we have over 6-year long-term data on one of these antibodies, and we've got long enough data with these oral CGRP receptor antagonists with enough of a sample size to know what the adverse event profile is of blocking CGRP, so I feel confident.

I also feel confident that if you're starting a patient, especially with chronic migraine, on a preventive medicine — let's say one of the older drugs — we know that 80% of patients discontinue that drug by 12 months. So 8 times out of 10, they're off the drug. They can't be on it long-term. Why? Because it either didn't work or there were too many adverse events.

The benefit of these new drugs is that while the efficacy is comparable, by and large, the adverse event profile is more favorable. The number needed to treat may be similar, but the number needed to harm is much different. Therefore, the likelihood of being helped or harmed or the benefit-to-risk ratio favors these drugs because patients are able to tolerate them and stay on them. I've had patients who have been on the first antibody when it was first approved who are still on the antibody because there are no side effects and they're obviously responding very well.

I should say one more thing. For people who are on many medicines — who have polypharmacy, if you will — the monoclonal antibodies may be attractive. Why? Because they're proteins. They're peptides. They're not metabolized by the liver or excreted in the kidneys, so they don't interact with other drugs. You don't have to worry about drug-drug interactions if someone has many comorbidities and they're on many medicines — not true with oral drugs, of course. Those are some of the reasons why, if cost were no issue, I would definitely be starting some of these newer medicines in selected patients.

Wilner: Dr Dodick, that was great. That's exactly what I wanted to learn. Is there anything you'd like to add before we conclude?

Dodick: These new medicines have legitimized this disease and legitimized the patients who suffer from this disease. I say that because when you can develop a biologic that targets a molecule, a peptide, or its receptor, you understand the biology of that disease pretty well. That disease now has biological underpinnings and a molecular biology that's understood, so it gives the disease and those who suffer, I think, legitimacy.

Also, it's exciting to be able, for the first time, to have a preventive treatment that actually targets the biology of the disease and not take hand-me-down medicines that have been developed for other diseases. Yes, they've shown to be effective, but it's finally satisfying to be able to say to a patient, I'm going to give you this acute medicine and this preventive medicine that was specifically developed to treat migraine and only approved to treat migraine.

Having done this for 32 years now—I'm aging myself—but having done this for over 3 decades, I'm finally at a stage where I have disease-specific therapy that targets the biology of the illness, and that's a great day.

The nice thing is that the pipeline is rich. We understand this disease. CGRP is not everything because there are people who clearly don't respond and there are clearly other factors, other neuropeptides, and other neurotransmitters. Fortunately, we have a very clear understanding of what those targets are, and new therapies are now being developed to go after those targets.

Wilner: Dr Dodick, I want to thank you for this very informative discussion.

Dodick: My pleasure, Dr Wilner. Good to see you again.

Wilner: I'm Dr Andrew Wilner, reporting for Medscape.

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