Understanding Early CGRP Therapy Initiation in Migraine Treatment

Featuring Lucy Myint-Wilks, BMBS, MSc, MRCS (ENT), Medical Monitor

Welcome back to Pophealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more. 

Lucy Myint-Wilks, BMBS, MSc, MRCS (ENT): My name is Lucy Myint-Wilks, I'm a physician and I have 4 years of experience in clinical development focusing on the advancement of novel therapies across various diseases including migraine. And in 2020 I served as a principal investigator for a migraine study involving the development of the CGRP inhibitor eptinezumab. In this role, I also provided therapeutic area training on migraine and CGRP inhibitors as well to my clinical team. And currently, I work as a contractor with Lindus Health contributing to their medical monitoring team across quite a diverse portfolio of clinical trials.

Perfect. So then the first question that I have is can you discuss the latest research on the underlying causes of migraines and how this information has influenced treatment options?

Dr Myint-Wilks: Absolutely. It's a really exciting time for migraine research, which I'm sure is no coincidence, that’s why you’re asking. In recent research, we’ve seen several important insights into the causes of migraines which have informed new treatment strategies, and I have 3 things that come to mind immediately as the sort of most important. 

The first one would be cortical spreading depression. And migraines with aura often originate from a wave of neuro-polarization across the brain’s cortex and this we now know as cortical spreading depression. This disrupts the brain activity and releases inflammatory proteins into CSF, cerebral spinal fluid, including CGRP to casitone gene regulate, sorry, muddling my words here. Gene-related peptides which then activate sensory nerves in the trigeminal ganglion. And this knowledge has led to the development of CGRP inhibitors which are now widely used for both acute and preventative migraine treatment in the form of gepants, which were the first, and now the mAbs, the monoclonal antibodies which are showing even more promise for long-term prevention. So that’s the first thing that came to mind as a recent piece of research that’s been really valuable. 

The second thing would be protein signaling pathways. And beyond CGRP, researchers have identified other proteins that contribute to migraines offering the potential for new targets for our drug development. And these findings are especially promising for individuals who don't respond to current CGRP-based therapies, which in some studies is up to 47%. And it could lead to more tailored treatment options. For example, specific proteins have been identified to be significantly raised during acute migraine attacks for those sufferers of menstrual migraine. And those are unique from non-menstrual migraine. So that gives us something else to look for. Something else that we can treat. 

And the third thing that’s worthy of note is around brain fluid dynamics and the blood CSF homeostasis. So, research into brain fluid dynamics has uncovered interesting links between CSF composition and migraines. Specifically, we’ve seen elevated levels of sodium observed in the CSF migraine sufferers which suggests a potential dysfunction in the blood-CSF barrier’s ability to maintain its homeostasis biochemically. And this impaired area may facilitate the transport of inflammatory proteins into the trigeminal ganglion which would trigger the same sort of migraine symptoms as we talked about. And it might amplify sensory-nerve activation and contribute to migraine pain. So these findings provide an additional layer of understanding and present novel therapeutic targets for addressing this dysfunction. And what I mean by that is there's a huge scope there for, you know, minimally invasive surgical procedures, perhaps, that could be, you know, a long way in the future with quite a lot of research. But it's an exciting door or a window even to look through to potential future treatments there.

Great, yeah, wonderful. Thank you so much. For our next question, can you explain the significance of early initiation of CGRP therapy in the treatment of migraines?

Dr Myint-Wilks: Yeah, so the significance on the patient level with early initiation of CGRP antagonists, we see significant clinical benefits such as reduced migraine frequency, improved quality of life, and increased productivity for individual patients. And these are critical outcomes for people with high migraine burden. Migraine can be a truly debilitating disease. And for those with frequent and/or severe symptoms, these treatments can be life-changing in immeasurable ways. So as well as the immediate benefit, we may also see the avoidance of related conditions from developing. And by that, I mean things that we often see in patients who suffer from chronic migraines like anxiety, depression, sleep disorders, and in very rare situations, patients can develop neurological complications such as central sensitization. And that’s a horrible condition where the CSF becomes so overwhelmed by repeated migraine that even a light touch of the skin feels painful. I'm sure you can imagine that being particularly debilitating for some people. And in terms of the wider public health outcomes, it's feasible, but wide use of these medications could lead to reduced emergency department visits and health care utilization, placing less strain on our resources and our ability to provide a high standard of care. 

So has research supported that early CGRP therapy initiation for migraine treatment may be a cost-effective option? And how do the costs of early CGRP therapy initiation compare to traditional migraine treatments in terms of long-term health care costs?

Dr Myint-Wilks: So I'm not an economist, but there are two studies that come to mind that I read this year when considering the answer to that question. So the first is about the cost-effectiveness of oral CGRP antagonists. So those are the gepants, the slightly older ones, that are more designed for relief. And that study was published this year and shows the use of QALYs, so quality-adjusted life years, to demonstrate that gepants were not entirely cost-effective when using the accepted ratio of $150 000 per QALY due to their high monthly cost. And whilst these incremental cost-effectiveness ratios are useful when comparing treatments that are public health level, I don’t find them to be entirely conclusive when analyzing the class of drugs. 

So this study basically is saying that gepants are not cost-effective. But the study was also conducted- it has some limitations- and the study was conducted in the US where health care costs are very high, and it can't claim to be globally representative. And also it uses quite a finite measure of the benefit to the patient. So I think it's quite difficult for that one study to be able to make the claim that the gepants are not cost effective. 

