Where Do Ubrogepant and the Gepant Class Fit in Migraine Care?


The director of the Montefiore Headache Center discussed recent study findings on ubrogepant and offered insight into the possible future of the gepant class in migraine.

Dr Richard Lipton

Richard B. Lipton, MD, director, Montefiore Headache Center, and professor of neurology, Albert Einstein College of Medicine

Richard B. Lipton, MD

Recently, data originally scheduled to be presented at the American Academy of Neurology (AAN) 2020 Annual Meeting showed that patients with migraine treated with ubrogepant (Ubrelvy; Allergan) during headaches of mild pain intensity have a higher likelihood of achieving pain-freedom and symptoms associated with headache.1

The phase 3 open-label, 52-week extension trial (NCT02873221) randomized adults with migraine in 1:1:1 fashion to usual care, 50-mg ubrogepant, or 100-mg ubrogepant, and treated ≤8 migraine attacks of any pain severity every 4 weeks. The study authors included Richard B. Lipton, MD, director, Montefiore Headache Center, and professor of neurology, Albert Einstein College of Medicine, and colleagues.

With the cancellation of AAN 2020 and thus the presentation, NeurologyLive spoke to Lipton to find out more about the study and to gain some insight into the potential future of the gepant class in the treatment of migraine.

NeurologyLive: What was the basis for this analysis and what are the takeaways for their clinical community?

Richard Lipton, MD: Ubrogepant is a member of a class of drugs called Gepants, those are small-molecule receptor blockers that are taken orally that are currently approved for acute treatment of migraine. And that contrasts with the monoclonal antibodies that are injectables used for the preventive treatment of migraine.

There's an interesting regulatory gap. The FDA requires that, for new acute treatments, studies are done in people with moderate or severe pain and that we look at the proportion of people who get pain free 2 hours later. We've known for a long time that most acute migraine treatments work best if they're taken early in the attack while pain is still mild. So for ubrogepant, the 2 pivotal efficacy studies that led to approval were studies in moderate or severe pain, and then in the long-term safety study, we designed it to allow people to treat mild, moderate, or severe pain and record it in a daily diary how well treatment worked.

This was a very large study, there were 808 people who were treated for more than 21,000 migraine attacks, and when we analyze the data, we looked at people who were treated with ubrogepant 50 or 100 mg while pain was mild, and contrasted them with people who treated pain that was moderate or severe. For the people who treated moderate or severe pain, right around 20% of people were pain-free in 2 hours, and that's very, very similar to the results that were identified in the pivotal efficacy studies. We then looked at the 2-hour pain-free rates in people who treated mild pain and we saw with the 50-mg dose, 39% of people were pain-free, whereas with 100-mg dose 43% of people were pain-free. Similarly, when we looked at freedom from photophobia, photophobia, and nausea, we found that treatment was more effective in people who treated mild pain than people who treated moderate or severe pain.

I think the key takeaway for practicing doctors is that treatment outcomes will improve if patients are able to take treatment while their pain is still mild—and that's kind of intuitive. The longer the migraine attack goes on, the better, or more completely, the pathophysiology is established, and for a long time, the harder the attacks are to treat. From this, I conclude that ubrogepant, when it's prescribed, should be given to patients who have mild pain in hopes of delivering those benefits of higher rates of freedom from pain and associated symptoms.

Was anything specifically different between the 100-mg dose versus the lower 50-mg dose?

Overall rates of pain freedom were slightly higher for the 100-mg dose than the 50-mg dose. My personal practice is to start at 50-mg, and if the patient gets the benefit I'm looking for, I leave them there. There's probably a small subgroup of people who get greater benefits from the higher dose. With this particular drug, though, I think it's best to start at the lower dose and increase if need be.

Were the findings at all different from what was anticipated based on prior studies of ubrogepant?

No. I expected pain-free rates to be about twice as high for treating mild pain versus moderate or severe, and you know, this is a general attribute of acute migraine treatments. The same thing would be true for triptans, for example, which are the most widely used class of migraine drugs. But a drug like ubrogepant would often be used in a patient who didn't respond to triptans or had side effects to triptans that made the drugs intolerable, or in patients who had cardiovascular contraindications to triptans.

But you know, the bottom line is the study confirmed my expectation that if we treat our patients while their pain is mild, that they'll do better, and so I was very happy to see that result.

Is there anything you’d like to add about the study results?

Well, the one other thing that that I might add is that gepants, in addition to their role as acute treatments, are also being developed as preventive treatments. So, although ubrogepant is a treatment exclusively for the acute treatment of migraine, the mechanism of blocking CGRP receptors with monoclonal antibodies that are injectable or oral small molecules is a mechanism that's effective for acute and preventive treatment—and so that's a kind of “watch this space” sort of comment.

There's a drug being developed solely as a preventive treatment for migraine called atogepant—that's a drug that's made by Allergan, the same company that makes ubrogepant—and the other FDA approved gepant, which is called rimegepant. Rimegepant has already completed a study showing that it works not just acutely but preventative way as well.

Do you foresee gepants being used in tandem with the current preventive CGRP medicines in the future, or are you expecting them to be used in a more preventive fashion on their own?

Of the monoclonal antibodies that are available, 3 are given by subcutaneous injection, 1 is given by intravenous injection that's eptinezumab, which was just very recently approved. The evidence that gepants work on top of these monoclonal antibodies is very limited. There's a small series of case reports that show that rimegepant given on top of a monoclonal antibody retains its effectiveness as an acute treatment.2

I think one possibility is that we'll move towards a world where with gepants, people will use them both acutely and preventively. But we need to do more research to assess the efficacy of gepants on top of monoclonal antibodies.

Transcript edited for clarity. For more AAN coverage, click here.


1. Lipton R, Dodick D, Goadsby PJ, et al. Ubrogepant is Effective in the Acute Treatment of Migraine with Mild Pain. Neurology. 2020;94(15 Suppl): 4726.

2. 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.

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