Original Article

Cephalalgia
2020, Vol. 40(6) 543–553
Long-term safety and efficacy of ! International Headache Society 2020
Article reuse guidelines:
erenumab in patients with chronic sagepub.com/journals-permissions
DOI: 10.1177/0333102420912726
migraine: Results from a 52-week, journals.sagepub.com/home/cep

open-label extension study

Stewart J Tepper1, Messoud Ashina2, Uwe Reuter3,

Jan Lewis Brandes4, David Dole

zil5, Stephen D Silberstein6 ,
Paul Winner , Feng Zhang , Sunfa Cheng9 and Daniel D Mikol9
7 8

Abstract
Background: This study reports the long-term safety and efficacy of erenumab in chronic migraine patients.
Methods: This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the
double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-
label treatment phase, the initial monthly dose was erenumab 70 mg. Following protocol amendment, patients continued
to receive erenumab 70 mg if they had already completed their Week 28 visit, otherwise, patients switched from 70 mg
to 140 mg; if enrolled after the amendment, patients received 140 mg monthly throughout.
Results: In all, 451/609 (74.1%) enrolled patients completed the study. The exposure-adjusted patient incidence rate
for any adverse event was 126.3/100 patient-years for the overall erenumab group. Overall, the adverse event profile
was similar to that observed in the double-blind treatment phase. Adverse event incidence rates did not increase with
long-term erenumab treatment compared with the double-blind treatment phase, and no new serious or treatment-
emergent events were seen.
Efficacy was sustained throughout the 52 weeks. Clinically significant reductions from double-blind treatment phase
baseline (about half) were observed for monthly migraine days and migraine-specific medication days. Achievement of

50%,
75% and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at Week 52
were reported by 59.0%, 33.2% and 8.9% of patients, respectively, for the combined dose group. A numerically greater
benefit was observed with 140 mg compared with 70 mg at Weeks 40 and 52.
Conclusions: Sustained efficacy of long-term erenumab treatment in patients with chronic migraine is demonstrated,
with safety results consistent with the known safety profile of erenumab and adverse event rates comparable to placebo
adverse event rates in the double-blind treatment phase.
Trial registration: This study is registered at ClinicalTrials.gov (NCT02174861)

Keywords
Chronic migraine, efficacy, erenumab, long-term, open-label extension, preventive treatment, safety
Date received: 20 November 2019; revised: 31 January 2020; accepted: 24 February 2020

