S6:Ep5 – PACAP as a Future Migraine Treatment Target


Voice-over: Welcome to Spotlight on Migraine hosted by the Association of Migraine Disorders. In this episode, leading researcher, Dr. Messoud Ashina, explains what PACAP is, and how it’s involved in migraine pathophysiology. He also talks about how it differs from CGRP and why it could be a promising target for migraine and other headache disorders.

Molly O’Brien: Hello, and welcome to Spotlight on Migraine. I’m your host, Molly O’Brien. Today we’re talking about pituitary adenylate cyclase-activating polypeptide, and we call it PACAP for short. So what is this neuropeptide, and how does it relate to migraine? To fill us in, I’d like to welcome our guest, Dr. Messoud Ashina. Dr. Ashina is a Professor of Neurology at the University of Copenhagen and the director of the Human Migraine Research Unit at the Danish Headache Center and Department of Neurology. Dr. Ashina has been actively involved in headache research since 1995. He’s an associate editor at multiple peer-reviewed medical journals and was previously president of the International Headache Society and general secretary of the European Headache Federation. Dr. Ashina, thanks so much for joining us today.

Dr. Messoud Ashina: Hi, Molly, nice to meet you. Thank you for inviting me.

O’Brien: We’re so happy to have you. You’re an expert in the field. So to talk and fill us in all about PACAP and help us understand what it is, how it works, and the future and possible migraine treatment options. So we’ll get started on the very basic of topics. Let’s get a better understanding of what PACAP is, in the simplest of terms, what is it?

Ashina: PACAP is a neuropeptide found in all part of our human body. But in terms of migraine, it is located in so-called strategic structures associated with migraine, particularly so-called trigeminovascular system. So our blood vessels express this peptide, our nerves express this peptide, our brain express this peptide, and we know that this trigeminovascular system is very important for migraine pathogenesis, the way that the migraine occurs, migraine presents, and that’s why this peptide was stated. And we found that it might play a very important role in migraine pathophysiology.

O’Brien: So the more we understand PACAP the more we’re able to understand the role that it plays within migraine. But PACAP also does a lot of other stuff. What is the role of it in the body?

Ashina: Well, it is a multifunctional peptide. As I said, that it is expressed in many parts of human body, it can be expressed also in our intestine, you know, in our heart, in our kidneys, everywhere we see the PACAP. The exact role of PACAP in this these different organs. But I can say that in terms of migraine, it is, as I said, located in this migraine relevant structures, and it plays a very important role. If I can mention one of the important roles of PACAP, again in regard to migraine, it would be probably a rule of PACAP in regulation of the vascular tone. Meaning that it dilates the vessels, it dilates the vessels if you apply the PACAP, and it is also important as a neurotransmitter and neuromodulator. So meaning that all these painful signals transmitting by the nerves are modulated by this peptide.

O’Brien: When we’re thinking of PACAP, it might sound sort of familiar because we understand CGRP. Can you tell us are PACAP and CGRP sort of similar? If so how, and are they different?

Ashina: Well there are both peptides, CGRP and PACAP, but they are different. The difference is, first of all, because they belong to the different families, okay. For all peptides, we have some families, okay. For the CGRP let’s say, for the calcitonin gene-related peptide, we have a so-called family calcitonin family, okay. For the PACAP family, it is different, it is we call the secretin family, and there are other peptides in this family as well. I can mention a so-called vasoactive intestinal peptide, okay, so very much related to the PACAP. And there is another one that…another peptides important in the calcitonin family, amylin/adrenomedullin, so they are very similar to the calcitonin gene-related peptide, CGRP, because they share also receptors.

What does it mean? It means that when the molecules are free circulating in human body, they usually binds on so-called receptors. And you can imagine that each of our human cells contain this receptor specific for these peptides. And they are kind of doors which are open when the molecules binds to these doors, right. So, the PACAP and CGRP they have different doors they bind. That’s why it’s a different peptides. But they share some things such as they are both vasodilators, meaning that they dilate human vessels, in particular vessels located in the cranial region in all the brain vessels.

