CGRP Inhibitors: Transformative Therapy for Migraine
Experts describe the 4 monoclonal antibodies against calcitonin gene-related peptide that have been studied as preventive therapy for chronic migraine.
Stephen Silberstein, MD; David Dodick, MD; Stewart Tepper, MD; Peter Goadsby, MBBS; Jessica Ailani, MD
PUBLISHED January 01, 2019
Stephen Silberstein, MD: I think this leaves an opening to where we are, to where we’re going. And basically, for the first time in a long time, we have drugs that were developed and approved specifically for the treatment of all migraines, and these are the CGRP drugs. And the FDA has now approved 3 monoclonal antibodies for the treatment of migraines, and these are antibodies directed against calcitonin gene-related peptide, or CGRP. One is directed against CGRP targets, the actual receptor. The other 3 are directed against CGRP itself.
There are now 4 monoclonal antibodies that have either been approved or will be approved for the treatment of all migraines in adults. We have galcanezumab and erenumab, which we talked about—galcanezumab, its antibody against CGRP, where the erenumab is again CGRP itself—I’m sorry, the CGRP receptor. Fremanezumab and eptinezumab are both antibodies against CGRP itself. So we have 3 antibodies for CGRP, and 1 antibody to what Peter talked about earlier is the canonical CGRP receptor.
Now let’s talk a little bit about the differences in how they’re given So, fremanezumab can be given monthly or in a triple dose quarterly as a patient option. Erenumab is available as a monthly dosage formulation. Galcanezumab is available monthly. And last but not least, when eptinezumab comes on the market, it’s going to be available as an intravenous formulation, which should be given every 3 months.
We don’t know yet in practice—and correct me if I’m wrong—which is the best approach, and it may be individualized. There are some patients, for example, who do not want to give themselves injections, and if you’re seeing them quarterly, that might be better—those patients who don’t want to see us that often and would prefer to do it at home. So I think we have options of drugs with different mechanisms of action, with different groups of administration, and with different frequency of administration.
David Dodick, MD: I think your patients would love to see you every quarter, Steve.
Stephen Silberstein, MD: Unfortunately, you’re correct.
Stewart Tepper, MD: And I’ll just mention on dosing in the order in which they were released—so erenumab, the monoclonal antibody against the canonical CGRP receptor.
Peter, what’s the rationale for targeting CGRP in migraine? I think you had something to do with that, didn’t you?
Peter Goadsby, MBBS: Well, the rationale began as an exercise in trying to understand which of the trigeminal neuropeptide transmitters were important in migraine and whether one could target them to stop migraines, and I think there were 3 strings to that study I did that showed that you could—that during a very bad migraine, in the pretriptan era, it was elevated CGRP and not substance P in the cranial circulation. And then, when the triptans came along, we showed you could reverse that with a triptan, and then Jes Olesen, MD, some years later used CGRP to trigger a migraine in migraine patients. And the fact that it was elevated, you could reduce it and it would trigger a migraine attack—those 3 things, I think, went together to say to people interested in developing medicines that CGRP was a target. So we all owe this to you, don’t we?
Stephen Silberstein, MD: Oh no.
Peter Goadsby, MBBS: Everything, I mean everything’s of its time. You know, Wilder Penfield, MD; Francis McNaughton, MD]; and William Feindel, MD], have done incredibly good work showing that the crucial innervation, pain-producing intervention within the head was in the dura mater in the first division. What we did was just was build on that by activating trigeminal dural afferents and build on work that people had done, that had been done to identify CGRP in the trigeminal area and Lars had done, and put the 2 things together. And then probably the crucial thing we did was translate that into humans. Take that experiment to work and ask the question: In humans, if you try to do that and you try to block it, what would happen?
Stephen Silberstein, MD: We’re glad you did, Peter.
David Dodick, MD: So 1 of the questions that’s going to be important to answer is, if you don’t respond to a peptide targeted antibody, will you respond to one that targets the receptor or vice versa? And so we’re going to have fun sort of dissecting that apart.
Stephen Silberstein, MD: Anybody have any preliminary data?
Peter Goadsby, MBBS: What I’d like to say about the receptor—it might be worth saying in terms of the receptor— is, why are we using monoclonal antibodies? Sometimes colleagues will ask us that. The receptor system that’s involved is a combination of the 7-transmembrane G protein–coupled receptor, like a classic beta receptor, and a protein that sits next to it called the receptor activity modifying protein, or the RAMP, and there were 3 of those, and if in particular, the calcitoninlike receptor sits with RAMP1 on the cell surface. That’s the CGRP receptor—sometimes people hear the term “canonical CGRP receptor”—and that’s the one that erenumab binds to.
Now already, that’s a complex structure. Some years ago, there were small molecule CGRP receptor antagonists that were developed, and they had their problems with metabolize causing liver enzyme problems. The reason we’ve ended up with monoclonal antibodies is that it’s been difficult to develop these receptor blockers so that…there’s a certain logic to how we’ve come to where we are. I think it’s sometimes useful for colleagues to understand why we suddenly jumped there.
Stephen Silberstein, MD: I’d like to stop at this point in time. Peter, if it weren’t for you and me going to 1 of the companies and telling them how valuable their preclinical product was, it would never be on the market. I wanted to tell you that.
Peter Goadsby, MBBS: Thank you.
Stephen Silberstein, MD: It’s true.
Jessica Ailani, MD: Getting back to your earlier question about, do we have any early clinical data about if you don’t respond to the receptor binding, do you respond? We have seen some patients make the transition over, and they are responding to different items. So, those that were on the erenumab that was released earlier, who then transferred over to galcanezumab or fremanezumab…are starting to see responses when they weren’t seeing them before. That’s a very early, very small number, but we are seeing them.
David Dodick, MD: And the reason I bring it up, of course, is that I think it’s important for neurologists to be able to counsel and speak to their patients and say that, you know, there may be a reason to believe that you may respond to one even if you’ve not responded to the other, even if they target the same pathway. We’ve seen this with triptans, right? They’re all 1B, 1D agonists.
Stephen Silberstein, MD: And partially F.
David Dodick, MD: And partially F, a few of them. But nevertheless, they all sort of target the same receptor, so why would you respond to one and not the other? Yet we had 25 years of experience that tells us that that happens all the time.
Jessica Ailani, MD: Well, another interesting question is, if you respond to one CGRP-binding, ligand-binding drug, would you not respond or would you respond to the other? And if you have an adverse reaction to one, would you have that to another? Is the adverse reaction really related to the excipient, and the excipients are different in each 1 of these? Or is really related to the monoclonal antibody itself? And I think this is going to be an amazing time to learn about this because, I agree, I think there’s a similarity to the triptan, and sometimes the reactions that people have to the product that makes it “It doesn’t work because I’m not tolerating it,” and just by making the switch, they tolerate it better, and now it’s working well.