1
Geisel School of Medicine at Dartmouth, Hanover, NH, USA
2 7
Department of Neurology, Danish Headache Center, Rigshospitalet Premiere Research Institute, Nova Southeastern University, West Palm
Glostrup, University of Copenhagen, Copenhagen, Denmark Beach, FL, USA
3 8
Department of Neurology, Charite Universit€atsmedizin Berlin, Berlin, Global Biostatistical Science, Amgen Inc, Thousand Oaks, CA, USA
9
Germany Global Development, Amgen Inc, Thousand Oaks, CA, USA
4
Nashville Neuroscience Group and Vanderbilt University Department of
Neurology, Nashville, TN, USA Corresponding author:
5
Prague Headache Center DADO MEDICAL sro, Prague, Czech Republic Stewart Tepper, Geisel School of Medicine at Dartmouth, Hanover, NH
6
Jefferson Headache Center, Thomas Jefferson University, Philadelphia, 03756, USA.
PA, USA Email: sjtepper@gmail.com
544
Introduction
Chronic migraine (CM) is one of the most prevalent
types of headache encountered in tertiary care (1). The
high number of migraine days per month in patients
with CM impacts patients’ quality of life (2–4).
Treatment goals for management of CM include reduc-
tion in migraine frequency, reduction in use of acute
medications, and safety and tolerability at the admin-
istered doses. Conventional oral preventive therapies
have been the standard of care for migraine, but are
associated with low persistence and adherence rates
often leading to frequent switching or complete cessa-
tion of treatment (5, 6). As patients with CM often
require long-term preventive therapy, an effective and
tolerable preventive treatment for CM addresses a
major unmet need.
The calcitonin gene-related peptide (CGRP) binds
to the canonical CGRP receptor but can also bind to
other receptors in the calcitonin-like receptor family
including the amylin (to which CGRP binds with
comparable affinity as does amylin itself) and adreno-
medullin receptors (7). Erenumab, a fully human
monoclonal antibody, selectively targets and blocks
the canonical CGRP receptor with no affinity for any
related receptors (7). The efficacy and safety of erenu-
mab 70 mg and 140 mg has been demonstrated in both
episodic migraine and CM (8–11). Erenumab at doses
of 70 mg or 140 mg monthly is approved in the United
States for the preventive treatment of migraine in
adults (12) and in the EU for prophylaxis of migraine
in adults who have at least four migraine days per
month (13).
The long-term safety and tolerability profile and effi-
cacy of erenumab in patients with episodic migraine are
Double-blind
Treatment phase
1–4 5–8
Placebo X X
Screening
Erenumab 70 mg N = 350
N = 60
Erenumab 140 mg
N = 199
12 Weeks
Figure 1. Study design.
a
By Week 40, any patient who had a dose increase to 140 mg at or before Week 28 had received 140 mg for at least 12 weeks and
therefore had reached steady state.
Cephalalgia 40(6)
being studied in a 5-year, open-label study, and the
1-year preplanned interim analysis results have been
published (14). Here, we report the long-term safety,
tolerability and efficacy of erenumab for CM during a
1-year open-label treatment phase (OLTP). The results
from the parent 12-week, randomized, placebo-
controlled trial were published previously (11).
Methods
Study design
This was a multicenter, 52-week, open-label study
following a 12-week double-blind placebo-controlled
study, conducted from June 2014 to May 2017 at
64 centers across North America and Europe
(NCT02174861). Patients who completed the 12-week
parent study and met all eligibility criteria for the
OLTP were enrolled within 14 days of completion of
the double-blind study. The initial erenumab dose used
in the OLTP was 70 mg once monthly. The protocol
was subsequently amended to increase the dose to
140 mg monthly to have more long-term safety data
from CM patients on the higher dose. Following the
protocol amendment, patients who had already com-
pleted the Week 28 visit continued to receive erenumab
70 mg monthly for the remainder of the study; patients
who had not completed the Week 28 visit increased the
open-label erenumab dose from 70 mg to 140 mg
monthly at the next visit, and patients who enrolled
after the protocol amendment received erenumab
140 mg monthly throughout the study (Figure 1).
Concomitant treatments prohibited during the study
are listed in Supplemental material, Appendix 1.
X Efficacy evaluation
Open-label treatment phase
(12 weeks)
Study week
Follow-up
Safety
9–12 13–16 17–20 21–24 25–28 29–32 33–36 37–40* 41–44 45–48 49–52
X X X X
Completed
52 weeks
70 mg 70 mg
final dose
140 mg (N = 266)
140 mg
70 mg 140 mg (increased between weeks 4 and 28)a final dose
(N = 203)
52 Weeks
Tepper et al.
Eligibility criteria
Patients of either gender, aged 18–65 years with a
history of CM (with or without aura) of at least one
year, who completed the double-blind study without
discontinuing the study treatment and were considered
appropriate for continued treatment, were included.
Patients were excluded for the following reasons:
Development of an unstable or clinically significant
medical condition, laboratory or electrocardiogram
abnormality that, in the opinion of the investigator,
would pose a risk to patient safety or interfere with
study evaluation following randomization into the
double-blind study; demonstrated poorly controlled
hypertension following randomization into the double-
blind study; or systolic blood pressure
160 mm Hg
and/or diastolic blood pressure
100 mm Hg at screen-
ing/Day 1. Women of child-bearing potential not on an
acceptable and effective mode of contraception, as well
as pregnant and nursing women, were also excluded.
Eligibility criteria for enrollment in the double-blind
study have been reported previously (11).
The final study protocol, informed consent form and
accompanying materials provided to study patients
were all reviewed and approved by an Independent
Ethics Committee or Institutional Review Board at
all participating sites. Details of the participating cen-
ters are listed in the Supplemental material, Appendix
2. This study was conducted in accordance with
International Council for Harmonization Good
Clinical Practice regulations/guidelines and in accor-
