Anti-CGRP monoclonal antibodies for prevention of migraine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.24.2021
Released 03.26.2018
Expires For CME 03.24.2024

Anti-CGRP monoclonal antibodies for prevention of migraine

Author: K K Jain MD†

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Anti-CGRP monoclonal antibodies for prevention of migraine

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Introduction

Key points

	• Monoclonal antibodies (MAbs) for migraine prophylaxis target calcitonin gene-related peptide (CGRP) receptor.
	• The rationale for this approach is based on the role of CGRP in the pathogenesis of migraine.
	• Three of the 4 MAbs in development (eptinezumab, fremanezumab, and galcanezumab) target CGRP itself, whereas the fourth, erenumab, targets CGRP receptor.
	• Clinical trials have shown the efficacy and safety of anti-CGRP MAbs in reducing migraine attacks.
	• Erenumab (Aimovig) and galcanezumab were approved in 2018. Eptinezumab and fremanezumab were approved by the FDA in 2020 (25).

Historical note and terminology

Most preventive treatments for migraine are nonspecific, and their efficacy and safety are often unsatisfactory. Some monoclonal antibodies (MAbs), which target calcitonin gene-related peptide (CGRP) receptor or CGRP itself, are in development for migraine prophylaxis. CGRP is a neuropeptide that, along with its receptor, is found in both central and peripheral neurons and influences both neuronal modulation of pain as well as vascular activity (08; 13).

CGRP receptor (CGRP-R) is also a target for drugs for acute migraine attacks. Gepants, another CGRP-R antagonist class, are a new nonvasoconstrictive approach in the acute treatment of migraine. When compared with triptans, gepants show a similar efficacy profile. However, results of clinical trials of gepants have not been encouraging for their use in clinical practice. Some were discontinued during development due to concerns for hepatotoxicity or for unknown reasons. Clinical trials of other gepants for acute migraine continue but will not be discussed in this article.

Four anti-GRCP MAbs are in clinical trials and will be described in this article. The focus of this article will be on erenumab, the most advanced of these, which was the first to be approved.

	• ErenumabIt was approved by the U.S. Food and Drug Administration and the European Medicines Agency in Europe in 2018.
	• Eptinezumab
	• Fremanezumab
	• Galcanezumab

Pharmacology

Pharmacodynamics. The actions of CRGP antagonist MAbs are facilitated particularly by the location of CRGP in dorsal root and trigeminal ganglions, which makes its role in causing migraine plausible. CRGP is the main mediator of trigeminal pain signal and is involved in the cascade of molecular events leading to a painful crisis in migraine. Intravenous administration of CGRP to patients prone to migraine can induce migraine-like headache. CGRP, and not substance P, is elevated in the cranial circulation during acute migraine. This explains the failure of substance P/neurokinin-1 receptor antagonists and the success of blocking CGRP mechanisms for relieving the pain of acute migraine. CGRP promotes mast cell degranulation, which results in the release of several inflammatory and proinflammatory substances. By binding to its glial receptors, CGRP promotes the release of cytokines in the trigeminal ganglia and nerve, which, in turn, produces sensitization of sensory neurons. CGRP significantly increases the expression and activity of cyclooxygenase 2, as well as the expression of the inducible form of nitric oxide synthase and IL-1β, and these effects are reversed by a specific CGRP receptor antagonist (05). CGRP is also involved in other migraine-related phenomena, eg, photophobia and gastrointestinal symptoms, such as nausea.

Involvement of CGRP in the pathophysiological processes underlying migraine led to the development of CGRP antagonists: gepants and 4 monoclonal antibodies (MAbs) targeting CGRP receptor (erenumab) or targeting CGRP ligand (eptinezumab, fremanezumab, and galcanezumab). Anti-CGRP MAbs in development for migraine either remove the excessive CGRP released at the perivascular trigeminal sensory nerve fibers or block the receptor from signaling. Thus, MAbs against both the CGRP ligand and receptor would inhibit CGRP-induced activation of sensitized trigeminal pathways to decrease headache frequency over time (03). Studies to date have confirmed the peripheral site of action of MAbs, but central effect cannot be excluded. Compared with small molecules, MAbs are highly specific for their target. Anti-CGRP pathway MAbs specifically target the CGRP receptor or ligand and are not associated with the off-target toxicity that can occur when targeting the immune system. Due to their large size, MAbs do not penetrate the blood-brain barrier. This is not a limiting factor because the primary site of action of anti-CGRP, the trigeminovascular system, is outside the blood-brain barrier (09). It has been concluded that the efficacy of anti-CGRP MAbs goes beyond the mere control of pain and prevents the activation of mechanisms involved in the complete manifestations of the migraine attack (29).

Erenumab. This is the only MAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. The binding site of CGRP is with the calcitonin receptor-like receptor and receptor activity-modifying protein 1.

Pharmacokinetics. Most of the MAbs have nonlinear pharmacokinetics. Anti-CGRP MAbs have long terminal half-lives that allow for less frequent dosing, such as once monthly or greater, but, unlike small molecules, they must be injected. Subcutaneous bioavailability for most MAb therapeutics is 50% to 100%. They are not metabolized in the liver, and, therefore, hepatotoxicity is not expected. Most of these are administered subcutaneously, except eptinezumab, which has an intravenous formulation.

