Does CGRP Inhibition Quiet the “Migraine Brain”?

Three months of galcanezumab treatment reduced the incidence of premonitory symptoms and number of triggers followed by headache, even in patients classified as “non-responders” to the drug.

When a patient is prescribed an anti-calcitonin gene-related peptide (CGRP) antibody, does the treatment only alleviate symptoms? Or does it also have an effect on the “migraine brain,” quieting the abnormal neuronal hyperexcitability characteristic of the brain when a person with migraine is in between headaches? If the former, CGRP antibodies are still useful therapeutic options, but it’s far more exciting if the latter is true, since it would mean that these drugs affect the underlying disease mechanisms of migraine.

A new clinical study now brings the field one step closer to an answer.

The research, led by Rami Burstein, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US, examined the effects of galcanezumab on the incidence of premonitory symptoms followed by headache, and on the number of triggers followed by headache, in patients who had varying responses to the drug in terms of its effect on migraine frequency.

The investigators found that three months of galcanezumab decreased those premonitory symptoms and triggers – but even in those who only had a modest reduction in migraine frequency. The authors concluded that even a small improvement in the frequency of migraine, in response to the CGRP blocker, was enough to calm the migraine brain. They also suggest that it is time to change the definition of an anti-CGRP antibody “responder.”

“This paper shows good early evidence that treatment with CGRP monoclonal antibodies may reset hypersensitivity in the migraine brain. It’s pivotal because it looks at the differences between subgroups of patients, regarding super-responders and super non-responders” to galcanezumab, said Andreas Gantenbein, a neurologist at the pain and rehabilitation center at ZURZACH Care, Switzerland, in an interview. Gantenbein was not part of the study but was one of the peer reviewers of the work.

The research appeared March 16, 2023, in The Journal of Headache and Pain.

Setting up a study
The idea behind the migraine brain is that in people who have migraine, the brain is in a hyperexcitable state in between migraine attacks. Compared to people who don’t have migraine, that leaves them more likely to respond to small changes in the environment, such as alterations in light or sound, resulting in a headache. And it’s why they might experience a headache after yawning or feeling tired, for example.

To explore the idea of the migraine brain, the researchers did an observational, open-label, cohort study in people with migraine, treating them with galcanezumab.

“The primary endpoint was to see whether headache symptoms change after exposure to galcanezumab in responders and non-responders. We followed them one month prior to galcanezumab and three months after,” first author Sait Ashina told Migraine Science Collaborative.

The study team recruited 64 patients with episodic or chronic migraine who had not been treated previously with anti-CGRP antibodies. Forty-six of those patients would complete daily e-diary entries one month before treatment and for three months during treatment.

Patients were classified into one of four different subgroups based on their response to galcanezumab, as measured by a percentage reduction in monthly migraine days (MMD). Specifically, responders had at least a 50% reduction in MMD and super-responders at least a 70% reduction. Non-responders showed less than 50% reduction in MMD, while super non-responders had less than 30% reduction.

For example, in the responder group (27 patients), galcanezumab produced a MMD percentage reduction from approximately 42% at baseline to 15% after one month and 10% after three months of treatment. Non-responders (19 patients) had a MMD percentage reduction from 52% at baseline to 33% after three months of treatment; that was still a reduction, but below the 50% threshold that would have defined them as a “responder.”

Next, the investigators compared the effects of galcanezumab on a range of symptoms during migraine days, in responders versus non-responders. They tracked a variety of symptoms, including headache intensity, photophobia, phonophobia, and nausea. As expected, galcanezumab significantly reduced all symptoms except nausea in responders, over three months of treatment. Non-responders saw no improvement.

Premonitory symptoms and triggers
The team then tracked a variety of premonitory symptoms, defined as an early sign or symptom that often indicates the onset of a headache attack. The team highlighted 12 premonitory symptoms based on their incidence; 10 of the symptoms were similar in responders and non-responders before treatment. The researchers would compare the incidence of all premonitory symptoms, in all responders versus all non-responders, rather than the incidence of individual symptoms, considering within- and between-patient variability in those symptoms.

