Erenumab Dosage for Migraine Prevention

An Evidence-Based Narrative Review With Recommendations

Stewart J. Tepper MD; Huma U. Sheikh MD; Carrie O. Dougherty MD; Stephanie J. Nahas MD MSEd; Paul K. Winner DO; Ananda Krishna Karanam PhD; Andrew M. Blumenfeld MD; Ahmad Abdrabboh PharmD MPH; Soeren Rasmussen MD; Jamie L. Weiss PhD; Jessica Ailani MD

Disclosures

Headache. 2022;62(4):420-435.

Abstract and Introduction

Abstract

Background: Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options.

Objective: To evaluate therapeutic and tolerability differences between erenumab 70 and 140 mg based on evidence from published literature.

Methods: This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140 mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021.

Results: From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70 mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140 mg erenumab once monthly—especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140 mg has a numerically better efficacy than 70 mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine.

Conclusion: Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140 mg and a rationale for initiating 140 mg in selected patients.

Introduction

Migraine is a common, disabling, and complex neurological disease and is the second leading cause of years lived with disability.^[1] It has been established that calcitonin-gene related peptide (CGRP) plays a key role in the pathophysiology of migraine.^[2] The monoclonal antibody (mAb) erenumab targets the CGRP receptor and reduces CGRP activity. Treatment with erenumab reduces the burden of migraine and improves patients' quality-of-life.^[3] The American Headache Society (AHS) consensus statement^[4] and European Headache Federation (EHF) guidelines^[5] recommended the use of CGRP mAbs based on the robust clinical study data, especially in patients with significant disease burden (e.g., more than four disabling headache days a month).

Erenumab (erenumab-aooe in the United States; also known as AMG 334), a fully human mAb targeting canonical CGRP receptor,^[6] is approved as a preventive treatment of migraine in adults in many parts of the world, including the United States and the European Union (Figure 1).^[7–9] Results from the pivotal double-blind, placebo-controlled studies^[10,11] have demonstrated that erenumab 70 and 140 mg are well tolerated and provide clinically meaningful benefits to individuals with episodic and chronic migraine (EM and CM). However, these studies were not designed to compare the two erenumab doses. Despite the availability of data on the individual dosing, gaps in our knowledge (Table 1) regarding the comparative efficacy and safety of the two erenumab doses still remain. To address these knowledge gaps, we examined the available evidence from the literature to explore differences in efficacy and/or tolerability between the erenumab doses of 70 and 140 mg.

(Enlarge Image)

Figure 1.

Erenumab mechanism of action. CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein [Color figure can be viewed at wileyonlinelibrary.com]

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Table 1. Key knowledge gaps related to erenumab dosages
The studies on erenumab were not powered to provide direct clinical comparison of the two doses. However, there is a definite clinical need to evaluate whether erenumab 140 mg dosage might provide additional benefit compared with 70 mg. During the pivotal clinical studies, erenumab 70 mg was determined to be the minimum effective dose. While erenumab 70 mg dosage certainly provides effectiveness, there are many unanswered questions such as: 1. Where does erenumab 70 and 140 mg fall on a dose–response curve (i.e., does erenumab 140 mg impart greater efficacy without significantly greater adverse events [AEs])? 2. Should erenumab 140 mg be recommended as a preferred dosage option for some patients in clinical practice, or should it be reserved for more difficult-to-treat patients, or after erenumab 70 mg dosage fails? The evaluation of all of the data generated on the two erenumab dosages may shed light on these questions

Table 2. Definitions used in the review
Term	Definition
Chronic migraine	According to ICHD-3,¹² CM is occurrence of ≥15 headache days/month for more than 3 months, of which ≥8 days/month have the features of a migraine attack (with or without aura) or are headache days that respond to migraine specific acute treatments
Episodic migraine	Unlike CM, an explicit definition for EM is not available in ICHD-3,¹² but in the scientific literature, EM is characterized by 4–14 migraine days/month (with or without aura) and <15 headache days/month¹⁷
Therapeutic response	No therapeutic response in patients with EM or CM is defined as no reduction in the headache frequency, duration, or severity after administration of the migraine preventive treatment for at least 6 weeks at the appropriate dosage, as recorded by the investigator. Subgroups^a were defined on the basis of unsuccessful prior migraine preventive treatments either for lack of efficacy or unacceptable tolerability^13,14
Medication overuse	Medication overuse was examined in a sub-analysis¹⁵ and defined as use of simple analgesics (nonnarcotic analgesics, such as acetaminophen or nonsteroidal anti-inflammatory drugs) for ≥15 days (>3 days/week in each week with at least 5 diary days), triptans for ≥10 days (>2 days/week in each week with at least 5 diary days), or combination therapy (any combination of triptans, ergot derivatives, analgesics, or simple analgesics with opioids or butalbital) for ≥10 days (>3 days/week in each week with at least 5 diary days) per month
Response threshold analyses	Achievement of ≥50% reduction in MMD from baseline is considered to be of high clinical relevance.¹⁸ The response rate at ≥50% in MMD represents the proportion of patients achieving that response threshold. Response thresholds of ≥75% and 100% MMD represent more stringent levels of clinical response, and ≤0% defines nonresponse¹⁶
Reversion from CM to EM	Reversion from CM to EM was assessed in a post-hoc analyses¹⁹ of the Phase 2 CM study¹¹ followed by OLE and the following definitions applied: • Criteria for reversion from CM to EM is defined as decrease in monthly headache frequency to fewer than 45 days for at least 12 weeks in this post-hoc analyses • Monthly reversion to EM: participants moving to fewer than 15 headache days per month (any 4-week period) • Long-term reversion to EM: completers with reversion in the first 12 weeks of the OLTP and combined three 4-week assessment periods (Weeks 21–24, 37–40, and 49–52) during the OLTP regardless of their reversion status at the end of the DBTP • Delayed reversion to EM: participants continued to have CM at 12 weeks of DBTP, but met the criteria for reversion after 24 weeks of erenumab treatment (i.e., the first 12 weeks of the OLTP) • Delayed reversion to EM: participants with delayed reversion over the first 12 weeks of the OLTP and combined three 4-week assessment periods (Weeks 21–24, 37–40, and 49–52) during the OLTP