dance with the ethical principles set forth in the
Declaration of Helsinki. Written informed consent
was obtained from each patient prior to enrollment.
Outcomes
The primary endpoint was the incidence of adverse
events (AEs). The AE grading was based on the
Common Terminology Criteria for Adverse Events
(CTCAE) version 4.03, and AEs were coded using
the Medical Dictionary for Regulatory Activities
(MedDRa) version 20.0. Secondary endpoints included
evaluation of the efficacy parameters; that is, change
from DBTP baseline to Week 52 in monthly migraine
days (MMD), proportion of patients achieving
50%
reduction in MMD and change from baseline in
monthly acute migraine-specific medication days
(MSMD). In order to explore whether there might be
a difference in efficacy between the 70 and 140 mg
doses, a post-hoc analysis of efficacy parameters was
conducted in patients who completed the 52-week
OLTP treatment based on the last dose received.
Additional post-hoc exploratory endpoints included
achievement of
75% and 100% reduction in MMD
545
and change from baseline to Week 52 in MSMD in the
subset of patients using migraine-specific medications
at baseline.
A qualified migraine was defined as a migraine
with or without aura lasting at least 4 hours and
expressing at least two headache-associated features
or at least one associated non-headache feature, or
both (Supplemental material, Appendix 2). Any calen-
dar day on which acute migraine-specific medication
(triptan in 99% of the cases, or ergot derivative) was
used was also counted as a migraine day. Details on
migraine-related outcomes have been reported with the
parent study (11).
Assessments
Safety was assessed by monitoring AEs and reviewing
results of electrocardiograms, laboratory assessments
and vital signs. AEs and vital sign data were collected
throughout the OLTP and during a 12-week safety
follow-up phase after the last dose. Electrocardiograms
and hematology were performed at Weeks 4, 12, 24
(only for patients who increased erenumab to 140 mg
at Weeks 12, 16 or 20), 36 (only for patients who
increased erenumab to 140 mg at Weeks 24 or 28) and
52. Serum anti-erenumab antibodies were measured
during the double-blind treatment phase (DBTP) and
at Week 24 and Week 52 of the OLTP.
Efficacy was assessed using an electronic diary daily
during pre-specified time intervals: For the first 12
weeks, then from Weeks 21–24, Weeks 37–40 and
Weeks 49–52.
Statistical analysis
The full analysis set and safety analysis set included all
patients enrolled in the study who had received at least
one dose of erenumab during the OLTP. The efficacy
analysis set was a subset of the full analysis set of
patients who in addition had at least one change
from baseline measurement for endpoint of interest.
AEs were summarized as the exposure-adjusted
patient incidence rate of treatment-emergent AEs by
the dose level at which the AE occurred. An AE that
started in the parent study was considered treatment-
emergent in the OLTP only if there was a worsening
of the event. If the event continuing from the parent
study had no changes in severity during OLTP, then
it was not considered treatment-emergent in the
OLTP. The exposure-adjusted patient incidence of a
treatment-emergent AE at a dose level was defined as
the number of patients with at least one reported occur-
rence of the event divided by the total time (patient-
years) at risk for reporting the treatment-emergent AE
for patients exposed. For patients with events, only the
546
time until the first event contributed to the total
patient-years, and results are presented per 100
patient-years. All other safety data, except that on
anti-erenumab antibody levels, were analyzed based
on the treatment received during the OLTP (70 mg
only, 140 mg only or 70/140 mg).
For the analysis of efficacy endpoints, baseline was
defined as the 4-week baseline period of the parent
study (beginning the first day the patient used the
eDiary during baseline through the day prior to study
Day 1). Efficacy results presented in the OLTP are
either by the combined dose group or by last dose
received among completers. Summary descriptive sta-
tistics for efficacy endpoints were tabulated at each
visit. No formal statistical testing was performed.
Data were reported as observed, without imputation
for missing data. Efficacy endpoints were summarized
descriptively for all patients in the efficacy analysis set.
Summary by dose group for the first 28 weeks of the
OLTP was not appropriate since patients could switch
dose from 70 mg to 140 mg at different time points
between Week 4 and 28.
For the post-hoc efficacy analysis, analyses were per-
formed at Weeks 40 and 52, based on the final dose
received among completers; summary statistics were
calculated by last dose received as collected by the elec-
tronic diary over Weeks 36–40 and 48–52, respectively.
For patients switching from 70 mg to 140 mg between
Weeks 4–28, by Week 40 patients would have been on
139 (22.8%) patients discontinued open-label
treatment
Reasons for treatment discontinuation:
• Subject request, n = 64 (10.5%)
• Lack of efficacy, n = 39 (6.4%)
• Adverse event, n = 16 (2.6%)
• Lost to follow-up, n = 9 (1.5%)
• Requirement for alternative therapy, n = 3 (0.5%)
• Protocol deviation, n = 2 (0.3%)
• Non-compliance, n = 2 (0.3%)
• Decision by sponsor, n = 1 (0.2%)
• Pregnancy, n = 1 (0.2%)
• Other, n = 2 (0.3%)
549 patients on open-label erenumab 70 mg
• 545 analyzed for efficacy
• 549 analyzed for safety
350 patients received erenumab 70 mg alone
266 patients analyzed for efficacy based on
last dose received among those who
completed open-label treatment
Figure 2: Patient disposition.
Cephalalgia 40(6)
140 mg for at least 12 weeks and would have therefore
achieved steady state. Consequently, by Week 52,
patients would have been on 140 mg for at least 24 weeks.
Results
A total of 609 patients were enrolled, 451 (74.1%) com-
pleted the 64-week study (12 week DBTP þ 52 week
OLTP), and 158 (25.9%) patients discontinued the
study (eight [1.3%] due to decision of the sponsor,
124 [20.4%] withdrew consent from the study, and 26
patients [4.3%] were lost to follow-up). The most
