CGRP monoclonal antibodies and CGRP receptor antagonists (Gepants) in migraine prevention.

Migraine is a prevalent and disabling neurological disease. Its preventive treatment for decades has been rather limited due to the absence of disease-specific therapies with limited efficacy and tolerability. The advances made in migraine research have led to the discovery of the calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology. CGRP is a neuropeptide that acts as potent vasodilator and is involved in pain processing. Increased levels of plasma CGRP have been observed during migraine attacks as well as interictally when comparing patients with migraine and healthy controls. In the last years, two classes of drugs antagonizing CGRP have therefore been developed as the first migraine-specific preventive treatments: anti-CGRP monoclonal antibodies (mAbs) and gepants. Four mAbs have been approved: erenumab, galcanezumab, fremanezumab, and eptinezumab. Gepants are small molecules that antagonize the CGRP receptor; currently only rimegepant and atogepant have been approved for migraine prevention. These new drugs have demonstrated efficacy and safety in clinical trials for both episodic and chronic migraine, and results from their real-world experience are being increasingly reported in literature. In this review, we provide an overview of anti-CGRP drugs and their placement in migraine prevention.

Pharmacotherapies for Migraine and Translating Evidence From Bench to Bedside.

Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene-related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene-related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

BACKGROUND: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. METHODS: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. RESULTS: MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. CONCLUSIONS: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

New drugs targeting calcitonin gene-related peptide for the management of migraines.

INTRODUCTION: Significant advances in migraine research have contributed to the development of new drugs for the treatment of migraine. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) or its receptor and CGRP receptor antagonists (gepants) have been associated with a good safety profile and resulted in an overall efficacy in reducing the number of monthly migraine days both in episodic and chronic forms of migraine. AREAS COVERED: The results from main investigation studies (phase 2 or 3) of CGRP-targeting drugs (both anti-CGRP mAbs and gepants) are reported in this expert-opinion review. EXPERT OPINION: The introduction of new drugs targeting CGRP is a significant breakthrough in the migraine field, and represents a new generation of therapeutic agents that are available to manage migraine. The evaluation of efficacy and safety in the long-term follow-up and the development of trials comparing the available drugs could improve the current knowledge. The economic sustainability of these drugs remains to be clarified, and a cost-cutting campaign should be promoted based on the high burden of migraine.

Efficacy and safety of monoclonal antibodies targeting CGRP in migraine prevention. GRADE tables elaborated by the ad hoc working group of the International Headache Society.

OBJECTIVES: Grading of Recommendations, Assessment Development and Evaluation (GRADE) tables were created using a standardized and independent assessment of the efficacy and side effects of treatments with monoclonal antibodies (mAb) against calcitonin gene-related peptide (CGRP) or the CGRP receptor for the prevention of migraine. We hope to provide support for author groups writing national or regional treatment or management guidelines for migraine prevention. METHODS: We formulated patient/population, intervention, comparison and outcomes (PICO) questions for the efficacy and safety of mAb against CGRP or the CGRP-receptor for the prevention of migraine attacks. We performed a systematic literature research for randomized studies with eptinezumab, erenumab, fremanezumab and galcanezumab and a pooled analysis was done, using RevMan 5.4 software. For dichotomous outcomes we used risk ratio, and for continuous outcomes we used the mean difference to compare and summarize the evidence between groups. The evidence across studies, for each outcome, except serious adverse events, was assessed using GRADE evidence tables. Additionally, we report the serious adverse effects in the tables of the characteristics of the studies. RESULTS: All mAb are superior to placebo for the reduction in monthly migraine days (days in which a headache consistent with migraine occurred) in participants with episodic and chronic migraine. There are no major differences between the mAb. CONCLUSIONS: The GRADE evidence summary tables provided will support author groups to write treatment guidelines for the prevention of migraine with mAb.

Long-Term Effect of Switching From an Anti-CGRP Receptor to an Anti-CGRP Ligand Antibody in Treatment-Refractory Chronic Migraine: A Prospective Real-World Analysis.

