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Table of Contents
CLINICAL PHARMACOLOGY
Year : 2020  |  Volume : 36  |  Issue : 1  |  Page : 104-109

Erenumab: A novel calcitonin gene-related peptide receptor antagonist developed specifically for migraine prevention


1 Department of Anesthesia and Pain Medicine, Division of Headache Medicine, University of Cincinnati, Cincinnati, Ohio, USA
2 Department of Internal Medicine, Division of Headache Medicine, University of Cincinnati, Cincinnati, Ohio, USA
3 Department of Neurology and Rehab Medicine, Division of Headache Medicine, University of Cincinnati, Cincinnati, Ohio, USA

Date of Submission03-Jan-2019
Date of Acceptance24-May-2019
Date of Web Publication18-Feb-2020

Correspondence Address:
Dr. Shuchita Garg
Department of Anesthesia and Pain Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joacp.JOACP_3_19

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  Abstract 


Headaches and migraines continue to be a leading cause of suffering and disability. As per the Global Burden of Disease Survey conducted in 2010, the exact magnitude of the disease still is underestimated. Migraine alone continues to rank seventh as a cause of disability. Various therapeutic modalities exist and newer classes of medications are currently being trialed to provide effective treatment to this population of patients. Erenumab, a calcitonin gene-related peptide receptor inhibitor, is a recent addition to this armamentarium and has been approved by the FDA for use in 2018. It has shown modestly improved outcomes according to the current trials. However, long-term outcomes and adverse effects still are under research. The following article elaborates on the current literature and evidence on this novel drug.

Keywords: Calcitonin gene-related peptide receptor antagonist, Erenumab, migraine


How to cite this article:
Garg S, Vij M, Edward N, Vij B. Erenumab: A novel calcitonin gene-related peptide receptor antagonist developed specifically for migraine prevention. J Anaesthesiol Clin Pharmacol 2020;36:104-9

How to cite this URL:
Garg S, Vij M, Edward N, Vij B. Erenumab: A novel calcitonin gene-related peptide receptor antagonist developed specifically for migraine prevention. J Anaesthesiol Clin Pharmacol [serial online] 2020 [cited 2020 Oct 20];36:104-9. Available from: https://www.joacp.org/text.asp?2020/36/1/104/278459




  Introduction Top


Hippocrates described the occurrence of migraine attacks as headaches including the visual disturbances during its aura and the relief from vomiting. The origin of the word “migraine” comes from the Greek word “hemicrania,” which meant “half the skull.” The word hemicrania in relation to migraine-like headaches was later established by the Greek physician; Galen of Pergamon. It was not until 1988 that the International Headache Society (IHS) comprehensively classified migraine along with other headache disorders.[1]

Migraine affects around 1 in 7 people and is the third most common disease in the world, just behind dental caries and tension-type headaches.[2] In terms of its global burden as a disease, it is ranked among the top 10 and second only to stroke in its number of associated disability-adjusted life years, among all the neurological disorders.[3],[4] Its prevalence in Indian setting remains understudied due to lack of available studies and enough data and owing to the variations in population groups in different parts of the country. Ray et al.[5] estimated the prevalence of migraines to be about 14.12% in the eastern part of the country and Kulkarni et al.[6] estimated it as high as 25.2% in a southern Indian state.

As per the IHS, migraine is defined as[1] episodic headache (that can last from 4–72 h) with two of the following:

  1. Unilateral pain
  2. Throbbing
  3. Aggravation of movement
  4. Pain of moderate or severe intensity.


And one of the following:

  1. Nausea or vomiting
  2. Photophobia or phonophobia.


While chronic migraine has been defined as 15 or more headache days per month with at least 8 migraine days,[1] it is known to affect 5–8% of persons with migraine. Episodic migraine is defined as fewer than 15 migraine days or headache days per month, with or without aura and accounts for more than 90% of persons with migraine.[1]

As migraine is thought to have a polygenetic etiology with environmental modifiers, there has been a paucity of specific therapeutic directions. Until recently, the management of migraine involved a complex multipronged approach of abortive, preventive, and bio-behavioral therapies.

Numerous pharmacological preventive therapies have been used such as beta blockers, valproate, and topamax, which have relatively stronger evidence for use as compared to serotonin antagonists, calcium channel blockers.[7] However, an optimal prophylactic treatment option remains elusive. A newer drug, erenumab, which is a calcitonin gene-related peptide receptor (CGRP) antagonist, was recently approved by the FDA on May 17, 2018, which projects a promising role in the preventive therapy of migraine and related disability.[8]

Erenumab

Erenumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that has high-affinity binding to the CRGP. It has been developed by utilizing recombinant DNA technology in Chinese hamster ovary cells. It has an estimated molecular weight of 150 kDa and is made up of 2 heavy chains (each containing 456 amino acids) and 2 light chains (each containing 216 amino acids).

CGRP is a neuropeptide that, along with its receptor, is present in both central and peripheral neurons.[9],[10] The peptide equally impacts the neuronal modulation of nociceptive signaling and vascular activity. These actions are enabled predominantly by its location in dorsal root and trigeminal ganglions, and it is these two-fold actions that make its role in causing migraine plausible.[11]

CGRP levels have been shown to surge excessively during a migraine and return to normal with headache relief. Inhibition of the effects of CGRP could theoretically attenuate compensatory vasodilation in ischemic-related conditions. This knowledge of contribution of CGRP in the pathophysiological processes fundamental to migraine disorders led to the development of CGRP antagonists (the “-gepants”) and four different antibodies targeting the CGRP receptor, namely erenumab or targeting CGRP itself (fremanezumab, eptinezumab, and galcanezumab).

The role of CGRP in migraine has been further elucidated in phase 2 and phase 3 clinical trials of small-molecule CGRP-receptor antagonists in acute migraine and is further supported by phase 2 and phase 3 trials of monoclonal antibodies targeting the CGRP pathway, which suggests that the pathway could be a target for preventive migraine treatment.[12]

Erenumab is a fully human monoclonal antibody that selectively and potently binds to the canonical CGRP receptor. A subcutaneous injection (SC) formulation of this drug (AIMOVIG™) has been recently approved in the United States for the prevention of migraine in adults,[8] and it has also received a positive opinion on 31 May 2018 in the European Union.[13]

Pharmacodynamics properties of Erenumab

Mechanism of action

Erenumab antagonizes the CGRP function through competitive blockade with high affinity and specificity. It thereby antagonizes the accumulation of cAMP. This has been shown in bothin vivo andin vitro studies. cAMP through CGRP stimulation in neuroblastoma cells in humanin vitro studies [Figure 1] and [Figure 2]. In,in vitro studies, erenumab potently and competitively inhibited [125I]-CGRP binding to the canonical CGRP receptor and fully antagonized CGRP-stimulated cAMP accumulation in human SK-N-MC neuroblastoma cells.[10]
Figure 1: Mechanism of Action of Erenumab

Click here to view
Figure 2: Erenumab competitively blocks the CGRP receptor thereby antagonizing the CGRP receptor functions

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It does not have any reported activity on other calcitonin family receptors (e.g., adrenomedullin, calcitonin, and amylin), even at a higher concentration of 10 μM. The levels of CGRP increase throughout the duration of pain due to migraine and slowly come back to normal levels when pain diminishes. CGRP-R acts on cerebral blood vessels, which are thought to be responsible for the development of migraines. Erenumab reduces the number of monthly migraine attacks by blocking CGRP-R receptors on blood vessels. It has also been seen to inhibit capsaicin-induced increases in dermal blood flow inin vivo studies in monkeys.[10] When administered subcutaneously, in healthy volunteers or patients of migraine, subcutaneous injection of erenumab 140 mg inhibited capsaicin-induced increase in dermal blood flow by 74.6–94.6%. When given multiple doses, these were significantly inhibited at day 8 compared with placebo. Apparent erenumab dose dependency was not observed in this pharmacodynamic assay.[11]

Pharmacokinetics properties of erenumab

As a result of binding to the CGRP-R receptor, erenumab exhibits non-linear kinetics. Nevertheless, at therapeutic doses, following subcutaneous dosing every 4 weeks, the pharmacokinetics of erenumab exhibit predominantly linear kinetics, owing to saturation of binding to CGRP-R. After administration of 140 mg subcutaneous doses every 4 weeks, less than 2-fold accumulation was detected in serum concentrations, which subsided to a steady state by 12 weeks of initial dosing. In healthy volunteers, a single 70 mg dose produced a Cmax of 6.25 μg/ml after 6 days and an area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of 171 day ·μg/ml. In patients with migraine, a single 140 mg dose produced a Cmax of 9.93 μg/ml after 11 days and AUClast of 367 day μg/ml.[14]

Absorption

The median peak serum concentrations were attained in 4 to 6 days subsequent to a single subcutaneous dose of 140 mg or 70 mg administered to healthy adults, whereas the estimated absolute bioavailability was 82%.