common reasons for treatment discontinuation were
patient request (10.5%), lack of efficacy (6.4%) and
AEs (2.6%). During the study, 350 patients received
erenumab 70 mg alone, 60 patients received erenumab
140 mg alone, and 199 patients had a dose increase
from 70 to 140 mg erenumab by the Week 28 visit.
All 609 patients received the study medication and
were included in the full analysis and safety analysis
sets. Figure 2 presents the study patient disposition.
At DBTP baseline, the mean (standard deviation
[SD]) age of patients was 42.5 (11.3) years. Most
patients were Caucasian (94.3%), and the majority of
patients were women (83.6%); disease duration (mean
[SD]) was 21.8 (12.4) years (Table 1). Prior preventive
migraine medications were used by 454 patients
(74.5%). Among those prior preventive medication
users, the most frequently used medications were
609 patients enrolled in the Open-label treatment phase
• 470 (77.2) patients completed open-label treatment
60 patients on open-label erenumab 140 mg
• 60 analyzed for efficacy
• 60 analyzed for safety
After protocol amendment 3, 199 switched
to erenumab 140 mg prior to or at Week 28
203 analyzed for efficacy based on last dose
received in those who completed open-label
treatment
Tepper et al.
Table 1. Patient demographics and disease characteristics at
DBTP baseline (full analysis set).
Parameter
Age, years
Women, n (%)
Race, n (%)
Caucasian
Asian
Black or African American
Other
Prior migraine preventive medication, n (%)
Prior preventive treatment failure, n (%)
Disease duration, years
Targeted neurological disease diagnosis, n (%)
Migraine with aura#
Migraine without aura#
Monthly migraine days*
Monthly headache hours*
Acute migraine-specific medication use,* n (%)
Monthly acute migraine-specific
medication use days*
Note: Values are mean (SD) unless otherwise indicated.
#
Individual patients could fall into either migraine category or both (with
aura and without aura), based on investigator report; *Includes 605
patients who were included in the efficacy analysis set.
CM: chronic migraine; N: total number of patients; n: number of patients
with event; SD: standard deviation.
topiramate (68.5%), beta blockers (54.0%), and tricy-
clic antidepressants (48.9%); 92.3% discontinued pre-
ventive medication due to treatment failure, whether
due to lack of efficacy or poor tolerability.
Safety
Most patients (73.7%) received all 13 doses of erenu-
mab. Exposure to the 70 and 140 mg doses combined
was 527.0 patient-years.
Overall, 65.4% (398/609) of patients had treatment-
emergent AEs. The exposure-adjusted patient incidence
rate was 126.3/100 patient-years overall, and 132.0
and 148.5/100 patient-years, during erenumab
70 mg/140 mg exposure, respectively in the OLTP. In
the DBTP, the exposure-adjusted patient incidence
rates were 202.0/100 patient-years for placebo, and
250.3/100 and 282.3/100 patient-years for erenumab
70 mg and 140 mg, respectively; these values were
slightly higher than those observed in the OLTP. The
most common treatment-emergent AEs are listed in
Table 2. The AE with the highest incidence among all
erenumab-treated patients was viral upper respiratory
tract infection (16.4/100 patient-years in the OLTP,
Table 2). The frequencies of the most common AEs
were comparable between erenumab and placebo
547
during the DBTP. Most AEs were grade 1 or grade 2
in severity. Treatment-emergent AEs of grade 4 sever-
Patients ity or fatal AEs were not observed in any patient.
with CM The overall exposure-adjusted patient incidence of
(N ¼ 609) treatment-emergent serious AEs was lower during the
OLTP than was observed during the DBTP (3.8/100
42.5 (11.3) patient-years [24 patients] with erenumab overall in
509 (83.6)
the OLTP versus 12.1/100 patient-years [six patients],
574 (94.3) 4.1/100 patient-years [two patients], and 9.5/100
7 (1.1) patient-years [seven patients] with the erenumab
25 (4.1) 70 mg, erenumab 140 mg, and placebo, respectively, in
3 (0.5) the DBTP) (Table 2). The serious events reported in > 1
454 (74.5) patient included migraine (n ¼ 4, 0.6/100 patient-years),
419 (68.8) intervertebral disc protrusion (n ¼ 3, 0.5/100 patient-
21.8 (12.4) years), and depression (n ¼ 2, 0.3/100 patient-years).
During OLTP, treatment-emergent AEs led to
255 (41.9) treatment discontinuation in 16 patients (2.5/100
529 (86.9)
patient-years, Table 2) overall in the OLTP. The
18.1 (4.5)
226.8 (125.5) exposure-adjusted patient incidence of treatment-
474 (78.3) related treatment-emergent AEs was 20.5/100 patient-
9.5 (7.3) years (n ¼ 114 patients); events with incidence rate
> 1 patient/100 patient-years included injection site
pain, nausea, dizziness, injection site erythema, and
migraine. Exposure-adjusted incidence rates were
similar for both erenumab doses (21.6 and 20.9/
100 patient-years for erenumab 70 mg and 140 mg,
respectively).
No clinically meaningful alterations were observed
in laboratory values, vital signs, electrocardiogram
findings, blood pressure, or heart rate at any post-
baseline time point, which is consistent with observa-
tions during the DBTP (11).
Of the 587 patients with a post-baseline result, anti-
erenumab binding and neutralizing antibodies were
observed in 34 (5.8%) and three (0.5%) patients,
respectively. Of these patients, 17/34 and 2/3 showed
transient anti-erenumab antibodies; all tested negative
at the last study visit. The third patient with an anti-
erenumab neutralizing antibody positive refused to
participate in further neutralizing antibody follow-up
tests, and so it is unknown whether they returned to
antibody negativity. The neutralizing antibodies did
not show any effect on efficacy.
Efficacy
In the combined dose group, the mean (SD) MMD at
parent study baseline was 18.1 (4.5) days, and the mean
(95% CI) change from parent study baseline at Weeks
40 and 52 was 8.7 (9.3, 8.1) reducing MMD to
9.4 days and 9.3 (10.0, 8.6) reducing MMD to
8.8 days, respectively (Figure 3(a)). The proportion of
patients achieving a
50% reduction from parent
study baseline in MMD at Weeks 40 and 52
was 55.6% and 59.0%, respectively (Figure 4(a)).
548 Cephalalgia 40(6)