Note: CM and EM definitions have been based on ICHD-3¹² and as defined in the literature.¹⁰ Participants in whom prior preventive treatments were unsuccessful^{13, 14} and those with medication overuse¹⁵ were defined as having difficult-to-treat migraine.
The ≥50% response threshold (a reduction of at least 50% in MMD from baseline) is widely used in clinical trials as a measure of a clinically significant benefit; ≥75% or 100% thresholds are more stringent measures of clinical benefit and were also included.¹⁶
Week 52 of the OLTP is Week 64 of treatment with erenumab.¹⁹
Fewer than 45 days for at least 12 weeks in this study was used to identify those who had fewer than 15 headache days per month on average as assessed during 3 months (not continuous). These were the participants who attained categorical reversion from CM to EM.¹⁹
Abbreviations: CM, chronic migraine; DBTP, double-blind treatment phase; EM, episodic migraine; ICHD-3, International Classification of Headache Disorders, 3rd edition; MMD, monthly migraine days; OLE, open-label extension; OLTP, open-label treatment phase; TF, prior preventive treatment failure.
^aNo history of TF (0 TF), failure of one or more classes of preventive therapy (≥1 TF), and failure of two or more classes of preventive therapy (≥2 TF).

Table 3. Overview of key erenumab studies
Refs.	Overview of erenumab studies
Goadsby et al.¹⁰	STRIVE (ClinicalTrials.gov number, NCT02456740) was a Phase 3 study¹⁰ of erenumab in participants with EM. Participants who completed 24 weeks of the STRIVE study DBTP (monthly erenumab 70 or 140 mg, or placebo for 6 months), entered a dose-blinded Active Treatment Phase (ATP) of 28 weeks
Goadsby et al.²⁴	STRIVE ATP study²⁴ assessed sustained efficacy and the long-term safety of erenumab. Participants who entered into the STRIVE ATP study²⁴ were re-randomized to receive erenumab 70 or 140 mg for the next 28 weeks of the ATP
Buse et al.²⁵	Additional analyses²⁵ of the STRIVE study¹⁰ DBTP included an assessment of the effects of erenumab 70 and 140 mg on migraine-related disability, impact of headache, and health-related quality-of-life using PROs from 6 months of DBTP
Goadsby et al.¹³	A post-hoc analysis¹³ of STRIVE study¹⁰ was performed in a subgroup of participants with difficult-to-treat EM who did not benefit from prior migraine preventive treatment(s) (≥1 and ≥2 medication categories)
Lipton et al.²⁶	A subgroup analysis²⁶ of the STRIVE study¹⁰ focused on PROs in participants with EM who had more severe functional impairment (Headache Impact Test [HIT-6™] total score ≥60 or monthly modified MIDAS [mMIDAS] total score ≥7)
Schwedt et al.²⁷	Other facets related to the clinical utility of erenumab, for example, the onset of efficacy following the first 4 weeks after initial administration of erenumab (70 and 140 mg), have been assessed in a post-hoc analysis²⁷ of the STRIVE study¹⁰ and a pivotal Phase 2 CM study (ClinicalTrials.gov number, NCT02066415)¹¹
Sakai et al.²⁸	Global Phase 3 STRIVE study¹⁰ did not include participants from Japan, and to support registration of erenumab in this country, a Phase 2 study was performed specifically in Japanese population (ClinicalTrials.gov number, NCT02630459).²⁸ This study evaluated the efficacy and safety of erenumab for EM prevention
Tepper et al.¹¹	For CM, the registrational double-blind study¹¹ of erenumab provides Class 1b evidence regarding erenumab 70 or 140 mg as a preventive therapy for CM
Tepper et al.²⁹	Participants who completed 12 weeks of DBTP during the Phase 2 registration CM study¹¹ were eligible to participate in the 1-year OLE (ClinicalTrials.gov number, NCT02174861) where safety and efficacy of erenumab were assessed over a longer term²⁹ enrollment occurred within 14 days after the parent study's (NCT02066415)¹¹ week 12 visit. Participants who enrolled but had not completed the Week 28 visit at the time of Protocol Amendment 2 increased the open-label erenumab dose from 70 to 140 mg at the first available opportunity at Weeks 4, 8, 12, 16, 20, 24, or 28 visits
Lipton et al.¹⁹	A post-hoc analysis¹⁹ of the pivotal Phase 2 CM study¹¹ and subsequent OLE assessed the reversion rates from CM to EM during long-term treatment with erenumab 70 and 140 mg. This CM study¹¹ also included an assessment of the effect of erenumab 70 and 140 mg on PROs³
Ashina et al.¹⁴	A prespecified post-hoc analysis of the Phase 2 registration CM study was performed in a subgroup of participants with difficult-to-treat disease who did not benefit from prior migraine preventive treatment(s) (≥1 and ≥2 medication categories)¹⁴
Tepper et al.¹⁵	Effect of erenumab in participants with CM and medication overuse was assessed in a subgroup analysis¹⁵ of the Phase 2 pivotal CM study¹¹
Brandes et al.¹⁶	An exploratory analysis was performed using data from the Phase 2 registration CM study¹¹ to contextualize the actual treatment benefit in subgroups achieving prespecified response thresholds (≥50%, ≥75%, and 100% reduction in monthly migraine days [MMD])¹⁶
Tepper et al.³⁰	Temporal response patterns were assessed in participants with CM and EM^{30, 31}
McAllister et al.³¹
Bogdanov et al.³²	A retrospective observational study describes early use of erenumab in the US real-world practice³²
Ashina et al.³³	The integrated safety of erenumab was assessed in a pooled analysis of 4 placebo-controlled studies and their long-term extensions (ClinicalTrials.gov numbers NCT01952574, NCT02483585, NCT02456740, NCT02066415, and NCT02174861) for up to 3-plus years for nonvascular safety of erenumab³³
Kudrow et al.³⁴	A pooled analysis³⁴ evaluating the vascular safety across erenumab clinical studies was performed (ClinicalTrials.gov numbers NCT02066415, NCT02456740, NCT01952574, NCT02483585, NCT02174861, and NCT01723514)

