Calcitonin Gene-related Peptide Monoclonal Antibodies Research Articles

A new era for migraine: The role of calcitonin gene-related peptide in the trigeminovascular system.

There is a huge improvement in our understanding of migraine pathophysiology in the past decades. The activation of the trigeminovascular system has been proved to play a key role in migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are widely distributed in the trigeminovascular system. The CGRP is expressed on the C-fibers, and the CGRP receptors are distributed on the A-δ fibers of the trigeminal ganglion and nerves. Further studies found elevated serum CGRP level during migraine attacks, and infusion of CGRP can trigger migraine-like attacks, provide more direct evidence of the link between CGRP and migraine attack. Based on these findings, several treatment options have been designed for migraine treatment, including CGRP receptor antagonists (gepants) and monoclonal antibodies targeting CGRP or CGRP receptors. The clinical trials show both gepants and monoclonal antibodies are effective for migraine treatment. In this section, we describe the roles of the trigeminovascular system in migraine, the discovery of CGRP, and the CGRP signaling pathway.

Novel Medications for the Treatment of Migraine.

To describe the new classes of medication for headache management and their roles in clinical practice. Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT1F receptor to provide acute treatment without vasoconstrictive effects. This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications. At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019. The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

Exploring the effects of extracranial injections of botulinum toxin type A on prolonged intracranial meningeal nociceptors responses to cortical spreading depression in female rats.

BackgroundBotulinum neurotoxin type A, an FDA-approved prophylactic drug for chronic migraine, is thought to achieve its therapeutic effect through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with myelinated nociceptors and potentially the vasculature and immune cells. Prior investigations to determine botulinum neurotoxin type A effects on meningeal nociceptors were carried out in male rats and tested with stimuli that act outside the blood brain barrier. Here, we sought to explore the effects of extracranial injections of botulinum neurotoxin type A on activation of meningeal nociceptors by cortical spreading depression, an event which occurs inside the blood brain barrier, in female rats.Material and methodsUsing single-unit recording, we studied myelinated C- and unmyelinated Aδ-meningeal nociceptors' responses to cortical spreading depression 7–14 days after injection of botulinum neurotoxin type A or saline along calvarial sutures.ResultsIn female rats, responses to cortical spreading depression were typically more prolonged and, in some cases, began at relatively longer latencies post-cortical spreading depression, than had been observed in previous studies in male rats. Extracranial administration of botulinum neurotoxin type A reduced significantly the prolonged firing of the meningeal nociceptors, in the combined sample of Aδ- and C-fiber, but not their response probability.DiscussionThe findings suggest that the mechanism of action by which botulinum neurotoxin type A prevents migraine differ from the one by which calcitonin gene-related peptide monoclonal antibodies prevent migraine and that even when the origin of migraine is central (i.e. in the cortex), a peripherally acting drug can intercept/prevent the headache.

Fremanezumab in the treatment of migraines: evidence to date.

Calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology, and CGRP monoclonal antibodies including fremanezumab may be a safe effective preventive therapy. Phase IIb studies in episodic migraine (EM) and chronic migraine (CM) demonstrated efficacy at both the monthly 225 mg and quarterly 675 mg doses. The Phase III trials for EM and CM both showed a reduction in the primary endpoint of monthly migraine days (MMD). In the EM trial, the baseline MMD of 8.9 days was reduced to 5.3 at 12 weeks and to 4.0 days in the 6-month open-label extension (OLE) for monthly dosing. In the quarterly dosing, the baseline was 9.2 days reduced to 5.3 at 12 weeks and to 4.2 days in the OLE. In the CM data for monthly dosing, the baseline was 16.2 days decreased to 11.4 at 12 weeks then to 8.3 in the OLE. In the CM quarterly dosing, the baseline of 16.4 days was reduced to 11.9 at 12 weeks and 9.9 days in the OLE. Randomized controlled trials of fremanezumab in both episodic cluster and post-traumatic headache are underway, but the trial for chronic cluster headache was stopped for futility. The most common adverse events are injection site pain (24% vs 22% for placebo), induration (17% vs 13% for placebo), and erythema (16% vs 12% for placebo). Severe adverse events were reported in 3.9% of the fremanezumab vs 3.7% of the placebo. No changes in vitals or ECG were reported. The long-term effects are not known, but the American Headache Society recommends that CGRP monoclonal antibodies be considered in EM or CM depending on previous medication trials and headache disability/frequency. Further, post-market studies are required, but for EM and CM fremanezumab is a new option for migraine preventive treatment.

Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review.

Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.

The Role of Anti-calcitonin Gene-related Peptide in Migraine and its Implication in Developing Countries: A Reasonable Option to Consider Despite Higher Cost.

