Christopher Gottschalk, MD

 Before we get to the end of this program, it would be wonderful to give everyone a moment, 1 at a time, starting with Rebecca. Do you have any final words about this extremely exciting time in our field? Do you have any last words to give our audience members about what it’s like being a headache specialist with all the fun that we’re having?

 Thank you so much, Jessica. Yes, this is an exciting time to be in the field and caring for patients. One of the things that a lot of these new treatment options has done is bring awareness to migraine and to the many patients who experience migraine, that it’s not just a headache. Now there’s even a hashtag, “#NotJustAHeadache” because migraine is a complex neurological disorder. For some patients, the photophobia, or phonophobia, or nausea is more disabling than the headache pain itself and recognizing that a migraine attack has a prodromal period and lasts a long time. With the new CGRP options, we have a new pathophysiological target, and as Chris mentioned, it’s not viewed as being all in your head. Now we have neurobiological evidence with targets specifically affecting the outcomes of patients with migraine.

It’s so important to recognize what a burden this is on patients. And how important it is to decrease the stigma and take away the guilt and blame from individual patients and say, “This is a neurological disease, and we can do so many things to help you with this.” Ultimately it’s a neurological disease, and the awareness of migraine is critical because there are many people who aren’t aware of the impact that migraine can have on patients’ lives. We’re at a great point in history in terms of being able to have and offer so many treatment options.

 I agree with the point that having specific biology as a therapeutic target really goes a long way in reducing stigma. People can focus on the specific mechanisms rather than having this nebulous potentially functional emotional issue. There may be layers of those things that are important, but it’s validating for people to understand that there’s been research that’s done that’s identified this target in migraine patients now that treatments are exploiting it with, in some cases, spectacular effects. That’s exciting.

For me, as a scientist, the other incredibly exciting thing is that every time we have 1 of these major therapeutic advances, it has the potential to transform our understanding and we can take back to the bench what we’re learning at the bedside and try to understand where CGRP is being released, where are the receptors important, and then use that information to get better at individually treating specific patients with migraine.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN:

 I aspired to become a neurologist because I’m fascinated with the nervous system, especially the brain. But I didn’t aspire to become a headache specialist because I had no idea that becoming a headache specialist could feed that desire of understanding how the nervous system works, how our brains tick, how we tick. That’s been 1 of the most exciting and gratifying things for me landing in this career path. The other thing I will reiterate is the gratitude you receive from patients is so gratifying. The specialty of headache medicine is antiburnout way more than any other specialty could be. Maybe plastic surgery—I don’t know. No, that’s a joke. But we all have our bad days, there are lots of challenges, and we get burned out too. Our risk for burnout is a little lower, partly because we’re learning about the tools to combat burnout because those are the same tools that our patients with migraine can employ. If you’re not already excited about headache medicine, I hope folks start to get in the game, because you can’t make a difference in people’s lives, but you can make a difference in your own life.

 That’s a good point. I had a student who was like, “This is amazing.” She’s going into neurology, and she’d spent weeks as a sub-investigator. She said that was the first clinic that was a positive experience because everybody was so friendly and happy and doing well. I said, “You happened to come on 1 of those happy CGRP, days but I won’t say anything.” It was a great day to have somebody validate that what we do is so amazing. I hear you, Steph. Chris?

 I agree with all that. I love what you said, Stephanie, about the path you took to headache medicine. It occurred to me, at some point after I had become a headache specialist, that a lot of the illnesses that people focus on in neurology are things that happen to the nervous system, and that we can understand based on localization. But migraine is 1 of the best examples we have of an intrinsic disorder of the nervous system and the education that it provides, the insight it provides into the interactions between the cortex, and the thalamus, and the pain system. All the ways they affect different dimensions of function are absolutely fascinating. I get a thrill every day out of educating patients and giving them a different framework for understanding their own experience. They can then come back and say, “You’re right. If I look at this in a different way, I can treat it better. I can understand my symptom complex better. It’s much less of a sense of blame about what I did wrong and understanding how this process occurs.” Those are good days and good ways to motivate more practice and insight.

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A panel of expert neurologists shares advice for community neurologists on preventive migraine treatment and exciting therapies to look forward to.

The Changing Landscape of Preventative Migraine Treatments

 In this last segment, we’ll be talking about best practices in preventive treatment for migraine. Stephanie, at what point should a patient be referred to a headache specialist?

 Wow, what a great question. There’s no single best answer. It’s almost like when you know, you know. But you have to be paying attention to know when to know, right? Practice across the country varies a lot. It can be very tough to see a neurologist or even your primary care doctor because they see a lot of headaches, but they have higher-priority medical problems to take care of in a lot of their visits.

Migraine is very prevalent. It’s 12% of the waiting room, yet a small percentage of visits are dedicated to discussing or even looking for it. You have to be looking for it and trying to treat it in the first place. Then you have to know when you’ve reached your limit of what you’re comfortable with and what you’re willing to keep trying. You don’t want to keep trying and not have success. That detracts from even the strongest clinician-patient alliance, so know when. Maybe it’s like a “3 strikes and you’re out” scenario. Who knows? But that should be an individualized decision that’s discussed at length between the patient and their clinician.

Where headache specialists come in, obviously, is to offer some newer and more cutting-edge treatments that we’re more comfortable with because we’ve been using them longer. We know all the ins and outs and the tricks of how to deal with the payers to get them covered. We can do advanced therapeutic techniques, such as injections of onabotulinumtoxinA or nerve block and trigger-point injections, which can be done by anybody. But a lot of neurologists and primary care doctors don’t want to bother with it, so they’ll send them to us for that or more advanced care with infusion therapies, either through an outpatient infusion suite or in the hospital.

