Anti-CGRP Migraine Treatments: Your Questions Answered
Understanding fremanezumab (AJOVY™), the latest FDA-approved treatment for migraine
In a big win for the migraine community, fremanezumab (AJOVY™), was recently approved by the FDA for the treatment and prevention of migraine. 2018 was a landmark year for this new class of treatments specifically designed for migraine. The FDA approved the first monoclonal antibody, erenumab (Aimovig™) in May 2018. Clinical trials for both treatments found them to be effective at reducing headache frequency with few side effects.
In a recent Facebook Live hosted by the American Migraine Foundation, Dr. David Dodick, Chair of the American Migraine Foundation and Professor of Neurology at the Mayo Clinic Arizona, discussed the latest CGRP developments with the migraine community and answered questions about the two FDA-approved treatments for migraine. Read on for his responses to audience questions:
What is the difference between erenumab and fremanezumab?
The most important difference, from a biological standpoint is that fremanezumab targets the protein, erenumab targets the receptor. So, they have different targets. Practically speaking, they are both delivered as a single subcutaneous injection, or fremanezumab can be delivered as three injections once every three months. Their target is different, and that is something that I think is important, because it may be because their target’s different one antibody may be effective, whereas another may not be. That would be great for patients who don’t respond to one, if they can respond to another.
Could fremanezumab be a replacement for erenumab and vice versa?
Erenumab targets the receptors, whereas fremanezumab targets the protein. It is possible that if patients don’t respond to erenumab, they might respond to fremanezumab or vice versa. We don’t know whether that is going to be the case. But I’m cautiously optimistic that if history teaches us anything, it’s that rugs in the same drug class can be effective in different people.
How long does it take erenumab to take effect? Two months have passed, and my migraine attacks still persist.
Typically, patients in the first two months will notice even a partial response, and that response will grow over time. If after three injections there’s zero response, then it’s not likely to work.
If a 70 milligram dose of erenumab didn’t work, would it benefit patients to get a 140 milligram dose?
It’s too early to tell yet, but there may be some patients who respond to a higher dose. So, I would say that if you’re getting a partial response, or no response in the first month, or two, it’s absolutely worth it to bump up the dose to see if 140 milligram will work. While the two doses didn’t separate in the pivotal trials, there’s some evidence in subgroup analysis that the 140 milligram dose may be more effective. Before someone has considered a treatment failure, I would want to see if they failed on the 140 milligram dose as well.
What symptoms can anti-CGRP treatments alleviate?
Looking at some post-hoc analysis of the fremanezumab database, it seems that these antibodies actually provide crystal-clear days. On days when you’re not having a migraine headache, it seems to improve quality of life, performance and wellness.
It may be that these antibodies clear up some of these non-headache symptom, like dizziness, brain fog, trouble concentrating and sensitivity to light. Some early indicators would seem to suggest that people feel better on days when they have headache, but also better, and clearer, on days when they don’t have headache.
Can patients expect constipation or other side effects with erenumab?
Constipation occurred in about 2-3% percent of people exposed to erenumab in the clinical trials. That’s a pretty low percentage. It may be higher, though, in clinical practice for a variety of reasons. One is that if people are on the drug for a longer period of time, constipation may become more obvious. Another is that if you’re on other medications that causes constipation this may augment, or amplify the constipation.
Generally speaking, it’s mild, and it can be easily overcome with dietary modification or laxatives. The exact prevalence of it will remain to be seen.
Can the new anti-CGRP medications get patients off other preventive treatments?
Most of the patients that I’ve certainly treated so far are already on preventive medications, and I’ve added erenumab to whatever medications they’re already taking. People who get a significant response are then able to come off their preventive medications, and I have several examples of that already where patients really responded well to erenumab. It’s early, but in the patients that I’ve seen there’s no withdrawal, or rebound effect of coming off of those oral preventive medications.
When should patients seriously consider anti-CGRP medications?
That’s going to be decided in large part by insurance companies. If history tells us anything, patients will likely have to fail two, or more oral preventive therapies before they’re able to become eligible for these treatments.