Migraine is among the commonest causes of headache in all ages. It is the second most common cause of neurological disability. Currently, antihypertensive, antidepressants and antiepileptic drugs are reasonable preventable medications for chronic migraine. Despite the higher levels of stigma associated with this disease, fewer attempts were made in past regarding the treatment options for chronic migraine. Recently, a novelty treatment was introduced known as calcitonin gene-related peptide (CGRP) monoclonal antibodies as a possible mechanism for the prevention of migraine attacks. CGRP played an important role in the etiology of migraine headaches and was considered as the major peptide behind the cause of the headache disorders. We have reviewed the benefits of these monoclonal antibodies in terms of their efficacy and adverse effects with the available treatment choices. These drugs showed superior results when compared to the placebo and were considered generally safe in the majority of clinical trials. Earlier versions of CGRP antagonists, known as gepants, were less tolerable due to their tendency to cause liver and cardiovascular complications. Thus, in comparison to the earlier gepants, these CGRP monoclonal antibodies were safer and demonstrated excellent tolerability. Short-term side effects were only limited to mild-moderate injection site rash or pruritus, however, their long-term side effects are still unknown. Despite the higher cost of these drugs, we have analyzed the applicability of this drug in the developing countries. Although the quality-adjusted life year (QALY) gained per cost of the drug is still expensive and majority of people may not afford, its excellent tolerability and less adverse effects should also be considered a reason to implement this drug, particularly for resource-limited countries. Moreover, these medications could also become a prototype for future inventions and creations (cost-effective versions for resource-limited countries). In conclusion, this review suggests that CGRP monoclonal antibodies are safer and excellent alternate option for patients with chronic migraine as it has better efficacy, tolerability, and provides a hope to reduce the stigma associated with migraine. All these benefits should be the deciding factors when opting for this treatment and the decision should not be made solely on the socioeconomic status.

How much do calcitonin gene-related peptide monoclonal antibodies improve the quality of life in migraine? A patient's perspective.

Migraine is a prevalent and extremely disabling brain disorder, with an impact on the individual, family, workplace and society. This review focuses on describing Calcitonin Gene Related Peptide Monoclonal Antibodies (CGRP-mABs) efficacy on improving the quality of life (QoL) and decreasing the disability and impact of migraine measured with patient related outcomes (PROs), on patients who participated in clinical trials with erenumab, fremanezumab, galcanezumab and eptinezumab. The goal is to better reflect the effect of these preventive migraine treatments in the daily life of our patients. CGRP-mABs have been approved by the Food and Drug Administration's (FDA) and European Medicines Agency (EMA) as the first migraine specific treatment for the prevention of migraine. In clinical trials, CGRP-mABs have proven to achieve their primary endpoint which is to reduce the number of headache days, and also have shown to have an impact on disability, QoL and workplace productivity. CGRP-mABs have an impact on the disability, QoL, workplace productivity and global impression of improvement of migraine, which will translate into changes in the real world of migraine patients who are treated with CGRP-mABs.

CGRP ligand and receptor monoclonal antibodies for migraine prevention: Evidence review and clinical implications.

Monoclonal antibodies that target calcitonin gene-related peptide or the canonical calcitonin gene-related peptide receptor have emerged as effective and well tolerated for the preventive treatment of migraine. These large molecules appear ideally suited for migraine prevention. They have an extended biological half-life, are administered either monthly or quarterly either by subcutaneous injection or intravenous infusion, require minimal or no dose-titration and have the potential for a rapid onset of effect compared to conventional oral preventive drugs. There is high selectivity and they target an important mediator in the pathogenesis of migraine. Phase II and pivotal phase III studies have all yielded positive results with a favorable adverse event profile. No serious treatment-related adverse outcomes have thus far been reported in controlled or long-term open-label extension studies. This tolerability profile promises to improve adherence and, possibly, long-term outcomes. Calcitonin gene-related peptide monoclonal antibodies are effective and well tolerated for the preventive treatment of migraine. They have distinct advantages over currently available oral preventive drugs. While treatment-related serious adverse events have not been observed in open-label extension studies, long-term outcomes and safety will require broad exposure in heterogeneous patient populations in clinical practice. In addition, their safety in women, especially during pregnancy, will require longitudinal surveillance. Given the overlapping mechanism(s), the effectiveness of existing (triptans) and emerging (calcitonin gene-related peptide receptor antagonists) acute therapies in those using a calcitonin gene-related peptide mAb will require further study.

Migraine and CGRP: an overview of current preventive treatments and new CGRP pathway monoclonal antibodies

Migraine is a complex, disabling neurological disorder, characterised by repeated bouts of headache and associated symptoms. The ongoing management of frequent migraine relies on preventive treatments and several drugs that have been approved for migraine prevention. However, the majority of these drugs have been developed for other indications, and their regular use is limited by side effects, patient comorbidities and/or inadequate efficacy. This lack of appropriate, well-tolerated treatments leaves a substantial number of sufferers with unmet treatment needs. New migraine-specific treatments are therefore sought. On the horizon is a new class of compounds, monoclonal antibodies, targeting the CGRP (calcitonin gene-related peptide) pathway. In this paper we present an overview of migraine, current preventive treatments and the new CGRP monoclonal antibodies.

Migraine and cluster headache \u2013 the common link

Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.

The efficacy and safety of calcitonin gene-related peptide monoclonal antibody for episodic migraine: a meta-analysis.