That’s where we come in, but it can’t be a handoff and bye-bye. No, we need to be part of the existing team. This is not necessarily a transfer of care. It’s pulling a new expert into the treatment team because a busy headache practice can’t necessarily see a patient as frequently as they may need to be seen to make those little tweaks. We can get a patient on the road to success with several ideas of step A, step B, and where our bifurcation points may come in. Then we arm the local doctor with that information, and they can tinker with it and massage it along until they can get back to the specialists, where we make another overhaul to the plan if it’s not working out properly. I could go on about this, but that’s my simple superficial answer.

 These are really good points. It’s important to point out there are over 700 headache specialists in the United States to take care of around 40 million people with migraine—just migraine. We’re not talking about occipital neuralgia, cervicogenic headaches, or tension-type headache, which shouldn’t be seen by a headache specialist but sometimes end up with us. Trigeminal autonomic cephalgias also aren’t common but should be managed by a headache specialist and all the 200 other subtypes of headache disorders.

Oftentimes, the patient will come to us and want to stay with us, but we don’t always have the resources to do full-time management, so that partnership is essential. It’s an important thing to realize when you’re referring a patient over. Another essential thing is to understand there might be a wait. It’s always nice when I get a message from the patient’s primary care physician or neurologist saying, “What can I do in the meantime to help with all the work-up, or the studies, or a treatment that I should be starting this patient on? Here are their records.” I find that to be extremely helpful.

Just today I got a message like that from a primary care physician in my network, so I could see the patient’s chart. I saw that the patient had been on prevention and had just stopped it because she was lost to follow-up and had transitioned to our center, to our system. All I had to say was, “Why don’t you restart the patient’s prevention. I see that you already started her on her prior acute treatment, and you took documentation that she has a change in her headache type. Why don’t you order an MRI without gadolinium?” She’s already contacted us to make the appointment, so that’s awesome. While she’s waiting for the appointment, if all this gets done, she will be like 70% on her way by the time the appointment comes. She’ll be much better than calling us miserable every other day waiting for that appointment to start. Those are super-helpful things that people can do.

Chris, for the community neurologist who is starting a patient on preventive treatments for migraine, do you have any tips or tricks that you wanted to offer them?

The main message I have for my colleagues in general neurology is to keep up the good work. What’s remarkable to see in the last 10 years or more is that more of our neurology colleagues are taking migraine on as a disease that they’re willing to treat, that they’re able to treat, and that they’re enthusiastic about treating. That has a lot to do with the fact that we have more treatments that are clearly effective and well tolerated. It’s unfortunately true that in the era I grew up in, in a large academic center in the United States, that most of my preceptors had the attitude that migraine was not part of neurology or it was not even necessarily a medical disorder. That transition, thank goodness, has made it into the modern era, where we’re seeing more clinicians of various stripes who understand that this is something they can treat and should treat, and that it’s 1 of the most rewarding things they can do.

Giving people pointers about having clear guidelines and goals of treatment are not necessarily hard lines. They understand what matters to patients, and maybe a preventive treatment— that means no more ED [emergency department] visits or attacks that are half as likely to be disabling, something like that—is more than enough. It’s not about a cure but it’s about the management and restoring function in some number of domains that really matter to them.

A discussion on when a patient should be referred to a headache specialist for preventive migraine treatment.

Headache Specialists for Preventative Migraine Treatments

 These are important points. There are several measures looking at disability. We looked at 50%, 75%, and 100% reduction [in disability], also looking at the reduction of headache days. I don’t think it’s because this drug just decided to work. We’re seeing a learning pattern. This study looked at patients who were able to have up to 4 preventive treatments that had failed the patient. This was not done in earlier trials for migraine prevention.

They learned from the CGRP monoclonal trials, which had low placebo rates in patients who had experienced failure from other drugs. This is intelligent clinical trial designing. This is what we need to do. We need to learn from other trials and build upon them. The hope is that in the next trials that come around, we’re going to learn and keep building better trials. We all have so much to gain from this because then you get better drugs to patients, and they have better outcomes. Another example of this is when you look back to the CGRP monoclonal antibodies; eptinezumab came out later. It didn’t have a trial that looked at higher treatment failures, but they noticed that their IV [intravenous] infusion could start to work quickly. They designed a trial saying, “What if we infuse this drug? How soon could we see an effect?”

With galcanezumab and erenumab, they had done some studies looking back. They started to do calculations backward looking for the first day you could see an effect. Galcanezumab and eptinezumab had done backward math and said, “You could see an effect on day 1.” What if we proactively looked at the time effect you see after this infusion. They did a study looking at treating a migraine attack when it happens and how soon you see a response? They call this the RELIEF trial, and they measured that you could see a response at 4 hours. You could see the response occur at 2 hours. Imagine telling a patient who’s having a migraine that your preventive effect could start as soon as 2 hours and you’re protected for up to 3 months after.

When you have to have this conversation, as Rebecca was mentioning earlier, to a patient in clinic and you tell them here’s the migraine prevention, there are minimum adverse effects, you could start to see results within the first few hours, and those results can last a long time. And atogepant—they learned from that too, so they tried to measure back to how soon in the first few hours they can see a response. This is intelligent clinical trial designing. Let’s learn from one another and start to measure the first hour you could see a response because that’s what matters to the patient. They don’t have the patience to wait 3 months to see a response. They give up, and I don’t blame the patient. I don’t want to wait 3 months to feel better. That kind of trial design is meaningful. When we’re making specific medication that can quickly work, you want to see how fast I see onset. Rebecca, you wanted to comment.