In migraine patients with a poor response to a calcitonin gene-related peptide monoclonal antibody against the receptor, switching to a calcitonin gene-related peptide monoclonal antibodies against the ligand may be beneficial. This was a long-term real-world prospective analysis conducted in treatment-refractory chronic migraine patients coming from two large tertiary referral headache centres, who did not achieve a meaningful response to erenumab and were switched to fremanezumab. Responders to fremanezumab were considered those who achieved at least 30% reduction in monthly migraine days by month 3, compared to the post-erenumab baseline. Secondary efficacy and disability outcomes were analysed. Thirty-nine patients (female n = 32, 82.1%; median age: 49 years old, IQR = 29.0-56.0) were included. After three months of treatment with fremanezumab, ten out of 39 patients (25.6%) were considered responders. Four of the 11 patients who continued fremanezumab became responders at month 6, increasing the number of responders to 14 patients (35.9%). Responders received a median of 12 injections (IQR = 9.0-18.0) at the time of the analysis. After the last treatment, 13 patients (33.3%) remained responders. The number of mean monthly migraine days significantly decreased from 21.4 at baseline (IQR = 10.7-30.0) to 8.6 (IQR = 3.8-13.9) at the last follow-up. Painkillers intake and HIT-6 score were significantly reduced at the last follow-up. About 1/3 of patients with treatment refractory chronic migraine who have a disappointing response to erenumab and switch to fremanezumab, obtained a meaningful and sustained improvement of their migraine load over time, supporting the appropriateness of this therapeutic approach in clinical practice.

Pharmaceutical aspects of novel CGRP inhibitors used in the prophylaxis and treatment of migraine.

Migraine is one of the most prevalent neurological disorders known to have an immense adverse socio-economic impact. Neurogenic inflammation is thought to mediate migraine, and CGRP is known to be released during acute attacks of migraine that causes vasodilation in extracerebral arteries. Hence, CGRP is believed to play a key role in triggering migraine. Although there are several classes of medications used in the prevention and treatment of migraine pain, targeted therapies are fewer. Therefore, CGRP receptor inhibitors which bind to CGRP receptors in the cranial vasculature have been developed as drugs for migraine therapy. In this review article, we describe the basic pathophysiologic mechanism that causes migraine headaches and the pharmacotherapeutic aspects of CGRP inhibitors available for clinical use. For the purpose of this review, a search was performed on the pharmacological, pharmacokinetic, pharmaceutical, and therapeutic aspects of the FDA-approved CGRP inhibitors viz. erenumab, ubrogepant, rimegepant, atogepant, eptinezumab, fremanezumab, and galcanezumab in UpToDate database and PubMed beginning year 2000. Based on the data collected, a risk-benefit comparison of different classes of novel CGRP inhibitors available for clinical use is provided. This comparative review may help the healthcare providers in choosing the best pharmacotherapeutic agent for their patients based on patient-specific information.

Novel Migraine Treatments: A Review

Aims: To present a review of the mechanisms of action, available clinical data, and safety profiles of novel migraine therapeutics to inform practice. Methods: PubMed, Medline, and Google Scholar were searched for randomized controlled trials (24 publications), review articles (15 publications), and other pertinent literature (16 publications) discussing the novel migraine therapeutics available between the years 2010 and 2021. All publications were reviewed to assess the mechanism of action, relevant clinical data, and side effect profile for each novel treatment. Therapeutic gain was also recorded in studies that included a placebo arm. Results: A total of 55 studies were included in the final analysis. In the preventive treatment of migraine, novel medications target calcitonin gene-related peptide (CGRP) and fall into either the monoclonal anti-CGRP or gepant class. For the acute treatment of migraine, novel medications fall into either the ditan or gepant class. Several medical devices have been developed for the acute and preventive treatment of migraine. Conclusion: Novel therapeutics are available for both the prevention and acute treatment of migraine headaches. These new medications and neuromodulatory devices appear overall to be safe and effective in the management of migraine headaches.

Real-World Patient Experience of CGRP-Targeting Therapy for Migraine: a Narrative Review.

PURPOSE OF REVIEW: To summarize available calcitonin gene-related peptide (CGRP)-targeting therapies for migraine and discuss their use in real-world populations. BACKGROUND: CGRP has long been a topic of interest in migraine pathophysiology, with new therapies targeting CGRP since 2018 for both the preventive and acute treatment of migraine. METHODS: We searched PubMed using keywords including "migraine," "CGRP," "real-world," "erenumab," "galcanezumab," "fremanezumab," "eptinezumab," "ubrogepant," "rimegepant," and "atogepant." We reviewed all pertinent studies and summarized main findings. We also compiled detailed patient characteristics (e.g., migraine diagnoses, medication overuse, prior treatment failures) and treatment outcome measures, such as 50% responder rates, reduction in migraine days, and adverse event rates in several tables. Overall, studies reporting real-world patient experiences of CGRP-targeting therapies suggested meaningful effectiveness for migraine treatment with response rates comparable to the numbers reported in clinical trials. Furthermore, studies suggested benefit in patients with multiple prior unsuccessful treatment trials, medication overuse, and complex medical comorbidities. In some studies, adverse event rates have been notably higher than reported in clinical trials. Additional long-term data is needed to further evaluate sustained efficacy, predictors of treatment response, and adverse events.

