S2:Ep7 – Simplifying New Migraine Treatments: Gepants and Ditans

TRANSCRIPT

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.

Join us for an information-packed episode where Dr. Stewart Tepper simplifies what you need to know about gepants and ditans. Describing this as the best time to be a migraine patient, Dr. Tepper explains the impact of these new treatments and breaks down their side effects, drug interactions, insurance barriers, and more.

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 your host, Molly O’Brien. Recently, we’ve seen rapid development in new migraine treatment options, and today we’re talking with neurology professor and headache specialist Dr. Stewart Tepper.

Dr. Tepper, thank you so much for joining us.

Dr. Stewart Tepper: Thank you for inviting me.

Molly: I’m really excited to dive into this topic with you. Over the past couple years, we’ve seen rapid development of new migraine treatment options, all revolving around CGRPs, so let’s talk a little bit about that. But before we get started, can you refresh us on what CGRP is?

Dr. Tepper: CGRP stands for calcitonin gene-related peptide, and it is a small molecule that is released outside the brain in most people with migraine. And when it is released, it binds to a docking station, or receptor, and once that happens, a cascade of events occurs, which includes blood vessels getting big. It includes inflammation. And that combination of blood vessel change and inflammation hurts, and a signal goes back into the brain and is processed as a migraine. So the release of CGRP outside the brain leads to migraine being experienced within the brain.

Molly: Okay. Can I ask you, why do we have CGRP?

Dr. Tepper: CGRP is the most powerful blood vessel dilator that we make, and so there are times when we need blood vessels to dilate. In the setting of, for example, a head injury or an infection, we need inflammation to fight off infection. And CGRP also is involved in what is called, in the biz, gut motility. So that means that CGRP is involved in having the gut move and process food. There are other areas of the body where CGRP is involved as well, but from a neurologic standpoint, the primary feature of CGRP is that it causes blood vessels to get big and causes inflammation.

Molly: Okay. I think it helps put things in perspective if we know what it does good for us along with maybe why those with migraine can understand how it might be a bad guy. But it’s always good to know what it actually does for us on the good side as well.

So new medications have been released over the past couple years, and also the FDA approving some new medications, all again revolving around CGRP. Can you tell us about new medications and new treatment options that have recently been released?

Dr. Tepper: Well, it’s important to remember that some of the new FDA-approved treatments for migraine do not involve CGRP, so we may want to circle back on those later. But there have been six that have been approved for treatment of migraine that do target CGRP. And it is one of the most exciting aspects of treating migraine, that unlike other areas in neurology where targets did not work out — for example, in Alzheimer’s disease — in migraine, the target of CGRP has yielded these very exciting new treatments, which have totally changed people’s lives, and I can’t even begin to tell you. 

And one way to look at these new treatments is that they come in two broad categories: one is prevention of migraine, and one is for the acute treatment of migraine. The prevention of migraine involves people taking designed antibodies, and these antibodies, which are given once a month to once a quarter, either target the CGRP docking station — the receptor — or target the CGRP itself. And they work outside the brain, and for most people, they have no side effects because they’re so targeted at CGRP. Some people do get constipation because of the CGRP effect on the gut, and some people do get an injection site reaction, and there are rare allergic reactions. 

But there are four of these what are called monoclonal antibodies that have now received FDA approval, and they have similar effectiveness and a similar lack of side effects. So they’re pretty exciting.

On the other side of the ledger are what are called small-molecule CGRP receptor antagonists, and these are small molecules that basically sit in the CGRP docking station, or sit in the receptor, and prevent CGRP from binding, from getting in there. And two of those have been approved since December for the acute treatment of migraine, so to take as needed, similar to the way people currently take triptans or anti-inflammatories.

Molly: So let’s talk about those two that were recently approved targeting for the acute treatment of migraine. What are options like for patients?

Dr. Tepper: Options currently involve triptans, and triptans were the first designer acute medicines for migraine. And what they do is they prevent the release of CGRP, and they constrict the blood vessels that CGRP makes big or dilates, and they prevent the signal from coming back from the periphery to the brain. So triptans, even though when they were invented, we really didn’t fully appreciate that they were anti-CGRP drugs — in fact, they are anti-CGRP drugs. They work via a neurotransmitter called serotonin, but they actually prevent CGRP release and reverse CGRP blood vessel dilation and prevent the signal from going to the brain and terminate attacks.