 These are all excellent points. One additional point is with these older agents. If you tried someone on an antiseizure medicine and it didn’t work, typically what I do is jump classes. Then I’ll try a blood pressure medication or 1 of the other options in a different class. One thing I’ve been surprised by in clinical practice is how patients can try 1 of the CGRPs, which might not work, but then try a different 1 that does work. Initially, when there were just injections available, I typically tried to switch from 1 targeting the receptor to 1 targeting the peptide.

As we’ve described, we’ve got the injections, we’ve got the infusion, and we’ve got the oral options. We have a lot of options. The oral options have been on the market for a little bit, so I haven’t been able to see clinically in practice how these compare with the injections. But I’ve been surprised and want to acknowledge the difference between older agents and CGRP: although all these options are targeting CGRP, they’re doing so in different ways. If somebody fails 1 option, there are still a lot of other options. As I said, I’ve been surprised at how somebody would try 1, get no benefit, and then all of a sudden there’s a miracle medication.

 Very good point. Chris, you wanted to make a point?

 To reinforce something that you said, Jessica, about the evolution of our thinking and understanding about what migraine is as a disease and what treatments matter. For a long time we’ve been stuck with the notion that there are hard lines between preventive therapy and acute therapy, that you have things that will make headache attacks less likely or things that will help you when you need it. Lo and behold, we have a new class of therapies whose physiology we understand better, which say, “Wait a minute, you want to have not as many attacks that are not as severe or you have an attack that you want to be shorter and not as bad.” Is that different? Floor wax, dessert topping—doesn’t seem to matter. You can use a treatment that modifies migraine physiology, and it may work in different ways. That will inform our trial design and our thinking about what agents will matter in the future.

 It’s pretty mind-blowing. In clinical practice, there are times I see a patient who has been on all these treatments, every monoclonal, and suddenly responds to preventive gepant. You sit there and you’re like, “Is this real? Is this not real?” Then I think back to the trial data. This person does not have placebo left. There’s no placebo response. It’s like I’m throwing sticky tack, and they know it. It’s random. They didn’t expect it, I didn’t expect it, and they don’t even want to tell you. You look at them and you’re like, “How are you doing?” They don’t want to say anything. That’s when you know. They just give you that blank stare, and I’m like, “Really? They’re like, “Shhh.” You’re like, “No way!” They’re like, “Shhh. I’ll see you in a few months. Just write me a refill.”

 Like when you’re on call and haven’t gotten paged and you’re like, “Shhh, don’t say anything.”

 Because then it’s like you’re sitting there in your office, and you’re like, “What’s going on?” This is what keeps us going. This is what keeps me thinking and writing project proposals and making my fellows read more and keeping them up at night. I just have to say thank you. This has been an outstanding section about novel treatments. I agree with Stephanie. We’ve learned so much about refractory migraine, which is what I’ve been teaching about. Is it’s refractory because we haven’t found the right targets for these patients, which is why we need to keep pushing science. We need newer targets because it doesn’t end with CGRP.

We need that next, and the next, and the next—migraine is like snowflakes. I love it. Each is different, so we need individualized and different targets for our patients, so we can keep the hope for them and we can have all these amazing options, so most of our patients have the response where they’re telling us to shush, but they have calendars that are mostly empty. I hope you guys will join us for our next segment, which is going to be about best practices in preventive migraine.

Jessica Ailani, MD, details how the phase 3 ADVANCE trial will shape the research of future agents for preventive migraine treatment.

Preventative Migraine Therapies: The ADVANCE Trial and the Future

: Chris, why don’t you talk to us a little bit about gepants for preventive treatment of migraine?

: I’ll start with a little bit of background. The first phase of therapies that targeted CGRP [calcitonin gene-related peptide] were in fact agents in this class. Some oral agents were CGRP receptor antagonists. This is going back over 10 years ago now. The initial focus of those trials was all on acute therapy, so looking for a new class of new abortive therapies different from triptans based on the evidence that CGRP levels are increased during acute attacks of migraine and cluster headache, and that, in fact, infusing the CGRP into susceptible patients with migraine can trigger an episode. So, with all that, the idea of blocking its receptor was an understandable initial target.

The problem was with those initial drugs that several of them produced liver abnormalities and liver toxicity so most of those programs were abandoned. Then came the era of using monoclonal therapies to target receptors or even ligand as a different way of targeting that system and were extremely successful. I think it really carried along the momentum and enthusiasm of CGRP as a target again which led to the development of these newer gepants. Which, again, are things that target the receptor directly.

In the case of the 2 drugs that were initially approved, rimegepant or Nurtec, and ubrogepant or Ubrelvy, those were initially approved as acute abortive therapies and clearly provide benefit for many patients, often have lower side effects. But lo and behold, the second of those to be approved, rimegepant, found in its longer term exposure trials, where they were allowing patients to take this drug as much as every other day and sometimes more if needed than patients who were taking the drug consistently every 2 to 3 days, found that overall they had fewer headache days in a month on average. That has led to the approval of rimegepant as a preventive therapy. Along those lines, there are a couple of agents which were being studied specifically for migraine prevention, oral agents that block the receptor, and the most recent of those is a paper, whose lead author happens to have been Dr Jessica Ailani, giving us atogepant [Qulipta] as a daily preventive therapy.

