Cautious Optimism Amid Excitement About CGRP Inhibitors for Migraine Prevention

David Dodick, MD, MS, a neurologist at Mayo Clinic

David Dodick, MD, MS

Despite the game-changing approval of erenumab (Aimovig, Amgen/Novartis) in May 2018, and the potential addition of 2 more agents in the calcitonin gene-related peptide (CGRP) class, there remains much caution regarding the excitement building in the migraine space.

David Dodick, MD, MS, a neurologist at Mayo Clinic who’s been involved with multiple trials of headache medicines, shares this caution. However, he admits that this is still one of the most exciting times to work in migraine medicine, and the future of the disease’s treatment shines very brightly.

To provide further insight into the safety profile of the class and what makes it truly exciting for him, Dodick spoke with NeurologyLive in an exclusive interview.

NeurologyLive: There’s a lot of cautious optimism among headache specialists regarding the safety of the CGRP class. Do you feel there’s enough safety information for long-term use?

David Dodick, MD, MS: The cautious optimism is the appropriate term here. Look, we’ve all had the experience that drugs become approved based on a limited patient exposure. That’s true of any drug, and for rare adverse events that occur, there simply hasn’t been adequate patient exposure to uncover those. We’ve all had the experience that drugs become available, we start using them in clinical practice, and lo and behold, unexpected and unanticipated adverse events come to life. Sometimes drugs are taken off the market, and sometimes the prescribing guideline becomes very restricted based on adverse events that materialize the more patients who are exposed. Cautious optimism is the appropriate phraseology because as I said, there have been over 400 patients who have been on erenumab, for example—they presented this long-term open-label data over a 3-year period of time, and the safety and tolerability appeared to be very good. But that’s not a lot of patients, No. 1, and No. 2, these are patients who got into the clinical trial because they were otherwise healthy patients, and so we’re following healthy patients—generally young healthy patients—over a period of 3 years. What happens when we follow patients who are over 60, over 65, and we follow thousands of them? We follow thousands who have co-existing medical illnesses, is the safety profile going to look the same? We don’t know. Is there a reason to be concerned? No. But is there a reason to exercise caution to be at least cognizant of the potential that unanticipated adverse events might occur? Of course, like with any new drug.

Was there anything between these 3 agents that stood out for you that really makes the CGRP class exciting?

Glass half-empty people might look and say, “Well, the efficacy of the responder rates don’t look that much different than what we see with other treatments we’ve been using for years,” and that’s true. On the other hand, we know that at least with the oral treatments in use for migraine prevention, the tolerability is not very good. Studies have been published showing that over 80% of people who are started on an oral preventive drug for migraine prevention are no longer taking that drug after 1 year. And these are patients who have chronic migraine and have a very large unmet treatment need, who are the most disabled. If the most disabled patients in this group—8 out of every 10—can’t tolerate or don’t respond to these drugs and are not on them after 1 year, that’s a problem.

Now, what excites me about this particular class, and what I think is different, is the fact that it has, by and large, placebo-like tolerability, at least thus far in the clinical trials. Patients are able to adhere to the medication long-term. What excites me about this class is that, for those who do respond, it’s very likely that the tolerability profile is such that they’re able to stay on the medication and they’re able to tolerate it and they might not have any adverse effects. The longer they stay on it, if you look at the 1-year, open-label data for those that are staying on it, efficacy rates climb over time. So, while in 2 months, let’s say, you may have a reduction by 50%. At 6 months, you may be at 75%, and at 12 months you might have had an 80% or 90% reduction. The longer you’re able to adhere to a treatment that’s working for you, the better the patient outcome is over time. That’s the real difference here. We finally have a class that the adverse effect profile looks very good, so if patients are responding they are able to adhere. I wouldn’t expect that 80% of patients, after being started on an antibody, would have discounted at 1 year, which is what we’re seeing with the current class. That’s the real difference. And the fact that for those who GGRP appears to be a very important mechanism, we may see these super-responders. We may see these people for whom there’s just been a dramatic change in the expression of this disease because of the pivotal role that CGRP plays in the biology of their illness.

That being said, what is still left to learn for migraine prevention?

Now, it’s 1 peptide, it’s 1 receptor. We know that there are other peptides and neurotransmitters involved. The disease is not that simple and it’s not going to work in everybody. It’s exciting to see that there are other new targets for which biologics and treatments are becoming at least studied and may become available someday. Hopefully, someday, we’ll have multiple treatments that go after multiple different targets and hopefully one day we’ll be able to work out which target is relevant for which patient—truly individualized medicine and precision medicine—so we can know exactly what treatment to use based on the target that’s relevant in any particular patient. It may be that it’s not even that simple. It may be that multiple targets are involved, and we’ll need treatments that are specific for multiple targets. But, it’s an exciting time. This is truly a breakthrough period for patients with migraine because, for the first time, we have mechanism-based and disease-specific therapies. When I tell a patient that we know enough about the biology of the disease to be able to deliver a treatment that targets 1 protein that’s involved in treating migraine or it’s receptor, that’s a very exciting thing for patients and it’s a very exciting time for providers who look after those patients.

Transcript edited for clarity.