Abbreviations: CM, chronic migraine; DBTP, double-blind treatment phase; EM, episodic migraine; MIDAS, migraine disability assessment questionnaire; OLE, open-label extension; PRO, patient-reported outcome.

Table 4. Characteristics of studies (articles) included assessing erenumab (70 vs. 140 mg) for migraine prevention
Refs.	Participants/Study design	Study characteristics	Placebo	Erenumab 70 mg	Erenumab 140 mg
Goadsby et al.¹⁰	955 participants with EM. Randomized, double-blind, placebo-controlled, parallel group, multicenter Phase 3 study	No. of participants	319	317	319
		Age^a	41.3 (11.2)	41.1 (11.3)	40.4 (11.1)
		Women, n (%)	274 (85.9)	268 (84.5)	272 (85.3)
		Age at migraine onset^a	21.2 (10.2)	21.4 (11.0)	20.7 (9.9)
		TF, n (%)	127 (39.8)	127 (40.1)	116 (36.4)
		Disease duration^a	–	–	–
Goadsby et al.²⁴	845 of 955 participants with EM from STRIVE study¹⁰	No. of participants	–	421	424
	28-week dose-blinded ATP of the STRIVE study¹⁰	Age^a	–	41.3 (11.3)	41.9 (10.9)
		Women, n (%)	–	354 (84.1)	359 (84.7)
		Age at migraine onset^a	–	21.0 (10.6)	21.3 (10.3)
		TF, n (%)	–	–	–
		Disease duration^a	–	20.31 (12.29)	20.73 (12.26)
Goadsby et al.¹³	955 participants with EM from the STRIVE study¹⁰	No. of participants	319	317	319
	Prespecified subgroup analyses of the STRIVE study¹⁰	Age^a	0 TF: 39.5 (11.0)	39.8 (11.5)	39.8 (11.6)
			≥1 TF: 43.9 (11.0)	43.1 (10.6)	41.4 (10.3)
			≥2 TF: 46.4 (11.2)	42.5 (10.6)	42.5 (9.8)
		TF, n (%)	0 TF: 192 (60.2)	190 (59.9)	203 (63.6)
			≥1 TF: 127 (39.8)	127 (40.1)	116 (36.4)
			≥2 TF: 54 (16.9)	49 (15.5)	58 (18.2)
		Women, n (%)	0 TF: 167 (87.0)	151 (79.5)	165 (81.3)
			≥1 TF: 107 (84.3)	117 (92.1)	107 (92.2)
			≥2 TF: 44 (81.5)	47 (95.9)	53 (91.4)
		Disease duration^a	0 TF: 18.1 (11.8)	18.4 (12.0)	18.7 (12.5)
			≥1 TF: 23.0 (12.2)	21.9 (12.4)	21.5 (11.8)
			≥2 TF: 24.3 (12.1)	23.9 (12.0)	21.5 (12.6)
Tepper et al.¹¹	667 participants with CM	No. of participants	286	191	190
	667 participants with CM	Age^a	42.1 (11.3)	41.4 (11.3)	42.9 (11.1)
	Randomized, double-blind, placebo-controlled, multicenter Phase 2 study	Women, n (%)	226 (79)	166 (87)	160 (84)
		Age at migraine onset^a	20.4 (10.0)	21.1 (10.5)	21.5 (10.6)
		TF, n (%)	200 (70)	127 (67)	126 (66)
		Disease duration^a	22.2 (12.6)	20.7 (12.8)	21.9 (11.8)
Lipton et al.³	667 participants with CM	No. of participants	286	191	190
	667 participants with CM	Age^a	42.1 (11.3)	41.4 (11.3)	42.9 (11.1)
	Exploratory analysis of the Phase 2 CM study¹¹	Women, n (%)	226 (79)	166 (87)	160 (84)
	Exploratory analysis of the Phase 2 CM study¹¹	TF, n (%)	200 (70)	127 (67)	126 (66)
Tepper et al.¹⁵	667 participants with CM	Medication overuse category
	667 participants with CM	No. of participants	117	79	78
	Exploratory analysis of the Phase 2 CM study¹¹	Age^a	43.9 (10.4)	41.8 (11.2)	44.1 (10.3)
		Women, n (%)	90 (77)	74 (94)	69 (89)
		0 TF, n (%)	29 (25)	18 (23)	21 (27)
		≥1 1 TF, n (%)	88 (75)	61 (77)	57 (73)
		≥1 2 TF, n (%)	63 (54)	45 (57)	40 (51)
		Without medication overuse category
		No. of participants	169	112	112
		Age^a	40.8 (11.8)	41.1 (11.5)	42.2 (11.1)
		Women, n (%)	136 (81)	92 (82)	91 (81)
		0 TF, n (%)	57 (34)	46 (41)	43 (38)
		≥1 1 TF, n (%)	112 (66)	66 (59)	69 (62)
		≥1 2 TF, n (%)	79 (47)	48 (43)	52 (46)