Again, along with everything else, the fact that we are in an era where we have migraine-specific and target-specific therapies that can provide either acute or preventive relief for patients, and now we have the flexibility of a range of options from a pill every day, to a shot every month, to an infusion every quarter. All of these options provide more ways to help patients based on their individual needs and goals.

The remarkable thing is that for, let’s say, atogepant, the most recent addition to the group, that you’re again talking about significant improvement in their overall status, reduction in the number of days of migraine, or an improvement in the 50% responder rates that are as much as twice that of placebo. Even with this drug, atogepant, we also have dose flexibility. There’s a 10-, a 30-, a 60-milligram dose, so something that can be adjusted based on either their medical history or their side effect profile. But it’s an important option particularly because, as we’ve mentioned already in this discussion, there are patients who say, “I’m sorry but an injection is just not an option for me or I get injection site reactions and I’m not happy about that.” So we have various ways of approaching the individual needs of patients, and this latest addition I think is a remarkable one.

I’ll also comment that 1 of the beautiful things about the ADVANCE trial, the trial that led to the approval of atogepant, is that it was 1 of the better studies to focus on the direct impacts of this treatment on quality of life. Several different standardized validated measures like the migraine-specific quality of life scale and a diary that looked at day-to-day disability clearly showed significant benefits of all 3 doses on disability and function over time in a careful way. And I think in the long run that’s the thing that matters to us most, right? We are mandated by the FDA [Food and Drug Administration] to do preventive trials that measure mean migraine days and then reduction, fine, but our day-to-day experience is much more focused on has this treatment improved your quality of life, has it improved your sense of control, does it mean that you’re able to function in the roles that matter to you more often. We now have solid data for this treatment, as much as any others, that say absolutely. We’re not just talking about numbers here. We’re talking about your experience. I think that matters a lot.

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A key opinion leader discusses the use of oral agents for the preventive treatment of migraine.

Oral Agents for Preventative Migraine Treatment

: Just to reinforce some of those ideas and to sort of circle back to the conversation we were having about how our conversations with patients have changed in this new era. The fact is that we’ve grown up in a time where we had to have difficult conversations with patients about trying different prophylactic agents with the idea that this may take 3 to 6 months for you to titrate this, given that you may have tolerability issues. And then once we reach a targeted dose, we’re going to have to wait and see over months whether or not you really have a benefit, and there could be some fairly serious side effects, etc. It could take a year or more to even determine whether there’s a good treatment option under the old model.

When you look at the data from the agents that we’re looking at now, we’re talking about trials where the window of the initial trials might have been 6 months. But, in fact, most patients who respond to these new injectable therapies have a response within a month and most within a week. In the case of eptinezumab [Vyepti], patients who respond typically respond within 24 hours. So that is a life-changing conversation for me to say you don’t have to take something every single day and we’re not going to have to wrestle with this for the next 6 months to a year, but we can try a treatment that we will know whether or not it’s effective almost immediately. And the risk of side effects is dramatically less than the things that we’ve used in the past. All of us have the experience and we have data to support the idea that with the old oral agents that we had, the likelihood that patients were even still taking them 6 months later was like 20% because of all those tolerability issues and the delay in response.

I have rarely had the experience in the new era of somebody who comes back and says, “Yeah, I took a dose or 2 of that shot and I gave up.” They’ll still take it and some occasional patients will say, “I just don’t think it’s doing enough.” But they tend to hang in there. We mentioned earlier that with botulinum toxin, it’s a rare day that you have somebody who says, “No thanks.” All of these opportunities to have a treatment that is effective with minimal risk of side effects and fairly rapid responses allows for establishing, I think, a much stronger relationship with patients that you are providing targeted therapy, you understand much better what the risks and benefits might be and can get to an answer a lot sooner.

: I think it is important to point out that many will have a response very quickly. “Even if you respond quickly, it’s important to hang in there because,” I tell them, “This is just the start.” Which they’re always like, “What do you mean? I’m so much better.” I’m like, “Oh, oh but just you wait.”

What is very fascinating to me is we have data that points to long-term response and all of that data ends at around a year. We have data for erenumab [Aimovig] at 5 years, but we’re just starting to see these patients at year 3 to 4 now. I continue to be surprised at my chronic migraine patients who have not been chronic migraine for about 3 years now. I’m starting to feel comfortable dropping the label, they are consistently running 4 days a month and they were 28 or 30 days. And they’re like 4 days crystal clear in between. I mean, you just never thought you were ever going to see that in this lifetime.

Rebecca makes a very good comment. We wish we could figure out how to predict who’s going to be that super responder because that’s the one question we want to know and what the patients want us to answer. Stephanie, I’m going to have you make 1 comment before we turn it over to Chris to talk to us about gepants as preventive options.

: I was just reflecting on how this rapidity of response and extremely good tolerability has been so attractive with this class of drug. But, like you pointed out, Chris, some patients are more willing to stick with it for a while and see if it helps. And we have had some patients in our practice that took 9 to 12 months to see an improvement. Now, partly, that was like, well, I’ve got nothing else to do so I’m just going to keep taking it, and this really when these things first just came out. So that also struck me.

Something else that strikes me is that all of these treatments have data for patients who’ve experienced prior treatment failures and they all seem to do better. Their placebo responses are way down in the basement like they don’t expect anything out of it, and they still get some response to it. This is why it’s important not just to look at the actual numbers but to know the population and to look at what the placebo group experienced. Because it kind of challenges our notion of what refractory migraine is. It’s a debatable definition, to begin with, but in a way, we can maybe give some of our patients hope. “I tried 4 medications already, and none of them worked.” Well, it’s just because you didn’t have the right tool in your box perhaps. These medications are actually proven to be beneficial even for those who have experienced prior treatment failure. It’s another way that you can give your patients a little ray of hope and some optimism.

