Stewart Tepper, MD, on Erenumab as a Game-Changer for Chronic Migraine With or Without Acute Medication Overuse

In this video, Stewart Tepper, MD, from the Dartmouth Geisel School of Medicine, discusses the findings from his recent trial, “Long-term efficacy of erenumab in chronic migraine (CM) patients with or without acute medication overuse (AMO),” and how erenumab has changed the way he practices. This trial was featured in the 2020 American Academy of Neurology Science Highlights.



Stewart Tepper, MD, is a professor of neurology at the Dartmouth Geisel School of Medicine and director of the Dartmouth-Hitchcock Headache Center in New Hampshire.

Disclosures: Dr Tepper has received grants for research (no personal compensation) from the following: Alder, Allergan, Amgen, Biohaven, Dr. Reddy’s, ElectroCore, Eli Lilly, eNeura, Neurolief, Novartis, Scion Neurostim, Teva, Zosano.

Dr Tepper has received honoraria for serving on Consultant and/or Advisory Boards for the following: Acorda, Aeon, Alexsa, Align Strategies, Allergan, Alphasights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, Charleston Labs, CRG, Currax, Decision Resources, DeepBench, Eli Lilly, eNeura, Equinox, ExpertConnect, GLG, GSK, Guidepoint Global, Healthcare Consultancy Group, Health Science Communications, Impel, Lundbeck, M3 Global Research, Magellan Rx Management, Marcia Berenson Connected Research and Consulting, Medicxi, Navigant Consulting, Neurolief, Nordic BioTech, Novartis,  Pulmatrix, Reckner Healthcare, Relevale, Revance, SAI MedPartners, Satsuma, Scion Neurostim, Slingshot Insights, Sorrento, Spherix Global Insights, Sudler and Hennessey, Synapse Medical Communications, Teva, Theranica, Thought Leader Select, Trinity Partners, XOC, Zosano.

Dr Tepper receives a salary from Dartmouth-Hitchcock Medical Center and the American Headache Society.

Dr Tepper has stock options with the following: Nocira, Percept

Dr Tepper has received CME honoraria from the following: American Academy of Neurology, American Headache Society, Cleveland Clinic Foundation, Diamond Headache Clinic, Elsevier, Forefront Collaborative, Hamilton General Hospital, Ontario, Canada, Headache Cooperative of New England, Henry Ford Hospital, Detroit, Inova, Medical Learning Institute Peerview, Medical Education Speakers Network, Miller Medical Communications, North American Center for CME, Physicians’ Education Resource, Rockpointe, ScientiaCME, WebMD/Medscape.



Dr Tepper: I'm Dr. Stewart Tepper, professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center in New Hampshire. This study is the “[Long-term] efficacy of erenumab in chronic migraine (CM) patients with or without acute medication overuse,” a post-hoc analysis assessing outcomes using different definitions of remission.

Neurology Consultant: What prompted you to conduct this study on the long-term efficacy of erenumab in patients with chronic migraine with or without acute medication overuse?

Dr Tepper: The question as to why we do a study of safety and tolerability long-term is that from a regulatory standpoint, when new classes of medications are invented and then tested in the regulatory trials, the FDA requires randomized controlled trial data and then a safety and tolerability extension, in which there may be a pre-specified number of patients who are given the medication in an open pattern for a year and, in the case of erenumab, there was a 1-year open label chronic migraine study after the randomized control trial, and there was a 5-year open label extension for episodic migraine patients.

The next issue is that, going into the chronic migraine group, the kinds of patients that we see in practice and the kinds of patients who generally receive monoclonal antibodies for migraine prevention and who have chronic migraine are often the patients who are in rebound, who have acute medication overuse or medication overuse headache. So, it was very important for us to take a look at the population of chronic migraine patients in the randomized control trial and then in the open-label safety extension trial and pull out the patients that were in acute medication overuse and compare them to the patients who had chronic migraine who were not in medication overuse, and see how they did. And, 40% of the patients who entered the study with chronic migraine at the beginning of the randomized controlled trial had acute medication overuse, which is not uncommon in regulatory trials of chronic migraine.

The purpose of this subset analysis was to compare those who came in with acute medication overuse with those who did not, and also see what happened to the patients with acute medication overuse over time, when given erenumab.

Neurology Consultant: The findings from your study indicated that patients with chronic migraine with or without acute medication overuse who were treated with erenumab had sustained reductions in monthly migraine days, with remission of overuse in at least 70% of cases. Did you anticipate this finding, or was it surprising?

Dr Tepper: Well, we hoped for the finding that patients with medication overuse headache would have a remission based on treatment with erenumab. We knew overall that erenumab caused a majority of patients to convert from chronic migraine to episodic migraine across the 52 weeks, but we really wanted to see what happened to the acute medication overuse headache patients. It was a little complicated, because if one uses the International Classification of Headache Disorders, the Third Edition, the ICHD-3 classification, to get a remission for medication overuse headache requires reduction to less than 15 headache days per month or with a decrease in acute medication use below medication overuse thresholds, but we had study months that were only 4 weeks long rather than 31 days. And so, we had to adjust our cutoff to less than 14 headache days over 4 weeks, and in order to really look at this, we used 3 different remission definitions that the patients would convert to no medication overuse, or they would convert to less than 14 headache days over 4 weeks. So, both of those.