Note: Data are means (SD) unless specified.
Abbreviations: ATP, active treatment phase; CM, chronic migraine; EM, episodic migraine; TF, prior preventive treatment failure.
^aAge in years.

Table 5. Efficacy of erenumab (70 vs. 140 mg) for migraine prevention: EM and CM core studies
Refs.	Outcome measures	Placebo	Erenumab 70 mg	Erenumab 140 mg
Goadsby et al.¹⁰	No. of participants	316	312	318
	CFB in MMD^a	−1.8 (0.2)	−3.2 (0.2)	−3.7 (0.2)
	≥50% reduction in MMD, n (%)	84 (26.6)	135 (43.3)	159 (50.0)
	CFB in acute monthly MSMD^a	−0.2 (0.1)	−1.1 (0.1)	−1.6 (0.1)
Sakai et al.²⁸	No. of participants	136	135	136
	CFB in MMD^c	0.06 (−0.46 to 0.58)	−2.25 (−2.78 to −1.73)	−1.83 (−2.35 to −1.31)
	≥50% reduction in MMD, n (%)	10 (7.4)	39 (28.9)	37 (27.2)
	CFB in acute monthly MSMD^c	0.88 (0.44 to 1.33)	−1.19 (−1.64 to −0.74)	−1.16 (−1.60 to −0.71)
Tepper et al.¹¹	No. of participants	281	188	187
	CFB in MMD^b	−4.2 (0.4)	−6.6 (0.4)	−6.6 (0.4)
	≥50% reduction in MMD, n (%)	66 (23)	75 (40)	77 (41)
	CFB in acute monthly MSMD^b	−1.6 (0.2)	−3.5 (0.3)	−4.1 (0.3)
	Cumulative monthly headache hours^b	−55.2 (5.7)	−64.8 (6.9)	−74.5 (6.9)

Abbreviations: CFB, change from baseline; CM, chronic migraine; EM, episodic migraine; MMD, monthly migraine days; MSMD, migraine-specific medication treatment days.
^aData presented are least-squares means (SE).
^bData presented are mean (SE).
^cData presented are least-squares means (95% CI).

Table 6. Efficacy of erenumab (70 vs. 140 mg) for migraine prevention: EM and CM extension studies
Refs.	Outcome measures	Placebo	Erenumab 70 mg	Erenumab 140 mg
Goadsby et al.²⁴	No. of participants	–	421	424
	CFB (pre-DBTP) in MMD	–	−4.2 (0.2)	−4.6 (0.2)
	CFB (pre-ATP) in MMD	–	−1.1 (0.2)	−1.8 (0.2)
	≥50% reduction in MMD	–	225 (61.0)	239 (64.9)
	CFB (pre-DBTP) in acute monthly MSMD	–	−1.8 (0.1)	−2.0 (0.2)
	CFB (pre-ATP) in acute monthly MSMD	–	−0.7 (0.1)	−1.0 (0.1)
	CFB (pre-DBTP) in MPFID-EA score	–	−6.9 (0.5)	−7.1 (0.4)
	CFB (pre-ATP) in MPFID-EA score	–	−1.8 (0.4)	−2.3 (0.4)
	CFB (pre-DBTP) in MPFID-PI score	–	−5.4 (0.5)	−5.7 (0.5)
	CFB (pre-ATP) in MPFID-PI score	–	−1.3 (0.4)	−1.9 (0.3)
Tepper et al.²⁹	No. of participants	–
	CFB (parent) in MMD, mean (95% CI)	–	n = 214; −8.5 (−9.4, −7.6)	n = 165; −10.5 (−11.5, −9.4)
	≥50% reduction in MMD, n (%)	–	114 (53.3)	111 (67.3)
	≥70% reduction in MMD, n (%)	–	58 (27.1)	69 (41.8)
	100% reduction in MMD, n (%)	–	13 (6.1)	21 (12.7)
	CFB (parent) in acute monthly MSMD, mean (95% CI)	–	n = 176; −6.2 (−6.9, −5.4)	n = 122; −6.7 (−7.7, −5.8)

Note: Data are mean (SE) unless specified.
Abbreviations: ATP, active treatment phase; CFB, change from baseline; CM, chronic migraine; DBTP, double-blind treatment phase; EM, episodic migraine; MMD, monthly migraine days; MSMD, migraine-specific medication treatment days; MPFID-EA, Migraine Physical Function Impact Diary, everyday activities; MPFID-PI, Migraine Physical Function Impact Diary, physical impairment.