Dr Christopher Gottschalk shares how the clinical trial data for CGRP monoclonal antibodies affect patient selection for preventive migraine treatment.

CGRP Monoclonal Antibodies and Patient Treatment Selection

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: 

You can go a little bit into detail about what each of these clinical trials has shown.

: Well, you’ve done an excellent job of giving an overview of all of the different medications. I’ll add in a couple short details and then I’m happy to go into the clinical trials as well. It is interesting in terms of dosing. You mentioned eptinezumab [Vyepti] has 100 or 300 milligrams. Erenumab [Aimovig] also has a 70 or 140 milligram dose option. Since erenumab was the first 1 on the market, when it first came out, it was great to have both options because you could say, “Well, let’s start at the lower dose, and if you need a higher dose, we can go to it.” But now I rarely ever prescribe a 70-milligram dose because there are so many other options. Typically, when patients try medicine and it doesn’t work, in their head that medicine does not work. If I’m going to give an option, I’m going to go for the 140-milligram dose of erenumab. Then galcanezumab [Emgality] has a loading dose. First, you give 240 milligrams the first month and then every month after that, 120 milligrams.

Galcanezumab is the only one that’s also FDA [Food and Drug Administration] approved for cluster headache. The dose for the cluster treatment is 300 milligrams. Interestingly enough, they don’t have a 300-milligram injection pen yet. They only have the 100s, so people have to do 3-100s for episodic clusters. The FDA approved this for episodic, not chronic cluster to be used monthly until the attacks end. Those are some of the overall differences as well.

In terms of the decreased frequency, like which medicine is best, we do not have a head-to-head trial of all of the different medicines against each other. A lot of them had different inclusion and exclusion criteria. Some of the trials were conducted where patients could only be included if they had not failed 2 prior drugs, and then some of the trials were conducted where patients were only included if they had failed 2 prior preventive options. It’s really hard to just make a blanket statement about which medication option is best.

But 1 of the unique things that is clearly reported with all of these studies compared to a lot of the prior preventatives is not just a 50% responder rate, but some of the clinical trials reported 75% and even 100% responder rates. That’s really important to recognize that those rates are being seen in clinical trials and clinical practice. I don’t know about everyone else, but some patients have these dramatic super responses, and unfortunately, we don’t have predictors of response. We don’t know exactly which patient is going to be a super responder.

In terms of details from the clinical trials with eptinezumab, there was a clinical trial looking at 100-milligram and 300-milligram infusions compared to placebo. There was about 8 days fewer of migraine compared to 6 fewer days of migraine with the placebo. It’s important to realize that the placebo rate is pretty high. There’s a graded placebo response in terms of pills, injections, infusions, and surgeries. And we see a graded response. It’s expected to have a higher placebo rate with an infusion compared to injection. The 50% responder rate after 2 doses was about 61% to 64% compared to about 44%. The 75% responder rate was about 39% to 43% compared to about 24% placebo. Some individuals had pretty dramatic responses. With eptinezumab being an infusion you would think it must have lots of side effects but because it is specific in targeting CGRP [calcitonin gene-related peptide], side effects are really similar except for the hypersensitivity reactions, and even that was only about 2% of patients.

In terms of erenumab, 1 of the clinical trials was in people who had failed 2 to 4 prior preventatives, and that’s really helpful for us in clinical practice because those are the types of patients that we’re actually treating. The response was about 30% had a 50% reduction in frequency compared to about 14% in the placebo. Like I mentioned, comparing eptinezumab to erenumab, you see a difference in the placebo rate there. One other thing that initially was sort of a warning that I have not seen in clinical practice, and I don’t know if others have, was that the erenumab cap has latex on it. Initially, for anyone who had a life-threatening latex allergy, I would avoid erenumab but I haven’t seen that really play out much as being an issue.

Then you have the fremanezumab [Ajovy], which has monthly or quarterly injections. One of the clinical trials showed about 4 fewer migraine days per month compared to 2 less than the placebo. Then galcanezumab also was about 4 fewer migraines a month compared to 2 less than placebo. You can see with a lot of the clinical trials, there was a similar decrease in frequency. I’m right now just commenting on the frequency as we’ve already discussed disability and how it impacts patients’ lives and is a big factor as well.

It’s exciting to have all of these options because there are so many available now, and I can’t tell you how many times in the last year someone will come to me and say, “I’ve tried everything, and nothing works.” And I’ll get their history and I’ll discover they hadn’t tried one of the new CGRP options and I get really excited because I think, well, you actually haven’t tried everything yet. In our world, in the headache world, it’s like where have you been living because we are all so aware of it. I think there are still a lot of patients who are not aware of all of the newly available options.

: I love your enthusiasm about that because you know you could potentially change their life, which is exciting. Thank you to our audience for watching this 

A panel of neurologists review clinical trial data on several CGRP monoclonal antibodies for migraine preventive treatment.

CGRP Monoclonal Antibodies: A Review of Trial Data

Speaking of erenumab [Aimovig]. Stephanie, I’m going to turn to you first. Let’s do a quick overview of the 4 different CGRP [calcitonin gene-related peptide] monoclonal antibodies that are FDA [Food and Drug Administration] approved for the prevention of migraine. Just to remind our audience, these are erenumab, fremanezumab [Ajovy], galcanezumab [Emgality], and eptinezumab [Vyepti], which are FDA approved for preventive treatment in adults for both episodic and chronic migraines. We’re just going to quickly talk about comparing the outcomes for preventive treatment and side effects, and we’re going to go through the 4 [medications] very briefly. Stephanie and Rebecca, maybe you want to talk through them if you both want to have a little discussion about them.

