Will Gepants and Monoclonal Antibodies Be Used in Tandem for Migraine?

Kathleen Mullin, MD, medical director, clinical research, New England Institute for Clinical Research

Kathleen Mullin, MD

Recently, the publication of data from a 2-patient cohort has offered data in favor of something that many migraine specialists have theorized: that the concomitant use of acute and preventive migraine therapies targeting calcitonin gene-related peptide (CGRP) can be successful and safe.

The data conducted by Kathleen Mullin, MD, medical director, clinical research, New England Institute for Clinical Research, and colleagues, is the first clinical report that 2 therapies—rimegepant (Biohaven) and erenumab (Aimovig; Amgen)—can effectively treat refractory migraine.¹

The patients were in a long-term safety study of the small molecule CGRP receptor antagonist who began erenumab subcutaneously. Patient 1 used rimegepant for 6 months prior to initiating 70 mg erenumab monthly, and as-needed use of rimegepant successfully quelled 100% (n = 7) of her acute attacks. Patient 2 had used rimegepant for 60 days before beginning 140 mg erenumab monthly. Similarly, 100% (n = 9) of her acute attacks treated with rimegepant was successful.

To find out more about these data and what their clinical significance might be if further study corroborates them, NeurologyLive spoke with Mullin.

NeurologyLive: What were the findings of the study?

Kathleen Mullin, MD: So essentially, you know, it's a 2-person case study on patients that were using erenumab, a CGRP monoclonal antibody as prevention, and then they used rimegepant, the CGRP receptor antagonist as an acute therapy to abort their migraine. The total doses were 16, but what it found was that these patients not only had no safety signal—so it was safe to use these medications together—but also that the rimegepant was effective when used concomitantly with a CGRP monoclonal antibody

How might these data inform, in theory, the concomitant use of other acute CGRP agents and preventives?

It needs to be emphasized is that with an n = 2, no one's going to make a statement or a protocol that these should always be used together. Actually, Biohaven has worked to get more data looking at the use of the CGRP monoclonal antibodies with rimegepant in terms of safety and efficacy.

But there's something to be said—if you think about it, these patients that respond to the monoclonal antibodies as their preventative. By response, we look at their monthly migraine headache days. So, if these patients that we put on CGRP monoclonal antibodies have a successful reduction in the monthly migraine days—what we call CGRP responders—then why wouldn't something that sort of further suppresses that pathway in an acute way be effective for them to abort their migraines as they come? Because again, all of our preventatives, while effective at reducing monthly migraine days, are not cures. These patients will still need an acute treatment. It might be something that we look at—if the patient's responses to something that blocks their CGRP receptor as a preventive, why wouldn't we then further look at that same pathway for their acute treatment?

Were there any particularly surprising or unexpected data points identified?

Not particularly. I think that we were thankful to see safety. But I think again because the patients had already shown that they were responsive to CGRP blockage, it makes sense, mechanistically that they would respond to an acute medication that also blocks the CGRP.

What was nice to see was that these patients were on rimegepant before they are on erenumab. At least my patient said that—subjectively—she actually thought rimegepant worked better when it was used to conjunctively with the monoclonal antibody. That was, again not necessarily surprising, but reassuring and nice to see that they may even have sort of a synergistic effect.

What is the clinical significance of being able to use these in tandem, and how could that improve the provider's ability to help patients?

We've been looking for new drugs that target new pathways in migraines for decades, and the fact that these 2 drugs that are targeting the same pathway but in different ways are coming out at the same time widely opens our treatment protocols and our paradigms. It sort of changes the whole face of how we look at our treatment management now, especially because these CGRP small molecules at least are safe and patients with whom we had our hands tied for acute treatment for a long time.

So, while the CGRP monoclonal antibodies are open to everybody for prevention, the small molecules really are filling an even more particular niche because the triptans had contraindications with cardiovascular risk factors. So now we have a whole population of patients who are not able to use them together. But the CGRP molecule rimegepant, specifically, is safe in these patients where we've sort of been twiddling our thumbs trying to come up with second and third best choices because the first best choice just wasn't available to them.

What still remains to be fleshed out in the study of tandem use of acute and preventive CGRP agents?

What we need are numbers. A study, in order to be clinically valid, needs to have power. In order to get power, you need to have a good number of patients that show your data, and those data need to show what will make clinicians feel confident prescribing it—first and foremost safety.

The rimegepant trials and the erenumab trials showed no signals from a safety perspective that were worrisome. But we know when drugs are used synergistically and conjunctively, sometimes that changes. We need to follow patients that are taking both medications over a good period of time for safety, check their liver functions and all their blood work, and make sure that these drugs, when used together, are as safe as they are when you separately—and efficacy. It's wonderful that they're safe when used together, but both the erenumab has to be efficacious in reducing migraine frequency, and rimegepant still has to have its strong efficacy profile in aborting the migraine headache as it comes. The 2-hour pain relief and relief from the most bothersome symptom still needs to be significant when used in conjunction with erenumab.

I know that headache specialist, when they see that, will be encouraged and feel confident in using the 2 drugs together. I hope that primary care doctors and general neurologists will also see that data, which Biohaven is working on collecting, and have the confidence to use the medications together.

Anything to add?

This is really exciting. I know it's just 2 patients, but everyone is looking to see as these gepants come out in conjunction with the mAbs, if, if they can be used together and while 2 patients is not enough to make that a protocol, it's 2 patients that had really positive results and had these profiles. So, it's a step in the right direction for the potential of these medications being used as a team.

Transcript edited for clarity.

REFERENCE

Mullin K, Kudrow D, Croop R, et al. Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy. Neurology. 2020;00:1-5. doi:10.1212/WNL.0000000000008944.