Table 7. Efficacy of erenumab (70 vs. 140 mg) for migraine prevention—Difficult-to-treat migraine
Refs.	Outcome measures	Placebo	Erenumab 70 mg	Erenumab 140 mg
Goadsby et al.¹³	CFB in MMD, mean	0 TF: −2.2	−3.5	−3.7
		≥1 TF: −0.4	−2.4	−3.3
		≥2 TF: −0.1	−1.2	−3.1
	≥50% reduction in MMD	0 TF: 32.6	46.5	55.9
		≥1 TF: 17.5	38.6	39.7
		≥2 TF: 11.1	26.5	36.2
	≥75% reduction in MMD	0 TF: 12.1	24.3	24.8
		≥1 TF: 1.6	15.7	17.2
		≥2 TF: 0	10.2	8.6
	CFB in acute monthly MSMD, mean	0 TF: −0.2	−1.0	−1.3
		≥1 TF: 0.3	−1.4	−2.3
		≥2 TF: 0.5	−0.7	−2.3
Ashina et al.¹⁴	CFB in MMD, LSM	0 TF: −5.7	−7.9	−6.1
		≥1 TF: −3.5	−6.0	−6.8
		≥2 TF: −2.7	−5.4	−7.0
	≥50% reduction in MMD	0 TF: 38.1	50.0	41.9
		≥1 TF: 17.3	34.7	40.8
		≥2 TF: 14.2	35.6	41.3
	≥75% reduction in MMD	0 TF: 14.3	23.4	22.6
		≥1 TF: 5.1	13.7	20.0
		≥2 TF: 3.5	11.1	21.7
	CFB in acute monthly MSMD, LSM	0 TF: −1.8	−2.5	−2.5
		≥1 TF: −1.5	−3.8	−4.9
		≥2 TF: −1.3	−4.1	−5.4
Tepper et al.¹⁵		Medication overuse category
	CFB in MMD, mean	−3.5	−6.6	−6.6
	CFB in acute monthly MSMD, mean	−2.1	−5.4	−4.9
	≥50% reduction in MMD	17.7	36.4	34.6
Brandes et al.¹⁶	MMD (≥50% reduction in MMD)	23.5	39.9	41.2
	MMD (≥75% reduction in MMD)	7.8	17.0	20.9
	MMD (100% reduction in MMD)	0.4	4.3	2.7
	CFB in MMD (≥50% reduction in MMD), mean	–	−12.2	−12.5
	CFB in MMD (≥75% reduction in MMD), mean	–	−13.9	−14.8
	CFB in MMD (100% reduction in MMD), mean	–	−14.5	−14.9
	CFB in MSMD (≥50% reduction in MMD), mean	–	−5.2	−6.9
	CFB in MSMD (≥75% reduction in MMD), mean	–	−4.3	−8.5
	CFB in MSMD (100% reduction in MMD), mean	–	−2.5	−4.7
Schwedt et al.²⁷	CFB in WMD at Week 1 (EM study), LSM	−0.1	−0.3	−0.6
	CFB in WMD Week 1 (CM study), LSM	−0.5	−0.9	−0.8
	CFB in WMD at Week 4 (EM study), LSM	−0.4	−0.6	−0.6
	CFB in WMD Week 4 (CM study), LSM	−0.8	−1.5	−1.4
	Odds achieving 50% reduction in MMD at Week 1 (EM), adjusted OR	–	1.3	2.0
	Odds achieving 50% reduction in MMD at Week 1 (CM), adjusted OR	–	1.8	1.9
	Odds achieving 50% reduction in MMD at Week 4 (EM), adjusted OR	–	1.5	1.4
	Odds achieving 50% reduction in MMD at Week 4 (CM), adjusted OR	–	2.2	2.4

Note: Data are % unless specified.
Abbreviations: CFB, change from baseline; CM, chronic migraine; EM, episodic migraine; LSM, least squares mean; MMD, monthly migraine days; MSMD, migraine-specific medication treatment days; TF, prior preventive treatment failure; WMD, weekly migraine days.

