Unprecedented Efficacy of CGRP Inhibitors for Migraine
Experts discuss the use of monoclonal antibodies targeting calcitonin gene-related peptide as preventive therapy for migraine and the encouraging efficacy of these agents, as well as results in clinical practice that appear to surpass those seen in the phase 3 trials.
Stewart Tepper, MD; Stephen Silberstein, MD; David Dodick, MD; Peter Goadsby, MBBS; Jessica Ailani, MD
Stewart Tepper, MD: In all the studies regarding fremanezumab, eptinezumab, erenumab, and galcanezumab—in the population of patients studied, whether episodic or chronic—they separate it from placebo effects within a week. They all showed meaningful clinical benefit within a month. There was not a titration necessary. All of them showed reductions in mean monthly migraine days, by the time a year elapses, at really unprecedented levels. For example, in a placebo-controlled trial, for a year with eptinezumab, 54% of the patients had at least a 75% reduction in their mean monthly migraine days at a year. So that’s a level of efficacy that we’ve never seen before, and it’s a standard that we’ve never used before for our migraine medicines when we’re talking about less than half having a 50% reduction.
Stephen Silberstein, MD: What was the therapeutic gain?
David Dodick, MD: I don’t remember.
Stephen Silberstein, MD: Here’s the point. You’re absolutely correct. We once did a study of an injectable neuroleptic, and our placebo response rate was 60%. And one of the things, when we compare all these antibodies, is the following: When the efficacy is high, so is the placebo response rate.
Stewart Tepper, MD: But it turns out, Steve, that the more previous preventive agents these patients have had, the lower their placebo response rate….
Stephen Silberstein, MD: I’m not disagreeing with you. What I’m saying to you now is you do the analyses and you compare every single monoclonal antibody, which, I hate to say the word in public…they’re more alike than similar. And if you analyze the data and you compare it with, for example, topiramate or botulinum toxin, they’re very similar.
What I think we need to realize is the following. Insurance companies are going to demand, and they do demand, that you fail 2 drugs before you get them, just like with Botox. Some are requiring 3; some crazy people even require a triptan. So I don’t think it’s going to be the older drugs versus the newer drugs. We have patients who are going to have to fail on the older drugs, and we’ve got tons of patients like that. We have a brand-new therapeutic option, which will work even if the old drugs don’t work, and that’s what’s amazing.
Peter Goadsby, MBBS: And interestingly enough, in the patients with chronic migraine, it’s nothing about expectations. The chronic migraine placebo rates for the subcutaneous medicines—fremanezumab, erenumab, galcanezumab—are lower than the placebo rates in the Botox preempt trials or in the chronic migraine topiramate study, taking with liberty this study that shows that between 2 and 4 previous classes of failure have low placebo rates than patients if you look at them broadly speaking in patients who haven’t had other treatments.
What really encourages me is clearly the people who need something, those who failed previous things, are the ones who are going to do really well.
Stephen Silberstein, MD: That’s very important.
Stewart Tepper, MD: And high therapeutic gains.
Stephen Silberstein, MD: We were under the false belief that failing on the other drugs would make a trial impossible. We now learn it’s opposite—patients who fail more drugs have less placebo response rates, but they still respond, and they can separate it from placebo easier.
David Dodick, MD: Let me challenge you on 1 thing.
Stephen Silberstein, MD: Sure.
David Dodick, MD: There’s the business of therapeutic gain. I think it’s meaningless in clinical practice. I pay no attention to it whatsoever.
Stephen Silberstein, MD: You’re 100% correct. I’m talking about clinical trial methodology. For example, the best drug I want is a drug with a placebo response rate. And that’s the problem with the ICER analysis. They only look at the separation from active drugs from placebo, and more important than that, they assume it’s like a cardiac medicine, where you take it for 10 years and you’ve got to do it. If a patient doesn’t respond to a migraine preventive medicine, they’re going to stop taking it. So it’s not the entire population initially treated; it’s only the responders. And in real life, what we care about is how well the patient does, not how much is placebo and how much is active drug.
David Dodick, MD: I just think the take-home message for clinicians should be to look at the magnitude of the response and use that to determine whether or not that’s going to be meaningful to you and your patients.
Stephen Silberstein, MD: A hundred percent correct.
David Dodick, MD: Because inevitably what happens is you not only mirror that magnitude of response, but you’re better than it. The reason is you’ve taken placebo off the table. So the patient’s not wondering, Do I have a fifty-fifty chance of getting a placebo, number 1. And number 2, you’re doing more things for the patient. You’re not just writing a prescription, right? So I think actually we do better in clinical practice than the results we get in clinical trials. So my advice to clinicians is use the magnitude of the response when you determine clinical benefit and not look at 1.8 or 2.2 or 2.4 days and the difference….
Stephen Silberstein, MD: I agree with you 100%, and you and I have written letters to ICER complaining about it. But the only reason I brought up the therapeutic gain is if you look at all the antibodies in the absence of head-to-head trials, my only point was, look at the difference in therapeutic gains. And that was the point. So you can’t say one is better than the other.
David Dodick, MD: No, no, no.
Stephen Silberstein, MD: That’s what I was using, David.
David Dodick, MD: Yeah.
Stephen Silberstein, MD: In real life, I don’t care about therapeutic gains. In real life, I want to know how well my patients are going to do.
Stewart Tepper, MD: I want to say 1 thing about what David just said. So this is a request to my colleagues, my neurology colleagues. Look at the drop from baseline. So if one looks at patients who took erenumab for a year for chronic migraines, the drop from baseline was 10 migraine days per month. Ten migraine days per month times 12 months. That’s 4 months of no migraine per year that these patients got with erenumab, who stayed on it for a year. And there are comparable numbers for the others. I’m not saying one is better than the other. But the magnitude of this effect is huge, and I really believe it is unprecedented.
Stephen Silberstein, MD: We’re not disagreeing with you, I think, for 2 reasons. One, the shots are given, which means that compliance is a 2, the adverse effect profile is wonderful. There’s no disagreement about that. And I think that people who say topiramate or beta-blockers versus antibody are missing the story. Because it’s not one or the other; one is a precursor.
Jessica Ailani, MD: Well, not only a precursor, but I want to bring up the point of layering. Going back to the chronic migraine patient, 50% or 60% reduction still leaves them an episodic migrainous. There are a lot of days on there, and sometimes a single agent is not enough. And so we have evidence in these trials that if we combine medications that are safe, that can potentially get greater efficacy. So I think that’s an important feature, but we should think about layering and combining different methods of treating patients.
Stewart Tepper, MD: I think that’s a good point.
Stephen Silberstein, MD: The majority of my patients with antibody are layered. And I think what you’re hearing today is, these are wonderful new medicines. But it’s like an epileptic patient. They’re on an antiepileptic drug; the seizure comes under control. You don’t stop it; you layer. And I think that’s where we’re getting in migraine.