O’Brien: As we’re still continuing to learn more about PACAP, it’s my understanding that there are two different types. Is that important to understand that there are two different types of PACAPs? And if so why, and what are the differences?

Ashina: Yeah, we can again, draw the similarities with the CGRP. In human body, the CGRP consists in two isoforms, two forms of CGRP. One is beta, another one is alpha CGRP. Beta CGRP is more located in our gastrointestinal tract. It plays very important role for motility of our intestinal system, you know, the gastrointestinal system. In case with the PACAP, pituitary adenylate cyclase-activating polypeptide – if I will spell it – so it is a different in all…it consists of two isoforms, PACAP27 and PACAP38. The only difference is the number of amino acids, that’s it. And another important thing is that in human body, the most of the PACAP we have it’s a PACAP38. So PACAP27 in the less concentration compared to the PACAP38.

O’Brien: Okay, and as we move forward, we’re going to get into more of your research and research into potential migraine treatment drugs. Does it matter that we know about the differences between the types of PACAP?

Ashina: In case with the PACAP, I would say no. And the reason for that is that we…I mean some years ago, when we investigated the role of PACAP38, first we showed that if we infuse this peptide into people with migraine, then more than 50% of people with migraine will report migraine attacks. And when we later did another experiment with the PACAP27, we found the similar number of patients – again more than 50% – also developed migraine attacks. So meaning that both isoforms of PACAP can induce migraine attacks. It is important to mention that if you infuse these peptides into people without history of migraine – they never, never had migraine before and don’t have any first-degree family suffering from migraine – they only develop a very mild headache, which is transient.

It usually goes away in a matter of one hour. But in case of migraine, it gradually evolves, the mild headache gradually evolves into the full-blown migraine attack. And this usually occurs within the two or three hours after the start of infusion. And duration of infusion is usually 20 minutes, okay. And what is interesting is that normally when you stop the infusion, the half-life of both peptides, both isoforms of the PACAP, are very short, should be gone. But apparently it binds to the receptors and effect it is long lasting. And that’s why it probably results in migraine attacks.

O’Brien: We’ll talk about that a little bit more; you have been leading human clinical trials about PACAP. Can you tell us more about what you have learned when you infuse people with PACAP and some of the results, or has anything stood out or surprised you?

Ashina: You know, Molly, before we talk about that, it is important to explain that migraine is quite unique disease in a way that we can understand and investigate migraine in humans directly. Usually when we think about, you know, studying disease investigating the mechanisms underlying disease, we think about preclinical research, research in animals. And then from animals, we take the data and translate that into humans. But in case of migraines are different. And the reason for that is that it is a unique feature of migraine, that you can express the disease by provoking the disease. Like in the normal spontaneous attacks that we experience, we have different factors triggering the attacks. We have a menstrual cycle in women with migraine. We have, let’s say, red wine. You know, many people report red wine, or any kind of food, or different factors that we associated, you know, as triggers for migraine. We usually say those are triggers. And we try to avoid those triggers.

So meaning that you can express the disease for a while to study the specific molecules which can trigger the disease. They’re important for the genesis of the attacks. And this is a way you can provoke attack in experimental lab. You cannot do it with other neurological conditions of diseases. You cannot provoke Parkinson to understand the Parkinson. You cannot provoke multiple sclerosis. But in case of migraine, you can provoke because you know it will go away. And you know you can offer immediately a rescue medication if patient feels uncomfortable. Of course, everything is done upon the concept. You know, and many people with migraine they’re very brave people, and they do everything for the research for us, you know, to understand the mechanisms. So just imagine if the molecule A is inducing migraine attack, then you study that expression of this molecule in all migraine strategic areas.

And then you can speculate, if you block the molecule itself, free circulating around the doors, and prevent this molecule to bind the door, to bind the receptor, then you have a maybe a new drug. Or you can find another molecule, which goes not blocking the molecule but blocks the receptor, and thereby avoiding you know, the molecule cannot bind to this door to this receptor. And then again, you have another drug. And it could be acute medication, you know, you take it during attack, or it could be like in case with a CGRP and possibly, in the future, with the PACAP medication for migraine prevention. So you can reduce the number of attacks, you can reduce the number of attacks and also reduce the intensity and duration of attacks. And this is important measures that we have usually when we evaluate the efficacy of medications for migraine prevention.