And the second study, which I prefer, was also published this year, looking at the cost-effectiveness of the monoclonal antibodies. And that was published by Carlos Lazaro-Hernandez in the Journal of Headache and Pain this year. And what I love about the study is its relevance in focusing on the working-age population. So it demonstrates real-world effects on those people who are driving the economy. And this study looked at 256 working-age participants and was able to demonstrate a positive cost-benefit balance for all of the responders to the medication. And they define a responder by someone who has a reduction of 50% in the number of headaches they have per month. It did show a negative cost-benefit for the non-responders as these participants didn’t see the same reduction in absenteeism from work and they’re obviously still accessing health care resources in the same way they would have done without medication, and they might also be seeking alternative medications to manage their symptoms. So, a balance. It's clear that the cost-effectiveness of such a medication is extremely hard to measure and should be addressed on an individual level due to the extreme variation in symptoms, the impact on a patient's life, and the response seen to the medication. So I would sum up saying that there has been some research into the cost-effectiveness of these medications but not enough to draw a solid conclusion.

Great. And on the patient side, what are the potential benefits and challenges for patients when CGRP therapy is initiated early in the treatment of migraine?

Dr Myint-Wilks: So, the potential benefits are easier to immediately think of having seen patients take these medications. The reduction in migraine frequency and severity is the most obvious. So early use of these therapies can help significantly reduce the frequency and severity of migraines which improves quality of life for our patients. There are preventative benefits, CGRP therapies are particularly effective as preventative treatments and starting them early may prevent the development of chronic migraine which is still defined as more than 15 headaches per month. They may decrease disability. By reducing migraine burden, patients may experience less disruption to their daily activities, to their work productivity, and to their social lives and social interactions. It can reduce their reliance on acute treatments such as triptans and NSAIDs. There are a lot of risks for using NSAIDs, for example. Reducing the risk of medication overuse. Headaches, as well. There's improved patient adherence as CGRP monoclonal antibodies are often administered monthly or even quarterly. They offer a more convenient option compared to daily preventative treatments and that potentially improves adherence for our patients. There are fewer side effects compared to traditional preventative medications. So they have fewer side effects compared to the older options like beta blockers or anti-epileptic drugs, that sort of thing. In terms of the challenges, the most obvious challenge you have alluded to which is the expense. So CGRP therapies are expensive, and insurance coverage may be limited. This can pose quite a significant financial challenge for patients, especially in countries without an NHS or universal health care.

There is an uncertainty about long-term safety for some people because they are new drugs and safety data is still being gathered which might raise some concerns for some patients. Delayed diagnosis in that migraines are often undiagnosed. Underdiagnosed, sorry. And patients might not receive CGRP therapy early enough to fully realize its benefits. There is limited evidence for early-stage use. So particularly in my experience, the study I was principal investigator for, we used eptinezumab for patients with very severe and frequent migraines that had been diagnosed years ago and they were chronic sufferers. So in terms of early-stage use, there is not a huge amount of evidence for the cost-effectiveness of these inhibitors in very early or less frequent episodes. Other challenges include potential side effects. So while they are doing really well being tolerated, they can cause some side effects like injection-site reactions, constipation, or some people can suffer hypersensitivity reactions. Patients may need education about the benefits of early treatment to assure adherence as some may not see immediate results of preventative therapies. And often, preventative therapies are a hard sell in many ways because if you feel well, you don’t want to take a medication whereas the relief medications, they’re obvious. When you have pain, you take painkillers. 

The last challenge I was considering is co-morbidities and contraindications. So there are patients with certain conditions like cardiovascular diseases that might be less suitable for CGRP therapy. And those are not proven but there are theoretical concerns about vascular effects because they are inherently vasoconstrictors. So, overall, there's a balance that health care providers need to consider when recommending CGRP therapy. And we should be taking an individual approach to make sure that the benefits to the patient and the potential risks are well-balanced.

Great. So I just have one final question, and that is how do advancements in technology play a role in monitoring and managing migraine, and what potential benefits do these tools offer for patients and health care providers?

Dr Myint-Wilks: Okay, so this is particularly new to me in that I've been learning a lot about the digital health platforms and AI opportunities that Lindus, in particular, are looking into. So, the first area of technology that I’ve learned can be beneficial is digital health platforms and apps. They can be useful for tracking symptoms. Smartphone apps in particular can allow patients to log migraine symptoms, triggers, frequencies, severity, and other related factors. And that can provide quite a comprehensive view of the condition over time. These can also be personalized, personalized insights using these platforms and algorithms to analyze patterns in the data and offering patients tailored insights about their migraine triggers and lifestyle factors and potential interventions to avoid those. And data sharing. Patients can share real-time data with their health care providers, enabling more informed decision-making and remote monitoring of migraine patterns. 

The second area, or second technological advancement, would be wearable devices. So that’s biofeedback and neurostimulation devices like, well, there are a couple that provide transcranial magnetic stimulation or electrical neurostimulation and they aim to reduce migraine frequency or intensity and these wearables they offer a non-pharmacological approach to treatment and often with fewer side effects but slightly more invasive. Continuous monitoring, so wearables such as smartwatches or headbands designed for migraine patients can track physiological data like your heart rate, your skin temperature, and those can be used to detect early warning signs of an impending migraine allowing for timely intervention. 

And the third area of technological advancement that I feel is really helping the field of migraine is AI and machine learning. That includes predictive models, so AI-powered systems that can analyze large data sets from electronic health records, wearable devices and patient logs for prevention to predict migraine attacks and suggest preventative strategies. And these models can learn and adapt to individual patient profiles over time. And they can also optimize treatments. So machine learning algorithms can help identify the most effective treatment plans for individual patients by comparing the outcomes of various therapies in real-world settings. There is also more scope for personalized medicine using technological advances. So advancements in genetic testing may lead to more personalized treatments for migraines, particularly for patients with specific genetic predispositions to migraine attacks. And new biomarkers might also enable earlier diagnosis and more precise treatment interventions.

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