2020-09-02| R&DTechnology

Spotlight: The Revitalization of Chronic Migraine Therapies

by GeneOnline
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The recent FDA approvals of eptinezumab (Vyepti) and other CGRP blockers signal a new era of evidence-based treatment options for chronic migraines.

By Bhavya Ravi, Ph.D.


Chronic migraine is a disabling condition that impacts about 2% of all adults, but it remains an underdiagnosed and undertreated condition. The international headache society classification of headache disorders (ICHD-3) defines a chronic migraine (CM) as a headache that occurs ≥ 15 days/month for > 3 months with features of migraine on ≥ 8 days a month. CM and episodic migraine (EM) are both parts of the spectrum of migraine disorders, but CM and EM do have clinically distinct features.

CM is associated with greater disability and thereby has far greater deleterious impacts on occupational functioning and quality of life. Current therapies for CM function by acting as prophylactic agents to reduce the frequency of migraines. There is a large unmet need for more effective and well-tolerated prophylactic treatments for both forms of migraine. With recent FDA approvals of eptinezumab-jjmr (Vyepti) and rimegepant (Nurtec ODT), the field is transforming into a dynamic and rapidly expanding area for future research and drug discovery.


Pathophysiology of Chronic Migraine

The pathogenesis of CM is not entirely understood. Still, both genetic factors and environmental triggers play a role in the functional changes that occur in the brains of patients with CM. In some cases, EM progresses into CM by mechanisms that are complex and poorly understood. However, risk factors include a high frequency of headache attacks, overuse of migraine medication, anxiety, and stress.

Key functional changes that have been reported to occur in the brains of CM patients include increased cortical hyperexcitability, central trigemino-thalamic sensitization, and dysfunctions in descending pain modulatory pathways. Increased excitability in the visual and somatosensory cortices of CM patients have been assessed by electrophysiological as well as cutting-edge neuroimaging techniques, but further longitudinal studies are required to determine causative relationships between these structural/functional changes and the onset of CM.

Besides alterations in cortical excitability, dysregulations in the descending pain modulatory pathways in the brainstem, particularly in the periaqueductal grey (PAG), which sends projections to facilitate or inhibit pain transmission in the spinal cord, also play a role in CM pathogenesis. Lastly, central and peripheral sensitization in the trigeminal system is a critical clinical indicator of CM. Patients with CM frequently present with cutaneous allodynia and have lower pain thresholds than patients with EM when quantitative sensory tests are performed. Central sensitization involving second and third-order neurons in the sensory pathway to the brain, which is a physiological feature of chronic pain conditions in general, is also observed in CM. The increased presence of TRPV1 immunoreactive fibers in the periphery of CM patients indicates that peripheral sensitization may also be a key component in CM.


Calcitonin Gene-Related Peptide (CGRP) – a Key Molecule Involved in CM

CGRP is secreted by trigeminal afferents and mediates vasodilation and inflammatory events in the dura and the trigeminal ganglion, and can therefore trigger or amplify migraine attacks. CGRP levels are elevated in the saliva and peripheral blood of CM patients during the migraine phase as compared to baseline (interictal) levels, indicating the promising applicability of CGRP as a CM biomarker to facilitate accurate diagnosis and determining effective treatment response. In addition to CGRP, other molecules such as serotonin, pituitary adenylyl cyclase-activating peptide-38 (PACAP), tumor necrosis factor α, endocannabinoids, and orexin-A have been implicated in CM.


Current Treatment Options for CM

While the goal of acute therapy is to treat an ongoing migraine attack by effectively blocking it, patients with CM invariably require prophylactic treatments to prevent attacks and to decrease over-reliance on acute treatments, which in the long run may lead to complications associated with medication overuse headaches (MOH). Prophylactic treatments may also serve in preventing EM patients from progressing to CM. Orally administered drugs that are prescribed for prophylaxis of CM include beta-blockers, anticonvulsants, calcium-channel blockers, tricyclic antidepressants, serotonin antagonists, antihypertensives, and antidepressants that act as serotonin or norepinephrine reuptake inhibitors. Onabotulinumtoxin-A (OBT-A), which is administered by intramuscular injection, and topiramate have shown to be effective in randomized controlled trials as having a preventative effect on migraines. OBT-A was approved in Italy for the prophylactic treatment of CM in 2013 and was shown to be well-tolerated and effective in the prevention of CM in phase III PREEMPT clinical trial (NCT00156910).