Distribution

Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) liters.

Biotransformation and elimination

Erenumab is predominantly eliminated using a non-specific proteolytic pathway. At higher concentrations, the elimination is basically through a non-specific, non-saturable proteolytic pathway, whereas at lower concentrations, the elimination is majorly through saturable binding to target (CGRP-R). Erenumab was detectable in serum levels 30 to 160 days post-dose, with doses of ≥70 mg resulting in detectable levels at ≥100 days post-dose.[15] Erenumab has an effective half-life of 28 days.[8]

Dosing and route of administration

The drug is administered in dosages of 70 mg, once a month, however, some patients may benefit from 140 mg a month dosing. It is administered subcutaneously into the abdomen, thigh, or upper arm.

Aimovig is available in a single dose prefilled autoinjector formulation, with a strength of 70 mg/ml, available in one or two per pack.

Special populations

On the basis of population pharmacokinetics analysis, the pharmacokinetics of erenumab was not affected by age, gender, race, or in either episodic or chronic migraine subtypes. However, there is still lack of clear evidence for certain patient population groups. Patients with hemiplegic migraine and who had cardiovascular and cerebrovascular events were excluded from the trials. There is no clarity if it could be used in pregnant or lactating patients either as these patients were not included either. Another area that would need further research would be acceptable to have patients on concomitant botox and aimovig therapy. The current trials only enrolled patients after 4 months of use of last Botox therapy.

Patients with renal impairment

Patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) have not been studied. Population pharmacokinetic analysis of integrated data from the erenumab clinical studies did not reveal a difference in its pharmacokinetics in patients with mild or moderate renal impairment relative to those with normal renal function.

Patients with hepatic impairment

There have been no studies performed in patients with hepatic impairment. Erenumab, as a human monoclonal antibody, is not metabolized by cytochrome P450 enzymes, and hepatic clearance is not a major clearance pathway for erenumab.

Erenumab exposure increased more than dose proportionally after SC administration of single 1 to 70 mg doses and approximately dose proportionally at higher doses (70 to 210 mg) in a phase I study in healthy volunteers (n = 49) and patients with migraine (n = 12).

Clinical efficacy and safety

Conduct of various phase I, II, and III trials that have successfully demonstrated the efficacy of erenumab in this regard have led to this fruition [Table 1].
Table 1: Clinical drug trials for erunuma

Click here to view


Sun et al. conducted a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial,[16] compared three doses of erenumab, 7, 21, and 70 mg and concluded that the 70 mg dosing might be a potential therapy for prevention of episodic migraine.

A randomized, phase II, double-blind, placebo-controlled, study[17] conducted by Tepper et al. provided, class 1b evidence that erenumab either in 70 or 140 mg dosing could be a potential new preventive therapy in patients with chronic migraine. They included adults aged 18–65 years with chronic migraine, a total of 667 patients. This was a multi-center trial and enrolled patients from multiple centers in North America and Europe.

Patients were divided into three groups randomly. They received subcutaneous placebo, erenumab 70 mg or erenumab 140 mg, given every 4 weeks for 12 weeks. It was concluded that erenumab 70 mg and 140 mg reduced monthly migraine days (MMD) vs. placebo (both doses −6·6 days vs. placebo −4·2 days; difference −2·5, 95% CI −3·5 to −1·4, P < 0·0001). The most frequent adverse events were injection-site pain, upper respiratory tract infection, constipation, and nausea.

Goadsby and colleagues[12] conducted their trial (STRIVE) on a group of 955 patients and randomly assigned them to three groups being administered either a 70 or 140 mg dosing of erenumab or a placebo. The treatment was given subcutaneously and monthly over a period of 6 months. The mean number of MMD at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70 mg erenumab group and by 3.7 in the 140 mg erenumab group, as compared with 1.8 days in the placebo group (P < 0.001 for each dose vs. placebo). The number of days of use of acute migraine–specific medication treatment days (MSMD) was reduced by 1.1 days in the 70 mg erenumab group and by 1.6 days in the 140 mg erenumab group, as compared with 0.2 days in the placebo group (P < 0.001 for each dose vs. placebo). A significant improvement in physical impairment scores and everyday activities was also reported with this trial.