At three months, galcanezumab decreased the incidence of all premonitory symptoms that preceded headache by 48% in the 27 responders, and by 28% in the 19 non-responders. The investigators also saw decreases of 50% in the 11 super-responders versus 12% in the eight super non-responders.

Of the different premonitory symptoms, seven were reduced in responders and non-responders, while two (irritability and cognitive impairment) were reduced only in the responders. Meanwhile, seven premonitory symptoms resulting in headache were reduced only in super-responders versus super non-responders.

Similar findings emerged with respect to migraine triggers; study participants recorded a number of triggers in their headache diaries, such as stress, skipping a meal, being too hot, menses, or not drinking enough water, among others. Galcanezumab reduced the number of triggers followed by migraine by 38% in responders versus 13% in non-responders. Super-responders showed a 31% reduction versus 4% in super non-responders.

Finally, the study found that visual and sensory aura followed by headache decreased in all groups except super non-responders, in response to the drug.

Allowing the migraine brain to recover
According to Burstein, galcanezumab reduces the continuous nociceptive input, originating in the meninges and reaching various regions of the brain, that is responsible for the hyperexcitable migraine brain. That means those with migraine will now have fewer headaches after experiencing premonitory symptoms or triggers.

“The takeaway message from our paper is that if you give galcanezumab for long enough, the migraine brain begins to recover as it gets a break from pain signals,” he told Migraine Science Collaborative.

“While the site of action of galcanezumab is outside the brain, the mechanism of action is inside the brain,” Burstein continued. “The drug allows the migraine brain to begin a long journey to recovery, which takes a long time, but we see the first steps at three months,” said Burstein.

“It’s a similar idea to giving a nerve block; give the CNS a break from pain signals and it begins to recover. What is new here is that we can turn it off for months,” he added.

“It does seem like galcanezumab treatment calms down the brain of migraine patients over time. This study is very supportive of this, but it’s a small study and more studies need to be done to show a reduction in neuronal hypersensitivity,” said Gantenbein.

Is a “non-responder” really a non-responder?
One of the implications of the new paper is that the definition of a “non-responder” may stand in need of revision. In migraine clinical trials, responders are defined as those whose MMD decrease by more than 50%, according to US Food and Drug Administration (FDA) criteria.

But in the current paper, a modest effect on MMD from galcanezumab in non-responders still reduced the incidence of premonitory symptoms and triggers leading to headache in that subgroup.

“We found that among the non-responders there’s a group whose headache days are reduced by 30% to 50%. Even at a 30% reduction, we show that galcanezumab has a positive effect on the migraine brain,” said Burstein.

“The fact that galcanezumab had an effect in non-responders has implications for the entire field,” he added.

Burstein said that drug companies have been pushing to change the definition of a drug responder to a 30% reduction in MMD, an approach that the new findings support.

“A 30% reduction has more clinical relevance, too. Any change in pain frequency – even one or two days per month – can have a major impact on someone’s life. A 50% reduction is too rigid, in our opinion,” said Ashina.

Gantenbein agreed, saying that the current definition (by regulatory authorities in most countries) of responders and non-responders does not reflect what he sees in clinical practice.

“The big problem is that even if treatment successfully reduces their most bothersome symptom, say, photophobia, and their life is much better, they’re still not classified as a responder because the treatment didn’t reduce the number of migraine days,” Gantenbein said.

As for future research, the authors said the next question is to find out what happens after three months, and especially six to 12 months, after treatment.

“We will have to find out how long it takes for the migraine brain to return to a normal state,” said Burstein.

He and his team are now following patients with migraine over a year and doing functional and structural brain imaging to understand the extent of brain recovery after galcanezumab treatment – that is, whether anti-CGRP antibodies reverse the hyperexcitability of the migraine brain. The aim is to broaden the focus of the study to investigate how cognitive aspects of migraine change in the migraine brain.

“There are 85 different regions of the brain involved with cognition. We are looking at how the treatment allows the brain to recover, not just in one area, but in the entire networks involved in cognition,” Burstein said.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Reference
Galcanezumab effects on incidence of headache after occurrence of triggers, premonitory symptoms, and aura in responders, non-responders, super-responders, and super non-responders.
Ashina et al.
J Headache Pain. 2023 Mar 16;24(1):26.