What they do, however, in constricting the blood vessels can occur also in the heart or other areas of the body, so that people with vascular disease are not supposed to take triptans because triptans narrow coronary arteries and other arteries in people with vascular disease, and that can put them at risk for a heart attack or a stroke. The triptan receptor, the portal that results in the blood vessels constricting, is called the serotonin 1B receptor, B for “blood vessel.” And the other serotonin receptors that triptans activate are the serotonin 1D receptor, D for “dog.” 

And what the gepants do is they sit in the CGRP receptor, and they prevent CGRP from getting to the receptor. So they prevent the blood vessels from dilating, but they don’t cause the blood vessels to constrict. Gepants are therefore, at least so far, safe in people with vascular disease, and a lot of people who get older or develop vascular disease who cannot take triptans can take gepants, these small-molecule CGRP receptor antagonists.

The two that have been approved are ubrogepant, which has a brand name of Ubrelvy, and rimegepant, which has a brand name of Nurtec. Ubrogepant and Nurtec are incredibly similar. They work with almost identical effectiveness at two hours, and almost nobody has any side effects with these two medicines. And I was involved in the studies on both, and I have to tell you, I have never seen a person have a side effect with a gepants, and I mean no side effects. 

The disadvantages of gepants are that they’re relatively slow in onset. Triptans come in two forms — fast-onset oral triptans and slower-onset oral triptans — and gepants behave a little bit more like the slower-onset oral triptans in terms of the likelihood of pain freedom at two hours. But they make up for that in not having any side effects at all, and people who take triptans often have some other unusual side effects. They might get chest symptoms such as tightness or discomfort or jaw tightening or hot or cold sensations, and those are called triptan sensations. 

Gepants don’t have that problem, so patients can take them in the middle of the day early on in an attack, which is when we really encourage them to do so because of the relatively slow onset, and they won’t notice that they’ve taken them except that two to four hours later, they may be headache free, which is pretty great.

Because we’re going to talk in some detail about gepants, I’m going to talk a little bit about the differences between ubrogepant and rimegepant. Ubrogepant is a tablet, and it comes in two doses, a 50 mg and a 100 mg tablet, that a provider can prescribe; and the maximum amount of ubrogepant in a day is 200 mg. Rimegepant is currently available as what the FDA calls an orally dissolvable tablet, or an ODT, and an ODT is a melting tablet. It’s kind of a granular substance. A person puts it on the tongue, it dissolves, and they swallow it, and then they get the results from that. And rimegepant only comes in a single dose, 75 mg, and that’s the maximum dose in a 24-hour period. So people cannot repeat a rimegepant dose, whereas they can repeat a ubrogepant dose. And those are really the differences. 

From a side effect standpoint, from an effectiveness standpoint, there are no differences. One very encouraging [11:14 inaudible] of these gepants is that in studies on both in which patients were given these gepants to use across time on an as-needed basis for their migraines, the number of migraines they had started to go down. So it looked like the gepants actually had preventive effect as well as acute effect. And that was pretty exciting because with our other medications for acute treatment such as anti-inflammatories or triptans, when people take them too often, they get something that used to be called “rebound” that is now called “medication overuse headache,” and the number of headache days starts to go up. And it looks like with gepants, the reverse may be true. 

And because of that, gepants are being studied for prevention of migraine, and this is where the barrier between acute treatment and preventive treatment is going to fall, I think. So rimegepant — the melting tablet, the orally dissolvable tablet — is in the process of being studied for the prevention of migraine in a tablet form, and if rimegepant proves to be effective for prevention when taken frequently, it will be the first medication ever approved for both the acute treatment of migraine and the preventive treatment of migraine both, which is pretty exciting.

On the other hand, there’s another gepant called atogepant, and atogepant was studied in daily use for the prevention of migraine, and it was studied for episodic migraine, so migraine less than 15 headache days per month. And it was effective in reducing episodic migraine, very similarly to the monoclonal antibodies. So there are two gepants that are being studied for prevention, which will join the two gepants that have been approved for the acute treatment.

Finally, there is another gepant called vazegepant, which has been studied in a nasal form as a nasal spray for the acute treatment of migraine. What we expect within the next several years is that there will be three gepants for acute treatment of migraine — ubrogepant, rimegepant, and vazegepant in the nasal form — and two gepants approved for the prevention of migraine, taken daily or near daily in order to prevent migraine, as an alternative to the injectable monoclonal antibodies.

Molly: It’s so exciting to hear you say this and very exciting for those out there with migraine. So hopefully we see a lot more coming out of this, so I really appreciate you sharing this information.

When we first started hearing about these new types of medications revolving around CGRP, we learned a little bit about the liver toxicity. Have we seen or learned anything about that with the gepants?