Table 2. Exposure-adjusted patient incidence rates (i.e. patients/100 patient-years) of treatment-emergent AEs (summarized based
on the dose received when the AE occurred) (safety analysis set).

12-week DBTP 52-week OLTP

Placebo Erenumab Erenumab Total

70 mg 140 mg 70 mg 140 mg
(N ¼ 282) (N ¼ 190) (N ¼ 188) (N ¼ 549) (N ¼ 259) (N ¼ 609)#
Event n (r) n (r) n (r) n (r) n (r) n (r)

Any AE 110 (202.0) 83 (250.3) 88 (282.3) 311 (132.0) 157 (148.5) 398 (126.3)
Grade
3 13 (18.0) 11 (22.6) 4 (8.3) 28 (6.6) 8 (3.7) 34 (5.4)
Serious AEs 7 (9.5) 6 (12.1) 2 (4.1) 14 (3.3) 10 (4.7) 24 (3.8)
AE leading to discontinuation 2 (2.7) 0 (0.0) 2 (4.1) 9 (2.1) 7 (3.3) 16 (2.5)
of erenumab
Most frequent AEs*
Viral upper respiratory 14 (19.3) 6 (12.2) 3 (6.1) 68 (17.1) 35 (17.8) 96 (16.4)
tract infection
Upper respiratory 4 (5.4) 5 (10.1) 6 (12.5) 33 (7.8) 13 (6.2) 45 (7.2)
tract infection
Sinusitis 6 (8.1) 3 (6.0) 2 (4.1) 31 (7.5) 14 (6.7) 44 (7.1)
Arthralgia 3 (4.0) 2 (4.0) 1 (2.1) 16 (3.8) 11 (5.2) 27 (4.2)
#
The numbers for the two dose groups (N ¼ 549, N ¼ 259) are not additive to the total (N ¼ 609), as 199 patients were exposed to both doses, and
are represented in both columns depending on the dose level at which the AE occurred.
*Events with
4.2 patients per 100 patient-years in the total erenumab group during open-label treatment phase; time at risk during the study is the
time from first dose of erenumab through to onset of first event or the minimum (end-of-study date, last dose date þ 112).
Note: Grading categories determined using CTCAE version 4.03; preferred terms coded using MedDRA v20.0.
AE: adverse event; CTCAE: common terminology criteria for AEs; DBTP: double-blind treatment phase; MedDRA: Medical Dictionary for Regulatory
Activities; N: total number of patients; n: number of patients with an event; OLTP: open-label treatment phase; r: exposure-adjusted patient incidence
rate per 100 patient-years (n/e*100), where e, sum across all patients, the total time at risk in the study in years.

The proportion of patients achieving a
75% reduc-
tion from parent study baseline in MMD was 28.1% at
Week 40 and 33.2% at Week 52 (Figure 4(a)). The
corresponding values for a 100% reduction from
parent study baseline in MMD were 7.4% at Week
40 and 8.9% at Week 52 (Figure 4(a)). The overall
mean (SD) MSMD at parent study baseline was
9.5 (7.3), and the overall mean (95% CI) change from
parent study baseline was 4.6 (5.1, 4.1), reducing
the MSMD to 4.9 days at Week 40 and 5.0 (5.5,
4.4), reducing the MSMD to 4.5 days at Week 52.
Post-hoc analyses. At both, 40 and 52 weeks, a greater
benefit was observed with the erenumab 140 mg dose
compared with the 70 mg dose. The mean (SD) MMD
at parent study baseline was 17.9 (4.4) and 17.8 (4.6) in
the erenumab 70 and 140 mg groups, respectively.
These were the long-term treatment completers who
received erenumab 70 mg and 140 mg for at least 12
weeks at Week 40 and at least 24 weeks for Week 52.
The mean change from parent study baseline was
greater with erenumab 140 mg than with 70 mg, with
an additional reduction of 2 migraine days/month
at both Week 40 and Week 52 (Figure 3(b)). The reduc-
tion in MMD from parent study baseline was
7.8 days for erenumab 70 mg to 10.1 days, and
10.0 days to 7.8 days for erenumab 140 mg at Week
40. The reduction in MMD from parent study baseline
was 8.5 days to 9.4 days for the 70 mg dose and 10.5
days to 7.3 days for the 140 mg dose at Week 52.
Similarly, the
50%,
75% and 100% MMD
responder rates were higher with the 140 mg dose
than with the 70 mg dose among completers (Figure 4
(b)). At Week 40, 47.4% of the 70 mg group and 67.4%
of the 140 mg group reported a
50% reduction in
MMD; at Week 52, 53.3% of the 70 mg and 67.3%
of the 140 mg group had a
50% reduction in MMD.
The numerical difference between the 70 mg and
140 mg responder rates was also seen for the
75%
responder rates. At Week 40, 24.1% of the 70 mg
group and 33.7% of the 140 mg reported a
75%
reduction in MMD. At Week 52, 27.1% of the 70 mg
group and 41.8% of the 140 mg group had achieved a

75% reduction in MMD (Figure 4(b)).
Finally, the 100% responder rate was nearly two-
fold higher with the 140 mg dose at both Weeks 40
and 52 than with the 70 mg dose. At Week 40, 4.8%
of the 70 mg group and 10.7% of the 140 mg group
reported at least a month of no migraines (i.e. a
100% decrease in MMD). At Week 52, 6.1% of the
70 mg group and 12.7% of the 140 mg group had at
least a month of no migraines (Figure 4(b)).
Tepper et al. 549

(a) DBTP OLTP

0

Change from baseline in

–2

MMD, mean (95% CI)

–4

–6

−8.7
–8 −9.3

–10
0 4 8 12
0 4 8 12 24 40 52
Time (weeks)
N values 561 574 560 481 430 383
P-279 P-271 P-267
70 mg-188 70 mg-183 70 mg-178
140 mg-187 140 mg-184 140 mg-182

Placebo Erenumab 140 mg

Erenumab 70 mg Erenumab OLTP (70 and 140 mg combined)

(b) Week 40 Week 52

0
Change from baseline in

N = 228 N = 187 N = 214 N = 165

MMD, mean (95% CI)

–2
–4
–6
–8
–10 –7.8
(–8.6, –7.0) –10.0 –8.5
–12
(–9.4, –7.6) –10.5
–14 (–10.9, –9.0)
(–11.5, –9.4)
Erenumab 70 mg Erenumab 140 mg

Figure 3. The change from baseline in number of monthly migraine days (MMD) (a) during the parent study and the OLE study; that
is, DBTP and OLTP (efficacy analysis set), (b) during the OLTP at Weeks 40 and 52 by last dose received.
Note: Dashed lines indicate transition from end of the parent study to Week 4 of the OLTP.
CI: confidence interval; DBTP: double-blind treatment phase; MMD: monthly migraine days; N: number of patients with observed data
at corresponding visit; SD: standard deviation; OLTP: open-label treatment phase; P: placebo; 70 mg: erenumab 70 mg dose; 140 mg:
erenumab 140 mg dose.

