CGRP - A New Weapon in the Battle for Migraine Freedom

Vincent S. DeOrchis, MD MS - Director of Neurology - St. Francis Hospital and Heart Center, Roslyn NY

December 28, 2022

As a neurology resident in the mid 2000s, I faced many challenges while learning to manage syndromes for which neuroscience provided little satisfying pathophysiologic explanation. None greater was the encounter with the migraine patient. The history was often a medley of symptoms editorialized to emphasize the devastating impact these attacks had on the patient’s quality of life. Lost days at work, limited academic prospects, missed family events and vacations, and most importantly a loss of the sense of self control and confidence inflicted by a condition which comes on often without warning and at its worse will impair all facets of cognition.

The burden of headache ripple far beyond the impact of the individual patient. Estimates of direct spending on medical therapies, including ER and urgent care visits, has now reached $11 billion per year. Indirect costs in terms of lost productivity, missed days of work and employer burden have been calculated to be as much as $13 billion per year - often affecting individuals in a time of their life when earning potential and academic ascent are at their highest. As a migraineur myself, I am aware of these impacts all too well.

Early in my career the choice of an appropriate prophylactic migraine agent was often accompanied by a long discussion with the patient to assess which side effect profile would best suit their lifestyle and medical history. Abortive agents were for the most part limited to the triptan family of drugs which acted as agonists of the 5HT-1B and 5HT-1D serotonin receptors - though these were greatly limited by their theoretical vasospastic effects in the cardiac population as well as tolerability and risk of overuse/rebound headaches. Prophylactic and abortive agents were often felt to be relatively equivocal in efficacy with differences in response often attributed to their pharmacokinetic profiles as well as the mysterious and poorly defined patient to patient variations in what neurologists would refer to as the trigeminovascular pain pathway - a complex feedback loop connecting the dorsal pons and hypothalamus to the trigeminal ganglion and spinal trigeminal nucleus where a feedback loop was created with the thalamus and cortex - the terminus where pain would be consciously perceived.

Headache presentations to the ER were at an all time high and members of the neurology department would often express frustration with our limited therapeutic options.

Fortunately for myself and the other 1 billion sufferers of migraine worldwide, the year 2020 would bring a revolution in the management of headaches with the release of a new class of drugs targeting the calcitonin gene-related peptide (CGRP) receptor as well as the CGRP ligand.

CGRP was first identified as a molecule of interest in the headache-pain pathway in 1986, but it wasn’t until 2000 when the first agents targeting the CGRP receptor (“gepants”) were developed. The first proof-of-concept study which took place in 2004 demonstrated a significant reduction in migraine symptoms when administered during the attack. Unfortunately future progress was stymied in 2009 when an early molecule, oral talcagepant, was associated with elevated liver enzymes and the trial was subsequently halted. The progress these agents made nevertheless supported further development and spurred the creation of second generation agents which showed far more promise without the risk of liver toxicity and better tolerability than was seen with the triptan agents.

Success of these therapies was clearly visible in the emergency room at St. Francis Hospital where visits for headaches dropped substantially over the subsequent two years.

Presently available prophylactic CGRP therapies for episodic migraines include the parenteral monoclonal agents erenumab (Aimovig) targeting the CGRP receptor, as well as galcanezumab (Emgality), fremanezumab (Ajovy) and eptinezumab (Vyepti). The former three are monthly subcutaneous injections and the latter (eptinezumab) a quarterly IV infusion. These agents are widely well tolerated with a higher incidence of constipation with erenumab, an effect thought to be due to its influence on the CGRP receptor which is also localized to the GI system.

Additionally, an oral CGRP receptor antagonist atogepant (Qulipta) is approved for migraine prevention as a daily dose.

Abortive agents include ubrogepant (Ubrelvy) and rimegepant (Nurtec), the latter being an oral dissolvable regimen with a 48 hour half life. Rimegapant has an additional FDA approved use as a prophylactic agent when prescribed as standing every other day dosing.

Migraines remain a devastating, chronic and complex neurologic disorder whose consequences stretch far beyond the impact to the patient. Fortunately, years of extensive research into migraine pathogenesis has now produced a novel target for migraine therapeutics. The monoclonal CGRP and oral gepant agents have been shown to have a dramatic effect in the prevention and treatment of migraine headaches. The Neurology Department at St. Francis Hospital continues to directly support research in the field of future migraine therapeutics and eagerly participates in the care of our migraine population.