And Then There Were 3 …
 Understanding the CGRP Antagonists

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In the Summer 2018 issue of Migraineur (volume 4), our feature article, Therapies for Migraine Prevention: From Famine to Feast, involved prevention therapies for migraine, and within the "Brand Spanking New" portion of that article was briefly discussed a new class of medications, the CGRP antagonists.  “CGRP” (calcitonin gene related peptide) is a protein that is key to the conduction of head pain signal within the brain circuitry that produces migraine headache.  The CGRP antagonists prevent CGRP from activating the migraine circuitry by either blocking the protein directly or blocking the receptor with which it must link.

In the highly competitive sector of the pharmaceutical industry that deals with migraine therapeutics, the CGRP antagonists have been rolling out like hens’ eggs.  First, in May of this year, there was Amgen's erenumab (Aimovig).  Then on September 17 the FDA approved Teva's fremanezumab (Ajovy), and just 10 days later Lilly announced FDA approval of their product, galcanezumab (Emgality).  All 3 are now available for general clinical use.  All 3 are indicated as prevention therapy for patients with either episodic or chronic migraine.  All 3 are self-administered subcutaneously (under the skin) on a monthly basis via simple-to-use injection devices similar to the EpiPen or the autoinjectors used to administer sumatriptan for acute migraine treatment; in the case of Ajovy, there is the option for treatment every 3 months at a higher dose. During their development all 3 were found to be safe and very well tolerated.

Which one is best?  Are the CGRP antagonists better than onabotulinumtoxinA (BotoxA) or other therapies used for migraine prevention?  How expensive is the medication?  If I fail to respond to one, should I try one of the others?  I don’t like needles; do I have to self-inject?

All good questions, and at this point some of those questions lack evidence-based answers.

Which one is best? 

There have been no studies comparing any of these 3 CGRP antagonists to one another or to any other therapy for migraine prevention.  In the research studies which earned each of the medications its FDA approval, the subject populations were randomized either to placebo or the particular CGRP antagonist under investigation.  In all of those studies each of the 3 currently available CGRP antagonists was significantly superior to placebo, and while the degrees of superiority (over placebo) differed somewhat from one medication to another, we simply do not have the type of meaningful evidence which would allow healthcare providers and their patients to rank one CGRP antagonist above or below another.  Each antagonist has a somewhat different mechanism of action from the other, but whether those differences translate into clinical superiority or inferiority is as yet unknown.

Are the CGRP antagonists better than BotoxA? 

Again, none of the antagonists has been compared directly with serial Botox injection therapy or any other active therapy.  Response rates relative to placebo from the research studies that earned BotoxA its FDA approval in 2010 were similar to what was observed in the studies involving the CGRP antagonists, but it is scientifically tenuous to compare different therapies according to their performance in placebo-controlled trials that may have used different methods and involved different types of patients. Of note, BotoxA is indicated only for prevention therapy in the setting of chronic migraine (patients with migraine who experience 15 or more days of headache per month), whereas all 3 of the currently available CGRP antagonists are indicated for prevention therapy in both chronic migraine and episodic migraine (patients with migraine who experience less than 15 days of headache per month).

How expensive this medication? 

All 3 of the currently available CGRP antagonists are priced about the same from the insurers’ perspective, and their respective companies are utilizing unique patient assistance programs that will enable patients to receive the respective medication at little or no cost.  At this point all of the major insurers will require preauthorization before permitting patients to obtain treatment through their insurance plans, but - again -in this hotly competitive environment all 3 companies have programs in place to enable patients to begin treatment in advance of preauthorization… and potentially to continue treatment even if preauthorization is denied.

If I fail 1 CGRP antagonist, should I try another? 

Again, unknown.  While on the one hand it might seem to make sense to try another therapy with an entirely different mechanism of action for suppressing migraine, the possibility exists that there is enough difference between the antagonists to justify moving on to another if the first (or second) has failed.  As yet, we simply do not know.

I hate needles.  Is there an alternative to self injection? 

If it is the self-injection that has you stymied, then it’s simple enough to have someone else administer the injection (a sympathetic significant other will do).  If it’s the prospect of needing injections on a monthly basis that gives you the shivers, then consider Ajovy with its "every 3 months" option.  Alternatively, we can anticipate the eventual availability of an oral CGRP antagonist, and many headache subspecialists eagerly are eyeing the development of an intravenous antagonist that will be administered every 3 months.

While these 3 CGRP antagonists have been in development for years, the fact that all 3 suddenly have become available within less than 6 months has everyone – patients and providers alike – excited, optimistic...and a little bewildered.  Fortunately, there is a great deal of information available to assist us in understanding these new therapies and what to expect from them, and with time and rapidly accumulating experience we can anticipate meaningful answers to the questions posed here.