ARISE[18] is a phase 3, randomized, double-blind, placebo-controlled study conducted by Dodick et al., which included 577 adults with episodic migraine and were randomized to placebo or 70 mg erenumab. They showed that patients treated with erenumab 70 mg SC once monthly experienced a least-squares mean reduction from baseline of 2.9 days in MMD after 3 months compared with a 1.8 day reduction in the placebo group (n = 288; P < 0.001); MMD at baseline were 8.1 and 8.4 days for erenumab and placebo recipients, respectively. 39.7% (erenumab) and 29.5% (placebo) of patients received a >50% reduction in monthly migraine days (OR: 1.59 (95% CI: 1.12, 2.27) (P = 0.010). Migraine-specific medication treatment days were reduced by -1.2 (erenumab) and -0.6 (placebo) days, (P = 0.002). The LIBERTY trial[19] conducted by Reuter et al., evaluated the efficacy of erenumab in patients who had failed 2–4 other prophylactic migraine treatments; At week 12, 30.3% of patients treated with erenumab 140 mg SC achieved a ≥50% reduction in MMD compared with 13.7% for placebo (odds ratio: 2.73; P = 0.002). Significant improvements were also seen with erenumab 140 mg in terms of MMD (mean improvement of 1.61 days vs. placebo; P = 0.004) and MSMD (mean improvement of 1.73 days vs. placebo; P < 0.001).

Lattanzi et al.[20] in their recently published systematic review discuss erenumab with regards to the above-mentioned trials, their limitations, and outcomes. Their analysis suggests that all the conducted trials were associated with a greater reduction in MMD and MSMD either with the monthly dose of 70mg or 140mg. Further, subgroup analyses demonstrated that erenumab was effective in reducing MMD and MSMD either in patients with episodic or with chronic migraine, at any dose and any time point. The mean reduction in MMD with erenumab at the 7 mg and the 21 mg doses were not significantly different from those with placebo.

Phase III EMPOWER studies are in progress. A recent metanalysis by Dr Zhu[21] has analyzed eight randomized controlled trials, including 2,292 patients and concluded that not only do the CGRP antagonists help reduce the MMD significantly but also help reduce the acute migraine-specific medication intake. The adverse events were similar between the CGRP monoclonal antibody group and placebo group.

Sussman et al.[22] have suggested that the use of erenumab may be a cost-effective approach to prevent monthly migraine days among patients with chronic migraine vs. onabotulinumtoxin A.


  Adverse Effects Top


There were no major concerns noted with the safety profile with the medication across all the trials. The occurrence of cardiovascular events throughout the double-blind treatment phase of the trials was low and did not differ between the erenumab and placebo groups with either dose. There were no significant changes noted in the serum chemistry, hematology laboratory values, ECG findings, and vital signs.[20]

Adverse reactions occurring with an incidence of ≥2%, and at least a 2% greater incidence than with placebo, in patients treated with erenumab during the first 3 months of the phase III STRIVE and ARISE trials, and one phase II trial included injection site reactions (6 and 5% of erenumab 70 [n = 787] and 140 mg [n = 507] once monthly recipients, respectively, compared with 3% of placebo recipients [n = 890]), constipation (1 and 3%, respectively, vs. 1%), and cramps/muscle spasms (<1 and 2%, respectively, vs. <1%). Few (1.3%) patients treated with erenumab in these three studies discontinued double-blind treatment because of adverse events.[8] With the exception of the LIBERTY trial, there was an overall incidence of 4.3–8.0% of anti-erenumab-binding-antibodies noted. This was noted to be of infrequent occurrence.

Further research areas

A high proportion of migraine patients in clinical practice present with one or more comorbidities such as fibromyalgia, pelvic pain, and low back pain. Whether the use of this medication is an effective approach toward these conditions is still unclear and needs further research. Humanized monoclonal antibodies binding the CGRP ligand such as fremanezumab, galcanezumab, and eptinezumab are currently under investigation trials and are expected to be introduced soon. In addition, erenumab being a specific CGRP antagonist, drugs acting at other targets of CGRP warrant looking at other medications for the plausible treatment of headaches.