: You already gave the overview of the names. There are some subtle differences between and among them all. Erenumab was approved first. It is a subcutaneous monthly injection available in 2 dosing regimens, either 70 milligrams or 140 milligrams monthly, which is best dosed every 28 days to try to get away from that wearing off effect. If you can sync up, just going back to the prior topic, if you can sync it up that way and also sync it so it’s not coinciding with their menstrual cycle for your women who have menstrual-related migraine, that’s another challenge that we face. Anyway, the mechanism for erenumab is to stick to the receptor for CGRP. All of the others stick to CGRP itself. The end result is the same. The lock can’t fit in the key, but the effects that an individual patient may experience could vary and we’re still trying to sort that out. We may get some clue from the adverse events, which have been reported, in clinical trials and post-marketing.

Across the board, the subcutaneous injectables, erenumab, fremanezumab, and galcanezumab, all came out the same year. Injection site reaction is the predominant adverse event and that’s just a localized reaction like a welt that can be itchy, red, swollen, painful, etc. We almost expect it. It seems to occur randomly and does not indicate that there is an allergy to that medication. Allergic reactions are reported. We call that hypersensitivity to the product but that’s a bit different.

Where erenumab is a little different in terms of the adverse events in the clinical trials, constipation was also reported. Now in post-marketing, since there have been so many exposures, we’re getting signals for hypertension, signals for alopecia, and constipation that can be severe enough to lead to bowel obstruction even requiring surgery. These have all made it into the label as updates for cautions with this drug.

For the other 3, as I said, they all antagonize or stick to the peptide themselves, and the dosing is monthly for both of the other subcutaneous injectables, galcanezumab, and fremanezumab. But fremanezumab also has the option of dosing it quarterly. Instead of taking a single dose every 4 weeks, you can do a triple dose every 12 weeks or every quarter. They call it monthly vs quarterly. Now, eptinezumab is also a blocker of the peptide itself but it’s intravenous and dosed in a quarterly fashion. There are 2 dosing options available, 100 milligrams and 300 milligrams.

The bottom line is that they all work in the clinical trials for both episodic migraine and chronic migraine when you look at primary end points of reducing migraine frequency. When you look at other secondary end points like 50%, 75%, 100% reduction, this is one of the reasons we’re now raising the bar for what we expect from preventive treatment. We used to be happy with 25% to 30% improvement, but that’s not success at all anymore. But measures of disability, function, and quality of life are also very, very important.

Expert neurologists discuss the use of CGRP monoclonal antibodies to prevent migraines.

Preventing Migraine with CGRP Monoclonal Antibodies

: Stephanie, while I have you and you mentioned onabotulinumtoxinA, it is funny because even though it’s onabotulinumtoxin, Andy mentioned earlier that it is really considered an older treatment now. I had a patient who said to me the other day that her friends were all telling her about some of the new monoclonal antibodies, but she has been on onabotulinumtoxin, one of the “old drugs” forever and she’ll remain on it because it’s doing well. I looked at her and I was like, huh. I don’t really think of onabotulinumtoxin as one of the old drugs but OK, so be it, it is pretty old now.

How do you find onabotulinumtoxin working in your clinic? I know you have still quite a few patients on it, how well do you think it’s working in comparison to say some of the newer treatment options? We’ve talked a little bit, Chris mentioned its use in the concomitant therapy with the CGRP [calcitonin gene-related peptide antibodies] monoclonal antibodies and some science showing that they can be combined. Do you find that it’s a tolerable treatment? Really, how are you using it in clinical practice today?

: Well, of course, it’s FDA approved only for chronic migraine, 15 days a month or more for at least 3 months, 8 of those days have to be migraine, “blah, blah, blah.” So you do have to carve out a specialized population of patients who are eligible for it. Thankfully for us, that’s most of what we see. We have a lot of patients that are treated with it, and like with any case, how you measure success varies from person to person. We have plenty of patients who had constant 8 to 10 out of 10 headache all the time and debilitating migraine-associated symptoms. We get them started on “onabot” which I’ll use for short for the name because onabotulinumtoxinA is a bit of a mouthful, they still never become pain free, but they go from that 8 to 10 every day down to a 3 to 5 every day, and there are many days when their associated symptoms are really not there. Now, in the clinical trials that would be a treatment failure but for that patient that’s a whopping success.

We’ve seen a lot of patients also who have had “onabot” elsewhere and they say it didn’t work. And I like to ask more details, “Well, what dose were you getting? How often were you getting it? How many times did you try it?” And I hear the craziest things, which sometimes I can verify with some office notes that they got like 2 injections on each side of their forehead and that’s it or they were going 4 and 5 months in between their treatments. So the dosing has to be correct. You have the ability and your own clinical creativity to go a little bit beyond the label. The label dictates that there are prespecified sites. You have to use this dose and only this dose, but there is no one-size-fits-all. Some patients actually do better with lower doses. Most of our patients need higher doses and they need some creative placement of where those injections go.