Table 8. Efficacy of erenumab (70 vs. 140 mg) for migraine prevention—Patient reported outcomes
Refs.	Outcome measures	Placebo	Erenumab 70 mg	Erenumab 140 mg
Goadsby et al.¹⁰	No. of participants	316	312	318
	CFB in monthly MPFID-EA score, LSM (SE)	−3.3 (0.4)	−5.5 (0.4)	−5.9 (0.4)
	CFB in monthly MPFID-PI score, LSM (SE)	−2.4 (0.4)	−4.2 (0.4)	−4.8 (0.4)
Brandes et al.¹⁶	CFB in HIT-6™ (≥50% reduction in MMD), mean	–	n = 74	n = 76
	CFB in HIT-6™ (≥50% reduction in MMD), mean	–	−10.0	−10.7
	CFB in HIT-6™ (≥75% reduction in MMD), mean	–	n = 32	n = 38
	CFB in HIT-6™ (≥75% reduction in MMD), mean	–	−10.4	−13.6
	CFB in HIT-6™ (100% reduction in MMD), mean	–	n = 8	N = 5
	CFB in HIT-6™ (100% reduction in MMD), mean	–	−12.4	−20.8
	CFB in total MIDAS (≥50% reduction in MMD), mean	–	n = 73	n = 74
	CFB in total MIDAS (≥50% reduction in MMD), mean	–	−29.1	−35.0
	CFB in total MIDAS (≥75% reduction in MMD), mean	–	n = 32	n = 36
	CFB in total MIDAS (≥75% reduction in MMD), mean	–	−30.1	−37.1
	CFB in total MIDAS (100% reduction in MMD), mean	–	n = 8	n = 5
	CFB in total MIDAS (100% reduction in MMD), mean	–	−30.4	−41.4
Sakai et al.²⁸	No. of participants	136	135	136
	CFB in HIT-6™ total score, LSM (95% CI)	2.2 (−3.1 to −1.3)	−4.3 (−5.2 to −3.4)	4.2 (−5.1 to −3.3)
	CFB in MPFID, LSM (95% CI)	0.20 (−0.70 to 1.10)	−2.32 (−3.23 to −1.41)	−2.13 (−3.02 to −1.23)
Buse et al.²⁵	No. of participants	316	312	318
	CFB in mMIDAS, LSM (SE)	−4.6 (0.4)	−6.7 (0.4)	−7.5 (0.4)
	CFB in mMIDAS absenteeism, LSM (SE)	−2.6 (0.2)	−3.6 (0.2)	−4.2 (0.2)
	CFB in mMIDAS presenteeism, LSM (SE)	−2.0 (0.2)	−3.1 (0.2)	−3.3 (0.2)
	CFB in HIT-6™, LSM (SE)	−4.6 (0.4)	−6.7 (0.3)	−6.9 (0.3)
	CFB in MSQ-role function restrictive, LSM (SE)	11.7 (0.85)	16.8 (0.85)	18.1 (0.84)
	CFB in MSQ-role function preventive, LSM (SE)	8.5 (0.76)	12.7 (0.76)	13.9 (0.75)
	MSQ-emotional functioning, LSM (SE)	7.7 (0.88)	12.9 (0.87)	14.4 (0.87)
Lipton et al.³	No. of participants	281	188	187
	CFB in MSQ- role function restrictive, LSM (95% CI)	11.8 (9.4, 14.1)	17.7 (14.9, 20.6)	19.1 (16.3, 22.0)
	CFB in MSQ- role function preventive, LSM (95% CI)	8.9 (6.8, 11.0)	13.0 (10.5, 15.6)	13.8 (11.3, 16.4)
	CFB in MSQ- emotional functioning, LSM (95% CI)	9.9 (7.3, 12.5)	18.2 (15.0, 21.3)	18.8 (15.6, 21.9)
	CFB in HIT-6™, LSM (95% CI)	−3.1 (−3.9, −2.3)	−5.6 (−6.5, −4.6)	−5.6 (−6.5, −4.6)
	CFB in MIDAS, LSM (95% CI)	−7.5 (−12.4, −2.7)	−19.4 (−25.2, −13.6)	−19.8 (−25.6, −14.0)
	CFB in MIDAS-absenteeism, LSM (95% CI)	−5.2 (−8.0, −2.4)	−10.3 (−13.6, −6.9)	−10.2 (−13.6, −6.8)
	CFB in MIDAS-presenteeism, LSM (95% CI)	−1.9 (−4.7, 0.8)	−9.3 (−12.6, −6.1)	−9.9 (−13.2, −6.7)
	CFB in patient-reported outcomes measurement information system scores, LSM (95% CI)	−4.5 (−5.2, −3.8)	−6.5 (−7.4, −5.6)	−7.1 (−8.0, −6.2)
Lipton et al.²⁶	HIT-6™ total score
	HIT-6™ total score >60 subgroup, n	145	159	142
	CFB in the HIT-6™ total score, mean (SD)	−5.7 (7.2)	−8.8 (7.5)	−8.9 (7.6)
	mMIDAS total score >7 subgroup, n	211	212	195
	CFB in the HIT-6™ total score, mean (SD)	−5.0 (6.9)	−7.6 (7.3)	−7.7 (7.5)
	mMIDAS total score
	HIT-6™ total score >60 subgroup, n	145	159	142
	CFB in the mMIDAS total score, mean (SD)	8.2 (12.7)	−9.8 (10.9)	−10.2 (10.7)
	mMIDAS total score >7 subgroup, n	211	212	195
	CFB in the mMIDAS total score, mean (SD)	−7.2 (11.7)	−9.7 (10.9)	−10.3 (9.6)

Abbreviations: CFB, change from baseline; HIT-6™, Headache Impact Test; LSM, least squares mean; MMD, monthly migraine days; MIDAS, Migraine Disability Assessment; mMIDAS, modified Migraine Disability Assessment; MPFID, Migraine Physical Function Impact Diary; MPFID-EA, Migraine Physical Function Impact Diary, everyday activities; MPFID-PI, Migraine Physical Function Impact Diary, physical impairment; MSMD, migraine-specific medication treatment days; MSQ, migraine-specific quality-of-life questionnaire.

