NeuroVoices: Jessica Ailani, MD, on Emerging Research in Migraine, CGRPs, and PACAP Pathway

Jessica Ailani, MD

Over the past 30 years, both clinical and preclinical studies have documented the role of the neuropeptide calcitonin gene-related peptide (CGRP), the most potent vasodilatory peptide known, in migraine pathophysiology. This led to the first approved CGRP inhibitor, erenumab (Aimovig; Amgen), in 2018, followed by several other similarly acting agents. There are currently 2 types of CGRP inhibitors: monoclonal antibodies and CGRP receptor antagonists, or gepants.

At the recently concluded 2023 International Congress on the Future of Neurology (IFN) Annual Meeting, held September 22-23, in Jersey City, New Jersey, a session featured updates in migraine therapy, highlighting recently approved medications and promising agents in the pipeline. The session covered the advances in how CGRP-targeting therapies are used, their role within the field, and the need for other types of migraine treatments for patients who continually fail CGRPs.

Jessica Ailani, MD, a clinical professor of neurology at MedStar’s Georgetown University Hospital and director of the MedStar Georgetown Headache Center, served as the cochair for the meeting. Following the session, she sat down with NeurologyLive® to discuss advances in migraine treatment, better ways to implement newer medications, and the importance of understanding primary vs secondary headaches in the grand scheme of treatment. Additionally, she spoke on the emergence of pituitary adenylate cyclase-activating polypeptide (PACAP), a new pathway implicated in the pathophysiology of migraine, and where research currently stands.

How can we utilize CGRP-targeting medications more effectively?

I believe the most complicated aspect of using treatment options is ensuring that patients can access them. This is the first step. Confirming that they've attempted generic preventive treatments can facilitate their eligibility for newer treatment options. Subsequently, it's crucial to engage in conversations with the patients, understanding their goals and addressing their concerns regarding potential side effects. It's also important to determine their preferences for the type of treatment, such as oral or injectable options. When discussing newer therapeutic modules with patients, I often start by asking whether they are comfortable with taking a pill daily or every other day, or if they prefer an injectable medicine.

Research indicates that individuals who haven't previously used CGRP-based treatments may be apprehensive about monthly injections or infusions every few months, making them more inclined to choose oral options initially. However, I've found that some patients prefer not to add more oral medications to their regimen, particularly if they already have comorbid conditions and are taking multiple oral medications. In such cases, they may prefer the convenience of a monthly injection, although it's important to clarify that they will administer it themselves at home. Some patients mistakenly assume that I will administer the injection during their monthly visits. It's crucial to address this misconception early on. Therefore, the key steps in optimizing patient access to the right treatment involve ensuring they meet criteria for the new treatment, determining their preference for oral or injectable treatment, and considering factors like their gender and contraceptive use, as safety during pregnancy remains uncertain for these new treatments.

Consequently, if patients plan to start trying for pregnancy, we advise discontinuing the treatment in advance to minimize risks. These are a couple of strategies we can employ to enhance patient access to and utilization of new treatment options in clinical practice.

What is the clinical importance of understanding the origin of a patient’s headache?

The most critical aspect when seeing a patient in a clinical setting is establishing a diagnosis. Initiating a treatment plan without a clear diagnosis is not advisable, as it can lead to ineffective treatment. Simply prescribing medications without a proper understanding of the headache type can result in suboptimal outcomes. Therefore, it's essential to invest time in obtaining a comprehensive medical history to determine if the patient fits the criteria for a major headache disorder. This process involves distinguishing between primary headache disorders like migraine, tension-type headache, and cluster headache, and secondary headache disorders that may be caused by factors such as high or low pressure, infections, aneurysms, or head trauma. The differentiation between these types of headaches not only informs treatment decisions but also guides the necessary diagnostic tests. Secondary headache disorders often require brain scans, such as MRI and MRA, and sometimes specific lab tests to explore potential underlying causes. Although ordering labs for headache patients is relatively infrequent, a thorough history is essential for identifying the appropriate diagnostic and treatment pathways. Incorrectly diagnosing a headache type can lead to misguided treatment strategies.

What are the current knowns and unknowns surrounding PACAP?

While there has been extensive focus on CGRP, it's important to recognize that multiple peptides have been investigated to understand migraine triggers and pathophysiology. Researchers initially explored various neuropeptides elevated during migraine attacks and tested whether blocking their activity would reduce migraine frequency and severity. Surprisingly, blocking PACAP and CGRP in initial studies showed potential in influencing migraine outcomes. Subsequently, investigations have revisited other molecules, acknowledging that some earlier trials may not have been well-designed. As a result, there is hope for the discovery of additional peptides that could be relevant to migraine treatment. However, PACAP presents unique challenges due to its complexity. Unlike CGRP, which primarily targets one receptor complex, PACAP interacts with multiple receptors. The difficulty lies in identifying the most effective target within this complex system. This underscores the need for precise dosing, selecting the right target, and designing appropriate clinical trials. The pursuit of PACAP as a potential treatment option is ongoing, demonstrating the commitment of researchers and the medical community to address migraine comprehensively. While CGRP and PACAP may benefit some patients, there is a recognition that other, as-yet-unidentified targets may exist, emphasizing the ongoing need for scientific inquiry and research in this field.

As the treatment toolbox continues to expand, what are the challenges associated with individualizing therapy strategies for patients with migraine?

The complexity of tailoring therapy strategies for migraine patients lies in addressing their fears, understanding their unique stories, and fostering a comfortable environment for open communication. Building trust with patients is paramount because personalized medicine involves not only medication but also lifestyle adjustments, stress management, behavioral therapies, and neuromodulation. In the context of migraine treatment, it's essential to establish a therapeutic bond with patients. However, this process can be challenging, as patients may have difficulty expressing themselves due to past negative experiences or societal skepticism about their condition. Achieving a level of trust where patients feel comfortable sharing their full story can take time, sometimes spanning multiple visits. Patience on the part of the clinician is vital to reaching this point.

Another challenge is managing patients' expectations and addressing their desire to try different treatments, even when their current treatment is effective. Patients often seek alternatives based on comparisons with what their friends are using, which may not be appropriate or necessary. It's crucial to guide patients toward the most suitable treatment based on their individual needs and circumstances. This can be particularly challenging in a busy clinical setting, where time constraints can strain the patient-clinician relationship. Nonetheless, these challenges are preferable to the lack of treatment options, and the ability to work through them reflects the increasing availability of diverse migraine treatments. Building trust and individualizing treatment plans remain essential aspects of providing effective migraine care.

Transcript edited by artificial intelligence.