The mean (SD) monthly MSMD in the subset
of patients using acute migraine-specific medications
at parent study baseline was 12.2 (5.9) with change
from parent study baseline (mean [95% CI]) reported
at Weeks 40 and 52 as 5.8 (6.3, 5.2) to 6.4
days and 6.4 (7.0, 5.8) to 5.8 days, respectively
(Figure 5(a)). Among the completers, the mean (SD)
monthly acute MSMD among the subset of patients
using acute migraine-specific medications at parent
study baseline was 12.4 (5.5) days with the 70 mg
dose and 11.3 (6.5) days with 140 mg dose. The reduc-
tion in mean MSMD was also greater with the 140 mg
dose versus 70 mg dose (Figure 5(b)). At Week 40, the
decrease in monthly MSMD for the 70 mg group was
5.6, reducing the monthly MSMD to 7.1 days; for the
140 mg dose group it was 6.2, reducing the monthly
MSMD to 5.2 days. At Week 52, the decrease in
monthly MSMD for the 70 mg group was 6.2, reduc-
ing the MSMD to 6.5 days; for the 140 mg group the
decrease was 6.7, reducing the monthly MSMD to
5.0 days.
Discussion
Results from this OLTP study demonstrate the long-
term safety and efficacy of erenumab over a 52-week
period in patients with CM following the 12-week
DBTP. Clinical characteristics specific to migraine at
baseline were consistent with a patient population
with CM (11). The Summary of Product characteristics
550 Cephalalgia 40(6)

(a)
DBTP OLTP DBTP OLTP DBTP OLTP
reduction in MMD, mean (95% CI)

reduction in MMD, mean (95% CI)

reduction in MMD, mean (95% CI)

Patients (%) achieving ≥50%

Patients (%) achieving ≥75%

75

Patients (%) achieving 100%

75 75
59.0
56.0

50 50 50
33.2
28.1
25 25 25
7.4 8.9
10 10 10
0 0 0
0 4 8 12 0 4 8 12 0 4 8 12
0 4 8 12 24 40 52 0 4 8 1 24 40 52 0 4 8 12 24 40 52

220 262 256

Week Week Week
258 (53.6)/ 239 (55.6)/ 226 (59.0)/ 97 132 128 20 22 32
(39.2)/(45.6)/ (45.7)/ 125 (26.0) 121 (28.1)/ 127 (33.2)/ 32 (6.7)/ 32 (7.4)/ 34 (8.9)/
481 430 383 (17.3)/(23.0)/(22.9)/ (3.6)/(3.8)/ (6.7)/
561 574 560 /481 430 383 481 430 383
561 574 560 561 574 560
n (%)/N values
P-32 (11.5)/281 P-6 (2.1)/281 P-22 (7.8)/281 P-0 (0)/281 P-1 (0.4)/281
P-66 (23.5)/281 70 mg-0 (0)/188
70 mg-45 (23.9)/188 70 mg-11 (5.9)/188 70 mg-32 (17.0)/188 70 mg-8 (4.3)/188
70 mg-75 (39.9)/188 140 mg-2 (1.1)/187
140 mg-53 (28.3)/187 140 mg-16 (8.6)/187 140 mg-39 (20.9)/187 140 mg-5 (2.7)/187
140 mg-77 (41.2)/187
P-53 (18.9)/281 P-20 (7.1)/281 P-2 (0.7)/281
70 mg-73 (38.8)/188 70 mg-27 (14.4)/188 70 mg-1 (0.5)/188
140 mg-75 (40.1)/187 140 mg-29 (15.5)/187 140 mg-7 (3.7)/187

Placebo Erenumab 70 mg Erenumab 140 mg Erenumab OLTP (70 and 140 mg combined)

(b) Week 40 Week 52 Week 40 Week 52 Week 40 Week 52

reduction in MMD, mean (95% CI)
reduction in MMD, mean (95% CI)

reduction in MMD, mean (95% CI)

80 67.4 67.3 75 75
Patients (%) achieving ≥75%

Patients (%) achieving 100%

Patients (%) achieving ≥50%

70
53.3
60 47.4 41.8
50 50
50 33.7
40 24.1 27.1
30
25 25
20 12.7
10.7 6.1
4.8
10
0 0 0
n/N values 108/228 126/187 114/214 111/165 55/228 63/187 58/214 69/165 11/228 20/187 13/214 21/165
Erenumab 70 mg Erenumab 140 mg

Figure 4. The proportion of patients with a
50%,
75% and 100% reduction from baseline in number of monthly migraine days
(MMD) (a) during the parent study and the OLE study; that is, DBTP and OLTP (efficacy analysis set), (b) during the OLTP at Weeks 40
and 52 by last dose received.
Note: Dashed lines indicate transition from end of the parent study to Week 4 of the OLTP. Values reported the percentage of
patients with outcome (%), % ¼ n/N * 100.
CI: confidence interval; DBTP: double-blind treatment phase; MMD: monthly migraine days; n: number of responders at corre-
sponding visit; N: number of patients at corresponding visit; OLTP: open-label treatment phase; P: placebo; 70 mg: erenumab 70 mg
dose; 140 mg: erenumab 140 mg dose.

