Disease-Specific, Mechanism-Based Migraine Treatments: Only The Beginning

Amaal Starling, MD, assistant professor of neurology, divisions of concussion and headache, Mayo Clinic Scottsdale

Amaal Starling, MD

In this 2-part interview, NeurologyLive sat down with Amaal Starling, MD, to discuss her thoughts on the state of headache medicine in light of the newest developments in research and approved therapies. To read part 1 of this interview, click here.

The treatment of migraine has been drastically altered over the last few years. The first disease-specific and mechanism-targeting therapies have begun to enter the market, and a number of neuromodulation devices have offered effective, nonpharmacologic approaches to treatment.

Although, as Amaal Starling, MD, pointed out to NeurologyLive, it’s important for the health care community to realize that this is merely the beginning for the field. Additional therapeutic options are being developed and investigated, and the future holds massive potential to mark another turning point in the care of this disease.

Starling, who is an assistant professor of neurology in the divisions of concussion and headache at Mayo Clinic Scottsdale, spoke to the ongoing developments in the space, diving into what is still to come, as well as what challenges and goals remain to be addressed. As well, she shed light on what she hopes to see at the upcoming American Headache Society Scottsdale Symposium.

NeurologyLive: Are there any ongoing developments that you believe have not garnered enough attention in the migraine and headache space?

Amaal Starling, MD: What's really important for not just headache specialists, but more general neurologists and primary care providers, as well as patients, to understand is that this is just the beginning. That's really important because I've had patients that have come to me or expressed to me that “The CGRP monoclonal antibodies and antagonists—that's the last resort. If those things fail me, then there's nothing else that's going to ever work for me.” That is not true. This is just the beginning of us developing more and more disease-specific, mechanism-based targeted treatment options.

It's important to know that there are phase 3 clinical trials that are ongoing involving other novel targets. One of them is the pituitary adenylate cyclase-activating polypeptide, or PACAP, which is going to be another arena in which we will have monoclonal antibodies, as well as potentially small molecule antagonists that will target that pathway. That's so important to recognize it because of the heterogeneity, from a genetic perspective, of the migraine patient population. It's going to require us to have multiple different mechanisms that we're targeting with our different treatment options. And the CGRP pathway is one of them. The PACAP pathway is going to be another one, and there will be multiple other pathways that are continuing to be identified.

There is a lot of research going on right now looking at different types of neuropeptides and hormones that would impact the origination of where that spontaneous migraine attack starts from. Migraine attacks we've seen imaging studies demonstrate that the hypothalamus lights up first in a spontaneous migraine attack, and we do not have novel targets for the hypothalamus yet. Those are things that we need to continue to develop. As we learn more about a spontaneous migraine attack, we're going to be able to identify those windows of opportunity and identify those novel drug targets, and now we have the technology. Once we identify them, we can create not just a small molecule antagonist for it, but also a monoclonal antibody for it. And that'll have to go through phase 1, 2, and 3 clinical trials, and then will become available for our patient population.

We're not anywhere near the end. We're not even in the middle. We're just at the beginning. And I expect that over the next 10 to 20 years, we're going to have so many more therapeutic options available for our patient population.

What would you consider the biggest challenge remaining in this space despite recent advancements?

Two things come to mind. One is going to be individualized medicine. I dream about the day where based on clinical characteristics or based on other types of biomarkers—such as a blood biomarker or an imaging biomarker or some sort of physiology study biomarker—I will be able to identify which patient is going to respond to which medication. Right now, it ends up being a little bit of trial and error. After I say, “I have all these medications that seemed to work in about 50% of patients,” I have to say, “It is going to be a trial and error to figure out which medication is going to work for you.” But I dream about that day that I can determine based on some sort of objective marker that based on your genetic profile, this medication is going to work for which patients. That this one's not going to work for you and this one's going to give you adverse effects. We're not there yet. But we're working towards it.

The ARMR registry, the migraine registry that the American Migraine Foundation has been supporting, is something that will help with that. It's collecting large amounts of clinical data, imaging data, as well as blood biomarker and genetic data, from large populations of patients that are going to these different headache clinics—not just at Mayo Clinic, but at multiple others, both national as well as international. Once we have all of that data, we’ll be able to do Artificial Intelligence work, looking at kind of big data mining and figuring out what are those predictive markers that will help us determine which medication needs to go to which patient? From a scientific level, I think that that's the next big hurdle that we really need to approach from a clinical and, really, a public health perspective.

The biggest barrier is still the stigma of migraine. And this is the stigma of migraine, not just within the lay public, but also within the patient population themselves. There's a lot of internalized stigma that results from the external stigma that they've experienced their entire lives, as well as the stigma of patients with migraine that exists within the healthcare provider arena as well, amongst primary care providers and general neurologists, that we need to continue to work at. From a public perspective, we need patients to come to see a headache specialist or a neurologist. There are studies that still show that even in people who have chronic migraines, 50% of people aren't even presenting to a doctor about their symptoms because they think that it's just a headache and it's something they just have to deal with. And that's just not true. We have options available for them once they get to the doctor. They need to get the right diagnosis rather than just being told that they have tension-type headaches or stress headaches and they need to just relax more, get a massage, or drink more water. Then after that, we need to make sure that our health care providers not only can appropriately diagnose but apply the standard of care treatment options and refer to a headache specialist when appropriate. On that level, we need a lot more headaches specialists to be available. There are 40 million people in the US with migraine and it's unacceptable that there are only 600 or fewer headache specialists nationally.

With the 2019 American Headache Society Scottsdale Symposium coming up, are there any specific topics of discussion you’re looking forward to exploring with colleagues?

The lovely thing about the Scottsdale meeting is that it's very clinically relevant. It's actually my favorite headache meeting all year. I've been going to it since I was a resident—it is the meeting that got me interested in headache medicine. I went to my first meeting and I thought, “Oh my gosh, these are the people that I want to work with for the rest of my life. And this is the disease state that I want to work on for my entire career.” One of the big things that we're all really interested in is to hear about from all the experts in the field is there are all these different new therapeutic options—where do they fit in the patient journey? Where do the nonpharmacologic treatment options, the neuromodulation devices, the new preventive options, and the new acute treatment options? How are we all going to be thinking about how we incorporate these things into our patient journey? Are they the first, second, or third thing that we're going to recommend? Are we going to use them in combination with other options? Are we going to use them in solely just on their own? I think we're all very, very interested in seeing that. Then another of the things that I'm really looking forward to is seeing the topics regarding advocacy and seeing how we as headache providers, as patients, and advocacy organizations like the American Migraine Foundation, are going to be working on making sure that our patients, as well as headache providers and other medical providers, are advocating for the disease as well as advocating for each other and working on reducing stigma.

Transcript edited for clarity.