S5:Ep3 – Atogepant for the Preventive Treatment of Episodic Migraine
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. Atogepant is FDA approved for the prevention of episodic migraine and is under review, for the prevention of chronic migraine, at the time of publication. Stay tuned as Dr. Cynthia E. Armand discusses the goals of migraine prevention, atogepant clinical trial data, how it compares to other gepant medications, side effects, and more.
Cynthia E. Armand, MD: Good afternoon, everyone. These are my disclosures, none of which are relevant for this talk. Our objectives for today – we’re going to understand the goals of migraine preventive treatment just as a baseline, so we can go on and talk about atogepant. And I’m going to characterize the approaches of migraine prevention. I’m going to review the efficacy and safety evidence behind atogepant for migraine prevention. And within that, talk about indications for use in clinical practice.
So again, goals of migraine preventive treatment. There isn’t a cure, but we want to manage migraine disease because it’s a neurologic disease just as any other disease that we manage. So we want to reduce the attack frequency, severity, and duration. We want to impact the disease progression by doing that effectively by reducing the chances of progression. And by doing that, the baseline for attacks lessen and improve, and so they enhance the responsiveness to acute attack treatment when they do occur. Within that, our ultimate goal is to improve quality of life and reduce disability. And while we do that, there are less resources that are needed for attacks when things improve, and so we lessen the cost and care of escalation.
These are the approaches to migraine prevention. We talk about pharmacologic and nonpharmacologic groups. Today, we’re here in the pharmacologic section. And you see here for decades, we’ve had non-migraine-specific medications. These are categories of medicines that are created for other ailments, and research has been done with their use in migraine, and they’ve shown to be FDA approved and effective and safe, and you see them there. But today we’re honing in on migraine-specific therapy. Research has been so robust over the past couple of years. So we have here calcitonin gene receptor peptide targeting agents. We have the monoclonal antibodies that are available, and today we’re honing in on the small molecule agents.
This is the timeline of FDA approvals that have occurred over the past several years. We see it started in May 2018 with a monoclonal antibody called erenumab. And you see here most recently the medication that we’re discussing today is atogepant with approval in September of 2021, and we know it’s not going to end there, which is pretty exciting. So atogepant it’s a second-generation CGRP receptor antagonist. And you think to yourselves really, second generation? Well actually, before it was developed, there were several other small molecules that were tried in clinical trials, but those were suspended because of safety issues. And atogepant noncompetitively binds the CGRP receptor. It was specifically develop for migraine prevention. There’s another medication on the market called rimegepant that has dual use for prevention and acute therapy. Atogepant is for prevention.
So I wanted to over two trials. This trial is one of the main trials that pushed it forward to FDA approval. It’s the Phase 3 portion of the ADVANCE trial. And it’s a double-blind, randomized, placebo-controlled, about 910 participants – specifically those with episodic migraine. And atogepant’s available in 3 doses. Participants were treated with a daily dose of 10 mg, 30 mg, 60 mg, or placebo. And the primary objective was to look at the change in mean migraine days per month, and this was done across 12 weeks. And as you can see here, those are the results below. You can see the change in mean migraine days per month with placebo at 2.5 days. But you can see the different doses of atogepant that were affected. They were statistically significant. 10 mg at 3 days and you see it escalated as the dose escalated at 60 mg.
There were secondary objectives that were looked at – was looking at whether or not there was a greater than 50% mean migraine reduction across 12 weeks and if there was 100% mean migraine reduction. And you can see the only dose that crossed that endpoint was atogepant 60 mg. The other endpoint that was looked at was whether or not atogepant improved quality of life. And what they did was they had participants keep quality improvement migraine diaries that they recorded activities of quality of life. And you can see here atogepant at 30 mg and at 60 mg crossed that as well.
So really, when we’re looking at these parameters in these clinical trials, how it translates clinically to the chair and bedside is when I’m talking to my doctor about what dose I want to take, we really look at the clinical trials and see which doses crossed certain endpoints. And we talk about why – the rationale behind choosing a certain dose over another. Again, that’s one factor. But that’s a good question, when you’re seeing your doctors, to ask how good is this dose as compared to the others? What did it look like in terms of crossing all of the endpoints within the study? And you can see here the difference between the doses.
So, this is atogepant Phase 3 PROGRESS trial. So the ADVANCE trial that I just showed you looked at episodic migraine. Atogepant is approved for prevention of episodic migraine. This is looking into chronic migraine. You can see here there are over 750 participants. And what they did was they treated participants with atogepant basically 60 mg a day, but the first arm was dividing that dosage into two, so 30 mg twice daily, and the second one was 60 mg a day. And then, of course, you compare that to placebo. We looked at mean migraine day reduction, and you can see the differences between placebo and the difference between atogepant 30 mg twice daily and 60 mg – again, better than placebo. And again, this is something that’s still in progress here in terms of chronic migraine.
I wanted to show you a comparison profile of atogepant as compared to the other CGRP targeting agents we have here. And you can see the first 4 columns are the monoclonal antibodies, and you see the last 2 columns rimegepant and atogepant. And you can see the differences. And again, I wanted to put that here for you because these are what we talk about to our patients as to choosing medications. How many doses are available? What does it look like? Is it oral? Is it IV infusion or subQ injectable? And you can see here atogepant has a half-life of 11 hours; that means how long does it take for half of it leave the system? And you can see it’s fairly similar to rimegepant, and both have FDA approvals.