I would say that I have the sense that most of our patients who start on onabotulinumtoxinA in our practice wind up staying on it. Some of them can give up some of their other preventive medications, some of them can’t. We have a lot of patients who we try to do this juggling act of rational polypharmacy, but what has made this rational polypharmacy easier is not only having a treatment like onabotulinumtoxinA but also having the monoclonal antibodies, which can be synergistic together. And we’ve seen it. We’re looking at our own clinic data to prove what other centers have already proven, that when you combine the 2 together it’s like Reese’s Peanut Butter Cups. You get 2 great things that are great on their own, you combine them together and you get some amount of synergy and a lot of patient satisfaction.

: I was thinking PB&J but there’s nothing better than Reese’s Peanut Butter Cups, so that’s a pretty good analogy there. I almost want to see, Andy, do you have any controversial comments about this? Because I feel like this is something you might argue.

: No. I’ve been much more skeptical than others in the field about Botox in the past. I’ll say that I’ve certainly come around and appreciate that there’s a subset of patients who do spectacularly well with that. The one issue that actually comes up with other preventive therapies as well, even some of the new ones, is the end of the dose wearing off. That was another variable Steph mentioned. Some of the other variables like how much you give and where you put it, but then the other thing is you’re sort of stuck by payers with this dosing interval that may be too long for some individuals. So that is something that we run into, that comes 2 weeks before their next dose and they start having an increased frequency of attacks again. It’s not particularly controversial, it’s just one of the other issues that we deal with.

To the point of combining with some of the monoclonal antibodies, there, unfortunately, for me or our practice, is that situation that Steph brought up where if you put it out there, it raises hope but it’s so hard to get payers to approve both. It’s a real challenge, so I almost don’t even want to think about it even though I should but it’s just literally an impossibility for people to actually get it covered.

: These are good points. I think depending regionally where you are there are definitely coverage issues. I think it’s a constant struggle for a portion of patients with the wear-off and we do see it with onabotulinumtoxin, which sometimes you can treat with trigger point injections or occipital nerve blocks or just nerve blocks in general. But sometimes that’s not effective for those patients. There is a study actually that used erenumab [Aimovig] for wear-off effect trying to get the dosing just right and showed efficacy. But I will tell you in the long run it doesn’t work because the dosing interval just starts to end up where they ended up not lining up properly, and, at some point, they’re wearing off from everything. It seems like it should work, but at some point over the course of a year they’re wearing off from everything at the same time and it becomes quite a disaster.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN, provides an overview of the use of onabotulinumtoxinA as a preventive migraine treatment.

OnabotulinumtoxinA for Preventative Migraine Treatment

Speaking of when we’re taking these treatments to the patient, Rebecca, bringing it back to you, how do we take this and discuss it with a patient? When you’re taking a new treatment vs the older treatments? What does that conversation sound like?

: That’s just so important and I highlight a lot of what Andy said.When patients are interested in preventive treatment options, I say, “We have pharmacological and we have nonpharmacological [treatments] and sometimes it’s important to try both.” Then when we’re talking about pharmacological options I say, “You know, we have a long history of treating migraine. People have had migraines for so long and we have a lot of older options that were developed for other indications but many have FDA approval for migraine.Those can be excellent options and sometimes in addition to migraine may target other comorbidities in terms of sleep, or insomnia, or weight, and obesity, depression, anxiety. So those can be helpful. Then I say, ‘But we’re in a really exciting time where we have new medications that were specifically designed to target the pathophysiology of migraine.”

In the past, we were borrowing medications from other classes of drugs but now we have medications specifically designed and created for migraine. It’s a fun time to be treating migraine because we have all these new available options. I explain that enthusiasm to patients like, “It is so wonderful that we have all these options available and you are at a great time to come to me to seek care because we have so many more options available to target what is impacting your life.”

: If I were your patient I’d be excited because you sound so excited about treatment. Do you use that enthusiasm to convince them to start prevention like when they come to see you if they have disability? Do you talk to them about being hesitant because people often are about taking something every day? How do you really loop that fear into well, ‘let’s get you feeling better?’

: Yeah, that’s a great question. One of the most valuable questions I have found in asking patients is, “What are the goals of your care?” Of course, I’m always surprised by the number of patients who will say, “I want to cure my migraine.” I will then sometimes explain that that’s not the goal of our care. Our goal is to decrease the frequency and have a plan of action when they do happen.

By asking that question, “What are the goals of your care,” I can understand what is most important to them. Whether it’s being able to function when they have that attack, or decrease the frequency of their attacks, or being able to participate in their children’s lives in a more meaningful way. I dig out what it is that’s driving them to want to improve their lives.

Then I walk them through the different options because some patients will be very clear and say, “I am not interested in an injection.” Like, you know, that is not something I want. And then other patients will say, “I don’t want to take a medicine every single day like that. I can’t keep up with that.” Walking the patient through the different options, what they entail, and what side effects or what comorbidities can be treated, I think is really, really helpful in their understanding so that we’re really experiencing a sort of shared decision and then patients feel like they’re involved in making the decision.

One of the tools that I learned from one of my mentors was sometimes doing nothing is OK too. Just providing the options and the opportunities in what’s available and letting patients think about it and say, “So we’ve discussed a lot today. I’m going to give you some more information that you can read about these options. Why don’t we schedule a fuller visit and then we can talk about it more.” Because it’s I think one of the key aspects of being able to treat patients while developing a therapeutic alliance.

The last thing we want to do is try to pretend that we know what the patient really wants, or assume that we know which treatment option is best when really the patient themselves can tell us what they’re most interested in. What we can do is provide all of the options available so that they can recognize what they may want to try.

