Development of Oral CGRP Molecule Inhibitors for Acute Migraines

Stephen Silberstein, MD: I want to talk about the other antibody in development.

Deborah Friedman, MD, MPH: Other formulations.

Stephen Silberstein, MD: Other formulations. You want to tell us quickly about them?

Stewart J. Tepper, MD: About the gepants?

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

Stewart J. Tepper, MD: The gepants, as you said, are small molecule CGRP [calcitonin gene-related peptide] receptor antagonists. Two of them in early development had liver toxicity. They do go through the liver. There has never been a gepant studied in humans in which there was a lack of efficacy. They always effectively terminate migraine acutely. There are 3 gepants in clinical development. One is ubrogepant, which was submitted to FDA early in 2019 and is effective in the acute treatment of migraine. That’s what it will get the approval for next year. Second is rimegepant, which is also about to be submitted to the FDA for acute treatment of migraine, and we expect that that will also be approved within the next year.

The third gepant is atogepant. That has been studied in a daily dosing regimen for prevention of migraine. Episodic migraine phase 2 trial was positive with a magnitude of effect similar to monoclonal antibodies. Then, to make things more complicated, rimegepant, which has been studied for acute treatment of migraine, is also being studied in a daily dosing for preventive treatment of migraine.

Stephen Silberstein, MD: Isn’t there a fourth?

Stewart J. Tepper, MD: There is one, BHV-3500. I don’t know how that’s going to be developed. There’s one that is going to be studied in the nasal formulation. There’s one that has been studied in an orally dissolvable tablet. There’s another company in England that has a set of gepants, as well. We’re just at the beginning of this second wave of gepants, and by this time next year, we should have 2 for acute treatment that work similarly to triptans with very good tolerability.

Stephen Silberstein, MD: If somebody is on a monoclonal antibody, would an oral gepant work to control an acute attack?

Andrew Blumenfeld, MD: I anticipate that it will work. It hasn’t been studied, to date. The reason I think it would work is that these monoclonal antibodies, firstly, saturate the system, but not 100%. You’re continually manufacturing CGRP, and at some point, you may have breakthrough levels, where CGRP levels are elevated or receptors are unbound. The antibodies have an on/off binding.

Stephen Silberstein, MD: No. I will wager you anything.

Andrew Blumenfeld, MD: Then I will be forced to disagree on that.

Stephen Silberstein, MD: If you look at the kinetics, when an antibody sticks to the receptor, it almost dies on the receptor. It’s not like small molecule.

Andrew Blumenfeld, MD: I went through a long discussion on this recently, because I was also of the opinion that there was this suicide binding, but that isn’t the case.

Stephen Silberstein, MD: It is. The bottom line is, even when it gets internalized to the receptor, it doesn’t get digested, but it gets recirculated. There’s a paper that’s impressive—it hasn’t been published yet—carefully looking at the binding of the monoclonal antibody to the CGRP canonical receptor and seeing what happens to it. The first issue is, if it gets bound and any of the receptors are recycled, it was felt that they would be all degraded. If they’re not, they go back to the surface. The dissociation constant of all antibodies from their ligand is extraordinarily low, so in a chemical reaction, there’s no binding. The other drug I know, as a class, is D.H.E. [dihydroergotamine], which binds to its receptor. The antibodies are very tight, and if you have 100,000 molecules bound to an antibody, maybe 1 will get out. I’m simply stating that in equilibrium, unlike small molecules and everything else, the binding is such that 99.9% of the receptor will be bound.

Andrew Blumenfeld, MD: Yes, but not 100%. That’s why the gepants will work.

Stephen Silberstein, MD: No. Think about it. If 99% of the receptors are bound and have all those antibodies, the little molecules are never going to sneak their way in.

Andrew Blumenfeld, MD: I disagree. They may penetrate a lot better.

Stephen Silberstein, MD: The gepants will not work in the presence of an antibody to the receptor, but they could work in the presence of an antibody to the ligand.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Maybe some people respond better if you tickle their receptors, as opposed to squashing them with an antibody.

Stephen Silberstein, MD: The bottom line is, then you would have to compare an antibody to a receptor, not in combination.

Stewart J. Tepper, MD: I’m interested in a vote here. We have 1 and 1. How do you think it’s going to turn out? Will gepants work with an antibody on board? I’m curious.

Stephen Silberstein, MD: Let’s just start. Bifurcate—receptor versus ligand.

Deborah Friedman, MD, MPH: I think it may make a difference whether all of them target the ligand, versus 1 of them targets the receptor and the other targets the ligand. I suspect that before we’re going to know, someone is going to have to do a safety study.

Stephen Silberstein, MD: Of course.

Stewart J. Tepper, MD: But do you think either would work?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Logic would dictate, why would you block a receptor 2 ways and expect better results, but we don’t know. I’m not convinced that 100% of the receptors are totally inactivated all of the time, especially during an attack. Who knows? With the ligand, it’s even more likely that you could have success, because as you said, you could have a burst of CGRP at the onset of an attack and during an attack, and there’s not enough antibodies to do the job. You’ve got to have a safety net, and that safety net is going to be the receptor blocker.

Stephen Silberstein, MD: I agree 100%. The way I look at it is, when you have CGRP being released, the concentration is higher and it has to diffuse out and eventually be sucked up.

Andrew Blumenfeld, MD: Yes.

Stephen Silberstein, MD: That’s the situation for an antibody to CGRP itself. The difference is that when you have an antibody to the receptor, for all intents and purposes, it’s like a knockout. There’s no receptor left, but there is 1 other possibility. You still have the amylin receptor, and some of the gepants have affinities to the amylin receptor. Under those circumstances, to the best of my knowledge, if you look at the published data, they have very little affinity to the amylin receptor.

Andrew Blumenfeld, MD: Stew, do you have an opinion?

Stewart J. Tepper, MD: I think if they work at all, it’s going to be very modest.

Andrew Blumenfeld, MD: We know that the triptans worked for breakthrough.

Stephen Silberstein, MD: That’s because triptans work by an entirely different mechanism.

Andrew Blumenfeld, MD: Partially different.

Stephen Silberstein, MD: Entirely different. They prevent the release of CGRP, glutamate, substance P, and other chemicals. As we talked about earlier, if migraine is multichemical, we’re getting the rest of the chemicals. That’s why it works.

Thank you for your contributions to this discussion. On behalf of our panel, thank you for joining us. We hope you found this Peer Exchange discussion useful, informative, and exciting. It was for us.