In 2019, the American Headache Society (AHS) issued guidelines to help clinicians incorporate emerging migraine therapies, such as the monoclonal antibodies (mAbs), that target the CGRP or its receptor. Recommendations on when to initiate preventive treatment were unchanged; however, we included new guidance on the use of emerging therapies. In developing these guidelines, we felt that it was important to state that any licensed medical provider who can write a prescription should be able to prescribe the mAbs, not just neurologists or migraine specialists.

Four such biologics (ie, erenumab, fremanezumab, galcanezumab, and eptinezumab) have been approved by the US Food and Drug Administration, and all of them have shown efficacy in reducing the frequency of monthly migraine days with generally good tolerability. Unlike mAbs used for rheumatoid arthritis and other autoimmune inflammatory disorders, the anti-CGRP mAbs do not target the immune system and are not associated with infection risk. Clinical trials and real-world studies show that 45% to 60% of those treated can have at least a 50% reduction in headache frequency at the time of assessment, regardless of which mAb was used. Remarkably, improvements are observed even in patients who have failed numerous other preventative treatments and in those with medication overuse headache. The anti-CGRP mAbs are not metabolized by the liver or excreted in the kidney, but they are instead broken down by the reticuloendothelial system. Thus, they have a low potential for drug interactions and can easily be added to existing preventive treatments. Further, monthly or quarterly dosing is attractive from the adherence perspective.

In the AHS guidelines, we suggested that patients with episodic migraine who have at least 4 to 7 headache days per month, moderate levels of disability, and failed at least 2 oral preventive agents are candidates for 1 or more of the mAbs. Patients with 8 to 14 monthly headache days are automatically eligible without showing any level of disability. In addition, patients with chronic migraine (ie, 15 or more headache days per month) are eligible for mAb treatment if they fail 2 oral preventive medications or 2 treatment cycles with onabotulinum toxin A.

All 4 of the CGRP mAb treatments demonstrated efficacy, tolerability, and safety as migraine prophylactic treatments in clinical trials. Our general experience has been consistent with the clinical trial experience (ie, all of the mAbs have the potential to be quite efficacious in patients with migraine). There are no head-to-head data to guide us on whether 1 of these treatments is more effective than another. Further, we do not yet have precision testing to predict which individuals with migraine may have a better response with a particular treatment, something that applies to mAbs but also to migraine treatments more generally. As the anti-CGRP therapies were introduced more recently, the long-term safety data are limited. As with any new treatment, when larger and more heterogeneous populations are exposed to the therapy for long durations, safety signals often arise that were not apparent in clinical trials. Contraindications or precautions are relatively few; however, it may be prudent to avoid the use of CGRP mAb treatments in patients at high cardiovascular risk. Additionally, we do not yet know what their effects may be in pregnancy. The elimination of mAbs from the body takes several months, so anti-CGRP treatments are best avoided in women who are pregnant or are planning to become pregnant. Another consideration with anti-CGRP therapies is that third-party payers often determine which treatments may be used. Owing to these issues, unfortunately, physicians often do not have much independence when selecting therapies for patients with migraine.

Many headache specialists believe that migraine is somewhat of an umbrella term that encompasses many different subtypes. This might explain the phenomenon of super responders, which refers to individuals whose response to a particular treatment, often at a subtherapeutic dose, is quite remarkable in comparison with typical responses to treatment. The concept of super responders also punctuates that there are multiple mechanisms involved in the pathogenesis of migraine, and the degree to which each mechanism affects different individuals likely varies. 

Regarding CGRP antibody therapies, although improvement of migraine may be seen early in the course of treatment, there are good data to suggest that the overall therapeutic yield tends to improve over time with serial dosing. As such, patients who do not demonstrate robust improvement in the absence of significant side effects after the first cycle of treatment should continue for 3 to 5 cycles before a decision to terminate therapy should be considered. Furthermore, as Dr Dodick mentioned, the low potential for drug interactions with anti-CGRP mAbs is important, particularly in more complex patients who are on multiple medications. 

As Dr Friedman noted, the treatments that may be prescribed for any given patient are often dictated by the formulary preferences of insurance carriers. Considering that the data for all of the CGRP-based therapies are reasonably good, prescribing the treatments on formulary will likely improve access with similar efficacy. In terms of socioeconomics, the funds necessary to treat patients with migraine are not unlimited. Older, less expensive migraine preventatives such as a beta blocker or an anticonvulsant (eg, topiramate) can be quite effective at surprisingly low doses and at less cost than many newer medications. Consequently, a patient who can be treated effectively with an inexpensive generic medication can generate a cost savings, which can get passed on to treat a more refractory patient who may require combination therapies such as onabotulinum toxin A and anti-CGRP mAb therapy. Insurance companies are realizing that combination therapy can be very effective for many patients who find monotherapy inadequate, and I am optimistic that coverage for combination therapy will become increasingly common.