This meta-analysis was performed to evaluate the efficacy and safety of monoclonal antibodies against calcitonin gene-related peptide (CGRP) for episodic migraine prevention. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from inception to April 2018. Studies considered to be eligible were randomized controlled trials about efficacy and safety of calcitonin gene-related peptide monoclonal antibody for episodic migraine prevention. Eight randomized controlled trials involving 2292 patients were included. The outcomes of this meta-analysis presented that CGRP monoclonal antibodies for preventive treatment of episodic migraine significantly reduced the monthly migraine days from baseline [weighted mean difference (WMD) = - 1.52; 95%CI, - 1.92 to - 1.11; Z = 7.40; P < 0.001] and monthly acute migraine-specific medication consumption from baseline [WMD = - 1.45; 95%CI, - 2.17 to - 0.72; Z = 3.93; P < 0.001], as compared with placebo group. CGRP monoclonal antibodies for preventive treatment of episodic migraine significantly increased the ≥ 50% reduction from baseline in migraine days per month [RR = 1.54; 95%CI, 1.38 to1.71; Z = 7.88; P < 0.001]. The adverse events were similar between the CGRP monoclonal antibody group and placebo group (P = 0.998). The outcomes of subgroup analysis showed that erenumab, galcanezumab, and fremanezumab significantly reduced the monthly migraine days from baseline and increased the ≥ 50% reduction from baseline in migraine days per month. Both erenumab and fremanezumab significantly reduced from baseline. Based on the results of this meta-analysis, CGRP monoclonal antibodies significantly reduced the monthly migraine days and acute migraine-specific medication. CGRP monoclonal antibodies were effective and safe for preventive treatment of episodic migraine.

Polygenic risk score: use in migraine research

BackgroundThe latest Genome-Wide Association Study identified 38 genetic variants associated with migraine. In this type of studies the significance level is very difficult to achieve (5 × 10− 8) due to multiple testing. Thus, the identified variants only explain a small fraction of the genetic risk. It is expected that hundreds of thousands of variants also confer an increased risk but do not reach significance levels. One way to capture this information is by constructing a Polygenic Risk Score. Polygenic Risk Score has been widely used with success in genetics studies within neuropsychiatric disorders. The use of polygenic scores is highly relevant as data from a large migraine Genome-Wide Association Study are now available, which will form an excellent basis for Polygenic Risk Score in migraine studies.ResultsPolygenic Risk Score has been used in studies of neuropsychiatric disorders to assess prediction of disease status in case-control studies, shared genetic correlation between co-morbid diseases, and shared genetic correlation between a disease and specific endophenotypes.ConclusionPolygenic Risk Score provides an opportunity to investigate the shared genetic risk between known and previously unestablished co-morbidities in migraine research, and may lead to better and personalized treatment of migraine if used as a clinical assistant when identifying responders to specific drugs. Polygenic Risk Score can be used to analyze the genetic relationship between different headache types and migraine endophenotypes. Finally, Polygenic Risk Score can be used to assess pharmacogenetic effects, and perhaps help to predict efficacy of the Calcitonin Gene-Related Peptide monoclonal antibodies that soon become available as migraine treatment.KeywordsMigraine genetics; Genome-Wide Association Studies; Polygenic Risk Score; pleiotropy; endophenotype.

CGRP in Animal Models of Migraine.

With the approval of calcitonin gene-related peptide (CGRP) and CGRP receptor monoclonal antibodies by the Federal Drug Administration, a new era in the treatment of migraine patients is beginning. However, there are still many unknowns in terms of CGRP mechanisms of action that need to be elucidated to allow new advances in migraine therapies. CGRP has been studied both clinically and preclinically since its discovery. Here we review some of the preclinical data regarding CGRP in animal models of migraine.

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress.

Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.

Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors.

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.SIGNIFICANCE STATEMENT Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.

Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment.

Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody.

A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action.

Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies

The results of phase 2 randomized controlled trials for the prevention of episodic and chronic migraine demonstrating the efficacy and safety of four mAbs targeting the calcitonin gene-related peptide (CGRP) pathway [ALD403 (eptinezumab), AMG334 (erenumab), LY2951742 (galcanezumab) and TEV48125 (fremanezumab)] have been published recently, and phase 3 trials are in process. This development will change headache management fundamentally. We aim to summarize and compare the phase 2 data. The change from baseline in the number of migraine days at the end of treatment in high-frequency episodic migraine was -1 (at weeks 5-8), -1.1 (at weeks 9-12), -1.2 (at weeks 9-12) and -2.6 (at weeks 9-12) days for ALD403, AMG344, LY2951742 and TEV48125 (225 mg), respectively. Number needed to treats for responders and odds ratio for any adverse event were 4.7, 6.2, 4.0 and 4.0 and 1.09, 0.96, 1.07 and 1.05, respectively. All four CGRP antibodies display comparable efficacy that does not differ significantly from that of the currently available oral antimigraine drugs. However, their safety and tolerability profiles as well as low frequency of administration looks promising but remains to be verified in long-term and large-scale trials. Considerations related to pregnancy, risk for cardiovascular effects and cost are subject for further evaluation.

The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine.

The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites, peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in understanding the complexity of the trigeminovascular pathway and its peptide transmitters.

Targeting CGRP: A New Era for Migraine Treatment.

Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs).