S4:Ep6 – Eptinezumab for Migraine Prevention



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.

Vyepti, or eptinezumab, is the first and only FDA-approved intravenous treatment for migraine prevention. Neurologist Dr. Stewart Tepper describes how eptinezumab works and who could benefit from it the most.

Dr. Stewart Tepper: Hello, I’m Dr. Stewart Tepper. I’m a professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center. And I’m going to talk about eptinezumab for migraine.

Most people with migraine have as the cause of their migraine the release of a chemical, calcitonin gene-related peptide, which is abbreviated CGRP and which has become a target for our treatment of migraine. What happens in migraine is that the brain turns on a signal that goes out to the coverings of the brain, to the meninges, and CGRP is released. And it causes blood vessels to enlarge, it causes inflammation, and that is the cause of the pain of migraine. And you can see that in the picture in the upper left. 

The CGRP-caused mechanisms of pain can be stopped by getting rid of CGRP, and that’s why a group of medicines has been developed to try to get CGRP out of the picture.

Eptinezumab is a monoclonal antibody against CGRP. The brand name is Vyepti. And monoclonal antibodies are large molecules that do not penetrate the brain, and they are eliminated by a system called the reticuloendothelial system. They don’t go through the liver and kidney, so they don’t cause liver or kidney problems. And because they’re so targeted — eptinezumab just against CGRP — they don’t interact with other medications. Therefore, monoclonal antibodies have a lot of advantages for our patients. 

Eptinezumab was designed to very strongly bind to CGRP. Eptinezumab is the monoclonal antibody that’s shown here in lavender, and the CGRP is in turquoise. And you can see that the monoclonal antibody grabs that CGRP, puts it into a deep pocket, and holds it there so that it can’t cause the mechanisms of migraine.

Eptinezumab was designed to very specifically bind to the CGRP and to bind it strongly, which is called a high affinity. That strong binding — which you can see at the bottom in that yellow-to-red arrow, with the red being where eptinezumab sits — that strong binding means that the eptinezumab doesn’t let the CGRP loose, doesn’t drop the CGRP, and that results in a long duration of action. It works for a long time, and it only needs to be given by an intravenous or IV treatment every three months because it binds to the CGRP so strongly and takes it out of circulation.

Because eptinezumab is an intravenous treatment, it works very rapidly. And what happens is eptinezumab is given over about a half an hour by IV, and at the end of that half an hour, all of it is available to be of benefit in the blood and in the nervous system, and it reaches the maximal blood level by the end of the infusion, by 30 minutes. So eptinezumab works very rapidly in terminating — or preventing migraine. It is approved by the FDA for the prevention of migraine.

The FDA requires what are called pivotal trials. These are trials where placebo is given or eptinezumab is given over periods of time. And there were two trials for eptinezumab, Promise 1 and Promise 2, that led to the FDA approval.

Promise 1 was a year-long study. Several doses of eptinezumab were given; the FDA approved 100-milligram and 300-milligram doses. And you can see on the left that half the patients got eptinezumab and half got placebo. And the mean age of people in the study was about 40, and 80 percent of the people that participated were women. 

And, very importantly, the average number of migraine days per month for people with episodic migraine in the study was about eight migraine days per month. Remember that episodic migraine is — people with episodic migraine have less than 15 headache days per month. So, in this study, it was eight days per month.

Promise 2 study was a chronic-migraine study. It was six months in duration. The average number of migraine days per month was 16. Remember, the patients had to have at least 15 migraine days per month. Again, the average age was about 40. Again, more than 80 percent of the people that were involved in this were women. And, again, it was placebo controlled, where half the people got placebo and half got eptinezumab.

And, after the first dose, the eptinezumab worked very well for both episodic and chronic migraine. If you remember, the average number of migraine days per month in the chronic-migraine group before they got treated was about 16 migraine days per month, and the eptinezumab reduced that by about eight, so cut in half the number of migraine days per month. 

Same thing for episodic migraine. With episodic migraine, the average number of migraine days per month before treatment was eight, and the drop was about four. So, in both episodic and chronic migraine, the eptinezumab significantly reduced the monthly migraine days.

Remember that I mentioned that the eptinezumab reaches a maximal concentration very rapidly, within 30 minutes. And so the question was, How fast does it work? What was done in these studies was to evaluate what the likelihood was of a migraine in any given day before the patient was treated with the eptinezumab, so in the month before the study. And they calculated what the likelihood was of a migraine in any given day, then they gave the eptinezumab or placebo. And what they found was that within 24 hours of the infusion, the likelihood of a migraine day was reduced by more than half, and this was for both episodic and chronic migraine. Eptinezumab works really fast, and it drops the likelihood of a migraine for the next day very rapidly.

The monthly migraine days go down very rapidly, as I pointed out, within the first day, within the first month. And they stay reduced as somebody gets eptinezumab every three months. You can see here, they got the eptinezumab at the upper left where the gray ball is, and then at three months, they got a second dose. And the chronic migraine, eptinezumab is in red, and the episodic migraine, eptinezumab is in blue, and the gray is the placebo. And there was a very dramatic drop in the monthly migraine days for both episodic and chronic migraine, and it stayed good across six months. So works fast, lasts a long time.

One way to look at how well people do, what percentage of people do well, is called a responder rate. And that’s the percentage of those with a particular percent of monthly migraine decrease, and let me explain that. So what we’re interested in is what percentage of people would have at least a 50 percent drop in monthly migraine days. And the answer was pretty amazing.

If one looked across the year, in people who received eptinezumab 300 milligrams, almost 70 percent of them had at least a 50 percent decrease in their monthly migraine days. Almost 70 percent of people treated with 300 milligrams of IV eptinezumab every three months had at least a 50 percent drop in their monthly migraine days. 

If you raise the bar even higher and you ask what percentage of people have at least a 75 percent drop in their monthly migraine days — because a 75 percent drop is linked to having a lot less impact on day-to-day life — the answer is that for 100 milligrams for chronic migraine, after a couple of doses, almost 40 percent of people had at least a 75 percent drop in their monthly migraine days and over a third for the episodic people had at least a 75 percent drop in their monthly migraine days.

But, remember, the study on episodic migraine went on for a year, and at the end of a year, more than half the patients treated with 300 milligrams of eptinezumab had at least a 75 percent drop in their monthly migraine days. And these are unprecedented responder rates and suggest that these monoclonal antibodies really are a change in how we should be treating patients with migraine.

You could also ask, What about people who get 30 days in a row of no headache at all? That’s called a 100 percent response rate. They may get a headache the next month, but they still got 30 days in a row of no headache. And if one looks after a couple of doses, 17 — almost 18 percent of people who were treated with a lower dose of eptinezumab had 30 days in a row of no headache, and almost a fifth of the patients who received 100 milligrams of eptinezumab who were treated for episodic migraine had at least 30 days in a row of no headache.

And the likelihood of getting 30 days in row of no headache keeps going up across the months, as you can see, and that continued in the study, which is why I tell my own patients that I want them to stay on this for at least 6 to 12 months to really see what is the percentage of migraine days they are left with. How much does it drop? Do they get 30 days in a row?

Eptinezumab is extremely well tolerated, and almost nobody gets any side effects with it. If one looks at the side effects in over 2,000 patients in these pivotal trials, the biggest side effect, the one that occurred in at least 2 percent of people who got eptinezumab and over 2 percent more than placebo was a runny nose or a sore throat. And in all the patients I’ve treated with eptinezumab, I’ve only seen a couple of them get that runny nose. 

So it’s pretty well tolerated. You can be allergic to it, but it’s very rare. Most people have no side effects whatsoever when they are treated.

Because eptinezumab is so fast in its action and because we’re getting more and more medications that seem to work to prevent migraine and to be used acutely, eptinezumab was studied for the acute treatment of migraine. Now, remember, it’s FDA approved for the prevention of migraine. But this was a study in which eptinezumab 100 milligrams or placebo was given in an emergency room or in an office to people within one to six hours of onset of episodic migraine to see if it would actually make people pain free within a couple of hours or give relief within a couple of hours.

And you can see the pain freedom at two hours was 23.5 percent. It eliminated whatever was most bothersome for people: nausea, dislike of light, or dislike of noise. Within two hours, it gave relief and it reduced the amount of rescue medicine that people needed. So eptinezumab works so rapidly, it does have an acute effect, although it’s not approved for that.

And on the right, you can see that the time to the next migraine in the eptinezumab group was delayed after the people received their eptinezumab, and, of course, that’s because the eptinezumab had a preventive effect as well as an acute effect. The difference between acute and preventive medicine is slowly narrowing, and eptinezumab appears to work both acutely and preventively.

So, in conclusion, eptinezumab is the only available anti-CGRP monoclonal antibody that is used as an intravenous quarterly infusion, in either 100-milligram or 300-milligram doses. It binds to CGRP tightly, and it lasts a long time, has a prolonged benefit, which is why it only needs to be infused quarterly for migraine prevention. 

The onset of effect is noted within 24 hours of administration, with a decrease in the likelihood of migraine by more than 50 percent for that first 24 hours after giving it for both episodic and chronic migraine. The speed of onset was studied in a study measuring whether the medicine had acute benefit for migraine, and it worked both acutely and preventively.

The side effects have been minimal, it’s very well tolerated, and the responder rates are very high, with more than 50 percent of patients having at least a 75 percent reduction in monthly migraine days by one year at the 300-milligram dose.

So this is a very effective monoclonal antibody that we’re using more and more in our practice, and I thank you for your attention.


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

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