Injection of Human Antibodies for Migraine Prevention: Where Do We Stand?

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If every human brain contains within it the equivalent of an electronic circuit board which is capable of sensing head pain, then the circuit boards of those individuals who are said to have "migraine" are biologically sensitized to such a degree that the circuitry may spontaneously generate head pain.  Migraine prevention therapy is intended to reduce this biologic sensitivity, reduce activity within the circuit board that generates head pain and thus reduce headache frequency.

Calcitonin gene related peptide (CGRP) is a protein that exists in the nervous system of all humans and serves as an important "connector" in the electro-chemical circuit that transmits the signals which produce headache.  Given CGRP's importance in the headache circuitry, it seemed logical to assume that  blocking CGRP should "short circuit" the circuit and reduce the sensitivity of the system just as a rheostat on a light switch can dim a lamp’s brightness. 

As of this writing (September 2019) and for a little over 1 year, 3 anti-CGRP monoclonal antibodies (Mabs) have been available for clinical use: erenumab (Aimovig), galcanezumab (Emgality) and fremanezumab (Ajovy).  Worldwide, hundreds of thousands of migraine patients have tried at least one of these therapies.  Each is self-administered subcutaneously (under the skin), typically on a monthly basis.  What have we learned thus far regarding their safety, tolerability and effectiveness?

Clinical experience with the 3 Mabs more or less has replicated the results from the randomized, placebo-controlled research studies that earned each therapy its approval from the Federal Drug Administration. Aside from a low incidence of injection site skin reactions and a similarly low incidence of constipation, the therapies tend to be extremely well-tolerated. Data from patients followed for up to 3 years have demonstrated no long-term safety concerns. When therapy is extended to more than six months, the effectiveness of treatment generally is maintained and in some patients may even increase.

As regards effectiveness, no clear leader has emerged from the "gang of 3".  With each there are patients who experience a rapidly developing and significant decrease in headache burden ("super responders"), those whose decline in headache burden is less prominent, more slowly developing or both ("partial positive responders") and those who experience no clinical improvement.  Dr. Amanda Tinsley, director of the George Washington University Headache Center, stresses the importance of setting realistic expectations.  “In discussing the option of beginning monoclonal antibody prevention therapy with a migraine patient, " Tinsley advises, "the provider should emphasize that many patients so treated experience no improvement, and many who do improve require a period of weeks and multiple administrations before that improvement becomes evident."

Question Still Lacking Answers

  1. Given that Aimovig possesses a mechanism of action somewhat different than that of Emgality and Ajovy, will patients whose headache disorders fail to improve while administering Aimovig or who experience treatment-limiting side effects such as severe constipation benefit from a switch to Emgality or Ajovy? Conversely, will those patients who failed Emgality or Ajovy benefit from a switch to Aimovig? If a switch is to be made, how long should one wait after stopping one Mab before switching to another?
    While switching from one anti-CGRP Mab to another already is common in clinical practice, at this point we do not have sufficient clinical evidence to provide patients with solid answers.

  2. If a patient experiences a positive partial positive response to treatment with 1 of these 3 Mabs, will adding a migraine prevention therapy belonging to a different pharmacologic class lead to further improvement in the treatment response?
    Again, no clear answer. Many patients with chronic migraine have been treated simultaneously with onabotulinumtoxinA (BOTOXA) and 1 of the Mabs. While no reports of any safety issues related to such combination therapy have emerged, there has been no scientifically rigorous evaluation of whether such treatment is both safe and effective.

  3. In “super-responders” who become headache-free or nearly so following initiation of treatment with 1 of the 3 Mabs, when - if ever -should treatment be discontinued?
    This particular question is relevant to all migraine prevention therapies. At this point there are relatively few published studies which have examined the issue, but the consistent trend in the results from those studies has suggested that patients who respond very positively to prevention therapy may eventually discontinue that therapy without experiencing a rapid increase in headache burden. None of those studies has involved the Mabs. Moreover, even amongst clinical investigators who have examined the issue there is no clear consensus on how long treatment should be administered before an attempt at discontinuation is made.

  4. If a chronic migraine patient has failed to respond to serial BOTOXA injection therapy, will he or she potentially respond positively to a Mab?
    While there is accumulating evidence to suggest that migraine patients who previously have failed oral medications intended for migraine prevention may respond quite well to a Mab, it remains unclear whether BOTOXA failure predicts Mab failure. Hopefully not. At this point we have very few evidence-based prevention therapies for chronic migraine, and it will do little to reduce the tremendous public health problem posed by that this costly variant of migraine if BOTOXA and the Mabs are effective only in the same subpopulation of chronic migraine patients.

Whatever answers come, Dr. John F. Rothrock, vice chair and professor of neurology at George Washington University, takes an optimistic view of the anti-CGRP Mabs and their impact on migraine.  “The release of sumatriptan almost 30 years ago led to nothing less than a revolution in migraine diagnosis and treatment," suggests Rothrock.  "These anti-CGRP monoclonal antibodies, therapies which, like the triptans, were developed specifically for migraine, represent a second revolution in migraine therapeutics.  They are far from the "cure" for the complex disorder which we identify as "migraine", but they are proving to be a game-changer both for many patients and, no less important, for the way in which migraine is viewed and managed."