O’Brien: It’s absolutely fascinating. I never thought about the fact that you can actually trigger this type of disease, you can trigger an attack think people who are so you can provoke it. I think people within the migraine community are so used to hearing things like that you don’t really compare it to other neurological diseases. So that is pretty fascinating.

Ashina: Yeah, and this is a way we discovered the role of PACAP. You know, when we went back, we went back and start studying the role of PACAP in the trigeminal vascular system, the system which consists of three very important structures – vessels, nerves surrounding this vessels, and all these signals why these nerves going to the brain, right. And we found that these different peptides, including PACAP27 and PACAP38, they are located in these structures. And since they are vasodilators, we also knew that from the preclinical research, we first studied how it dilates the vessels. And we found yes, they dilate the vessels, but this dilation eventually led to the full-blown migraine attack. And that was the first discovery when we show that PACAP can, in fact, induce migraine attacks. And we start speculating whether the drugs blocking the receptor or the PACAP itself, I mean, could be a new drug target, you know, for treatment of migraine.

And the first one which tried to block the specific receptor, the specific door for the PACAP38, unfortunately failed. You know, the monoclonal antibody against this receptor didn’t show any efficacy. But later another company developed a drug which binds directly, or they block directly the molecule itself, not the receptor. And so far the results that we have, the preliminary results we have, from the proof of concept study, you know, with the first study that you should show that whether it is efficacious or not are positive. So we we are now expecting that there will be new studies to confirm the efficacy of the monoclonal antibody against the PACAP and possibly offer another drug for people with migraine.

O’Brien: Absolutely. And as we talk about where we’re at in this research process, is it really…I mean I think everyone with migraine is thinking, oh, potentially a new treatment. So that’s exciting. But we don’t want to jump ahead of ourselves. That being said, people are still curious. So is it too early really to determine what possible treatments might look like targeting these receptors?

Ashina: Yeah, I mean, what we have to, to mention here is that the new medications that we have now the anti-CGRP, or anti-CGRP receptor medications, whether they are gepants or they are monoclonal antibodies, they are efficacious, and it is documented in the randomized clinical trials. So there is no doubt about that. And in terms of safety and tolerability, they’re also very – how to say – well performed, right. Of course, we have some patients having some side effects, but mostly they are very well-tolerated medications. And what we see that, that our practice change that because adherence and persistence, you know, in terms of these medications very, very good. But we have to know, and we have to remember that there are a number of people not responding for these medications, right. It’s something roughly about 40%.

We have to remember that there are also patients that responding but maybe not optimally, they still have some very bad attacks and still need to take some acute medications. So just imagine that if you have a chronic migraine, and you have 25, 26 days a month migraine days, right migraine attacks, and you reduce it to 10 to 12. You still have a 10 to 12 migraine days per month, right. And so you are responder, you are happy, you are very grateful. But you want more, right. You want to reduce the intensity of those attacks which are left, or you want to reduce the frequency. My point is that there is still unmet need for new medications. And more medications in our armamentarium we have the more advantages for our patients, right. And it’s also very rewarding for us physicians to offer these different medications.

Now, if patients not responding, what to do now? The problem is that now we would say well, we don’t have any other medications left, you have received the newest one, the best ones, and apparently you’re not responding. So what to do? It means that there is always room for improvement, and we need to offer other medication. That’s why science research is very, very important in this context. And by doing this kind of research, we’re trying to address these questions what are other molecules involved in case was migraine? And we discovered the role of PACAP. So in the future, if PACAP passes this exam, you know, with the Phase 3 trials, I would say we will have another drug that we can offer, which is developed/designed to target the disease mechanisms, right, as equal as anti-CGRP medications.