for erenumab lists constipation, itching, muscle longer be classified as having CM. Similarly, at the
spasms, and injection site reactions as common AEs individual level, more than 50% of patients achieved
affecting up to 1 in 10 patients. Most AEs reported at least a 50% reduction in MMD at Week 52. Due to
in the current study were grade 1 or grade 2 in severity. the protocol amendment allowing a dose increase of
Treatment-emergent AEs of grade 4 severity and fatal erenumab by Week 28, patients whose dose increased
AEs were not reported in any patient. The safety profile to 140 mg would have been on 140 mg for at least 12
of erenumab in the OLTP was consistent with that in weeks at Week 40, which is sufficient to have reached
the DBTP, with no new safety concerns emerging. steady state concentrations. Thus, Week 40 provided
Across the placebo-controlled clinical trials of the first opportunity to assess efficacy in the study pop-
erenumab (including the DBTP of this OLTP study), ulation based on the final dose received, 70 mg or
there was a low incidence of binding and neutralizing 140 mg. A post-hoc analysis of efficacy at Week 40
anti-erenumab antibodies (10, 11). The development of and Week 52 based on the last dose received showed
anti-erenumab antibodies has not been associated with a numerically greater benefit for the 140 mg dose over
any clinical outcomes or safety events. The generation the 70 mg dose on a variety of endpoints including
of binding and neutralizing antibodies post-baseline MMD, responder rates, and reduction in the MSMD
was transient in the majority of patients. for acute medications.
Erenumab treatment demonstrated sustained effica- The proportion of patients with a
50% response
cy during the 52-week OLTP. Overall, there was a was greater in the OLTP at Week 52 (67.3% and
nearly 50% reduction in mean MMD and MSMD at 53.3%, with 140 mg and 70 mg), compared with the
Week 52 with erenumab treatment. This reduction in DBTP (41% and 40%, respectively) (11), suggesting
MMD means that, on average, most patients would no sustained or increased efficacy with long-term
Tepper et al. 551

(a) DBTP OLTP

0

monthly MSMD use days,

Change from baseline in
–1

mean (95% CI)

–2
–3
–4
–5 −5.8
−6.4
–6
–7
0 4 8 12
0 4 8 12 24 40 52
Time (weeks)
N values 448 453 439 373 342 300
P-219 P-213 P-212
70 mg-140 70 mg-138 70 mg-134
140 mg-147 140 mg-146 140 mg-145

Placebo Erenumab 140 mg

Erenumab 70 mg Erenumab OLTP (70 and 140 mg combined)

(b) Week 40 Week 52

0
in monthly MSMD use
Change from baseline

days, mean (95% CI)

–1 N = 191 N = 139 N = 176 N = 122

–2
–3
–4
–5
–6
–7 –5.6
–8 (–6.3, –4.9)
–6.2
–6.2 (–6.9, –5.4) –6.7
(–7.0, –5.3) (–7.7, –5.8)
Erenumab 70 mg Erenumab 140 mg

Figure 5. The change from parent study baseline in monthly migraine-specific medication use days (MSMD) in acute migraine-specific
medication users at baseline (a) during the parent study and OLE study; that is, DBTP and OLTP (efficacy analysis set), (b) during the
OLTP at Weeks 40 and 52 by last dose received.
Note: Dashed lines indicate transition from end of parent study to Week 4 of OLTP.
CI: confidence interval; DBTP: double-blind treatment phase; MSMD: migraine-specific medication use days; N: number of patients at
corresponding visit; SD: standard deviation; OLTP: open-label treatment phase; P: placebo; 70 mg: erenumab 70 mg dose; 140 mg:
erenumab 140 mg dose.

treatment, although it is possible that withdrawal of
patients not responding to treatment might have
impacted these results. Similarly, the reduction in
MSMD at Week 52 was numerically higher with both
doses (6.2 days for the 70-mg dose and 6.7 days for
the 140-mg dose) compared with the DBTP (3.5 and
4.1 days, respectively), showing a reduction of nearly 3
monthly MSMD from Week 12 of the DBTP (11). A
reduction in the MSMD is important, as this is an
important risk factor for chronification of migraine (15).
While this might suggest that efficacy increases over
time across endpoints, given the open-label nature of
the study and the loss of patients over time, not unusu-
al for open-label extensions, our overall interpretation
is that efficacy is at least sustained throughout the
study, given the possibility of bias introduced by the
loss of patients who did not experience the same level
of efficacy as those who remained in the study.
Approximately 25.9% of patients discontinued the
OLTP, and 22.8% of patients discontinued the inves-
tigational product. The number of patients who discon-
tinued treatment as a result of AEs was small. The data
from this OLTP study show sustained efficacy com-
pared with the findings from the 12-week parent
study and support a durable effect of treatment, with
a safety profile at 52 weeks similar to that in the parent
study at 12 weeks.
Limitations of the study include that it was non-
randomized, and erenumab was administered open-
label, without blinding of dose. Nonetheless, the results
for efficacy endpoints favored the 140-mg dose of
erenumab.
552 Cephalalgia 40(6)

Conclusion of endpoints including reduction in mean MMD,

The results from this 52-week open-label extension
study demonstrate the long-term safety and tolerability
of erenumab in patients with CM. The spectrum of
AEs was similar to that observed during the
placebo-controlled study, with no new safety concerns
and no increase in the rate of AEs. Efficacy was
sustained throughout the 52-week period.
A numerically greater efficacy was observed with
the erenumab 140 mg versus 70 mg dose on a variety
responder rates, and reduction in MSMD for use
of acute medications, suggesting erenumab 140 mg
may provide better long-term efficacy in CM than
70 mg. Overall, the favorable safety, tolerability,
and efficacy profile in this study, and its
once-monthly administration, may mean that subcu-
taneous erenumab has the potential to increase
real-world adherence to treatment in patients with
chronic migraine.