Erenumab. The pharmacokinetics of erenumab, as well as its inhibitory effect on capsaicin-induced dermal blood flow (CIDBF), a tool for assessing the target engagement of compounds that inhibit CGRP for migraine therapy, were studied in a 2-compartment target-mediated drug disposition model (30). Important findings include the following:

	• The mean absorption time is about 2 days, and the estimated absorption half-life is 1.6 days, suggesting that subcutaneous absorption is complete in approximately 8 days.
	• The estimate of subcutaneous bioavailability for erenumab is 74%.
	• There are 2 parallel antibody elimination pathways: a slow nonspecific elimination pathway through the hepatic reticuloendothelial system, ie, linear clearance, and a rapid saturable elimination pathway, ie, nonlinear clearance, which is mediated by degradation or internalization of the erenumab-receptor complex.
	• Total clearance of erenumab decreases significantly and approaches linear clearance as its concentrations increase. Therefore, the dose regimen of 70 mg subcutaneously per month can produce a concentration that saturates the nonlinear elimination pathway at a steady state.
	• Compared to other anti-CGRP ligand MAbs in development, erenumab requires a lower concentration to achieve and maintain maximum CIDBF inhibition.

Galcanezumab. The pharmacokinetics of galcanezumab have been studied in healthy volunteers (17). Following a single subcutaneous dose, there was an extended period of absorption, with a median time to peak concentration (Tmax) between day 7 and day 14. Cmax and the area under the concentration-time curve were proportional to a full range of dosage from 1 to 600 mg. The mean serum half-life (t1/2) of galcanezumab was similar at all dose levels 1 month later.

Eptinezumab. This is the first and the only drug for intravenous prophylaxis of migraine so far. The pharmacokinetics of eptinezumab is characterized by rapid attainment of maximum plasma concentration and a terminal half‐life of 27 days (01). Dose‐ and exposure‐response analyses found a plateau of effect between 100 and 300 mg. A saturable inhibitory Emax model found the exposure over 12 weeks produced by single‐dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy.

Clinical trials

The status of anti-CGRP MAbs in development for migraine is shown in Table 1.

Table 1. Clinical Trials of Anti-CGRP Monoclonal Antibodies for Migraine Prevention

Drug	Results of clinical trials	Status
Erenumab (Aimovig or AMG 334)	Patients who received a monthly subcutaneous dose of the drug had greater reductions in MMDs and greater improvements in physical impairment and everyday activities scores.	Approved in U.S. and Europe
Fremanezumab (TEV-48125)	The trial met its primary endpoint, showing that patients taking the drug subcutaneously experienced a statistically significant reduction in the number of monthly headache days of at least moderate severity compared with placebo.	Phase III completed; BLA being submitted
Galcanezumab (LY2951742)	Treatment groups had significantly greater improvements in response rates to subcutaneous injections and on daily activity measures than did the placebo groups.	Phase III, Fast Track designation
Eptinezumab (ALD403)	Patients who received a single intravenous dose of the drug had a 75% reduction in migraine during 12 weeks of the trial.	Phase III
BLA= Biologics License Application, MMD=monthly migraine days

The randomized, placebo-controlled trial results of CGRP-antagonist MAbs eptinezumab, galcanezumab, fremanezumab, and erenumab have been published (06; 07; 02; 26; 24). They showed an increase in migraine-free days versus baseline. These MAbs appear to be well-tolerated, with no significant adverse events across the studies and no emerging safety issues from earlier studies (31; 10). Two phase 2 trials (one for episodic migraine and one for chronic migraine) and 2 phase III trials for episodic migraine have shown the efficacy and safety of erenumab in the prevention of migraine (14).

Fremanezumab, a humanized MAb targeting CGRP, is being investigated as a preventive treatment for migraine. A 12-week, phase III, randomized clinical trial found that fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo (23). Erenumab (AMG334, Amgen and Novartis), a subcutaneous anti-CGRP MAb, significantly reduced migraine frequency, effects of migraines on daily activities, and the use of acute migraine-specific medication in the randomized phase III STRIVE trial (11). In a phase II, randomized, double-blind, placebo-controlled, multicenter study of erenumab for adults aged 18 to 65 years with chronic migraine, erenumab (70 mg and 140 mg) reduced the number of monthly migraine days with a safety profile like placebo, providing evidence that erenumab could be a potential therapy for migraine prevention (28). Further research is needed to understand the long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings.

Review of literature and discussion of clinical data from phase II and III trials of the 4 MAbs targeting the CGRP pathway—eptinezumab, erenumab, fremanezumab, and galcanezumab—collectively show a positive effect in the preventive treatment of episodic and chronic migraine (15). A systematic review of randomized controlled clinical trials found significant reduction of monthly migraine days with CGRP-MAbs versus placebo and few adverse reactions, but trials of larger sample sizes are recommended to verify the current findings (12). Another review of clinical trials shows that the efficacy of all 4 MAbs is modest over placebo in the prevention of episodic and chronic migraine (21).