So I just wanted to kind of put a comparison to the two. Rimegepant is, again, a small molecule. It’s available in one dose, but it’s dosed every other day. The difference between rimegepant and atogepant in that dosing is because in the clinical trials for rimegepant, it showed up to 48 hours of symptom relief and reduction. So that’s the rationale behind the FDA approval for dosing of every other day, and atogepant is a daily dosing. So that’s, again, something to think about in terms of your quality of life of how do I want to take this medication? Do I want to remember this every other day, or do I want to just take something daily and call it a day?
Onto the atogepant safety profile, so you can see here most common side effects that were reported by participants. We have nausea, constipation, fatigue, decrease of appetite, and weight loss. And you can see here, as compared to placebo, the different milligrams and dosages of each of them. Now, in terms of a provider and looking at this, many may tell you the side effect profile across the board is very similar for all of these medications and fairly is the same. These are very low percentages. But as a patient, of course, this is my body – if there’s a percentage there, it’s still a percentage.
So, it’s really important to take a look at this and discuss that with your providers to see what dose would be best for you. Many times many providers may want to start with the 60 mg, again, for reasons that I showed you in the clinical trials, and they may want to go to 30 mg. I talk to my patients because if they have any particular concerns such as constipation, you can see constipation is equivalent across the board. But many of the times we want to go a little slowly and start low at maybe 10 or 30 and start from there and see how they feel. So again, the percentages are fairly similar, but again, because it’s specific to how you feel about taking the medication, really important to have that conversation.
So one of the factors that stopped the earlier first-generation trials was liver function test abnormalities. Because many of these medications are metabolized by the liver, and it’s really important to see if that metabolism is really impacting the health of the liver. In terms of the trials of atogepant, there were no findings of liver abnormalities that they thought were due to atogepant. And so that’s a really important point because many patients have that as a question. In terms of drug-drug interactions, it’s really important to keep an open dialog with all of your providers when you’re on any medication because there are certain medications that can rev up atogepant; meaning kind of make it linger on for a while and enhance the side effects because the metabolism and the breakdown goes much more slowly with the presence of those meds.
Or it can metabolize it even more, and so the length of the half-life of the atogepant is lessened thereby lowering the efficacy. So we call that here CYP3A4; that’s the system that’s breaking down these medications. And so there are certain medications that interact to rev up that system or lower that system. And so you see here most of them are other anticonvulsant medications and then other antiviral medications. So, whenever you see any of your providers, let them know what you’re taking because they want to make sure to do an interaction check to see how the medicine is being impacted.
And simply it might lead to an adjustment. What does that mean? Maybe they’ll tell you, let’s give you a lower dose or take that medicine every other day while you’re on that therapeutic regimen that may interact with atogepant. Atogepant does not interact with acetaminophen, NSAIDs, triptans, or oral contraceptives. Really important point because you would be taking this medication for prevention. And you would need acute therapy if you were to have a migraine attack during that time, so it doesn’t interact with those.
So, with the new medications that have been developed – the monoclonal antibodies targeting CGRP – the American Headache Society had put out consensus statement, earlier in 2021, recommending really how to incorporate these therapies. And sometimes it’s a little bit…my patients tell me it’s a little painful to go by these recommendations because why should I have to go through all these other therapies when there’s this new medication I saw, on television, that can really change my life? And really it’s a combination of two things. It’s a combination of what’s been out there prior to that has long-term evidence in terms of safety? And also, what headache is the insurance company going to give us trying to get this medication because they might need you to kind of take these medications?
So you see here different criteria for starting the newer medications. Basically, the gist of these tables is that they recommend that you would start with preexisting therapies like the oral therapies. Start them or either intolerate or fail them before you move on to the newer therapies. Now, this came out for the monoclonal antibodies. But atogepant, which is a gepant, and rimegepant as well those two medications there hasn’t been a newer one that has been released. But I’m sure with the advent of other therapies, there will be.
The other hot topic question I get is whether or not if I am already on a medication such as onabotulinum toxin A, can I use something like atogepant? Well, there has been studies to show that onabotulinum toxin A and other CGRP-targeting medications work really well together, and they’re synergistic. They can actually help each other achieve migraine prevention. You can see first the study that showed fremanezumab inhibited different pain fibers than onabotulinum toxin A inhibiting fibers. So that is great rationale for attacking the migraine at two different junctions.
There are many other cases studies that show improvement of mean migraine reduction days with monoclonal antibodies targeting CGRP and onabotulinum toxin A. We don’t quite yet have them for atogepant or the other small molecules, but I’m sure that’s there in the pipeline. You can see here there are some animal studies that show that they do impact the trigeminal vascular system neurons, which is the main system of neurons that’s involved in the migraine pathway.
So in summary, we talked about the goals of migraine prevention therapy. Atogepant is an FDA-approved small molecule CGRP receptor antagonist for migraine disease preventive therapy. It’s available in three doses – 10, 30, and 60. You should always talk to your providers about the safety profile and what your concerns are. And ask any other providers starting medications to do an interaction check to make sure they’re safe. And currently, no studies for concomitant use with atogepant and onabotulinum toxin A, but I’m pretty sure they’re not far down the line because providers today are utilizing this therapy in individuals who are already on onabotulinum toxin A. Thank you so much for your time.
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