Tuesday, June 11, 2019

Calcitonin gene-related peptide receptor antagonists for migraine

While attending this year's annual meeting of the American Academy of Neurology (AAN), Medscape contributor Andrew Wilner, MD, interviewed Christopher Gottschalk, MD, FAHS, assistant professor of neurology and chief of the Division of General Neurology at Yale School of Medicine in New Haven, Connecticut. Wilner and Gottschalk discussed how injectable monoclonal antibodies are transforming the treatment of headache, and the remaining questions surrounding their use.

Changing the Conversation Around Headache

There have been a lot of new therapeutic modalities for the treatment of headache, everything ranging from magnetic stimulation to monthly injections. How does this change general practice for the neurologist in their office treating people with headache?

Certainly for me as a headache specialist, the current generation of injectable drugs that you mentioned, the calcitonin gene-related peptide (CGRP) receptor antagonists, has completely changed my approach and the conversation with virtually every patient that I see. Before, we were in an era where there were a range of potentially helpful drugs I could give you for headache prevention that we kind of stumbled upon, which do some good but also have a high potential for side effects, such as topiramate, divalproex sodium, and beta-blockers. Now we've moved to having a disease-specific agent based on our understanding of the physiology of the problem that is easy to administer, works really well, and has essentially no side effects. 

There is very little argument against using them, and in most cases, they're probably the best option we've have ever had.

It was my first impression that this was something reserved only for patients with intractable migraine who didn't respond to all the other drugs you mentioned, but it sounds like that's not your impression.

That's not the case, and I think that partly has to do with the idea that because they are new drugs, they would only be for that group. As time goes on, I hope that more and more physicians will shift their thinking about that, precisely because, for example, up until now there's only been one treatment that's specifically approved for chronic migraine—Botox. Then that is unavailable for everybody who doesn't quite meet those criteria, whereas CGRPs are eligible for anyone with migraine. There's no restriction on frequency of attacks at all.

Once again, you're talking about a simple, easy-to-use, and effective thing with really no side effects, as opposed to something where you can get some benefit but you also may gain weight, lose hair, not be able to think, and even have nightmares and what have you. To me, that says that there is no clinically, and in some ways ethically, good reason to restrict access to these drugs on the basis of the worst cases.

How They Work and Which Ones to Use

If these drugs are so important, I want to know a little bit about how they work.

How they work is not fully understood, but the story behind it is pretty fascinating. It was about 30 years ago in the laboratories of Lars Edvinsson and his colleagues where it was discovered using animal models of migraine, which basically allowed you to hook a battery up to the trigeminal nerve to overstimulate it and see what happens. One of the things they discovered was this new small peptide that was released by the trigeminal nerve. When they characterized that and later cloned it, they realized that it was a CGRP.

They then went on to test whether that was relevant in humans. Sure enough, if you sample the venous blood during a migraine attack, elevated CGRP is found, which correlates with the acute severity and goes down when you administer a triptan.  And perhaps the most interesting finding was that if you administer CGRP to a patient with migraine, you have about a 30% chance of getting a typical migraine attack within 6 or 8 hours, very much like what we're seeing with nitroglycerin.  A related study also showed that if you administer CGRP to a patient with cluster headache, you can induce cluster only if they're in their cluster cycle, which I found really cool. All of those together say that we understand that this is a very specific piece of the acute migraine physiology.

We've also learned that CGRP in the brain is almost exclusively localized in the trigeminal nucleus, so that's where it lives. When it's released during attacks, it causes, among other things, increased sensitization of the trigeminal.

There's more than one of these injectable drugs. Are they all the same, or should I use one over the other?

These drugs are the really the second wave of an effort to block CGRP. About 10 years ago, we had the first phase of oral agents for blocking CGRP. Those were all aimed at the receptor, and several of them turned out to cause liver abnormalities,  so those projects were abandoned. Thank goodness some clever people said, "Gee, maybe we could just use antibodies and get the same kind of results."

Now we have one monoclonal, erenumab, which is aimed at the receptor, and two others (galcanezumab, fremanezumab-vfrm) are also available. Then, the one that will come to market next year is aimed at the ligand, so at CGRP itself.

Interestingly enough, among the three currently available self-injected monoclonals, there doesn't appear to be a huge difference in their clinical profiles. They all have good results, whether you're looking at mean migraine days, 50% responders, or 75% responders, and side effects are minimal. We don't have any compelling evidence saying one is superior.

I certainly am among the group that hopes it is true that there will be patients who will respond better to one or the other, so that we have something to go on, but at least people have options at the moment. There have been some cases where somebody might have side effects with one but not another, which will put us back in the same boat we've always been in, trying slightly different variations on the theme to get the best response.

There probably is a meaningful clinical difference with the last one that will come to market, eptinezumab, because it's administered by intravenous infusion. That certainly has a faster onset of efficacy and probably overall better measures of total efficacy over time. So for some number of factors, that would be the right choice.


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