NeuroVoices: Andrew Blumenfeld, MD, on a Combination Approach to Treating Chronic Migraine

Andrew Blumenfeld, MD

It has been hypothesized that a multimodal approach layering treatments that target different pathways involved in migraine pathophysiology may improve outcomes in patients with chronic migraine (CM). Lead author Andrew Blumenfeld, MD, and colleagues conducted a retrospective, longitudinal review of patients with CM who met American Headache Society (AHS) criteria and were treated with 2 or more consecutive cycles of onabotunlinumtoxinA (Botox; Abbvie) followed by at least 1 month of subsequent combination treatment with calcitonin gene-related peptide (CGRP) monoclonal antibody and onabotunlinumtoxinA.

Patients were followed up for a 12-month stretch and evaluated on safety and efficacy outcomes including change in monthly headache days (MHDs) and at least 50% reduction of MHDs from baseline. At the end of the study period, patients showed clinically meaningful responses to the combination treatment approach, with the study authors also concluding that additional real-world and controlled trials should be considered.

As part of a new iteration of NeuroVoices, Blumenfeld, who is director of the Headache Center in Southern California, sat down to discuss his study, which was presented at the 2021 Virtual AHS 63rd Scientific Annual Meeting, June 3-6. He spoke about what prompted he and colleagues to conduct the study, what has been previously observed with this combined treatment approach, and whether the results showed additive or synergistic benefits to patients with CM.

NeurologyLive: What prompted the idea to conduct this study of layered treatment?

Andrew Blumenfeld, MD: I direct a headache center where I predominately see patients with chronic migraine. These are patients who are very disabled, experience frequent headaches, and their headache problem is difficult to control. What we’re constantly looking for are methods of decreasing headache frequency and headache intensity. In many cases with chronic migraine, using a monotherapeutic approach is not successful. This raises the issue of combination treatments.

When you look at combination treatments, what you’re ideally looking for are different mechanisms of action that will potentially work synergistically together. At the same time, you need to look for combinations that are well-tolerated and easy for a patient to take so that they can remain on the treatments long-term. If we look at well-tolerated treatments like onabotulinumtoxinA and CGRP monoclonal antibodies, these don’t have a lot of systemic issues, and they become relatively easy for patients to take. Also, there are injectable treatments given quarterly like onabotulinumtoxinA or monthly for some of the monoclonal antibodies. It becomes easy to adhere to a long-term treatment algorithm.

If you’re doing a study like this, you have to have long-term data because it takes time for medications to work in chronic migraine. You don’t see effects quickly. You want to be able to follow patients for about a year on treatment and then be able to judge them. The way this study was done was to take patients who had been diagnosed with chronic migraine in the clinic setting, randomize them, and then observe the subgroup of those with onabotulinumtoxinA.

These patients had insurance payments for this drug, which required that they have a minimum of 2 or more treatment failures which would allow for their payment to occur. These patients we observed had to have a minimum of 2 onabotulinumtoxinA based cycles 12-weeks apart, equating to 6 months at a minimum on treatment. A majority of them were actually on treatment for many years, not just the 2 cycles. That was just the minimum that was set.

What has previously been observed with onabotunlinumtoxinA in migraine and how have CGRPs affected the paradigm?

When we look back at the data before they got on onabotulinumtoxinA, this population had 20 headache days a month. That is not dissimilar from the pivotal trial data. If you look at the PREEMPT trial for onabotulinumtoxinA approval, the patients had 19 to 20 headache days per month. This is similar to that trial data, but now in a real-world setting. We see an 8-day reduction after they’ve done this minimum of 2 treatment cycles. Now they’re down to 12 days a month of headache.

If you go to the American Headache Society’s guideline on when it’s appropriate to use a CGRP monoclonal antibody, there are criteria that have been set. When you get to chronic migraine, the criteria includes those failing on oral preventives or not doing well with onabotunlinumtoxinA. But in the lower end of the schedule for patients with episodic migraine, if they have 4 or more disabling attacks per month having failed on 2 oral medications, then that would be an appropriate candidate. These patients with chronic migraine are still having 12 days a month of headache, way more than 4. Clearly, there are appropriate candidates for additional treatment based on guidelines.

Monoclonal antibodies came to market in May 2018. The first one to market was erenumab. The recommended starting dose was 70 mg. The majority of the patients that I included in this analysis had erenumab added at 70 mg a month with subcutaneous injection on top of onabotunlinumtoxinA injections which continued every 3 months. We then followed these patients over a year, for 4 additional visits, 3 months apart.

As other CGRP monoclonal antibodies came to market, they were also used in a similar way. We have a wide spectrum across the CGRP monoclonal antibody class, but a majority of the patients were on erenumab and the majority were on the 70 mg dose. On average, we saw an additional 4-day reduction across a full year of treatment. We were at 12, now we’re at 8. That’s interesting because it didn’t go to zero. If it gone to zero, you might have argued that the monoclonal antibody was the driving force that wiped out the headache and you don’t need the onabotunlinumtoxinA. But because, they don’t go to zero, they’re still quite limited. Eight migraine days a month is still a lot, but it’s a lot better than 12.

What were you hoping to observe by undertaking this combination approach?

[That] the combination makes sense. The next question that comes up is, is this additive? In other words, 1 + 1 = 2. Or is this synergistic? 1 + 1 = 3. If it’s synergistic, it would mean that onabotunlinumtoxinA is helping CGRP monoclonal and vice versa. The way we try to evaluate that is by looking back at the pivotal data from erenumab which included a group of patients who failed on at least 2 oral preventives. Very similar population to ours. What we saw in the other study was a 2-day reduction, not 4-days, which was what we found in our trial. This suggest that there might be a synergistic effect.

If you look at some of the work Rami Burstein, PhD, has done, he’s shown that CGRP is release predominately from C fibers in the trigeminal nerve. That release binds to blood vessels, but also bind to delta fibers in the trigeminal nerve. OnabotunlinumtoxinA has been shown to decrease the release of GCRP from the C fiber. Erenumab blocks the receptor on the A delta fiber. Now, you’re hitting that pathway in 2 differnet locations, and that allow for synergism. There’s a mechanistic basis, and if we follow the data, a suggestion of synergistic basis. Clearly, more studies are needed to look at this combination. But you have to start somewhere. At the moment, this real-world data with a relative population of over 200 patients, allows for the design of prospective studies to look at this more in detail.

Transcript edited for clarity. For more coverage of AHS 2021, click here.

REFERENCE

Blumenfeld A, Frishberg BM, Schim JD, Hughes O, Manack Adams A. Real-world evidence for control of patients with chronic migraine who received calcitonin gene-related peptide monoclonal antibody therapy added to onabotunlinumtoxinA treatment. Presented at 2021 AHS Scientific Annual Meeting; June 3-6. Abstract P191.