The CGRP Monoclonal Antibodies: Revolutionary Breakthrough or Over-priced Hype?

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In May of last year, the US Food and Drug Administration (FDA) approved erenumab (Aimovig), the first of the anti-calcitonin gene related peptide (CGRP) therapies for the indication of migraine prevention. Aimovig quickly became available for general clinical use and already has been prescribed for well over 100,000 patients with episodic or chronic migraine. Within a period of months 2 more received similar FDA approval and entered the market: galcanezumab (Emgality) and fremanezumab (Ajovy).  

CGRP is a protein that appears to play a critical role in the biologic circuitry that produces migraine headache. All three of  the medications currently available are monoclonal antibodies (MABs) that defuse the action of CGRP by either blocking the head pain receptor it otherwise would activate (Aimovig) or binding directly to a portion of the CGRP molecule (Emgality and Ajovy) itself and rendering the molecule ineffective.

Unlike oral medications for migraine prevention, which must be taken on a daily basis, or onabotulinumtoxinA (BotoxA), which must be administered by a medical provider every 12 weeks, all three of these medications can be self-administered once-monthly via simple to use devices that inject the medication under the skin.  Along with the obvious convenience this conveys, patients typically tolerate treatment with the antibodies quite well; side effects are few and infrequent, and all research and clinical use evidence to date have demonstrated no significant concerns regarding safety. The newness of the monoclonal antibodies necessarily limit any evidence-based conclusions regarding their long-term safety, but no major safety concerns have arisen from the hundreds of patients  who now have been on these medications for up to five years.  

So what’s not to like?  After all, the FDA agreed that each of these 3 drugs was superior to placebo in preventing headache in patients with episodic or chronic migraine, that each was well-tolerated by patients, and that each appeared to be safe.  The once per month dosing regimen is regarded by many patients as a more attractive option than taking a pill or capsule on a daily basis, and in contrast to BotoxA, the self-administration angle untethers patient from provider.  For now at least, each of the companies possessing a marketable antibody - Amgen/Novartis for Aimovig, Lilly for Emgality, and Teva for Ajovy - offers patient assistance programs that allow many migraine patients to receive the medication at no or little out of pocket cost (these programs vary in how they can be accessed).

Despite this rosy picture the United Kingdom's National Institute for Health and Care Excellence (NICE) recently issued the results of its evaluation of Aimovig, concluding that the cost of treatment with it could not be justified by its clinical effectiveness. As part of its mandate, NICE publishes guidelines regarding the use of new and existing medications within the UK's National Health Service (NHS), and if the NICE guidelines related to Aimovig are implemented no new prescriptions for Aimovig will be approved for NHS patients. In reaching its conclusion, NICE noted that in the setting of episodic migraine there are available for headache prevention a number of oral medications less expensive than Aimovig.  As for chronic migraine, NICE noted that Aimovig appears no more effective than BotoxA.

In July of last year the Institute for Clinical and Economic Review (ICER), the US equivalent of NICE, issued a report which also indicated low enthusiasm for the use of Aimovig in the setting of episodic migraine but "net health benefit" for patients with chronic migraine in the absence of any other available treatment option.  From the economic perspective, ICER concluded that Aimovig was of "intermediate" value for adults with chronic migraine and of low to intermediate value for patients with episodic migraine.  Given that Emgality and Ajovy have demonstrated efficacy, tolerability and safety profiles similar to that of Aimovig and that the 3 treatments are similarly priced, it seems reasonable to anticipate that the NICE and ICER guidelines and conclusions regarding the two more recently released medications will be similar to those pertaining to Aimovig.

What’s a migraine sufferer to think? Are these new medications legit? Or is all this talk of “revolutionary therapies” just a lot of hot air spewing from pharmaceutical companies seeking a profit?

Before addressing this question or, more specifically, critiquing the NICE and ICER conclusions, one should keep in mind what we know – and don’t know – in regards to these MABs . In particular, it’s important to emphasize that in the clinical research studies which earned each of these 3 antibodies its FDA approval, the relevant drug was compared to injections of placebo; individuals with migraine who participated in the studies were assigned at random to receive either active drug or placebo, and both the patient and the physician investigator were "blinded" as to which of these a given participant was receiving until the study had been concluded.  None of the 3 has been directly compared to another active therapy.

Consequently, at this point we have no solid base of evidence that would permit us to compare any one of these antibodies either to another anti-CGRP treatment or to another "active" therapy intended for migraine prevention (eg, BotoxA or oral medications such as topiramate).  Without data from studies involving a direct comparison of “active therapy vs active therapy”, it’s difficult to make any definitive statements regarding the
effectiveness of a given  MAB relative to any other migraine prevention therapy.


The NICE Report: Are Its Conclusions Justified?

