A NEW CLASS OF DRUG WITH NOVEL MECHANISM OF ACTION FOR MIGRAINE
17 July 2021
Migraine is a neurological condition that can cause multiple symptoms. It's frequently characterized by intense, debilitating headaches. Symptoms may include nausea, vomiting, difficulty speaking, numbness or tingling, and sensitivity to light and sound.
Migraines often present with complex phenomena, such as autonomic dysfunction, tactile, visual, and/or auditory manifestations. They might be preceded by premonitory symptoms called “aura” that herald the onset of pain, even three days ahead of time. A migraine complex is comprised of four stages: prodrome, aura, headache, and postdrome. The pathophysiology remains unclear. Imaging studies suggest causality by activation of central nervous system areas that control physiologic functions, rather than the previously believed vascular etiology. A cascade of inflammatory pathways triggered by a “cortical spreading depression” results in pain. The glutamate, dopamine, serotonin, and gamma-aminobutyric acid neurotransmitter systems are implicated in the pathology of migraine headaches.
Migraine therapy is classified into preventive, abortive, and biofeedback. Existing treatments are often deficient in pain relief, induce adverse effects, and yield the probability of medication-overuse headaches. Acute interventions are classified as migraine-specific medication and nonspecific analgesic therapy. They include ergotamine derivatives, triptans, nonsteroidal anti-inflammatory drugs, anti-emetic medications, acetaminophen, neuromodulation using devices, and combination therapies.
Ergot alkaloids are the oldest medicines in the migraine-specific category, but they are poorly tolerated. Triptans (5-HT1B/1D agonists) are a better tolerated group. However, ergots and triptans provide inadequate pain relief and are rarely prescribed for people with cardiovascular diseases. A big risk associated with these acutely acting drugs is medication-overuse headaches, that potentially occurs due to receptor down-regulation in the pharmaceutical response pathway.
Although several therapeutics are available to stop migraine attacks after they are already underway and some drugs include migraine prevention among several approved indications, the new class of CGRP-targeted drugs is the first to be specifically designed for the preventive treatment of migraine, marking a significant new era of migraine therapeutics.
Understanding the Role of CGRP and the Trigeminal Pain System in Migraine
Migraine is a neurovascular disorder associated with dysfunction of the cerebral nerve cells and blood vessels. Although scientists initially believed that migraine attacks originated in the cerebral blood vessels, more recent research suggests that migraine probably results from primary dysfunction in the brainstem centers that regulate vascular tone and pain sensation. The migraine attack often begins when triggers, such as stress, certain foods, or hormonal changes, set off dysfunctional reactions in the brain, causing excessive relaxation or dilation of cranial blood vessels.
These dilated blood vessels then mechanically activate sensory fibers from the trigeminal nerve located in the vessel wall, which then convey pain impulses to the brainstem and from there to higher brain centers. These impulses prompt the nerve fibers to release vasoactive peptides such as CGRP, which intensify dilation of the cranial blood vessels and cause “neurogenic” inflammation. This chain of events results in increased leakiness of blood vessels and the release of toxic compounds from mast cells, a type of white blood cell found in connective tissue. These events further increase the activation of the sensory fibers and perpetuate the release of vasoactive peptides, including CGRP. Scientists believe that as the migraine attack progresses, the brainstem and spinal cord centers that are the first to receive the pain impulses from the trigeminal nerves amplify the headache pain and increase sensitivity to environmental and other stimuli affecting visual and auditory sensation.
How the New Drug Class Uses CGRP-Targeted Monoclonal Antibodies to Prevent Migraine
In the new class of migraine therapeutics, the primary mechanism of action is the blocking of the effects of CGRP. These specialized monoclonal antibodies that are designed to treat migraine are cloned subclasses of immunoglobulin G (IgG), the most common type of antibody circulating in the blood, and are designed to have little potential to interact with other drugs. They act as antagonists, sometimes called blockers or inhibitors.
In the case of the drug erenumab-aooe, the antagonist selectively targets and binds to the CGRP receptor, blocking CGRP from interacting with the receptor. In contrast, fremanezumab-vfrm and galcanezumab-gnlm block the ability of CGRP to bind to the CGRP receptor.
Older classes of CGRP antagonists, known as gepants, are smaller in molecular size and are for oral dosing. Major adversities included hepatotoxicity and transaminitis; lesser side effects include sensory abnormalities, such as paresthesia, headache, visual disturbances, and/or xerostomia, leading to drug discontinuation.9 Despite cardiac and/or hepatic concerns, the newer CGRP antagonists are evidenced as safer and better tolerated. Upper respiratory and urinary tract infections, fatigue, arthralgia, and injection-site pain are reported. No central nervous system toxicity has been described, possibly due to limited blood–brain barrier passage. The long-term role of nonselective CGRP blockade in effects such as pituitary gland dysfunction, ischemic events, hypertension, gastrointestinal disturbances are currently being researched.