Clinical implications
• This 52-week open-label extension study demonstrates the long-term safety and tolerability of erenumab in
patients with chronic migraine.
• Adverse events reported during the open-label treatment phase were similar to those observed during the
double-blind treatment phase, with no new safety events and no increase in adverse events.
• Erenumab 140 mg showed greater clinical benefit than the 70 mg dose in this study, as demonstrated by
post-hoc analyses of efficacy parameters, including reductions in mean monthly migraine days, responder
rates, and reduction in days of use of acute migraine-specific medications.
• Although dropouts occurred, as is typical in open-label extension trials, this study demonstrated at least
sustained benefit for trial completers using erenumab across 52 weeks.
• The favorable safety, tolerability, and efficacy profile for erenumab demonstrated in this study supports the
prolonged use of erenumab for migraine prophylaxis.

Previous presentations compensation) from Alder, Allergan, Amgen, ATI, Dr.

Data from this study was presented at the 60th Annual
Scientific Meeting of the American Headache Society (AHS),
28 June to 1 July, 2018, San Francisco, California, USA.
Contributors
All authors participated in the study design, implementation
and/or conduct of the study. All authors contributed to the
review of the protocol and approved the final manuscript.
Acknowledgements
The authors thank Aditi Kataria of Novartis Healthcare Pvt
Ltd for providing medical writing support/editorial support,
which was funded by Amgen, Thousand Oaks, CA, USA and
Novartis Pharma AG, Basel, Switzerland in accordance with
Good Publication Practice (GPP3) guidelines (http://www.
ismpp.org/gpp3).
Data sharing
Institutions wishing to analyze data from the study can apply
via www.clinicalstudydatarequest.com.
Declaration of conflicting interests
The authors declare the following potential conflicts of inter-
est with respect to the research, authorship, and/or publica-
tion of this article: ST was an employee of Cleveland Clinic
during this study and has research grants (no personal
Reddy’s, ElectroCore, eNeura, Neurolief, ScionNeurostim,
Teva, and Zosano; he has consulted for Acorda, Alder,
Alexsa, Allergan, Alphasights, Amgen, ATI, Axsome
Therapeutics, Biohaven, Charleston Labs, DeepBench, Dr.
Reddy’s, ElectroCore, Eli Lilly, eNeura, ExpertConnect,
Gerson Lehman Group, Guidepoint Global, GSK, Impel,
Magellan Rx Management, Navigant Consulting, Neurolief,
Nordic BioTech, Novartis, Pfizer, Reckner Healthcare,
Satsuma, ScionNeurostim, Slingshot Insights, Sorrento,
Sudler and Hennessey, Supernus, Teva, Theranica, Trinity
Partners, XOC, and Zosano; he has stock options for ATI;
receives a salary from the American Headache Society; and
royalties from Springer.
MA is consultant or scientific advisor for Allergan,
Amgen, Alder, Eli Lilly, Lundbeck, Novartis, and Teva; pri-
mary investigator for Allergan, Amgen, Eli Lilly,
ElectroCore, Novartis and Teva; has received grants from
Lundbeck Foundation, Novo Nordisk Foundation, and a
research grant from Novartis.
UR has received consulting fees, speaking/teaching fees,
and/or research grants from Allergan, Amgen, Autonomic
Technologies, CoLucid, ElectroCore, and Novartis.
JLB received consulting fees, speaking/teaching fees, and/
or research grants from Allergan, Amgen, Teva, Eli Lilly,
Alder, Lundbeck, Supernus, Clinvest, Theranica and
Biohaven.
Tepper et al.
DD received consulting fees and/or advisory panel
member and speaking and/or teaching fees from Allergan,
Amgen, Biogen Idec, Novartis, Bayer, and Teva.
SS was a consultant and/or advisory panel member, and
received honoraria from Alder Biopharmaceuticals, Allergan,
Amgen, Avanir, Dr. Reddy’s, eNeura, ElectroCore Medical,
LLC, Medscape LLC, Medtronic, Mitsubishi Tanabe
Pharma America, Inc., NINDS, Supernus Pharmaceuticals,
Inc., Trigemina, and Teva.
PW received consulting fees/honoraria from Allergan,
Amgen, Lilly, Teva and Supernus; speaker’s bureau:
Allergan, Amgen, Avanir, Teva and Supernus; research
grants: Allergan, Amgen, NuPathe, AstraZeneca, Avanir,
Eli Lilly, Novartis and Teva
SC, FZ, and DDM, employees and stocks: Amgen.
Funding
The authors disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: The study was funded by Amgen, Thousand Oaks,
CA, USA, and Novartis Pharma AG, Basel, Switzerland.
Employees of the sponsors were involved in study design,
data collection, analysis and interpretation. All authors,
including those who are employees of the study sponsors,
drafted and/or revised the manuscript and approved the
final version for submission.
ORCID iD
Stephen D Silberstein https://orcid.org/0000-0001-9467-5567
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