Table 9. Summary of key erenumab studies for the prevention of migraine—Safety
Ref.	Safety
Goadsby et al.¹⁰		Placebo	Erenumab 70 mg	Erenumab 140 mg
	No. of participants	319	314	319
	Any AE	201 (63.0)	180 (57.3)	177 (55.5)
	Discontinuation due to AEs	8 (2.5)	7 (2.2)	7 (2.2)
	Serious AEs	7 (2.2)	8 (2.5)	6 (1.9)
	Frequent AEs by PT (≥2% in both erenumab groups)
	Nasopharyngitis	32 (10.0)	31 (9.9)	35 (11.0)
	Upper RTI	18 (5.6)	21 (6.7)	15 (4.7)
	Sinusitis	7 (2.2)	7 (2.2)	11 (3.4)
	Arthralgia	6 (1.9)	7 (2.2)	7 (2.2)
Goadsby et al.²⁴		Placebo	Erenumab 70 mg, n (%)/e[r]	Erenumab 140 mg, n (%)/e[r]
	No. of participants	–	421	424
	Treatment emergent AEs	–	241 (57.2)/179.1 [134.6]	233 (55.0)/190.9 [122.0]
	Discontinuation due to AEs	–	6 (1.4)/304.9 [2.0]	10 (2.4)/308.7 [3.2]
	Serious AEs	–	14 (3.3)/299.7 [4.7]	14 (3.3)/307.8 [4.5]
	Frequent treatment emergent AEs by PT (≥2% in both erenumab groups)
	Viral upper RTI	–	58 (13.8)/282.9 [20.5]	44 (10.4)/293.3 [15.0]
	Upper RTI	–	25 (5.9)/293.9 [8.5]	19 (4.5)/303.0 [6.3]
	Nausea	–	12 (2.9)/299.7 [4.0]	11 (2.6)/305.9 [3.6]
	Urinary tract infection	–	15 (3.6)/300.5 [5.0]	7 (1.7)/307.7 [2.3]
	Influenza	–	13 (3.1)/304.5 [4.3]	9 (2.1)/307.1 [2.9]
Sakai et al.²⁷		Placebo	Erenumab 70 mg	Erenumab 140 mg
	No. of participants	136	135	137
	Any AE	92 (67.6)	95 (70.4)	95 (69.3)
	Discontinuation due to AEs	1 (0.7)	2 (1.5)	0 (0.0)
	Serious AEs	4 (2.9)	1 (0.7)	1 (0.7)
	Frequent AEs by PT (≥2% in both erenumab groups)
	Nasopharyngitis	40 (29.4)	39 (28.9)	45 (32.8)
	Constipation	2 (1.5)	6 (4.4)	7 (5.1)
	Pharyngitis	3 (2.2)	5 (3.7)	3 (2.2)
Tepper et al.¹¹		Placebo	Erenumab 70 mg	Erenumab 140 mg
	No. of participants	282	190	188
	Any AE	110 (39)	83 (44)	88 (47)
	Discontinuation due to AEs	2 (1)	0	2 (1)
	Serious AEs	7 (2)	6 (3)	2 (1)
	Frequent AEs by PT (≥2% in both erenumab groups)
	Injection-site pain	3 (1)	7 (4)	7 (4)
	Upper RTI	4 (1)	5 (3)	6 (3)
	Nausea	7 (2)	4 (2)	6 (3)
	Nasopharyngitis	16 (6)	6 (3)	3 (2)
	Migraine	3 (1)	3 (2)	5 (3)

Abbreviations: AE, adverse event; PT, preferred term; RTI, respiratory tract infection.

Authors and Disclosures

Stewart J. Tepper MD¹, Huma U. Sheikh MD², Carrie O. Dougherty MD³, Stephanie J. Nahas MD MSEd⁴, Paul K. Winner DO⁵, Ananda Krishna Karanam PhD⁶, Andrew M. Blumenfeld MD^7,8, Ahmad Abdrabboh PharmD MPH⁹, Soeren Rasmussen MD¹⁰, Jamie L. Weiss PhD⁹ and Jessica Ailani MD³

¹Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
²Department of Neurology, Mt. Sinai-Icahn School of Medicine, New York, New York, USA
³Department of Neurology, Medstar Georgetown University Hospital, Washington, DC, USA
⁴Department of Neurology, Thomas Jefferson University, Jefferson Headache Center, Philadelphia, Pennsylvania, USA
⁵Premiere Research Institute, Nova Southeastern University, West Palm Beach, Florida, USA
⁶Novartis Healthcare Private Limited, Hyderabad, India
⁷The Los Angeles Headache Center, Los Angeles, California, USA
⁸The San Diego Headache Center, San Diego, California, USA
⁹Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
¹⁰Amgen Inc., Thousand Oaks, California, USA

