CGRP inhibitors for migraine prophylaxis: a safety review

Figures & data

Figure 1. An overview of some antimigraine drugs that directly block CGRP or its receptor. Since CGRP plays an important role in the pathophysiology of migraine, in the last decades new antimigraine drugs have been developed for migraine treatment. These drugs include: (i) gepants, which act by directly blocking the CGRP receptor (i.e. rimegepant and atogepant); and (ii) monoclonal antibodies, which directly block CGRP (i.e. eptinezumab, fremanezumab and galcanezumab) or its receptor (i.e. erenumab). CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1

Table 1. The new antimigraine drugs targeting CGRP or its receptor

Compound	Mechanisms of action	Dosage	Indication (type of treatment)	Notes	Ref.
Gepants
Rimegepant (BMS-927,711)	CGRP receptor antagonist	75 mg Oral	Acute migraine treatment Ongoing for prophylactic treatment	FDA approved for the acute treatment of migraine Ongoing phase II/III clinical trial (NCT0372368) to evaluate its the effectiveness as preventive treatment for migraine in adults	[47,48,53–56]
Atogepant (MK-8031, AGN-241,689)	CGRP receptor antagonist	10, 30,60 mg Oral	Prophylactic treatment for episodic and chronic migraine	Phase IIb/III clinical trials Ongoing Phase III clinical trial (NCT03855137)	[49–52]
Monoclonal antibodies
Erenumab (AMG-334)	CGRP receptor blocker	70, 140 mg Subcutaneous	Prophylactic treatment for episodic and chronic migraine	The side effects were similar to placebo FDA approved in May 2018 EMA approved in July 2018	[24,60–66]
Eptinezumab (ALD-403)	CGRP blocker	30, 100, 300 mg Intravenous	Prophylactic treatment for episodic and chronic migraine	FDA approved in February 2020	[72–75]
Fremanezumab (TEV-48,125)	CGRP blocker	225, 675 mg Subcutaneous	Prophylactic treatment for episodic and chronic migraine	FDA approved in September 2018 EMA approved in March 2019	[76–85]
Galcanezumab (LY-2,951,742)	CGRP blocker	225, 675 mg Subcutaneous	Prophylactic treatment for episodic and chronic migraine	FDA approved in September 2018 EMA approved in November 2018	[86–93]

FDA, Food and Drug Administration; EMA, European Medicines Agency.

Figure 2. Composition of the human calcitonin-family receptors and the relative affinity/potency of binding of CGRP, AM and AMY to canonical and non-canonical receptors. CGRP can exert its pathophysiological effects via the activation of its receptor (CGRP receptor) or via the activation of distinct CGRP-responsive receptors with moderate affinity/potency for AM receptors, and practically the same potency for the AMY receptors, as compared to their endogenous ligands. CGRP, calcitonin gene-related peptide; AM, adrenomedullin; AMY, amylin; CLR, calcitonin receptor-like receptor; CTR, calcitonin receptor; RAMP, receptor activity-modifying protein. Human and *rodents values of ^apK_i, ^bpEC₅₀, and ^cpK_d [98,100]

Table 2. Overview of side effects reported for the prophylactuc anti-migraine drugs

Compound	Most common side effects (%)							Ref
Gepants
Rimegepant (BMS-927,711)	Placebo (11%); Rimegepant 75 mg (13%)							[24-25]
			Placebo		Rimegepant 75 mg
	Nausea		<1		2-8
	Vomiting		2		2-3
	Dizziness		<1		2-4
	Urinary tract infection		<1		2-3
Atogepant (MK-8031, AGN-241689)	Placebo (19.35%); Atogepant 10 mg^a (18.28%), 30 mg^a (25.68%), 60 mg^a (27.96%); Atogepant 30 mg^b (24.42%), 60 mg^b (28.57%)							[30-31]
		Placebo	10 mg^a	30 mg^a	60 mg^a	30 mg^b	60 mg^b
	Nausea	4.84	5.38	7.10	11.29	8.14	9.89
	Fatigue	3.20	1.08	1.64	2.69	2.33	9.89
	Constipation	2.15	2.15	5.46	4.84	3.49	6.59
	Nasopharyngitis	2.15	3.23	5.46	7.53	1.16	1.10
Monoclonal antibodies
Erenumab (AMG-334)	Placebo (39-63%); Erenumab 70 mg (40-58%); 140 mg (45-55%)							[35-38]
			Placebo	70 mg		140 mg
	Injection-site pain		0.3-4	3-6		0.3-4
	Fatigue		2-3	2-4		2-4
	Nasopharyngitis		2-8	3-10		<3
	Upper respiratory tract infection		1-6	3-7		3-5
	Nausea		1-5	2-3		<3
Eptinezumab (ALD-403)	Placebo (45-60%); Eptinezumab 30 mg (58%); 100 mg (40-63%); 300 mg (52-58%); 1000 mg (57%)							[41-43]
			Placebo	30 mg	100 mg	300 mg	1000 mg
	Upper respiratory tract infection		5-7	<11	4-10	5-10	9
	Urinary tract infection		1-6	-	<3	<4	1
	Fatigue		1-4	<3	2-3	1-4	4
	Nausea and vomiting		1-4	4	<2	<4	4
Fremanezumab (TEV-48125)	Placebo (40-65%); Fremanezumab 225 mg (46-66%); 675 mg (69-70%); 225 mg+675 mg (53-70%); 900 mg (47%)							[46-49]
			Placebo	225 mg	675 mg	225+675 mg	900 mg
	Injection-site pain		3-28	9-30	4-30	7-26	9
	Nausea		1-4	<2	<3	<2	-
	Upper respiratory tract infection		4-5	4-6	2-5	<4	-
	Nasopharyngitis		2-5	2-4	2-5	1-4	1
	Fatigue		<1	<2	2-3	-	-
	Urinary tract infection		1-3	<2	<4	<5	2
Galcanezumab (LY-2951742)	Placebo (50-63%); Galcanezumab 120 mg (51-65%); 240 mg (67-71%)							[55-59]
			Placebo	120 mg		240 mg
	Injection-site pain		2-17	6-17		7-20
	Nausea		2-4	2-8		3-6
	Upper respiratory tract infection		2-9	3-11		3-15
	Nasopharyngitis		2-9	6-18		2-13
	Fatigue		<3	<3		<3
	Urinary tract infection		1-4	<4		1-6

The doses were used for the treatment of both episodic or chronic migraine during short-term trials. ^aDaily doses; ^btwice-daily doses.

Biohaven Pharmaceutical Company Holding Ltd. Biohaven’s NURTEC™ ODT (rimegepant) receives FDA approval for the acute treatment of migraine in adults. [ cited 2020 Apr 6]. Available from: https://www.prnewswire.com/news-releases/biohavens-nurtec-odt-rimegepant-receives-fdaapproval-for-the-acute-treatment-of-migraine-in-adults-301013021.html

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