: Your mentor inspired an article by Atul Gawande, who is one of my favorite writers, who of course then inspired me to follow suit with a similar idea which is to provide the options to the patient but recognize very quickly when the patient is uncomfortable and not yet ready to make a decision. Because regret is the number one factor in dissatisfaction. The patient could actually end up cured of migraine, which is never really a goal, and not really something that happens often but every once in a while can stumble upon it by mistake. But the patient can still be unhappy and dissatisfied because they were not yet ready for that decision or really ready for that option.

It is very important that if you sense the patient is not yet ready to make a decision, you send them home with options and make a very quick follow-up. “In 2 weeks, let’s have a telehealth visit,” which is so wonderful to have this option now, or “Let’s schedule you to come back in. You have these tools, talk to all the people.” I encourage patients, to “Go on the internet. Go at it,” because they’re going to do it anyway. Come back with your list of the top 10 most absurd things you heard about these drugs, and I will come back at you with everything that is real and not real and all the gaps in between because when you make the choice, you should feel comfortable with it. So, yes, she is a wonderful mentor. Stephanie, you had some comments you wanted to make.

: I would echo all of this. I mean, it’s resonating so much with what I see in my practice, too, has to be individualized, and has to have buy-in to build that alliance. What I’ll say for anybody who’s not yet bought into this concept and think it takes too much time; it doesn’t really take all that much time and it saves you so much time later on. Another important aspect. When we do this, we are often kind of struck when the patient says, “Nobody has ever outlined that many options for me before and given me a choice. My other doctors just told me what to do. It’s like do this or go elsewhere.” So they really appreciate that. When it comes to the newer agents, there are a few other things to consider. I’ve had some patients who don’t want to take something new because it’s new and they’re afraid.

I have one patient in particular who I still cannot convince to try onabotulinumtoxinA, and it took 3 years to convince her to try a monoclonal antibody but now she’s doing it and she’s getting better. She’s not great but she’s getting better, and she was very thankful that we were persistent in continuing to ask, “Are you ready, are you ready?” Because she would shoot us down visit after visit, “No, I’m not ready.” So they have to be ready and you have to keep reminding them that I’m here when you’re ready and I’m here to answer all of your questions.

The other thing that has to go into this conversation with these new treatments though, unfortunately, is the cost because you and your patient may decide that yeah, one of these new treatments really is the way to go, but if there are so many hoops to jump through and that treatment is inaccessible for the patient, you’re kind of setting them up for disappointment. Then they may start to lose some of that connection that they had with you, not that they necessarily lose trust, but they get a little bit discouraged and see that the future is much farther out than they generally anticipated. Then they have to try a few more medicines or they have to try one that’s similar to the one that you recommended, all because of insurance or they can’t try it at all because it’s not within reach financially. Those are important things to also keep in mind with these newer treatments.

A thought leader explains how she involves the patient when selecting novel agents to add to a preventive migraine treatment plan.

Discussing Novel Agents for Preventative Migraine Therapy with Patients

In this segment, we’re going to be talking about novel agents for the prevention of migraine. Andy, because you started talking about the old stuff, we’re going to bring you as our young gentleman and have you talk about the new stuff. It would be nice if you told us a little about how you describe some of the newer agents vs some of the older agents.

 The major concept with the newer agents is that they’re very specific in different ways. First, they’re specifically for migraine. They were developed with migraine as an indication rather than for some other indication that we dwell on.

But they’re also specific in terms of therapeutic targets. Generally speaking, many of the other therapeutic approaches that we use for migraine prevention in the past have had multiple mechanisms of action. For example, anticonvulsants work on ion channels, and neurotransmitters, and multiple mechanisms. The same with antihypertensives. The same with antidepressants. Another distinguishing feature of some of these new therapies is that they have specific neurochemical targets or anatomical targets in the case of neuromodulation. We’re going after targets that have been identified as mechanisms of migraine and treating them with therapies that are much more specific to the target than previous therapies we had available.

 That’s a good overview. It’s interesting. The specificity of these targets is unique. It’s very special. It’s what makes some of these newer drugs have fewer adverse effects, which is a unique place for them. Sometimes, though, the broader action of older medications is important as well. We have to remember that. If a patient isn’t responding to an extremely specific model, sometimes we have to go broader.

Chris, I wonder what you think of that. You’re nodding. If you have a patient who’s not responding to a more specific model, do you go back to something that’s older, thinking maybe they need a more broad-acting molecule?

 Absolutely. That speaks to what’s fascinating and exciting about the era we live in. We have an opportunity to test these hypotheses where we know that CGRP is an intrinsic part of the migraine process, and cluster headaches as well, as far as we can tell. Having a probe that allows us to say, “Is CGRP modulation sufficient for this patient?” is a remarkable place to be and not something we had before. Sure, lots of people respond well, but if they don’t, then you’re exactly right. I say, “There’s more to this pharmacologically than we hoped or that we can play with.” I look forward to the emerging treatments in the future that will allow us to have other specific probes so that we can start to tease apart what makes up a profile of migraine in pharmacological and physiological terms.

I have…old agents and CGRP drugs, CGRP therapies, and Botox. Now we have some fascinating basic science that helps us understand why CGRP-targeted therapies in Botox would be predictably synergistic. It’s an amazing era to live in to be able to understand and see the results of combinations like that.

 Very interesting. Thinking about patients being, as Stephanie [Nahas-Geiger] said earlier, these are snowflakes in that they’re individuals. Think about our drugs as being individualistic, try to match that idea in our treatment plan.

An introduction to the use of novel agents for preventive migraine therapy.