Multiple phase III trials are underway to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the effects of long-term CGRP blockade.

A metaanalysis was conducted to identify placebo and nocebo phenomena in the placebo-controlled randomized trials with the monoclonal antibodies targeting the calcitonin gene-related peptide (anti-CGRP MAbs) pathway. Results showed that the stronger placebo and weaker nocebo phenomena in trials with anti-CGRP MAbs versus those with topiramate in the prophylaxis of episodic migraine may decisively determine the success of treatment with anti-CGRP MAbs (16). No differences were detected between the anti-CGRP MAbs and onabotulinum toxin A in the treatment of chronic migraine.

A clinical trial of long-term safety of acute treatment of migraine with rimegepant (a small molecule CGRP receptor antagonist) in 2 patients resulted in improvement of response to rimegepant in aborting 9 out of 9 attacks of migraine (19). The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.

References

01: Baker B, Schaeffler B, Beliveau M, et al. Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine. Pharmacol Res Perspect 2020;8(2):e00567. PMID 32155317
02: Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efﬁcacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015a;14(11):1081-90. PMID 26432182
03: Bigal ME, Walter S, Rapoport AM. Therapeutic antibodies against CGRP or its receptor. Br J Clin Pharmacol 2015b;79(6):886-95. PMID 25614243
04: Christensen CE, Younis S, Deen M, Khan S, Ghanizada H, Ashina M. Migraine induction with calcitonin gene-related peptide in patients from erenumab trials. J Headache Pain 2018;19(1):105. PMID 30409109
05: De Corato A, Lisi L, Capuano A, et al. Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1β pro-inflammatory effects. J Neuroimmunol 2011;237(1-2):39-46. PMID 21719118
06: Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014a;13(11):1100-7. PMID 25297013
07: Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014b;13(9):885-92. PMID 25127173
08: Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 2017;57 Suppl 2:47-55. PMID 28485848
09: Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia 2019;39(3):366-73. PMID 29020807
10: Goadsby PJ. Bench to bedside advances in the 21st century for primary headache disorders: migraine treatments for migraine patients. Brain 2016;139(Pt 10):2571-7. PMID 27671024
11: Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017;377(22):2123-32. PMID 29171821
12: Hou M, Xing H, Cai Y, et al. The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis. J Headache Pain 2017;18(1):42. PMID 28389966
13: Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain 2017;158(4):543-59. PMID 28301400
14: Jain S, Yuan H, Spare N, Silberstein SD. Erenumab in the treatment of migraine. Pain Manag 2018;8(6):415-26. PMID 30235976
15: Khan S, Olesen A, Ashina M. CGRP, a target for preventive therapy in migraine and cluster headache: systematic review of clinical data. Cephalalgia 2019;39(3):374-89. PMID 29110503
16: Kokoti L, Drellia K, Papadopoulos D, Mitsikostas DD. Placebo and nocebo phenomena in anti-CGRP monoclonal antibody trials for migraine prevention: a meta-analysis. J Neurol 2020;267(4):1158-70.** PMID 31919565
17: Monteith D, Collins EC, Vandermeulen C, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol 2017;8:740. PMID 29089894
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20: Oakes TMM, Skljarevski V, Zhang Q, et al. Safety of galcanezumab in patients with episodic migraine: a randomized placebo-controlled dose-ranging phase 2b study. Cephalalgia 2018;38(6):1015-25. PMID 29310444
21: Paemeleire K, MaassenVanDenBrink A. Calcitonin-gene-related peptide pathway mAbs and migraine prevention. Curr Opin Neurol 2018;31(3):274-80. PMID 29432219
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24: Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol 2018;75(2):187-93. PMID 29255900
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27: Sussman M, Benner J, Neumann P, Menzin J. Cost-effectiveness analysis of erenumab for the preventive treatment of episodic and chronic migraine: Results from the US societal and payer perspectives. Cephalalgia 2018;38(10):1644-57. PMID 30142988
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29: Tiseo C, Ornello R, Pistoia F, Sacco S. How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain 2019;20(1):49. PMID 31060490
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Anti-CGRP monoclonal antibodies for prevention of migraine

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Anti-CGRP monoclonal antibodies for prevention of migraine …

Anti-CGRP monoclonal antibodies for prevention of migraine

Introduction

Key points

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Anti-CGRP Monoclonal Antibodies for Migraine Prevention

Indications

Off-label uses.

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Management

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Serotonin syndrome

Eptinezumab	Single intravenous dose of 100 mg or 300 mg given once in 3 months
Erenumab	70 mg and 140 mg subcutaneously once a month by an autoinjector with no need for a loading dose
Fremanezumab	Starting dose of 675 mg subcutaneously followed by 225 mg every 4 weeks
Galcanezumab	120 mg subcutaneously every 4 weeks following a loading dose of 240 mg subcutaneously

Anti-CGRP monoclonal antibodies for prevention of migraine

Introduction

Key points

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Anti-CGRP Monoclonal Antibodies for Migraine Prevention

Indications

Off-label uses.

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Management

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Serotonin syndrome

This is an article preview.
Start a Free Account
to access the full version.