Correspondence
Stewart J. Tepper, Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Email: Stewart.J.Tepper@hitchcock.org, sjtepper@gmail.com

Conflict of Interest
Stewart J. Tepper—Grants for research (no personal compensation): Allergan, Amgen, ElectroCore, Eli Lilly, Neurolief, Novartis, Satsuma, Teva, Zosano. Consultant and/or Advisory Boards (honoraria): Aeon, Align Strategies, Allergan/Abbvie, Alphasights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, CoolTech, CRG, Currax, Decision Resources, DeepBench, DRG, Eli Lilly, Equinox, ExpertConnect, GLG, Guidepoint Global, Healthcare Consultancy Group, Health Science Communications, HMP Communications, Impel, Lundbeck, M3 Global Research, Magellan Rx Management, Medicxi, Navigant Consulting, Neurolief, Nordic BioTech, Novartis, Pulmatrix, Reckner Healthcare, Relevale, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Sudler and Hennessey, Synapse Medical Communications, System Analytic, Teva, Theranica, Thought Leader Select, Trinity Partners, XOC, Zosano. Salary: Dartmouth-Hitchcock Medical Center, American Headache Society, Thomas Jefferson University. CME honoraria: American Academy of Neurology, American Headache Society, Cleveland Clinic Foundation, Diamond Headache Clinic, Elsevier, Forefront Collaborative, Hamilton General Hospital, Ontario, Canada, Headache Cooperative of New England, Henry Ford Hospital, Detroit, Inova, Medical Learning Institute Peerview, Medical Education Speakers Network, Miller Medical Communications, North American Center for CME, Physicians' Education Resource, Rockpointe, ScientiaCME, WebMD/Medscape. Huma U. Sheikh—Consulting work for Biohaven, Lundbeck and Novartis, Amgen as well as Allergan. Carrie O. Dougherty—Funds received from Abbvie, Allergan, Alder, Amgen, Biohaven Eli Lilly, Impel, Lundbeck, Novartis, Teva, and Theranica. Stephanie J. Nahas—Advisory Board: Allergan/AbbVie, Zosano. Speaker: Allergan/AbbVie, Amgen/Novartis, Eli Lilly, Teva. Consultant: Alder/Lundbeck, Allergan/AbbVie, Amgen/Novartis, Axsome, BioDelivery Sciences, Biohaven, Eli Lilly, Fenix Group International, Impel, Nesos Corp (formerly Vorso Corp), Teva. Editorial Board: Springer (Current Pain and Headache Reports), Wolters-Kluwer (UpToDate), Neurology Learning Network. Contributing author: Massachusetts Medical Society, MedLink LLC (Neurology), Springer, Wolters-Kluwer. Education: American Academy of Neurology, American Headache Society, Continuing Education Company, Evolve Med Ed, MJH Life Sciences, NACCME, Neurology Learning Network, Pennsylvania Neurologic Society, WebMD/Medscape. Legal fees: Jackson & Campbell, P.C. Paul K. Winner—An investigator in clinical trials sponsored by Teva, Amgen, Genentech, Novartis, Allergan, AstraZeneca, Biogen Idec, Ipsen and Lilly, has participated in advisory boards for Teva, Amgen, Avanir, Novartis, Allergan, Supernus and Lilly, and has been on a speaker's bureau for Allergan, Amgen, Avanir, Lilly, Promius, Novartis, and Supernus. Ananda Krishna Karanam and Ahmad Abdrabboh—employees of Novartis. Jamie L. Weiss—employee of Novartis at the time of manuscript preparation and is a current employee of Prilenia Therapeutics. Andrew M. Blumenfeld—Funds received from Abbvie, Allergan, Aeon, Alder, Amgen, Axsome, Biohaven, Depomed, Eli Lilly, Impax, Lundbeck, Novartis, Revance, Supernus, Teva, and Theranica. Soeren Rasmussen—employee of Amgen Inc. at the time of manuscript preparation. Jessica Ailani—Honoraria received for independent consulting: Amgen, Allergan/Abbvie, Biohaven, Eli Lilly and Company, Lundbeck, Teva, Impel, Satsuma, Theranica, Neurodiem, Axsome. Honoraria for promotional speaking: Allergan/Abbvie, Amgen, Biohaven, Eli Lilly and Company, Lundbeck, Teva. Honoraria for editorial services: Current Pain and Headache Reports, NeurologyLive, Infomedica, SELF magazine. Clinical Trial Grants: (Fees to institution) American Migraine Foundation, Allergan, Biohaven, Eli Lilly and Company, Satsuma, Zosano.

Author Contributions
Conception and design: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani. Acquisition of data: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani. Analysis and interpretation of data: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani. Drafting the manuscript: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani. Revising it for intellectual content: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani. Final approval of the completed manuscript: Stewart J. Tepper, Huma U. Sheikh, Carrie O. Dougherty, Stephanie J. Nahas, Paul K. Winner, Ananda Krishna Karanam, Andrew M. Blumenfeld, Ahmad Abdrabboh, Soeren Rasmussen, Jamie L. Weiss, Jessica Ailani.

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Erenumab Dosage for Migraine Prevention

An Evidence-Based Narrative Review With Recommendations

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Authors and Disclosures

Authors and Disclosures

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