Additional
Information
Patients
with recent acute cardiovascular events (including MI, unstable
angina, CABG, stroke, DVT) and/or those deemed to be at serious
cardiovascular risk were excluded from the galcanezumab clinical
trials.1
Please
note that the results of a maintenance dose of 240 mg galcanezumab
once monthly are also included in this response. Even though this
dose has been tested in pivotal studies, it has not been approved and
therefore is not recommended.
Cardiovascular
Safety Migraine
Galcanezumab
has been studied in migraine prevention.2-4.
The CV safety profile summary is summarized below.
Description
of Pooled Analysis and Summary of Exposure
The
CV safety profile of galcanezumab was evaluated in phase 3
randomized, double-blind, placebo-controlled studies in adult
patients for the prevention of
episodic
migraine (EVOLVE-1 and EVOLVE-2),2,3
and
chronic
migraine (REGAIN).4
This
pooled analysis of 2886 adult patients included a total of 1435
patients that received monthly doses of galcanezumab (120 mg or
240 mg) administered subcutaneously.5
The
majority of patients were female (>80%) and Caucasian (>75%),
with a mean age of 41-42 years.6
Additional
results are provided when relevant from
a
phase 3 open-label, 12-month safety study of galcanezumab (120 mg or
240 mg) in 270 patients with episodic and chronic migraine (study
CGAJ)7
a
phase 3 double-blind, placebo-controlled study of galcanezumab 120
mg in 462 patients with treatment resistant migraine,8
or
a
pooled analysis of 2586 galcanezumab-treated patients from phase 2
and phase 3 migraine prevention clinical trials.9
Evaluation
of Cardiovascular Safety
Blood
Pressure and Pulse Changes
Treatment
with galcanezumab did not result in hemodynamic changes consistent
with vasoconstriction.10
Mean
changes in blood pressure and pulse were small, with no clinically
significant changes.5,10
There
were no significant differences between galcanezumab and placebo in
the frequency of
treatment-emergent
high, or
sustained
blood pressure elevation.5,9,10
Furthermore,
there were no differences in TEAEs between the pooled galcanezumab
(1.11%) and placebo (1.24%) groups in the proportion of patients with
at least 1 narrow scope preferred term in the Hypertension SMQ.9,10
The
percentages of patients with a categorical increase in systolic blood
pressure, diastolic blood pressure, or pulse rate at any time post
baseline were similar between treatment groups. The difference in the
percentage of patients between placebo and either galcanezumab
treatment group was less than 1%.10
Electrocardiogram
Changes
There
were no clinically important differences between galcanezumab and
placebo in ECG parameters including QTcF or in any qualitative
findings. No patient experienced a QTcF >500 msec.5,9,10
There
were significantly more galcanezumab-treated patients (n=8; 0.6%) who
met criteria for high QRS interval (≥120 msec) compared with
placebo (n=1; 0.2%; p≤.05).9,10
Of the 8 galcanezumab-treated patients,
6
had a preexisting condition of complete or incomplete bundle branch
block at study entry, of whom 5 had a QRS ≥120 msec prior to
dosing, and
1
patient discontinued treatment due to mild dyspepsia.9,10
No
patient discontinued due to high QRS interval.9
Blood
Pressure and Electrocardiogram Changes in Patients With Treatment
Resistant Migraine: CONQUER Study
CONQUER
was a phase 3 randomized double-blind, placebo-controlled study in
adult patients that assessed galcanezumab efficacy and safety in
patients with episodic migraine or chronic migraine who had not
benefited from multiple previous migraine preventive treatments.8
There
were no meaningful differences between the galcanezumab- and
placebo-treated patients on pulse and ECG parameters.9
Changes
in Vital Signs and Electrocardiograms in Elderly Patients: CONQUER
Study
In
patients who were older than 65 years at study entry, there were no
clinically meaningful differences between the galcanezumab- and
placebo-treated patients on vital signs and ECGs.9
There
were no treatment-emergent abnormal changes in vital signs in the
elderly patients during the double-blind treatment phase except for
1
placebo-treated patient with treatment-emergent high systolic blood
pressure at visit 4 (150 mm Hg), and
1
galcanezumab-treated patient with treatment-emergent high diastolic
blood pressure at visit 6 (92 mm Hg). This patient was noted as
having preexisting hypertension, with a diastolic blood pressure of
91 mm Hg at the screening visit.9
During
the open-label treatment phase, there were 3 elderly patients who
were previously randomized to placebo with treatment-emergent high
diastolic blood pressure.9
There
were no treatment-emergent abnormal changes in qualitative or
quantitative ECG parameters in the elderly patients except for
qualitative
changes in 1 placebo-treated patient in the double-blind phase, and
1
prior galcanezumab-treated patient in the open-label phase with
sinus bradycardia at visit 9 who had sinus bradycardia at
screening.9
Cardiovascular
TEAEs and SAEs
Evaluation
of CV TEAEs did not reveal any clinically important differences
compared to placebo (Table 1).10 A
low proportion of galcanezumab-treated patients and placebo-treated
patients reported CV TEAEs across all 9 SMQs, with the highest
frequency reported in the Hypertension SMQ. No statistically
significant differences were observed between both galcanezumab dose
groups and placebo in any SMQ based on the narrow scope preferred
terms.