  Conclusion Top


Erenumab, available in doses of 70 mg and 140 mg injections, is newly FDA approved injectable drug used for the prevention of episodic migraine headache attacks. It is a novel addition to the pharmacological armamentarium. There is a need for search for newer options as the currently available medications are either limited by their suboptimal efficacy and tolerability or associated with significant drug interactions. CGRP antagonists such as erenumab seem to be a positive stride in this regard. Various trials done so far report good efficacy and safety and have not reported significant adverse effects. However, larger follow-up studies including larger number of patients need to be done and further research needs to be done to further elucidate the efficacy of this drug. There are no reliable studies on Erenumab about its safety during pregnancy or while breastfeeding or for pediatric use at this point.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Brinder Vij is on advisory board of Amgen and is on speaker Bureau as well for Aimovig with Amgen Pharmaceuticals.



 
  References Top

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Headache Classification Committee of the International Headache Society (IHS). The International classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013;33:629-808.  Back to cited text no. 1
    
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Steiner TJ, Stovner LJ, Birbeck GL. Migraine: The seventh disabler. J Headache Pain 2013;14:1.  Back to cited text no. 2
    
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GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545-602.  Back to cited text no. 3
    
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GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 2017;16:877-97.  Back to cited text no. 4
    
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Ray BK, Paul N, Hazra A, Das S, Ghosal MK, Misra AK,et al. Prevalence, burden, and risk factors of migraine: A community-based study from Eastern India. Neurol India 2017;65:1280-8.  Back to cited text no. 5
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Kulkarni G, Rao G, Gururaj G, Subbakrishna DK, Steiner T, Stovner LJ. The prevalence and burden of migraine in India: Results of a population-based study in Karnataka state. J Headache Pain 2014;15(Suppl 1):B18.  Back to cited text no. 6
    
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Estemalik E, Tepper S. Preventive treatment in migraine and the new US guidelines. Neuropsychiatr Dis Treat 2013;9:709-20.  Back to cited text no. 7
    
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Amgen Inc. Erenumab (Aimovig™): US prescribing information. 2018. https://www.access data.fda.gov/drugs at fda docs/label/2018/76107 7s000 lbl.pdf. [Last accessed on 2018 Jun 08].  Back to cited text no. 8
    
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Edvinsson L. The trigeminovascular pathway: Role of CGRP and CGRP receptors in migraine. Headache 2017;57(Suppl 2):47-55.  Back to cited text no. 9
    
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Edvinsson L. Functional role of perivascular peptides in the control of the cerebral circulation. Trends Neurosci 1985;8:126-31.  Back to cited text no. 11
    
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Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, et al. A controlled Trial of Erunumab for Episodic Migraine. N Engl J Med 2017;377:2123-32.  Back to cited text no. 12
    
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Shi L, Lehto SG, Zhu DX, Sun H, Zhang J, Smith BP, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther 2016;356:223-31.  Back to cited text no. 14
    
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de Hoon J, Van Hecken A, Vandermeulen C, Yan L, Smith B, Chen JS. Phase I, randomized, double-blind, placebo-controlled, single-dose, and multiple-dose studies of erenumab in healthy subjects and patients with migraine. Clin Pharmacol Ther 2018;103:815-25.  Back to cited text no. 15
    
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Sun H, Dodick DW, Silberstein S, GoadsbyPJ, Reuter U, Ashina M, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: A randomized, double –blind, placebo-controlled, phase 2 trial. Lancet Neurol2016;15;4:382-90.  Back to cited text no. 16
    
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Tepper S, Ashina M, Reuter U, BrandesJL, Doležil D, Silberstein S,et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: A randomized, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017;16:425-34.  Back to cited text no. 17
    
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Dodick DW, Ashina M, BrandesJL, Kudrow D, Lanteri-Minet M, Osipova V,et al. ARISE: A phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018;38:1026-37.  Back to cited text no. 18
    
19.
Reuter U, GoadsbyPJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD,et al. Efficacy and safety of erenumab in episodic migraine patients with 2-4 prior preventive treatment failures: Results from the phase IIIb Liberty study [abstract no. 009]. In: American Academy of Neurology 70th Annual Meeting,2018.  Back to cited text no. 19
    
20.
Lattanzi S, Brigo F, Trinka E, Vernieri F, Corradetti T, Dobran M, et al. Erenumab for preventive treatment of migraine: A systematic review and meta-analysis of efficacy and safety. Drugs 2019;79:417-31.  Back to cited text no. 20
    
21.
Zhu Y, Liu Y, Zhao J, Han Q, Liu L, Shen X. The efficacy and safety of calcitonin gene-relate peptide monoclonal antibody for episodic migraine: A meta-analysis. Neurol Sci 2018;39:2097-2106.  Back to cited text no. 21
    
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