Gottschalk says CGRP inhibitors have made "...a life-changing transformation in how we think about and the kind of expectations we set for migraine treatment."
Christopher H. Gottschalk, MD, is professor of clinical neurology, director of headache medicine, and section chief, general neurology, at the Yale School of Medicine in New Havent, CT. Gottschalk is also current president of the Alliance for Headache Disorders Advocacy.
The following has been lightly edited for clarity and style.
Patient Care: Could give a brief history of the migraine-targeted therapies that are available now—the injectable calcitonin gene-related peptides, the oral gepants, and the load ditan? What were the research questions that drove those investigations and how did they evolve over time?
Dr Gottschalk: I'll start with the CGRP story, because there’s more there and it's certainly a great example of what medical research can be. Back in the 1990s when several labs, mostly in Scandinavia, were starting to explore the physiology of migraine—what is migraine; how can we model it in animals to better understand what's going on—one of the common approaches was to stimulate and typically overstimulate the trigeminal nerve in a rodent to try to create what was assumed to be some kind of inflammatory irritative process of the trigeminal nerve that would duplicate symptoms of migraine. Often that stimulation was performed with electricity; we used to hook the nerve up to a battery and zapped it until it started to do strange things. But in the process of finding ways of stimulating the trigeminal nerve, to model that kind of pain, they would also take samples of blood and look at what kinds of chemicals were released in that trigeminal system that might inform them about what kinds of signals were being created. And they found some small protein that they hadn't seen before that was being released in the situation that looked a little bit like another thing called calcitonin.
So they named it calcitonin gene-related peptide because they didn't know what it did. I think that name was probably intended to be a placeholder of some kind, but unfortunately, it's stuck. So we are left with a very long, very unwieldy word for what has become a major player in the field of migraine and pain science.
Having identified this chemical, the question was, how important is it? Is it really a major player in communicating the pain of migraine? The next steps included things like take patients who have a migraine, and maybe a cluster attack, and during an attack measure their blood. Is it true in the samples that the levels of CGRP increase with those attacks? If they do, do they then go down when the attack resolves? And do they go down faster when someone is given an effective treatment like sumatriptan which was available at that time? So all of those turned out to be true, that the level of CGRP matches the onset of an attack, and corresponds to treating the attack. So then, somebody got really gutsy and said, I wonder what would happen if we would infuse this chemical into the people who get migraines or cluster headaches? Can we trigger an attack? Can we precipitate one? And the answer was again, yes.
Now there's a whole discussion there to be had about triggers. But keep in mind that the pharmacological triggers we have, the drugs that we can infuse into people with migraine have a success rate of about 30% at 6 to 9 hours. So, it’s hard to trigger a headache experimentally, and the most reliable triggers that we have are these chemicals like CGRP, but even then, it's still again, about whether or not it works. But with all those lines of evidence about the relationship between CGRP level and or exposure and headache attacks, the next logical step was to see what happens if we block it. A series of small chemicals were developed to block the CGRP receptor. Those are the so-called gepants. And in the early 2000s, the first decade, there was a series of trials of those [gepants] by a number of companies, mostly being done as acute therapies. If we give a pill of this drug, can we stop it? Again, they showed definite promise. But in a couple of cases, unfortunately, those particular chemicals cause liver toxicity. And so, programs were abandoned.
So, after the trials of the small agents, the gepants, met with obstacles, some very creative people said, I wonder what would happen if we simply tried to use antibodies, if we use monoclonal therapies to block the receptor or maybe even just block CGRP itself. And that is what led to the modern era of treatments that we now see. And fortunately, those trials were designed with monoclonal therapies because those agents last for weeks and weeks in the system. Those are all preventive therapies, which show great benefits with minimal side effects and long-lasting effects.
So suddenly, we moved from my entire lifetime treating headache medicine, where we were telling people to take a medicine once or twice or 3 times a day for months in the hopes of finding a benefit and hopefully with not too many side effects now to a treatment that you can take once a month that will generally start to work very quickly and that has a very low hassle factor, very low toxicity, with great benefits. That has been an absolutely life changing transformation in terms of how we think about and the kinds of expectations that we set in the treatment of migraine.