Migraine: Safety & Efficacy of Anti-CGRPs and Patient Selection


Stephen Silberstein, MD: Why don’t you give us the background of the current antibodies, what their targets are, and how safe and effective they are?

Stewart J. Tepper, MD: Well, we’ll start with what we have. There are 4 monoclonal antibodies that have anti-CGRP [calcitonin gene-related peptide] effect, 3 of which are FDA approved. The first one that was FDA approved was erenumab, brand name is Aimovig. It is different from the other 3, in that it is a purely human monoclonal antibody, and is the only 1 that targets the canonical alpha-CGRP receptor.

Stephen Silberstein, MD: Is that religious, canonical?

Stewart J. Tepper, MD: The other 3 target the CGRP ligand itself. They do not target the receptor. The other 3 are humanized or fully humanized, meaning that they are 5% to 10% murine. We don’t know whether that has immunologic consequence, but most of our neurologic monoclonal antibodies that are used in practice are humanized.

Stephen Silberstein, MD: Can I comment?

Stewart J. Tepper, MD: Please.

Stephen Silberstein, MD: The naming organization for antibodies has changed the designation of all antibodies. For example, an antibody that’s 100% human is called “-umab” and antibody that’s minimal—mainly human, has a little bit of extra-human tissue as part of it—is called “-zumab”. The way I remember it is zoo for an animal. That has been eliminated. The authorities strongly believe that the current distinction between human and humanized is irrelevant, and that any antigenic ethnicity of the antibody is due to the specific structure of the Fab [antigen-binding fragment] that binds to the antigen. That’s just happened. So all antibodies in the future will never be indicated as humanized, or human, and that designation will exist with prior antibodies.

Stewart J. Tepper, MD: And just to finish on that, the “N” in the names of these monoclonal antibodies is for “neurologic.”

Stephen Silberstein, MD: Correct, and that will disappear too.

Stewart J. Tepper, MD: Steve taught me that. The second one that was approved was fremanezumab, brand name Ajovy. The third was galcanezumab, brand name Emgality. And the fourth, which is not yet FDA approved but which has been submitted to the FDA as of February of 2019, and which we anticipate next year, is eptinezumab. The first 3, which are approved, are available for home use with a subcutaneous injection. We’ll go over the doses and how that is done. The fourth one, eptinezumab, when it becomes available, will be available as a quarterly IV [intravenous] infusion.

Stephen Silberstein, MD: Which patients are eligible for antibodies?

Andrew Blumenfeld, MD: Now we have treatments that don’t have as many adverse effects as the oral medications. We don’t have as much of an issue with adherence, because these are self-injected, monthly or quarterly injections, as in the case of Ajovy. I think it has changed the whole dynamic. I would preferentially choose a monoclonal antibody as the starting point.

Stephen Silberstein, MD: But you can’t.

Deborah Friedman, MD, MPH: Right.

Andrew Blumenfeld, MD: In an ideal world—where costs have no bearing on our decision—I would feel that these were the ones that had the best safety, best tolerability, and the greatest efficacy. So why not use those as a starting point? Why walk through the hoops of medicines that have potential adverse effects and less efficacy?

Stephen Silberstein, MD: Who wants to comment on that?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: You were taking a deep breath as if you really have something to say.

Stewart J. Tepper, MD: All right. Well, first of all, I think that we ought to take 1 step back for a second and point out a number of other differentiating features about these. When we talked about OnabotulinumtoxinA, for example, we were talking about its utility in chronic migraine—patients who had 15 or more headache days per month. These monoclonal antibodies have taught us that migraine is migraine, and when you take out CGRP, these drugs work equally, in patients who have low-frequency episodic migraine, high-frequency episodic migraine, chronic migraine, migraine with aura, migraine without aura, migraine with medication overuse, acute medication overuse, and migraine without acute medication overuse. It is a very remarkable shift that we have such potent treatment for the entire gamut of migraine. So the first response to Steve is, these would work for any migraine patient that we have. Then, the reality sets in.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: In adults, at the moment, and not pregnant preferably.

Stewart J. Tepper, MD: In adults, thank you, and not pregnant patients. But the reality is, that payers are requiring patients to have had a lack of success with certain categories of previous treatment. As a result, the American Headache Society published a white paper in January of 2019 making reasonable recommendations to payers, as to what prerequisites would be present before we could do what we hoped the future will bear, which is, use it first.

They divided patients into 3 groups. They said if patients had low-frequency episodic migraine but demonstrable disability or impact, they should be considered for monoclonal antibodies. If they had high-frequency episodic migraine or chronic migraine, they were only required to have failed 2 previous treatments—and you didn’t have to demonstrate disability—because we know those patients are disabled or have impact. In the case of chronic migraine, 1 of the 2 categories that the patients could fail would be OnabotulinumtoxinA.

Stephen Silberstein, MD: No, no. Onabotulinumtoxin by itself.

Stewart J. Tepper, MD: For chronic migraine.

Stephen Silberstein, MD: For chronic migraine because, by definition, to get onabotulinumtoxin type A, you had to have failed in your system.

Stewart J. Tepper, MD: Thank you, yes.

Stephen Silberstein, MD: The fundamental difference between the 2—episodic and the chronic—is in the chronic, it’s 2 other or Botox. Whereas, in the episodic the difference is between low-frequency and high-frequency; low frequency, 2 failures, plus evidence of disability.

Deborah Friedman, MD, MPH: Just to be clear, it’s the drug, the treatment that fails, not the patient that fails.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Yes, thank you.

Stewart J. Tepper, MD: That’s right, it’s a lack of success.

Stephen Silberstein, MD: Thank you, Dr….

Stewart J. Tepper, MD: It’s really important to make that point.

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