Aimovig (and the other monoclonal antibodies) are not especially effective for headache prevention in patients with episodic migraine.  First, keep in mind that no therapy is universally effective for all migraine patients, whether the therapy is for acute headache or for prevention of headaches in the episodic or chronic migraine patient populations.  Data from multiple large scale, well-designed and well conducted clinical research studies clearly indicate that the anti-CGRP  MABs are superior to placebo for headache prevention in patients with episodic migraine.  Whether their cost justifies their routine use in episodic migraine may be open to debate, but for patients with high frequency episodic migraine who have failed to respond to oral prophylactic therapies that possess a solid evidence base, these  new medications would seem to represent an attractive option.

There are a number of oral therapies less expensive than the MABs which are available for headache prevention in patients with episodic migraine.  While it’s true that a wide variety of oral medications commonly are used for migraine prevention, it is also true that only 5 medications are FDA-approved for that indication; 1 of the 4 (timolol) is rarely used, 1 no longer is manufactured anywhere in the world, and 2 of the remaining 3 may cause birth defects in a developing fetus and are contraindicated for use in females who are pregnant or at risk for pregnancy.  There are a couple of other oral medications that are not FDA approved for migraine prevention and nevertheless possess a solid evidence base for such use. Beyond this handful there’s simply not much out there.  True, "there are number of oral therapies…available for headache prevention in patients with episodic migraine", but unless one includes therapies of little or no proven benefit, that number is small.

Aimovig appears no more effective than BotoxA for headache prevention in patients with chronic migraine.  As there have been no head-to-head research studies comparing BotoxA and any of the  MABs, comments regarding the effectiveness of one treatment versus the other must be drawn from comparisons of placebo-controlled trials involving different patient populations and different study protocols; statisticians invariably caution against making too much of such comparisons.  At present, BotoxA is the only therapy with an FDA indication specifically for chronic migraine.  Of the other therapies which have an FDA indication for "migraine prophylaxis", only the new anti-CGRP therapies were evaluated via phase III trials that involved both episodic and chronic migraine; the remaining therapies earned their indications from episodic migraine trials only.  Given that both BotoxA and the anti- CGRP therapies possess strong evidence of effectiveness in treating chronic migraine, that the cost of the therapies is roughly equivalent and the well-demonstrated fact that many chronic migraine patients fail to improve with BotoxA, the  MABs would seem to represent at least as attractive a treatment option.

Aside from these three issues, it may be worth considering other aspects of the MABs not addressed by NICE or ICER in their reviews. First, in the oral migraine prevention trials, a great number of patients dropped out of the studies before completion, often due to side effects. In fact, in one large database of migraine patients placed on currently available oral preventive medications, 83% of the patient stopped treatment  before the end of  one year,  frequently due to side effects. The high tolerability of the MABs should largely eliminate that obstacle to treatment.

Second, it may take  many months to evaluate the effectiveness of oral preventive migraine medications.  Results from large-scale research studies indicate that the new monoclonal antibodies  begin to exert their effect in the majority of positively responding patients within one month or less. 

 Finally, as  positively responding patients take the new MABs  for longer and longer periods of time, the magnitude of positive response tends to increase to unprecedented levels.  In one study of a MAB still  in development, more than half of patients taking it reported a 75% or greater reduction in monthly migraine days by one year. As for Aimovig, over 40% of those taking the MAB for a year had an equally high level of response. Similarly high “responder rates” have never been described for any oral migraine preventive drug. 


Conclusions
 

Do the CGRP monoclonal antibodies now available represent a “revolutionary” breakthrough in migraine therapeutics? In the sense that they are the first pharmacologic therapies to be developed specifically for the purpose of migraine prevention and to obtain an FDA indication for their use, yes. Absolutely. They are to migraine prevention what, in 1991, injectable sumatriptan was to acute migraine treatment.

More to the point for individuals suffering from frequent migraine headaches, are the MABs revolutionary in their effectiveness? Possibly. The phase III clinical research trials whose results were the basis of their FDA approval demonstrated that substantial percentages of trial participants with episodic or chronic migraine experienced no clinically meaningful benefit from the medication after 3 months of treatment. Furthermore, within the limits imposed by comparing “across” different active therapy vs placebo trials, the available antagonists do not appear to be clearly more effective in reducing migraine burden than other prevention therapies such as BotoxA (for chronic migraine) or topiramate, an oral medication.  Even so, because of their superior tolerability, patients tend to remain on the MABs longer than has been the case with  the  oral medications presently available, and  the reports of progressively higher levels of responsiveness seen with a MAB administered over time are encouraging. 

If the anti-CGRP therapies are relegated to “third string” status by insurers and typically are to be used only in patients who have failed treatment with BotoxA or oral prevention therapies, will they succeed where the others have failed? Probably. In the research trials referred to above, many participants previously had failed multiple other prevention therapies, and many of those participants responded well to treatment with the MAB. How to predict those who will respond, how long to continue treatment in responders, and whether combination therapy with  one of the new drugs and another migraine prevention therapy may for some patients prove more effective than either therapy alone remain nuances of MAB therapy that will require more investigation.  


John F.  Rothrock, MD
George Washington University

Stewart J. Tepper, MD
Dartmouth University