What are the out-of-pocket costs for these drugs?
These drugs are priced identically: $6,900 per year, or $575 per month. For erenumab, you get two months that are free. There’s also a bridge program where you can continue to get the drug for free, or for a reduced cost until your insurance carrier covers the treatment. For fremanezumab, it appears that there is a zero copay for qualifying patients up until December 31. Both drugs have incentives to allow individuals to try these treatments to see if they’re going to be effective for them.
What are the long-term concerns about blocking CGRP?
CGRP is a potent vasodilator, meaning it dilates blood vessels. One of the concerns was that people who have cardiovascular risk factors, or people who are having a heart attack or stroke, would be unable to compensate for that lack of blood supply by dilating other blood vessels. That concern has been somewhat alleviated by an erenumab study. The study took patients with coronary artery disease who developed chest pain when exercising and exercised all these patients on the treadmill, gave them either intravenous placebo, or intravenous erenumab. It saw no difference in the time taken to develop chest pain, or in the time taken to develop changes on their EKG. There was no difference between the two, and nothing happened to these patients. These patients had significant coronary artery disease, and some of them have had bypass surgery, or some of them have had angioplasty and stenting. That was relatively reassuring.
Is there a chance of immunogenicity with fremanezumab?
Yes. By immunogenicity, I suspect you mean the development of antibodies to the antibody itself. It doesn’t seem that when you look at those patients that it causes any more side effects, nor does it appear to actually neutralize the effectiveness of the antibody. But, we’re talking small numbers, fortunately, of patients who develop these antibodies. It’s important to note that these drug antibodies that develop can be transient. Thus far, there’s no question that antidrug antibodies can develop with any of these antibodies. But the extent to which it limits the effectiveness, or causes more side effects, doesn’t appear to be the case, at least in the small numbers who have developed antidrug antibodies in the clinical trials.
Can these treatments aid with intractable migraine?
We’re tending to use these treatments in some of our most treatment-resistant patients, or in patients who have failed to respond to many different treatments in the past. Surprisingly, the responses that we’re starting to see in clinical practice, even in these treatment-resistant patients, seem similar to what we were seeing in the clinical trials. So, if someone has had a very bad experience, and has been on a very long road of trying one drug after another, and either failing to tolerate, or failing to respond, I think that’s the perfect candidate for treatments like these.
Do anti-CGRP medications work for medication-overuse headache?
Yes, they do. They’ve never been formally tested in medication-overuse headache, but a substantial proportion of the patients in the chronic migraine studies for all of these antibodies were using acute medicine more than 10 days per month. There doesn’t seem to be any difference in the response for those patients compared to those who weren’t using acute medicine at a very frequent level. They do appear to be effective in people who are “overusing” acute medicine. Dedicated trials in patients with medication overuse headache are still something that’s needed, and I hope that those are done in the future.
Can anti-CGRP medications treat migraine with aura?
We believe aura begins at the cortical surface of the brain, and these monoclonal antibodies appear to work outside the brain. About a third of the patients in these clinical trials had aura. Patients who had a significant reduction in their migraine frequency not only had a reduction in the frequency of migraine attacks that weren’t associated with aura, but they also had a reduction in the number of attacks that were associated with aura. It does appear that erenumab and fremanezumab could be effective in people with migraine with aura.
Whether or not that extends to people who have hemiplegic migraine, or migraine with brainstem aura, or a vestibular migraine will remain to be seen. None of those patients were actually included in the clinical trials. It’s going to take time and experience in clinical practice to know whether or not these antibodies are going to be effective in people who have more complicated or intense aura. Certainly my experience in clinical practice seems to suggest that these antibodies can be effective and are effective in people who have aura.
Can it work with hemiplegic migraine?
Time will tell. It seems to work in patients with simple visual aura. Whether it works in patients with hemiplegic migraine, or basilar, or a migraine with brainstem aura, or vestibular migraine remain to be seen. I’m cautiously optimistic, however, that it will be beneficial.
