Episode 39: CGRP & Gepants: What We Know and What to Expect



Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease. This episode is brought to you in part by our generous sponsors, Amgen and Novartis.


We are more than a year out from the release of the first CGRP antagonist for the treatment of migraine. But just how well is this class of medications working? In this episode, we interview headache specialist Dr. Merle Diamond to get an update on efficacy and what we can expect in the coming year, as a new group of these medications is released.


Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in Alzheimer’s disease and migraine. Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and misconceptions surrounding this debilitating disease.


Molly O’Brien: Hello and welcome to Spotlight on Migraine. I’m Molly O’Brien. Today we’re looking at new medications specifically to treat migraine: CGRP inhibitors. I’m very excited to welcome our guest, Dr. Merle Diamond. She’s president and managing director of the Diamond Headache Clinic in Chicago. Dr. Diamond, thank you so much for joining us.


Dr. Merle Diamond: Thanks so much for having me, Molly. I’m excited to be here today.


Molly: Well, we’re excited to have you here. Can you talk to us a little bit about your background? You have worked, studied, and lectured on managing headache, treating headache, and much more. Can you talk to us a little bit about your background and a little bit about the Diamond Headache Clinic?


Dr. Diamond: Sure. So actually, I was genetically predisposed to come to this practice. My dad was one of the first headache doctors in the United States, Seymour Diamond, and he had a passion for patients with headache and that headache disorders were terribly disabling and needed to be addressed. So I kind of grew up with that, and then I went to medical school and decided I definitely wasn’t going to do headache, so I became an internal medicine and emergency physician. And I did that for a few years, and then the call of headache sort of dragged me in, and I’ve been doing this for the last 30 years.


The Diamond Headache Clinic was the first private headache clinic in the United States. There’s actually a funny thing my dad had in his office about — somebody who’d written a letter to one of the medical journals about a crazy guy in Chicago who wanted to treat headache patients back in the early 1970s, so he was quite a pioneer and kind of opened the door for patients. I really believe that.


Anyway, so I came to the clinic and loved treating headache patients, loved being able to see people get better. And we also have an in-patient unit at St. Joseph, AMITA St. Joseph, which is our current hospital affiliation, where we have a 43-bed in-patient unit for very disabled people with bad migraine and other chronic headache disorders. 


So we have a little different approach. Obviously, we want to diagnose and treat your migraines, but we also like to keep a holistic approach, so we use a lot of other therapies for patients, because the longer I’m a doctor and, particularly, a headache doctor, I see patients at all age levels, and different people require different therapies, depending where they are in their life.


Molly: And again, the Diamond Headache Clinic, it’s all about talking and working with patients, and also providing that continuum of care. Can you talk a little bit more about your treatment approach with patients?


Dr. Diamond: Right. So a lot of the patients we see have seen a number of other healthcare providers before they get to us, and so what we try to do is actually go back to the beginning with them and how their headaches began and really listen to the story of how they got to us — what was it like when it started, how did it change, and what brought you here? — and what diagnosis they think they have. It’s pretty amazing, but a lot of times, our patients don’t even have a diagnosis for what they have.


And we do that with sort of a group that works with the new patient in terms of taking a thorough history, reviewing any tests that they’ve had in the past, and then trying to make clinical decisions. But I think our approach is always to ask patients what their goals are, like what are your hopes? What are your needs? Because somebody who’s 27 and might want to have a baby in a year needs something very different than somebody who’s about to lose their job because their migraines are so bad. And so looking at the patient as a whole person. Do they do shift work? How do we modify that for them? There’s a lot that goes into it, and we try to really give patients a lot of different tools to access.


Molly: That’s really neat to be able to work with each patient individually, because we all know every person’s body’s different, every patient’s different, and everyone with migraine is different. So in 2018, CGRP blockers were introduced to market, and those with migraine are still being introduced to them and still discovering them. Can you talk a little bit about how these medications work?


