An Outlook on CGRP Therapies for Migraine: A Conversation with Antoinette Maassen van den Brink

“I don’t want to be the one who says, ‘Don’t use CGRP drugs,’ but I feel it’s my obligation to raise concerns and say where our knowledge is lacking, and where we need to do new research studies.” – Antoinette Maassen van den Brink

Antoinette Maassen van den Brink, PhD, is a professor of neurovascular pharmacology at Erasmus University Medical Center in Rotterdam, The Netherlands. She studies neurovascular aspects of migraine, with a special emphasis on the role of female sex steroids, and side effects of anti-migraine drugs. She is also the first president of the European Headache Federation who is not a clinician.

Here, she speaks with freelance writer Fred Schwaller about the role of sex hormones in migraine, her ongoing work to understand possible side effects of CGRP therapies, and the challenge of access to these drugs.

Your research has highlighted how migraine differs between men and women. What do we know about the reasons why?

There is an aspect of migraine that is exclusive to women: Many women have migraine attacks related to menstruation or other hormonal triggers like menopause. On the other hand, I’m convinced that sex hormones also play a role in men’s migraines. We have previously published that levels of estradiol are slightly different in men with migraine, only these changes are more pronounced in women. Of course, there is migraine that is independent of the sex hormones that both men and women may experience. But in women, there’s an extra layer on top of it. Women experience much more hormonal fluctuation than men, which may well explain the higher prevalence of migraine in women.

Antoinette Maassen van den Brink

The problem is that we’re very much at the beginning of understanding how sex hormones are involved in migraine. We are now conducting the first studies to systematically measure hormones during migraine. If we demonstrate that hormone levels differ slightly, what are the implications, and how do you tackle that?

We tend to say there are male/female differences in how sex hormones influence migraine, but that’s too simplified. Evidence for a role of the hormones is the fact that the male/female differences in migraine are the biggest between men and women in the fertile age range. But which hormones exactly are involved, and via which pathways do they act? There’s still so much more research to do.

Could sex hormones be targets for migraine treatments?

Yes. We tend to focus on estradiol and progesterone, but there are so many more hormones and metabolized hormones involved in the background that play a role in migraine. Oxytocin is currently being explored, but also hormones like prolactin could have a part in the pathophysiology of migraine. Further, we recently published that there are male/female differences in certain pain receptors that may be involved in migraine. I’m optimistic that future studies will show that drugs acting at these novel targets could be effective for some people with migraine, but there’s a lot of fine tuning that needs to be performed. If you look at how these hormones act, there are so many receptors they’re working on, and it’s very complex. Some of these receptors may have a beneficial effect in migraine, but some may have a negative effect in migraine.

It would be my dream to pinpoint really specific receptors that you can modulate without interfering with the rest of the system. But for that, we need a much better understanding of all the complex biological effects of hormones in the body and the brain, not just in migraine. We are now performing a clinical trial on a combined oral contraceptive for use in migraine, in collaboration with Leiden University.

Let’s turn to your research on CGRP therapies and their side effects. What does your research say about the cardiovascular effects of blocking CGRP?

Even before CGRP antibodies were used to treat migraine, we predicted some side effects that have now been observed in clinics. We need to do more research about the complex functions that CGRP has in the body.

One example is indeed in the cardiovascular system. We see some groups of patients reporting hypertension or increased blood pressure. Another issue is the risk for myocardial infarction or stroke. So far, the situation in the clinic is not discouraging, because there aren’t many incidents, but we just don’t know enough about the biological mechanisms yet.

There’s work needed to understand who might have higher risks of cardiovascular side effects when taking these drugs, and why. The aim is to identify which subgroups of patients might potentially be at risk for side effects, and to study how these side effects could be mitigated. Blood pressure is something that you can easily monitor, and you can also treat it when needed.

I don’t want to be the one who says, “Don’t use CGRP drugs,” but I feel it’s my obligation to raise concerns and say where our knowledge is lacking, and where we need to do new research studies. That’s why research in my lab is now looking at potential cardiovascular side effects of CGRP drugs in a pig model, because there’s a very big cardiovascular resemblance between pigs and humans. If we don’t find any side effects, then it would be wonderful. It’s not my mission to show that a drug should not be used, but it’s my mission to provide appropriate information about what side effects a drug may or may not have.

How concerned are you about patients experiencing side effects from CGRP drugs?

It’s a fact that drugs have side effects, but this isn’t necessarily a disaster. If you can provide the appropriate information to patients, then they know what to expect and what countermeasures to take with clinical support. It’s our duty as researchers to look out for side effects, but to do that we must work closely with clinicians and have open ways of communicating.

I wrote a review about CGRP drugs where we noted that they can cause constipation. This was not apparent in the original clinical trials that tested these drugs, but we’re seeing it more and more in the real world. Another side effect I’ve written about is erectile dysfunction and loss of libido in patients who take CGRP drugs. A clinician called me and said they have patients with erectile dysfunction that started after taking CGRP antibodies for migraine, and when they stopped taking the drugs it went away. We dove into the basic science literature around erectile function and found it could indeed be a phenomenon related to CGRP. However, we don’t know if this side effect is common or not, but I think it’s important to raise awareness that it could occur. This shows why we need more communication between basic researchers and clinicians.

What are the biggest challenges in treating migraine patients with anti-CGRP drugs?

One big challenge is finding out which drugs are most appropriate for whom and why. Anti-CGRP drugs are life changing for many people with migraine, but they do not work for everyone. We need to find out why, because these drugs are not the only solution for migraine and headache.

We should also not forget that there are many, many people with migraine or other headaches who don’t have access to these drugs. This comes to the second big challenge: Making CGRP drugs more accessible. We should realize that we currently only administer these drugs in parts of the world that are privileged enough to have access to them. There are large areas of the world where these drugs are not available, often because they are too expensive.

You are the current president of the European Headache Federation (EHF). How are communities like the EHF helping to overcome these challenges?

In my role as president of the EHF, I’m very happy that we are collaborating with the International Headache Society on initiatives to make the drugs more readily available for less privileged parts of the world, and part of that challenge is making these drugs cheaper. I must highlight that the president of the International Headache Society, Rami Burstein, shares this view, and we collaborate on this, so I should give him credit for what he’s doing.

I think many of the solutions to challenges in the migraine field will be solved by younger generations of researchers. One of the European Headache Federation initiatives that’s quite dear to me is the Future Headache Experts. It’s a flourishing group of young people who create their own network and form a community of young headache researchers. For example, we had a session at a recent conference about how artificial intelligence can be used in migraine research and clinical care. This really doesn’t come from my generation, but from younger researchers with really good ideas. That’s why it’s important to involve them.

Fred Schwaller, PhD, is a freelance science writer based in Germany.

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