Will the use of narcotics negate any effect?
We discourage narcotics because of the propensity to develop medication-overuse headache, but narcotics may neutralize the effects of preventive drugs and the monoclonal antibodies. If narcotics are being used, because all other options have been exhausted with regard to acute therapy, they should not be used more than once per week.
In the clinical trials, in fact, they excluded patients who used on average a narcotic more than one day per week, because of that very reason. So, it’s possible if the narcotic, or opioid, is being used more than one day per week, it could be neutralizing the effect, and not giving erenumab a fair chance to work.
Can Botox be used alongside erenumab and fremanezumab?
Fremanezumab has been shown to be effective in people who have failed Botox. If Botox is only causing partial relief, or a suboptimal benefit, then fremanezumab or erenumab can be used in conjunction with Botox. There’s no indication that there’s a safety concern when both are combined.
I’m not certain that insurance companies will cover both treatments, which are obviously more expensive than oral generic medications. It remains to be seen whether or not these antibodies can augment the effectiveness of those who are getting a response from Botox, whether or not the side effect profile is any different, and whether or not people will be able to stay on both if for no other reason than insurance may not cover it.
Can you take propranolol and erenumab simultaneously?
Yes. If you’re on a migraine preventive treatment and it’s providing some benefit, I don’t see any reason why you can’t add erenumab or fremanezumab to those oral preventive medications. An advantage of these antibodies is that they’re not metabolized by the liver, or excreted in the kidney. There shouldn’t be any drug-to-drug interactions, so adding these on top of medications that are already providing a little benefit is definitely a possibility.
Can anti-CGRP medications block the triptan effect?
No, in fact, in my experience, and in the clinical trials, triptans work just as well, if not better in patients on erenumab so far. Erenumab actually may enhance the effect of triptans.
Do triptans work on serotonin and monoclonal antibodies on CGRP?
Triptans do bind to serotonin receptors, but it so happens that when triptans bind to serotonin receptors, and the trigeminal nerve, they inhibit the release of CGRP in addition to other neuropeptides as well. So, actually both work on CGRP, but via different mechanisms. Triptans act through serotonin receptors that inhibit the release of CGRP, monoclonal antibodies act directly on CGRP, or its receptor.
What do you think of monoclonal antibodies in the treatment of migraine comorbidities?
I’m certainly hoping that these monoclonal antibodies might be effective in other functional pain syndromes that affect some of our patients, like fibromyalgia and irritable bowel syndrome in particular. Those, of course, weren’t evaluated in the clinical trials, so it’s going to be up to clinicians and patients in practice to take note of the effect of these antibodies in some of these other chronic pain conditions.
How can companies be better incentivized to include a wide array of patients in trials?
One of the things is that the patients in whom were using these antibodies initially are not generally the patients that were studied in the clinical trials—particularly with regard to treatment refractoriness. The patients that I’m treating, and that many of my colleagues are treating, are patients who have failed multiple preventive therapies, and multiple non-pharmacological therapies, and multiple neurostimulation therapies.
So, these are truly treatment-resistant patients. These were not the patients that were studied in clinical trials. For example, patients with significant cardiovascular, or cerebrovascular disease who have had heart attack, stroke or other significant liver disease, were not included in these clinical trials.
In the days following Dr. Dodick’s Facebook Live with the migraine community, Eli Lilly and Company announced that the U.S. Food and Drug Administration approved galcanezumab (Emgality™) for preventive migraine treatment in adults. For more information on galcanezumab, the third anti-CGRP treatment on the market, and breaking news about migraine research and treatment, visit our resource library.
Knowledge is a powerful tool for migraine management, which is why it’s important to stay up to date on news and the latest research. The American Migraine Foundation maintains a comprehensive resource library full of fact sheets, toolkits and advice sourced directly from the nation’s leading migraine specialists, and distributes a monthly newsletter with the latest migraine news you need to know. Visit AMF’s website to learn more and to find a headache doctor near you.