The second one was no medication overuse, and the third one was no medication overuse plus less than 14 headache days over 4 weeks, and it didn't matter which definition. As it turned out, everybody showed about the same result, regardless of the definition, and what was exciting was the point that you made, which was that over 70% of patients remitted from acute medication overuse to non-overuse, which means the majority of patients converted.

And, the other exciting aspect of this was that it didn't matter what they were overusing. We did exclude narcotics and barbiturates, but if they were over using simple analgesics, 81% converted to non-overuse. If they were using triptans, 72% converted to non-overuse. If they were using combination analgesics, 70% converted to non-overuse. And, that's where erenumab differentiated from previous preventive treatments because, for example, onobotulinumtoxinA was able to show a conversion for triptan overusers, but not a conversion for analgesics and combination analgesic overusers. And so, in this case what we were showing was that, if you took somebody with medication overuse headache, chronic migraine with medication overuse, gave them the erenumab, 70% or more were going to convert to non-overuse just by giving them the erenumab and keeping them on it for 52 weeks, and that actually changes the way that I practice.

Neurology Consultant: What does erenumab add to the existing landscape of treatment options for patients with chronic migraine with or without acute medication overuse?

Dr Tepper: That's the point that I was making. In the past, and this is before 2018 when the monoclonal antibodies became available, patients with chronic migraine medication overuse had to have a plan for a wean. So, we would explain to the patient that the medication overuse was associated with the transformation to chronic migraine and probably the propagating of the chronic migraine, and we would plan out how they would wean the overuse medications as we introduced prevention. And, this was true for conventional oral migraine prophylactic medications, even though not one of them is FDA-approved for use in chronic migraine or medication overuse headache, and this was true for onabotulinumtoxinA. So, we would either titrate up the preventive medicines or start the onobotulinumtoxinA, and simultaneously, we would laboriously work out with a patient a wean of the overuse medications to get to a 0 point, switch the acute treatment at that point, and see if we can get the patient over the bridge from chronic to episodic migraine and from acute medication overuse to non-overuse over a period of many months.

With this study, and with further evidence of other monoclonal antibodies such as fremanezumab showing similar results, what we now do in patients who are analgesic overusers, triptan overusers, combination overusers is, we simply put them on the monoclonal antibody, in this case, erenumab. And we let, as I tell my fellows, we let nature take its course, because the likelihood is that over the next year, the medication overuse will take care of itself, will drop as the headaches drop, and the likelihood is that when the patient returns for follow-up, they won't be in medication overuse anymore. If they are, then we can address the wean at that point.

And one other point in terms of the way this changes the way that I use medication: numerically, for all of the outcomes for chronic migraine with medication overuse, looking at in this particular post-hoc analysis, 140 mg looked numerically higher than 70. So, I use 140 mg of erenumab as my starting dose and then watch the acute medication overuse go down.

One final point is that, in one of the other posters presented at AHS, it turned out that if patients started with 70 mg of erenumab and had no response within a month, at that point, it's useful to switch to 140. So, one needs to make the switch to 140 pretty quickly if one is not starting a patient with 140 in order to optimize the likelihood of reversion from chronic to episodic and from acute medication overuse to non-overuse. But, I really can't overstate how dramatic the shift in clinical practice is as a result of these findings.

Neurology Consultant: What direction should future research take after this study?

Dr Tepper: This study was a post-hoc analysis of an open-label extension trial, and the fremanezumab data that were presented last year also were post-hoc analyses. And, I think to really be the currency with which we do evidence-based medicine, it probably is worthwhile to do a prospective randomized controlled trial to look at medication overuse headache, remission as the primary outcome. And my understanding is that at least one of the companies that makes monoclonal antibodies is planning to do a prospective MOH remission study. That would be a good idea. It would add a cherry on top of the sundae.

Neurology Consultant: What key takeaways do you hope to leave with neurologists on this topic?

Dr Tepper: The key takeaway is that this is a time of great change and great hope for the patients that have the most difficult-to-treat headaches, and a lack of success with prior prevention represents not only a difficult-to-treat population, but also a requirement by most payers. So, most payers are requiring a lack of success with prior preventive therapy, and usually it's 2 categories of prior prevention, sometimes it's 3 or 4 categories, depending on the payer. The American Headache Society recommends a lack of success with 2 prior preventions or on a onobotulinumtoxinA.

This post-hoc analysis shows that, if one adds up patients who have had a lack of success with prior prevention, who are in chronic migraine, who are overusing triptans or analgesics or combination analgesics or combinations of all 3 ,and one gives erenumab, the likelihood is 70% or greater that those patients who are really our target patients will remit to episodic migraine and to non-overuse of the acute medications over a year of use of erenumab, and the likelihood is greater if the patients take 140 mg rather than 70 mg.

So, I would encourage my colleagues to take patients who have chronic migraine and acute medication overuse and combination acute medication overuse and lack of success with a couple of previous preventive therapies, and start them with 140 mg of erenumab, and watch the migraine days and acute medications drop over time.

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