Calcitonin gene-related peptide and neurologic injury: An emerging target for headache management.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide known to be involved in the trigeminovascular system and to function as a potent vasodilator. Although it has emerged as a viable target for headache management with targeted treatments developed for migraine, a highly disabling neurovascular disorder, less is known about CGRP's role in other neurologic conditions such as traumatic brain injury and subarachnoid hemorrhage. The literature has shown that during these injury cascades, CGRP receptors are modulated in varying ways. Therefore, CGRP or its receptors might be viable targets to manage secondary injuries following acute brain injury. In this review, we highlight the pathophysiology of the CGRP pathway and its relation to migraine pathogenesis. Using these same principles, we assess the existing preclinical data for CGRP and its role in acute brain injury. The findings are promising, and set the basis for further work, with specific focus on the therapeutic benefit of CGRP modulation following neurologic injury.

Recent advances in targeting calcitonin gene-related peptide for the treatment of menstrual migraine: A narrative review.

ABSTRACT: Menstrual migraine (MM) has a longer duration and higher drug resistance than non-perimenstrual migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in the peripheral and central nervous systems throughout the trigeminovascular system. The CGRP/CGRP receptor axis plays an important role in sensory physiology and pharmacology. CGRP receptor antagonists and anti-CGRP monoclonal antibodies (mAbs) have shown consistent efficacy and tolerability in the prevention of chronic or episodic migraine and are now approved for clinical use. However, few studies have reported the use of these drugs in MM, and no specific treatment for MM has been approved. This review aimed to shed light on the recent advances in targeting calcitonin gene-related peptides for the treatment of menstrual migraines in PubMed. In this review, we first discuss the axis of the CGRP/CGRP receptor. We then discuss the role of CGRP receptor antagonists and anti-CGRP mAbs in MM treatment. Finally, we discuss the role of the combination of anti-CGRP mAbs and CGRP receptor antagonists in migraine treatment and the drugs that inhibit CGRP release. Altogether, the anti-CGRP mAbs or CGRP receptor antagonists showed good efficacy and safety in the treatment of MM.

Patient characteristics and treatment utilization among patients with migraine initiating self-injectable calcitonin gene-related peptide monoclonal antibody and novel acute medication.

OBJECTIVE: This study describes patient characteristics and utilization of recently approved novel acute medication and calcitonin gene-related peptide (CGRP) monoclonal antibodies. METHODS: This retrospective observational study utilized the IBM MarketScan Research Database and Optum's Clinformatics Data Mart from May 2017 through December 2020 (index period). Adult patients initiating self-injectable CGRP monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab) and novel acute migraine medications (lasmiditan, rimegepant, ubrogepant) with: (a) ≥3 months overlap between the index medication and second medication initiated along with it; (b) ≥1 claim for migraine diagnosis; and (c) continuous medical and pharmacy benefits 12 months pre- and 3 months post-index were included. Data are presented descriptively. RESULTS: A total of 2840 patients from the MarketScan database and 657 patients from the Optum database were included. Identified patients' (MarketScan/Optum) mean age was 44.7/51.2 years; they were mostly women (88.8%/87.7%); a majority had a chronic migraine diagnosis (64.4%/71.4%) and were prescribed both preventive and acute treatments for migraine in the pre-index period. Most patients received a combination of both preventive and acute medications binding CGRP receptors (43.6%/59.0%) or preventive medication binding CGRP ligands and acute medication binding CGRP receptors (51.9%/34.9%). Mean (SD) number of days of concomitant use of CGRP and novel acute medications were: MarketScan, 29.1 (18.7); Optum, 31.8 (20.4). Prescribing patterns were similar across healthcare provider types within each database. CONCLUSIONS: Understanding patient characteristics and treatment utilization patterns among patients prescribed both a CGRP mAb and novel acute medication may provide valuable insight regarding migraine treatment selection for healthcare decision makers.

Calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks-Successful translation of basic science to clinical practice.