O’Brien: Is there an idea, an estimate, on timeline? I mean, I know it really is too early to say. But do you have like a ballpark you think how long this process might take to find out if these drugs could be beneficial, could be safe, could be effective?

Ashina: I think, unfortunately, things takes you know things take time, right? You need to conduct proper randomized clinical trials, you know, to confirm the efficacy, safety, tolerability. By the way, I have to mention that in this preliminary data that we have published only in abstract for anti-PACAP monoclonal antibody seems to have a very good tolerability and safety profile. There were no signals. But that was only four weeks trial, of course. And we need more data. So let’s say that if, if we are lucky, maybe next year, the Phase 3 trial will start maybe in let’s say in three years from now, in three, four years. If we’re very optimistic, we’ll have another medication. If it again passes the exam and it is effective, then we’ll have another medication in addition to the anti-CGRP. But I don’t think it’s only PACAP.

There are other targets, you know, some of them that we studied, also, they’re from the same family like calcitonin gene-related peptide. I mentioned briefly before amylin/adrenomedullin they could be also targets. And the reason I’m saying that because they can also provoke migraine attacks. We did that in our lab, and we showed that they’re also provoking migraine attacks. So molecules, anti, you know, anti-ligands, you know, we call it the drugs acting against the molecule itself, or antireceptor, in case with amylin and adrenaline could be also.

I’m not aware about any companies that are investigating those mechanisms. But those are also important molecules and possible new targets future. In case with the PACAP, it’s more fascinating because PACAP also has very specific receptors. So we are not done with receptors. So we hope that there are some people in industry that are working on this specific receptors, and they maybe they can also come up with some new drugs against those receptors. So there is an interesting prospect, I would say, and we’re living in good time, because we have now good drugs. But we are never satisfied, we want more, and we will fight.

O’Brien: I love that – we’ll fight for it. We’ve been talking primarily about PACAP and migraine, but I have read a few things that we might be able to target these receptors to help with other types of headaches. Is that a thing, and what can you tell us about that?

Ashina: I would mention other two important headaches. One is a cluster headache. And what is interesting, we studied the role of PACAP also in cluster headache. And we show that you can, in fact, provoke cluster headaches with infusion of PACAP38, which is very interesting data. Not only because it’s provoking, but here it comes fascinating about the cluster headache. You know that the cluster headache patients, they can go into so-called remission period, when it’s completely silent, nothing happens. They don’t have any attacks. And guess what happen? If we give them PACAP when they are not in the cluster period, they’re in the remission period, happens, nothing.

O’Brien: Really.

Ashina: Nothing. Meaning that you infuse the PACAP, you get all physiological effect of PACAP, but you don’t get attacks because your system is switch off.

O’Brien: Wow.

Ashina: And we don’t know exactly why. It is fascinating. If you can do this kind of experiment in migraine, it will require that you have a long remission of migraine, let’s say after menopause, and then you try to provoke and see whether in this condition, when your body already, you know, turned off the button of migraine will not provoke attacks, you know, by infusing all these substances. It is a fascinating topic. But I can tell you that in case was a cluster headache, you can do it. And we tested a number of molecules, and they are not provoking attacks during the remission. In fact, we also tested the CGRP in cluster headache patients. So we started in my lab first with the CGRP, then we move to the PACAP.

And what is interesting later not myself but my colleague – in fact is my next generation of Ashina, my son – he did a study in the post-traumatic headache, which is also very important, not the primary but secondary headache, okay. It is headache attributed to the mild traumatic brain injury. Apparently about 30 to 35% of people they develop persistent headache after the head trauma. And we’re not talking about severe head trauma, we’re talking about mild trauma. Why exactly the mechanisms, we don’t know. But what is characteristic for this patient is, a typical presentation, they have a persistent headache all the time, which varies in terms of intensity but some days very bad days.

And in those days, they experience some of so-called migraine features, like they become very light sensitive, a bit more light sensitive, more sound sensitive and sometimes nausea and also worsening of the headache during the moment, right. Resembles migraine – not exactly migraine – and we know that the drugs that we are getting them not really well performing, really not working these people, right, unfortunately. And I usually say to my patients that in case with migraine, we expect that the drugs will work in about 50% of people. But in case was the post-traumatic headache, we’re going down to the less than 20% or something like 10 to 15%. So very, very few fortunate people responding to these medications, but the vast majority no response at all.