Dr. Diamond: Yeah. So some years ago, a migraine researcher named Peter Goadsby was able to separate out some different peptides, neuropeptides, that were released during migraine, and then with working with these different compounds, figuring out which ones might be most important in the pain process of migraine. And I think one of the reasons patients have suffered so long with migraine is that we didn’t have all the science together, and so as we understand the science of migraine better, we’ve been able to develop better drugs. And one of these groups of medications are the ones that block CGRP.


So a good way to think about CGRP is that it’s a neuropeptide, so it’s sort of a compound that’s released that can communicate to different areas in your brain and also the rest of your body, and it is pro-inflammatory. So when we think about migraine, we think about the dilation of the blood vessels and also the inflammation, but perhaps the most important part about CGRP is that it sends the pain message in migraine. And so the thought was if we could block that, if we could prevent that pain message from being sent, then perhaps we would impact our patients’ quality of life significantly. And as you may know, migraine is the second most disabling condition worldwide, so it’s not a little thing, and it’s so important for patients. 


So what happens with the medicines — and there are a number of them out on the market. The ones that are out right now are called monoclonal antibodies. The way I describe them to patients is you have a couple cups of antibodies in your bodies. They fight infections. They get rid of cells that don’t look well. They get rid of toxins. So your body has a lot of antibodies, and monoclonal antibodies in medicine can be developed that can target very specific things. So in the case of CGRP, we have one monoclonal antibody that actually blocks the receptor for where CGRP binds. So during a migraine, CGRP is released, and the chemical goes to the receptor to bind and cause the transmission of that pain signal, and with one of the monoclonal antibodies that’s developed against CGRP, it actually blocks the binding of it to the receptor.


And the way I describe it to patients is that the receptor is like a lock, and CGRP is the key. And the monoclonal antibody, which is erenumab in this particular case, is like putting clay in the lock so the key can’t fit. That’s my simplistic approach to it, but it works for me. The other two monoclonal antibodies that are currently on the market, galcanezumab and fremanezumab, vacuum up CGRP, so they block its transmission of the pain signal by binding the CGRP directly. 


All three of these compounds work really well for patients, have very limited side effect profile, and have been amazingly well tolerated. So the promise of them has really been fulfilled. The main side effect is really injection-site reaction. Because they’re monoclonal antibodies, they’re really big. If you tried to make pill out of them, you’d have to — I don’t think you could. They’re really, really big. So they have to be dissolved in solution, and the solution is thick, and so it has to be injected. 


So the main side effect is injection-site reaction and pain. Erenumab, the first one that came out, does have a constipation warning, particularly at the higher dose it’s at, and the other two, really, are much more inflammation. Because they’re relatively newer drugs, more will be revealed. I have to say that, in general, they’re incredibly well tolerated, and I haven’t had a lot of surprises in terms of side effects. But certainly, there are patients who have had side effects. Anaphylaxis and systemic allergic reaction has now been reported.


Molly: Let’s talk a little bit more about the three different products, and you described to us a little bit about how each one works and how you describe them to your own patients. Can you talk a little bit about how you approach your patients and if any one particular product might work better than another?


Dr. Diamond: So what I would say, when I’m talking to my patients about prevention, I go through sort of the whole description of what we can use for prevention. So I start at vitamins and other sort of alternative therapies, which can be very effective for people. And certainly for some of my young women who are thinking about pregnancy, even those, we need to say what’s safe and what’s not safe, right? And then I talk about the more traditional things we’ve used like blood pressure medicines, beta blockers, anti-seizure drugs, and anti-depressants, and then a few miscellaneous other items that we’ve learned to use over the years. And then I talk to them about onabotulinum toxin, which is Botox for migraine, and then last but not least, I talk about these three compounds that are available.


Because of the side effect profile of these drugs, many of my patients really opt for them. Many of our patients, because we see people from other places and other practices, have tried a number of other things. But because they’ve been well tolerated, a lot of patients really like to go with them.


Molly: Dr. Diamond, do you think treatment options using CGRP antagonists — do you think any patient is more suited for that type of treatment?


Dr. Diamond: Well, that’s kind of controversial, so especially for patients who have very difficult to manage migraine, I would like to give them the therapy I think is best first. The caveat in that or the little kind of restriction in that is I take care of a lot of young, healthy women, and I need to know what their reproductive plans are, because really, we don’t have any information about these drugs during pregnancy. So it’s possible they’re safe, but we really don’t have any data right now, and we don’t have any data with lactation. So certainly, with that population of patients, I’m going to go with something else for prevention that we know has some road-tested safety during pregnancy. And so that would be a population I wouldn’t go in.


The drugs were not tested for people under 18 yet. A couple of them go up to the age of 70, and so I think they’ll probably be perfectly safe and work, but we don’t have a lot of data on that yet. So I think it also depends on patients. Some of my patients don’t want to take something new. They want to let the dust settle and wait, and I’m not the one who has to put something in my mouth or a shot, so I really try to gauge how comfortable my patients will be with that.


Molly: When you’re sitting down with a patient and having a discussion, is it you that brings it up, to look into these new types of medications? Is it the patient? How do you go about treatment options? Do you kind of lay it all out there, and do you tell them about CGRP blockers?


Dr. Diamond: Yeah. So that’s interesting. I think when somebody comes to a tertiary headache clinic like we are, where they’ve been to a number of other people or have really difficult-to-manage headaches, a lot of our patients come with a lot of information, but not everybody. So I really, again — from soup to nuts — I go from the beginning to the end, and I try to see what works best for the patient. 


I have some patients who say, “I only want alternative therapies. I want to do acupuncture, biofeedback, and maybe some vitamins,” and I’m respectful of that, and we draw a line of what we expect impact-wise to think about what their therapies will do. But I’ve seen patients modify their diet, take vitamins, and feel a ton better, and I always say, “I’m not in charge. I can give you statistics, but every person is individual, and everyone needs to make a decision about what they’re comfortable with.”


Molly: So have you noticed — from your patients who have used CGRP antagonists, have you noticed anything that you didn’t expect, such as less dizziness or ear pressure?


Dr. Diamond: Yeah. So it’s very, very interesting. When you do a clinical trial to get a drug approved for migraine, one of the things that they look at — are you having less headaches, and what’s the side effects? We don’t look at what’s the prodrome or what other symptoms do you get with migraine, like dizzy or ear pain or neck pain. And so they’re not in the clinical trials, so you raise a very important question. 


And the answer is yes. Not only do people’s migraines get better, but some of those prodrome symptoms and postdrome, like the fog that people get after a migraine — I’ve seen that improve with these medicines. Is that mentioned in the clinical data? No, because it wasn’t an endpoint that the FDA was looking for. But if you turn off migraine, you get to turn off a lot of other things too.


The other interesting thing that we didn’t know when we started using these drugs is we knew what the endpoint was for episodic migraine in 6 months, like how many less headaches you might have, and we knew what the cutoff was at 3 months for chronic migraine. But now having had these drugs, one of them for a year and a half and the other two for a year, what I can tell you is what we see at 3 to 6 months, if you’re a responder, continues to improve, and you continue and get better and better. So that’s really awesome. It was a hope, but it wasn’t necessarily something we knew would happen. So that’s super exciting for patients. 


I think for the first time in my practice, when I see somebody on one of these compounds, they might not need their abortive drugs refilled, because they’re not using them. I just saw a guy from Mississippi. A lot of people fly to Chicago — I don’t know why I would have flown today; it’s a snowstorm — but anyway, since he started his drug, he’s had, like, one migraine. And so I said, “Well, I guess you don’t need your sumatriptan or your ketorolac.”


And he’s like, “All I need is my shot, please.” And not everybody gets that, obviously, but that’s really remarkable when that happens. That means you’re not impacted by your disease anymore. You can have your life back.


Molly: I’m trying not to get emotional over here [laughter].


Dr. Diamond: I mean, for me, when he said that, I get emotional. I treated his mom for 30 years, and to be able to give him a tool that works so fast for him, it’s really amazing.