Migraine is a highly prevalent neurovascular disorder afflicting more than 15% of the global population. Nearly three times more females are afflicted by migraine in the 18-50 years age group, compared to males. Migraine attacks are most often sporadic, but a subgroup of individuals experience a gradual increase in frequency over time; among these, up to 1%-2% of the global population develop chronic migraine. Although migraine symptoms have been known for centuries, the underlying mechanisms remain largely unknown. Two theories have dominated the current thinking-a neurovascular theory and a central neuronal theory with the origin of the attacks in the hypothalamus. During the last decades, the understanding of migraine has markedly advanced. This is supported by the early seminal demonstration of the trigeminovascular reflex 35 years ago and the insight that calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks. The more recent findings that gepants, small molecule CGRP receptor blockers, and monoclonal antibodies generated against CGRP, or its canonical receptor are useful for the treatment of migraine, are other important issues. CGRP has been established as a key molecule in the neurobiology of migraine. Moreover, monoclonal antibodies to CGRP or the CGRP receptor represent a breakthrough in the understanding of migraine pathophysiology and have emerged as an efficacious prophylactic treatment for patients with severe migraine with excellent tolerability. This review describes the progression of research to reach the clinical usefulness of a large group of molecules that have in common the interaction with CGRP mechanisms in the trigeminal system to alleviate the burden for individuals afflicted by migraine.

CGRP Targeting Therapy for Chronic Migraine-Evidence from Clinical Trials and Real-world Studies.

PURPOSE OF REVIEW: Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor have become part of the standard treatment for migraine in clinical practice. The current review focuses on the clinical evidence of CGRP monoclonal antibodies in patients with chronic migraine (CM), including more challenging cases. RECENT FINDINGS: CGRP monoclonal antibodies were more effective than placebo in reducing the number of monthly migraine days (MMDs), and the change relative to placebo in the treatment group was between - 1.2 and - 2.7 days at 3 months. CGRP monoclonal antibodies resulted in ≥ 50% response in 27.5 to 61.4% of patients, and doubled the odds for having ≥ 50% response. The findings were generally consistent in patients with coexisting medication overuse or with treatment failures to multiple preventive medications, including onabotulinumtoxinA. The results from real-world studies (RWS) were similar to those seen in clinical trials, and the changes from baseline in the number of MMDs and the response rates largely fell within the ranges of those reported in the treatment group in pivotal trials. The therapeutic effects typically started within a few days, and remained steady after regular treatment for up to 1 year. These agents were generally well tolerated, and the discontinuation rates due to adverse events in clinical trials and in many RWS were < 4.5%. CGRP monoclonal antibodies are effective and safe in the treatment of patients with CM, including clinical challenging cases. However, the role of CGRP monoclonal antibodies in a number of conditions, such as cardiovascular or cerebrovascular diseases, pregnancy, and overuse of opioids or barbiturates, needs to be further clarified.

Myocardial infarction associated with erenumab: A case report.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide or its receptor (CGRP-mabs) are novel drugs for resistant migraine prophylaxis. As CGRP-mabs cause inhibition of vasodilatation, their use is reserved to patients with no recent history of cardiovascular diseases. We report a case of myocardial infarction associated with erenumab. CASE: A 57-year-old woman with a familial history of coronaropathy was first treated with erenumab 70 mg for 6 months and then increased to 140 mg. Almost 5 months after, the patient presented chest pain, increased troponin, and abnormal electrocardiogram. A myocardial infarction without coronarography abnormality was diagnosed through MRI. CONCLUSION: Further evidence is needed to assess the risk of myocardial infarction in patients treated with a CGRP-mab. In patients over 40 years of age, the risk of coronary or cardiovascular events should be assessed using risk tables or algorithms to take into account cardiovascular risk factors. This may be complemented by appropriate examinations to measure the burden of coronary atherosclerosis, if necessary.

CGRP in Childhood and Adolescence Migraine: (Patho)physiological and Clinical Aspects.

PURPOSE OF REVIEW: To summarise and analyse the current knowledge of CGRP metabolism in childhood and adolescence and its role in childhood and adolescence migraine. RECENT FINDINGS: Influencing CGRP pathways is nowadays one of the main mechanisms to treat migraine. In adults, several clinical trials with different drug classes have supported this finding. However, only very little is known on these mechanisms in children and adolescents with migraine. Based on a literature search, it can be concluded that substantial parts of the CGRP pathways are already developed and working in the preterm fetus of animals. Newborn animals show high CGRP levels and high density of CGRP positive neurons and nerve fibres. In human studies, increased levels of CGRP were observed in childhood and adolescent migraine patients. Remedies based on influencing CGRP metabolism are also working in that age group. For triptans, this has clearly been shown; for gepants, no data are available, and for CGRP ligand/receptor antibodies, positive evidence is only available from case series. Only very little is known on CGRP metabolism in childhood and adolescence. However, placebo-controlled clinical trials both on CGRP antagonists and on CGRP ligand/receptor antibodies are under way and will show in some years whether these drug classes are efficacious also in children and adolescents.