Dr. Tepper: With the new gepants, there has not been appreciable liver toxicity, and this has been evaluated pretty aggressively because the early gepants did have liver toxicity. So, so far, so good. Everybody’s keeping an eye on them, but so far it does not appear that the newer gepants share that liver problem.

Molly: That’s great news, and the possibility for acute treatment and potentially preventative treatment I think is really exciting and hopeful for migraine patients out there. Do you have any idea, for the two that are approved right now and in use, who might benefit from these type of gepants?

Dr. Tepper: The AHS published a consensus statement in January 2019, which was worked out with the payers as to who should receive the new treatments. And what they worked out with the payers was that if a person had tried at least two triptans on several attacks and had had either a lack of effectiveness or a lack of tolerability, meaning side effects, that those patients should be eligible for the new acute treatments. And if a person had vascular disease or too many risk factors for vascular disease — that is, contraindications to the use of triptans — those patients should also be eligible to receive the new treatments.

There is another new treatment that was approved also in October of last year, which actually is not a gepant. So we actually have three new acute treatments that would be eligible for treatment based on the AHS consensus statement. The third treatment that was approved is called lasmiditan, which has a brand name of Reyvow. You want me to talk about that?

Molly: Sure, let’s dive into that one as well.

Dr. Tepper: Lasmiditan was also approved for the acute treatment of migraine, but it is not a gepant. And instead, what it does is it targets serotonin again, our old friend from the triptan era, but a different serotonin receptor. The serotonin receptor that lasmiditan targets is the serotonin 1F receptor. Gepants work primarily outside the brain in blocking the CGRP receptor. Lasmiditan, for the most part, works inside the brain, targeting the 1F receptors inside the brain to terminate the migraine inside and by a central effect.

The good part of lasmiditan is that it’s fast, so it works more like a triptan in terms of the speed of onset, like a fast triptan. The disadvantages of lasmiditan are a couple. First of all, because it works inside the brain, it can cause dizziness or drowsiness, and generally, that dizziness or drowsiness is mild. It’s a mild intoxicated feeling that people have, and that slight feeling is actually linked to getting success with the lasmiditan. So we tell patients, “When you get that feeling, that means the drug is likely going to work for you.” 

However, because of that central effect and the dizziness and the drowsiness, the FDA has said that patients who take lasmiditan are forbidden to drive for eight hours after they take it. And in fact, on a simulator, even patients who didn’t feel dizzy, drowsy, didn’t do that well on the driving simulator test. So for that reason, lasmiditan really can only be used in the evening for when patients don’t need to drive or on the weekend when they don’t need to drive. Or if they live in Manhattan, and they take the subway to work, then they would be eligible for use during the day. But it does limit for patients who want to treat during the day and are gainfully employed and drive back and forth or need their car.

The second aspect of lasmiditan, which is a little unusual, is that because it has central effect, the FDA has scheduled it, and that means that they require us to use a drug enforcement agency — a DEA number before we can write a prescription, based on the concern that it might be abused. It seems a pretty low likelihood for abuse, but it’s probably not zero, and it’s similar to the drug pregabalin, or Lyrica, which also has a similar requirement when we prescribe as neurologists.

So lasmiditan is different than the gepants in that it has a little more in the way of side effect baggage, and we have to be careful that people don’t drive, and we have to use our DEA license. But similar to the gepants, because it works on the 1F receptor in the brain, it does not cause blood vessels to constrict, and it is safe for people with vascular disease. So all of a sudden, we have three acute medications that are effective for patients with vascular disease and safe for them, as best as we can tell, which is a pretty great turn of events for our patients with migraine.

Molly: That is exciting and good to know that here are three new medications available. If someone has migraine, they’re doing okay in their treatment right now, or maybe they’re not doing okay with their treatment options right now, what’s a good approach if there’s someone who has migraine right now and is interested in these new medications? What kind of conversation should they have with their doctor?

Dr. Tepper: Well, they may have to work their way up the food chain. They may have to have a discussion with their primary care doctor and say they’re interested in the new treatments and that they’ve been unsuccessful with the older treatments. They may then get a referral to a neurologist, and depending on whether that neurologist is interested in headache, they may get a referral from the neurologist to a headache medicine specialist. And there are some areas of the country where the headache medicine specialists are not that enamored of the new drugs, so there’s a little bit of threading the needle involved here. I think the more that patients have discussions with their providers about these new opportunities, the more likely it is that they’ll receive them when appropriate.

Molly: Are there any interactions with these new medications with other medications out there? So say you have a treatment plan that you’re following already, and you want to take one of these new abortive or acute medications?

Dr. Tepper: With respect to the gepants, the gepants do go through the liver. That’s where they got in trouble originally. The newer gepants still go through the liver. They go through a very specific liver enzyme system, which is called cytochrome P450 3A4, or CYP3A4, and that’s a very common pathway to get rid of medications in the liver. And there are a number of medications that go through the same pathway in the liver and that can interact with the gepants. 

And it is important for patients to ask their provider who’s writing the prescription for the gepant to go over with them which medicines might be a problem. And for example, grapefruit juice can be a problem in patients who are using a gepant. Some medicines cause the gepant levels to go up. Some medicines cause the gepant levels to go down. And there is a list in the prescribing information on the gepants for providers to share with pati

ents so that they don’t inadvertently take drugs that might interact with the gepants.

With respect to the preventive monoclonal antibodies, the targeted monoclonal antibodies, there are no drug interactions. They’re so targeted, they don’t really interact with other medications, and they don’t go through the liver. They go through a different system entirely. So, fortunately, those are completely devoid of drug-drug interactions.

Molly: So are any general care providers able to prescribe these new medications?

Dr. Tepper: That’s a really, really important point. The American Headache Society took a very strong position that any licensed healthcare provider should be able to write the new medications if the patients meet the criteria that are in that consensus statement, which was published in January of 2019 in the journal Headache. The copyright is lifted. Anybody can download it and show it to providers and show it to payers and providers. As a provider, I show it to payers all the time.

Molly: Do you really have to go through failing these two types of medications? Do you have to have the failure? Is that what you’re saying with two other medications before you can even try the new medication? Because it’s really hard for people with migraine. Sometimes you get success, sometimes you don’t, and sometimes you don’t know because you’re just trying to get through the day. So I just want to make 

sure I have that clear.

Dr. Tepper: Well, first of all, one important point — it’s not the patient who fails; it’s the drug which fails. So you notice that I’m very careful to say a lack of success with the drugs, or the triptans fail, rather than the patient fails. That’s really important, and I try to explain that to my patients.

The issue of having these step edits was negotiated, and when we started talking to payers, they were talking about requiring patients to have a lack of success with four or five triptans before they could get the new drugs. And we fought and got it down to two. And the same thing is true for the monoclonal antibodies: there have to be at least two preventive categories to have failed before the patients are allowed, generally, to have a monoclonal antibody. 

Do I think that is right? No. I think that is wrong. I think we ought to match what patients need to the proper treatment. We don’t make people do step edits to get asthma medicines. We don’t make people do step edits to get epilepsy medicines. We get medicines which are designed for particular diseases, and those are the medicines that we recommend to patients. 

Right now, we’re unable to do that with our payers, and there are areas in the country where wealthy patients can go directly to the new drugs and not worry about whether they’re going to be covered or not, and more power to them. But in areas like where I practice in New Hampshire where there’s not a lot of wealthy people, then we continue to be obligated to do what are called step edits. I don’t think it’s right, and I hope that patients will lobby this to be torn down, and we’ll see.

Molly: I think it’s really valuable to hear someone advocating and the way that you word it. You as a patient are not failing. It’s the medication failing the patient.

I want to ask you one more thing before you go, Dr. Tepper. Obviously, you’ve been in the game for a little while. You know what you’re doing. You’ve worked with a lot of patients. And this is an exciting time in treating migraine and being a migraine patient. What is it like for you to be able to provide new options for your patients?

Dr. Tepper: This is the best time in my professional career. This is the most exciting time. I was there with the launch of triptans. Triptans were great, and that was the other exhilarating time in my career. But this is orders of magnitude more exciting because of the magnitude of effect in quality of life that patients are getting with the new preventive drugs, because of the opportunity with multiple treatments for acute treatment that can be given to people who have risk factors for use of our previous treatments. 

There’s so much that’s available for my patients now that my patient and I just sit there, and we get giddy because we’re so excited about the opportunities and what we can do. And I say to them, “Look, if this doesn’t work, we still got this, this, this, this, and this as possibilities for you.” So this is really something that we need to work through, but it is the best time to be a migraine patient and, I must say, the best time to be a headache medicine specialist.

Molly: That’s really exciting to hear, and a lot of hope out there for both providers and patients, so really exciting, and we thank you so much for joining us today. Thank you so much, Dr. Tepper.

Dr. Tepper: [inaudible] thank you.

Molly: And that wraps up this episode of Spotlig

ht on Migraine. I’d like to thank our guest, Dr. Stewart Tepper. Until next time, I’m Molly O’Brien.

[music]

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This podcast is sponsored in part by Amgen/Novartis.

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