Great Expectations: Trying On the Mabs and ‘Pants
Migraine accounts for roughly 60% of all neurological disability and, thanks to its clinical nature and high prevalence, more disability than depression, diabetes, asthma and osteoarthritis. Migraine actively afflicts approximately 12% of our general population (almost 40 million Americans). Given migraine’s massive impact on public health, it may come as a surprise that, until recently, no therapy ever had been developed specifically for the prevention of migraine headache.
Up until now, the pharmacologic options available for migraine prevention initially were developed to treat a host of conditions other than migraine, conditions as varied as hypertension, epilepsy, spasticity, “crow’s feet”, anxiety and depression. With the notable exception of onabotulinumtoxinA (BotoxA), used to suppress chronic migraine, these treatments typically have required that patients take medication on a daily basis. All carry the risk of potential side effects, and they are often ineffective. Wouldn’t it be nice if there existed a therapy to prevent migraine headaches that was created specifically for that purpose? that was safe and invariably effective? that you didn’t have to administer every day to obtain a positive result?
Well, none of the ‘pants or mabs currently under investigation, including erenumab (Aimovig) which Amgen released for general clinical use earlier this year, can claim all of these pleasant attributes, but all can boast at least one: these therapies, collectively referred to as the CGRP antagonists, were developed specifically for the purpose of treating migraine.
Calcitonin gene related peptide (CGRP) is a protein naturally found throughout body. The meninges that cover the brain are the site of most head pain receptors, and within the meninges CGRP is released from nerve endings, binds to its receptor and completes the circuitry that generates migraine. The “mabs” are genetically engineered monoclonal antibodies that work by blocking the receptor to CGRP or inhibiting CGRP directly, thus “short-circuiting” the migraine circuit. They are relatively large molecules. The “’pants” are smaller molecules that block the CGRP receptor and for the most part have been investigated for their utility in treating acute migraine headache rather than for migraine prevention. That said, it should be noted that atogepant, Allergan’s investigational oral CGRP receptor antagonist, thus far appears to be safe and effective for migraine prevention.
The good news: data from phase 3 studies have demonstrated these highly selective therapies to be extremely low in side effects, often effective and, when effective, to begin reducing headache burden as early as the first 2 weeks after treatment is started (as soon as the first 24 hours in the case of Alder’s intravenously administered eptinezumab!). In the case of erenumab (Aimovig), at present the sole CGRP antagonist currently available for general use, the only side effects that occurred more often in patients receiving the active drug than in patients receiving placebo were injection site reactions (typically minor) and constipation (3% of patients).
Erenumab (Aimovig) is self-injected subcutaneously by the patient on a monthly basis for prevention of
migraine headaches. Subcutaneously self-administered formulations of other CGRP antagonists currently are in development, along with an intravenous formulation to be administered every 3 months and an oral formulation to be taken daily. Soon patients will be able to choose which formulation best suits their particular needs. Patients with a horror of needles may opt for the oral antagonist, while those who wish to be untethered from the medical provider as much as possible may choose one of the subcutaneous formulations. Patients seeking a particularly rapid onset of action may find the intravenous option appealing.
The bad news: none of these individual therapies is guaranteed to work for all migraineurs, and some may find that none of them is effective. While the safety and tolerability profiles for all the antagonists appear to be excellent, as many as half of patients treated may fail to have experienced a 50% or greater reduction in headache burden after 3 months of treatment. Generally speaking, such treatment failure occurs more commonly in patients with chronic migraine than in those with episodic.
Even so, the CGRP antagonists are a glass at least half-full. Many patients will experience a meaningful reduction in headache burden, and in a high proportion of these patients the improvement is likely to begin quite soon after treatment is begun. The antagonists are easily tolerated, and soon one may be able to choose from a menu of formulations. The mabs and ‘pants may not be the final answer to subduing migraine, but they do represent a tremendous step forward in migraine therapeutics.