Since 2018, several small-molecule CGRP blockers and anti-CGRP monoclonal antibodies have been approved for the acute and prophylactic treatment of CM, and the key characteristics are listed below. The macromolecule anti-CGRP/R antibody drugs do not permeate the blood-brain barrier and are not metabolized in the liver. Therefore they do not exert CNS-effects or cause hepatotoxicity.


Treatment Mechanism Administration Approval status
Onabotulinumtoxin-A Inhibits peripherally released CGRP and interferes with TRP channels in nociceptive neurons, thereby reducing neuronal hyperexcitability and sensitization Intramuscular injection into at least 31 injection sites across 7 head and neck muscles (treatment every 3 months) Approved in EU since 2013 for CM

Phase III PREMPT clinical trial completed in the US and Canada (NCT00156910)TopiramatePrevents cortical spreading by ion channel modulation and neurotransmissionOral administrationFDA approved (100mg/day) in adults for the prophylaxis of migrainesFremanezumab (previously LR-101/ TEV-48125 or RN307)Binds CGRP ligands to block both α- and β-isoforms of CGRP from binding to the CGRP receptor, thereby preventing the activation of the trigeminal vascular systemSubcutaneous injection FDA approved in 2018 for the prevention of migraine in adultsGalcanezumab & erenumabHumanized monoclonal antibody that selectively binds to CGRPSubcutaneous injectionFDA approved in 2018 for the prevention of migraine in adultsUbrogepantOral small molecule CGRP receptor antagonist Oral tabletFDA approved in 2019

Acute treatment of migraine with or without auraLasmiditanHigh-Affinity 5-HT1F (serotonin) receptor agonistOral tabletFDA approved in 2019

Acute treatment of migraine with or without auraEptinezumab CGRP blocker30-minute intravenous infusion (once in 3 months)FDA approved in 2020 for the prevention of migraineRimegepantCGRP blockerFast-acting orally disintegrating tablet (ODT)FDA approved in 2020

Acute treatment of migraine with or without aura


Eptinezumab (Vyepti)- the First IV Administered CGRP Blocker

In April 2020, the FDA approved the CGRP blocker eptinezumab (Vyepti) for the prevention of migraines in adults. The drug is purported to offer unique benefits compared to other FDA-approved CGRP blockers. Clinical data for eptinezumab showed a stronger prophylactic effect seen as early as 1-day post-infusion. Data from the PROMISE-2 clinical trial (NCT02974153) showed that patients could achieve a reduction in migraine days of at least 75% and experience a sustained migraine improvement through 6 months. IV delivery allows for the quick and complete delivery of the drug into the bloodstream for effective prophylaxis in contrast to other FDA-approved CGRP blockers, which are administered subcutaneously and take anywhere between 2 days to 1 week to take effect.

In summary, monoclonal antibodies, specifically targeting CGRP, offer new hope to patients with CM. To fully realize the therapeutic potential of these drugs and to reduce the disability associated with CM, increased disease awareness and accurate diagnosis of CM is necessary. High-level multi-disciplinary care will be needed for CM patients at headache centers to provide effective and individualized evidence-based prophylactic treatment strategies. Fundamental research focused on the development of biochemical and clinical biomarkers will additionally assist clinicians in identifying good responders to the various migraine drugs, including topiramate, OBT-A, and anti-CGRP monoclonal antibodies in the future.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Spotlight: Infusion-Related Reactions Associated with Rapid Infusion of Daratumumab



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