Treating Migraine Before It Begins with a CGRP Inhibitor

By Kayt Sukel | February 8, 2024 | Posted in

A new trial shows that ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, prevents headache when taken during the prodrome phase. The findings have large clinical implications.

It is well established that the earlier you treat a migraine, the better, since people with migraine are more likely to respond to treatment when headache pain is mild. Less well understood is whether or not migraine might be treatable during the prodrome, the earliest phase of migraine. Also known as the premonitory phase, the prodrome is when symptoms such as fatigue, light sensitivity, and neck pain appear, hours or even a full day before headache pain sets in.

Now, researchers including first author David Dodick, Atria Academy of Science and Medicine, New York City, US, and Mayo Clinic, Phoenix, US, report that ubrogepant, a calcitonin gene-related peptide (CGRP) receptor inhibitor, prevented migraine attacks when taken during the prodrome.

This randomized, double-blind, placebo-controlled, crossover trial of more than 500 adults with migraine showed that an absence of moderate or severe headache within a day after a dose was roughly twice as likely to occur when a prodrome event was treated with ubrogepant, compared to treatment with placebo.

Amaal Starling, a neurologist at the Mayo Clinic, Scottsdale, US, who was not involved with the trial, said the results could have “a significant clinical impact” on future migraine treatment.

“Our current acute treatment recommendations are to treat at the first onset of pain. Prior studies using electronic diaries have shown us that about 80% of people diagnosed with migraine have prodrome symptoms, and about 70% can accurately predict when those symptoms will lead to later headache pain,” she said.

“The results from this trial,” Starling continued, “show us that we could recommend that patients treat before the headache or pain phase has set in – and what a wonderful opportunity for patients to be able to prevent the headache pain of a migraine attack altogether.”

The study was co-authored with additional investigators from Albert Einstein College of Medicine, New York City, US, and AbbVie, Madison, New Jersey, US. AbbVie is a pharmaceutical company that sells ubrogepant under the brand name Ubrelvy and funded the research.

The work appeared in the December 16, 2023, issue of The Lancet.

The rationale for treating early
Since the approval of CGRP inhibitor drugs for migraine treatment several years ago, many people living with migraine were relieved to finally have an effective treatment for their headache pain. Study co-author Peter Goadsby, King’s College London, UK, and University of California, Los Angeles, US, said the success of CGRP-targeted therapy made him and his colleagues wonder if these drugs might also be effective when given during the prodrome.

“CGRP antagonists are very useful in the treatment of acute migraine attacks when pain has already started. They are also useful in preventing migraine attacks,” he said. “So it seemed plausible that, if the CGRP receptor mechanism is involved in attack initiation, you could block it during the prodrome phase and stop the migraine attack from ever coming.”

Goadsby said that treatment during the prodrome has not been properly tested before with other types of common drugs used for migraine. That includes triptans, which can make headache worse when used too often, and nonsteroidal anti-inflammatory drugs (NSAIDs), whose overuse can lead to gastrointestinal issues.

“The nice thing about gepants,” he said, referring to the general class of small-molecule drugs, to which ubrogepant belongs, that target the CGRP receptor, “is that they are so well tolerated. There didn’t seem to be a downside to doing this kind of trial to see if it would work, and while we thought it was plausible, it had never really been tested before.”

The first clinical trial of its kind in the migraine field
The investigators recruited more than 1,000 adults, aged 18 to 75 years and with a one-year history of migraine with or without aura, across 75 research centers and headache clinics in the United States. Study inclusion criteria were a history of two to eight migraine attacks each month, along with moderate or severe headache in each of the three months before being screened to take part in the research.

The screening period determined how reliable the prodrome symptoms were as a headache predictor. Participants recorded each prodrome event and had to demonstrate that a migraine headache would follow their reported symptoms 75% or more of the time within six hours.

Starling said including the screening period was “critical” to the methodology.

“By including this 60-day screening period, the study authors showed that patients were not only having a prodrome phase, but they were also able to reliably predict the migraine pain phase the majority of the time,” she said. “It’s a great blueprint for others to use in future studies.”

Participants who met the screening criteria were then randomly assigned to receive treatment. They received instructions to treat two separate prodrome events with at least seven days between them. One group took a placebo at the first prodrome event and, after a seven-day washout period, took 100 mg of ubrogepant at the second prodrome event. This sequence of treatment was reversed in a second group.