And what he did, Hackman did, he started that in patients with post-traumatic headache. So he invited them when they had just a mild headache, normal headache that they usually have on the daily basis, and infuse the PACAP38. And in more than 90% of people – and this is a placebo-controlled study – they reported a worsening of headache, you know, resembling, again, the migraine with all migraine features. Meaning that suggesting that the PACAP plays important role in the genesis of this headache, the post-traumatic headache. And maybe – maybe we’re not sure – the drugs acting against the PACAP or PACAP receptor, maybe they can be efficacious, you know, in post-traumatic headache.

And just imagine that if we have some medications that we can offer these people, you know, that we know that they’re not really responding to the conventional medications and also the newer medications that we’re using now, that will be really good news for people with chronic post-traumatic headache. But this is something in the future. And I hope that when we have this medication, I mean, if they shows that, you know, I mean confirm the efficacy in migraine, and we can move further and start studying this efficacy of this medication in cluster headache patients and in patients with chronic post-traumatic headache.

O’Brien: So there’s a lot of potential here. It’s really, really exciting to hear about. Also, I love that you’re keeping it in the family, keeping the research going in the family. That’s awesome.

Ashina: So we all suffer from migraines, so we know what we’re talking about.

O’Brien: So you’re all working for yourselves and others. I like that. That’s incredible. Dr. Ashina, we only have a couple minutes left, but I just want to wrap up with one final question kind of a catch all, is there anything else you think people out there should know about PACAP and migraine, anything else?

Ashina: What I want people to know that migraine is, is a very, very important disease. And it affects so many people, you know. And in the world population, we will say more than 1 billion people worldwide, you know. And what really bothers me is that, despite of you know, its widespread prevalence, right, migraine remains underdiagnosed and undertreated. And this is really, I mean, this is not good. This is a big problem in my opinion. And that’s why I always advocate the more education in this field, you know, healthcare professionals, in particular, pregraduate education is very, very important.

And one of the reasons is also that you can really make a difference for these patients. And it’s really rewarding, right, not only for the patients but also for the physicians. And not in many specialities, we can actually say that we have medications specifically developed for the mechanisms of disease, which are so well-tolerated, you know, relative to other nonspecific medications and say that we can offer that. This is incredible, and unfortunately, there are a lot of people still undertreated/underdiagnosed. This is important point.

Another important point is that we have to remember that we are so privileged, you know – in the Western world, in Europe, and also in North America – representing rich societies that access for this medication is different from the rest of the world, which is a majority of people we’re talking about around the world, there are not at all have this access for this medication. I’m not talking about diagnosis; it’s even worse in terms of the diagnosis. That’s why we need to do more also, for the rest of the world, developing countries. We’re talking about Latin America, we’re talking about Southeast Asia, we’re talking about Africa, Middle East, you know. In all these countries, we as physicians, we need to do more. So this is an organizational, this is a political work, but this is very, very important.

And I’d like also to mention in this context, the role of the International Headache Society. It’s very, very important. The role also of other Pan-Asian and Pan-European organizations that we have ACN, we have Southeast Asian organization for headache disorders. We have European Headache Federation also in this context. In Latin America, we have also Latin American societies. They’re playing a very important role advocating the case of people suffering from headache disorders in migraine, in particular, migraine. So this is important work we have to do, and we need to remember that, and work with this in this field.

O’Brien: Absolutely. Dr. Ashina, thanks so much for spending time with us today. We really appreciate all your insight. It’s been a real pleasure chatting with you.

Ashina: Thank you. Thank you for inviting me.

O’Brien: And that wraps up this episode of Spotlight on Migraine. I’d like to say thank you to our guest, Dr. Messoud Ashina. And to all of our followers out there, thanks for watching this episode of Spotlight on Migraine. I’m Molly O’Brien. I’ll see you next time.

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