Molly: Another set of CGRP antagonists are coming to market called gepants. Dr. Diamond, can you tell us a little bit about what these medications are like and how they work.


Dr. Diamond: So gepants are actually small enough to be pills, and they are again CGRP blockers but in a tablet form. The thing about gepants was the first gepant was actually developed about 15 years ago, and there were clinical trials going on with something that blocked CGRP orally to take as an acute medicine, like you might use a triptan or an anti-inflammatory. And when we did those studies, the drug worked, but it also seemed to have a preventative signal to it. People had less frequent migraine with it. So we talked the pharmaceutical company into doing a preventative trial, and it worked. It did help prevent, but it also caused some liver toxicity, so they threw the drug out. 


Fast-forward, here we are with some new oral gepants that are just short of being approved by the FDA that do not cause liver toxicity and are going to be approved as acute medicines. So I’m getting a migraine. I’d better take my acute medicine, and a gepant might be that medicine. And the question is, and we don’t know this right now, could they also be used preventatively? But we know that they work acutely. 


And because they’re gepants and not a triptan, they seem to have much less risk for cardiovascular issues or some of the other annoying triptan-y feelings that people don’t like. I’m not throwing triptans under the bus. I love them. I’ve been using them for years, but it will be nice for patients to have another alternative and one that doesn’t really cross with the triptans, so that gives patients more tools. 


And I always tell my patients when I see them now — even the people who are so desperate, who can’t function — nobody wants to have migraine, but if you have to have it, this is a good time to have it. And I had migraine since I was 15. I didn’t have a lot of options, and so this is just life-altering for people. I’m so excited.


Molly: It’s a pretty great time.


Dr. Diamond: Not that you want migraines, but to be able to know that things are being developed — we’re actively really, really working on having good therapies for patients. It’s going to be amazing.


Molly: Do we [know?] if there are any type of patients where gepants might respond better?


Dr. Diamond: That’s stuff we don’t know yet, but what I will say is — and for my young women who are thinking about pregnancy, we also don’t know about the safety of gepants in pregnancy — but unlike a monoclonal antibody, you can take a gepant and it’s gone from your body in a day or two. So it gives women who are anticipating pregnancy some other tools to use. Again, we’re not going to go find some woman on the street who’s pregnant and say, “By the way, would you like to try this for me?” But again, having alternative tools in this class will be very, very helpful.


Molly: How much do we know about side effects yet?


Dr. Diamond: For most of the gepants, it doesn’t seem like much, maybe a little dizzy, mild nausea, so we’ll see. But again, they look incredibly clean and well tolerated. I think the thing that we’re doing now that we couldn’t do before is that because we understand, again, that neurological event that’s going on, we can more easily target different medications that can be helpful for patients.


Molly: Well, Dr. Diamond, it has been such a joy to speak with you about these new medications and medications that continue to be developed. And as we wrap up our conversation on CGRP blockers, I’d like to talk a little bit just more generally about migraine and your work within the headache sphere. Do you have any facts or one specific fact or bit of information that you like to share with your migraine patients?


Dr. Diamond: There are really good organizations to reach out to to try to find people that might treat headache in your community, and if not, they can also give you information where you could get some treatment. So I always say the National Headache Foundation is incredibly helpful for patients. It’s been there for over 30 years and really does amazing work on patient outreach. And there are other organizations: the American Migraine Foundation, I think, does a lot of work with patients. 


But we all have to stand together to get people better, and my dad just passed away a couple weeks ago, and we’re heartbroken. He had an amazing life. But what a legacy he left, that patients with migraine could get really good treatment and get better.


Molly: Well, I’m so sorry for your loss, and we are so grateful for your father and the legacy that he has left, and we’re thankful for you and the good work that you continue to do on behalf of all migraine patients.


That wraps up Spotlight on Migraine. I’d like to say thank you to our guest, Dr. Merle Diamond, with the Diamond Headache Clinic. Thank you so much for joining us. I’m Molly O’Brien.




Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.


This podcast is sponsored in part by Amgen/Novartis.

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