Ultimately, 264 participants were randomly assigned to the first sequence, and 254 to the second sequence. Roughly 90% of study participants were women, and the average age of participants was just over 42 years.

The researchers assessed the absence of moderate or severe headache within 24 hours of receiving treatment, the primary endpoint of the study. They documented this absence in 190 of 418 (46%) of qualifying prodrome events treated with ubrogepant, compared to only 121 of 423 (29%) of prodrome events treated with placebo. That translated to an odds ratio of 2.09, meaning that the absence of headache was about twice as likely to occur after prodrome events treated with the drug, compared to prodrome treated with placebo.

Very similar results became apparent when the researchers examined the trial’s secondary endpoints of absence of moderate or severe headache within 48 hours (odds ratio of 2.13); the absence of headache of any intensity within 24 hours of taking the study drug (odds ratio of 1.93); and “no disability, able to function normally” within 24 hours.

Finally, the treatment was safe, with adverse events within 48 hours after drug administration occurring in 17% of 456 qualifying prodrome events treated with the drug, and 12% of 462 prodrome events treated with placebo.

Better treatment, better understanding
Goadsby said that while the group was not necessarily surprised by the outcome of the trial, they were thrilled that this kind of preventative treatment worked so well.

“We set a fairly high bar with a 24-hour endpoint, and then a secondary endpoint of 48 hours, which we hit as well. More often than not, patients did not experience pain when they took the ubrogepant during prodrome,” he said. “You could probably do the same trial with other CGRP antagonists and get the same result. But the principal question to me, now that we’ve established that you can stop the pain, is if we can look at prodrome symptoms to see whether you can affect them in different ways over a different time course so we can understand the disease of migraine better.”

Starling agreed that this type of investigation is important. She added that, since functional magnetic resonance imaging (fMRI) studies have shown that prodrome is associated with abnormal hypothalamic activity, the results from those studies may offer new avenues of future research. While CGRP receptors are abundant in the hypothalamus, there may be other targets in this brain region that could one day lead to additional drugs to treat migraine.

“CGRP antagonists are great, but they don’t work for everybody,” she said. “The alignment of hypothalamic activity studies and these results suggests that if we continue to look at the hypothalamus, we could identify novel drug targets to help more people living with migraine.”

For his part, Goadsby said he hopes the results will change treatment protocols so that doctors and pharmacists will tell patients they need not wait for the pain of migraine to take ubrogepant – patients can do so during the prodrome phase to avoid the headache. He also hopes the findings will help give people who have migraine “a measure of certainty” so they can more fully participate in the experiences that matter to them.

“One of the things that migraine does is rob you of certainty. If there’s a wedding, an exam, something important you need to do tomorrow and you are feeling a bit wobbly, you may try to avoid it altogether because you think you are going to get a migraine,” he said. “The thing is, you never know for sure if you will get a migraine. But if you can take a drug the day before something important, a drug that doesn’t give you any side effects and gives you a sporting chance that you won’t experience any headache at all, it can give you more certainty. It can allow you to focus more on all the things you want to do and achieve in your life without always having to worry that migraine will get in the way.”

Kayt Sukel is a freelance writer based outside of Houston, Texas.

Disclosures: Dr. Goadsby receives financial support for this study and personal fees from AbbVie. In the last two years, Dr. Starling has received consulting fees from AbbVie.


Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA.
Dodick et al.
Lancet. 2023 Dec 16;402(10419):2307-16.

Image credit: casanowe/123RF Stock Photo.

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Kayt Sukel is a passionate traveler and science writer who has no problem tackling interesting (and often taboo) subjects spanning love, sex, science, technology, travel and politics. Her work has appeared in the Atlantic Monthly, New Scientist, USA Today, Pacific Standard, the Washington Post, ISLANDS, Parenting, the Bark, American Baby, National Geographic Traveler, and the AARP Bulletin, among others. She has written stories about out-of-body experiences, artificial intelligence in medicine, new advances in pain treatments, and why one should travel to exotic lands with young children.

She is the author of two books: Dirty Minds: How Our Brains Influence Love, Sex, and Relationships (re-titled as This Is Your Brain on Sex: The Science Behind the Search for Love in paperback) and The Art of Risk: The New Science of Courage, Caution, and Chance.



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