CGRP and CGRP-Receptor as Targets of Migraine Therapy: Brain Prize-2021.

BACKGROUND: Migraine is a highly prevalent primary headache with an unclear pathomechanism. During the last 40 years, numerous hypotheses have arisen; among them, the theory of the trigeminovascular system is the primary one. It serves as a skeleton in successful preclinical studies and in the development of effective therapeutic options for migraine headache. OBJECTIVE: The brain prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were Lars Edvinsson, Peter Goadsby, Michael Moskowitz and Jes Olesen. They are the fathers of migraine pathomechanism, which led to revolutionary new treatments. This review summarizes their landmark findings. METHODS: Data related to this topic were reviewed from PubMed records published between 1979 and May 2021. Searches were based on preclinical and clinical studies in the covered field. The findings were listed in chronological order. From a therapeutic perspective, only randomized controlled trials and meta-analysis were discussed. RESULTS: The calcitonin gene-related peptide-related pathogenesis of migraine is based on the activation of the trigeminovascular system. The therapeutic triad for migraine is triptans, gepants, and calcitonin gene-related peptide-targeted monoclonal antibodies. CONCLUSION: In the past 40 years, the systematic work of leading headache scientists has resulted in robust theoretical and therapeutic knowledge in the preclinical and clinical study of migraine.

Effect of single dose Erenumab on cortical responses evoked by cutaneous a-delta fibers: A pilot study in migraine patients.

BACKGROUND: Erenumab is a monoclonal antibody against calcitonin gene-related peptide receptors, which showed efficacy in migraine attack prevention. The aims of the present pilot study were to i) evaluate the effect of single dose of Erenumab 70 mg on laser evoked potentials from trigeminal and brachial stimulation in a cohort of migraine patients; ii) correlate the neurophysiological changes with clinical outcome after 3 months' treatment. METHODS: Laser evoked potentials were recorded by 61 electroencephalogram channels before (T0), 1 h (T1) and 7 days after (T2) Erenumab 70 mg injection, stimulating the left and right forehead and the right hand. Laser evoked potential control 1 h after the injection served as placebo session. RESULTS: Seventeen migraine patients were evaluated. The N1 and N2 component obtained from the right and left trigeminal stimulation diminished in amplitude at T2, compared to T0 and T1 conditions. N2 habituation reduction slightly recovered at T2. Laser evoked potential changes did not correlate with clinical improvement after 3 months of Erenumab treatment. CONCLUSIONS: A single dose of Erenumab has a mild inhibitory effect on cortical responses evoked from trigeminal cutaneous a-delta fibers. Though this phenomenon was not predictive of the clinical outcome, it confirms a wide representation of calcitonin gene-related peptide receptors on trigeminal afferents.

CGRP Antagonists for the Treatment of Chronic Migraines: a Comprehensive Review.

PURPOSE OF REVIEW: The purpose of the following review is to summarize the most recent understanding of migraine pathophysiology, as well as of basic and clinical science pharmacologic literature regarding the development of calcitonin gene receptor peptide (CGRP) antagonists as a novel therapeutic modality for the treatment of migraine headaches. A review is provided of erenumab, the first of its class FDA approved CGRP antagonist. RECENT FINDINGS: Despite its high prevalence, the occurrence and treatment of migraine headaches is poorly understood. Erenumab and CGRP antagonists as a whole significantly reduce the average number of migraine days experienced in migraine sufferers. CGRP antagonists appear to significantly improve treatment outcomes in patients who suffer from episodic and chronic migraines. Erenumab is the first CGRP antagonist to be FDA approved for public use; however, further development of biologics in this class is underway.

European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention

BACKGROUND AND AIM: Monoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention. METHODS: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic review and analysis of the literature, assessed the quality of available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. RESULTS: We found low to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in patients with episodic migraine and medium to high quality of evidence to recommend erenumab, fremanezumab, and galcanezumab in patients with chronic migraine. For several clinical questions, there was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts' opinion. CONCLUSION: Monoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention. Real life data will be useful to improve the use of those drugs in clinical practice