There
were no significant differences between galcanezumab and placebo in
the frequency of CV SAEs or discontinuations due to CV TEAEs.5,9,10
Table
1. Migraine Prevention: CV TEAEs - Phase 3, Placebo-Controlled
Analysis Set9,10
SMQab
|
PBO
N=1451
|
GMB
120 mg
N=705
|
GMB
240 mg
N=730
|
GMB
Pooled
N=1435
|
Cardiac
arrhythmias, n (%)
|
6
(0.41)
|
2
(0.28)
|
3
(0.41)
|
5
(0.35)
|
OR
vs PBOc
|
---
|
0.68
|
1.00
|
0.84
|
Cardiac
failure, n (%)
|
1
(0.07)
|
0
(0.00)
|
0
(0.00)
|
0
(0.00)
|
OR
vs PBOc
|
---
|
0.00
|
0.00
|
0.00
|
Cardiomyopathy,
n (%)
|
0
(0.00)
|
0
(0.00)
|
0
(0.00)
|
0
(0.00)
|
OR
vs PBOc
|
---
|
---
|
---
|
---
|
CNS
vascular disorder, n (%)
|
0
(0.00)
|
0
(0.00)
|
1
(0.14)
|
1
(0.07)
|
OR
vs PBOc
|
---
|
---
|
---
|
---
|
Embolic
and thrombotic events, n (%)
|
4
(0.28)
|
0
(0.00)
|
4
(0.55)
|
4
(0.28)
|
OR
vs PBOc
|
---
|
0.00
|
1.99
|
1.01
|
Hypertension,
n (%)
|
18
(1.24)
|
9
(1.28)
|
7
(0.96)
|
16
(1.11)
|
OR
vs PBOc
|
---
|
1.03
|
0.77
|
0.90
|
Ischemic
heart disease, n (%)
|
1
(0.07)
|
1
(0.14)
|
1
(0.14)
|
2
(0.14)
|
OR
vs PBOc
|
---
|
2.05
|
1.99
|
2.02
|
Pulmonary
hypertension, n (%)
|
0
(0.00)
|
0
(0.00)
|
0
(0.00)
|
0
(0.00)
|
OR
vs PBOc
|
---
|
---
|
---
|
---
|
Torsades
de pointes/QT prologation, n (%)
|
2
(0.14)
|
1
(0.14)
|
1
(0.14)
|
2
(0.14)
|
OR
vs PBOc
|
---
|
1.03
|
0.99
|
1.01
|
Abbreviations:
CNS = central nervous system; CV = cardiovascular; GMB =
galcanezumab; MedDRA = Medical Dictionary for Regulatory Activities;
N = number of patients in the analysis population; n = number of
patients within each specific category; PBO = placebo; SMQ =
Standardized MedDRA Query; TEAE = treatment-emergent adverse event.
a
Each preferred term for the SMQ represents the narrow scope
terms only.
b
MedDRA version 19.1.
c
Mantel-Haenszel odds ratio stratified by study and 95% CI (CI
calculated if ≥ 4 events in numerator and ≥ 1 event in
denominator).
Changes
in Use of CV Concomitant Medications
Concomitant
CV medication usage at baseline was comparable across all treatment
groups. At baseline, approximately
6.7%
to 8.8% of patients were taking antihypertensives
2.0%
to 2.5% were taking antithrombotics
0.8%
to 1.3% were taking antiarrhythmics, and
0.1%
to 0.3% were taking antianginals.10
During
the double-blind treatment phase, dose increases, or a new start of
CV medications was comparable across all treatment groups. These
findings provide additional evidence that galcanezumab did not have a
negative impact on CV function.9,10
Exposure-adjusted
Incidence Rates for CV TEAEs
There
were no significant differences between any galcanezumab dose group
and placebo in the EAIRs for the 9 SMQs and associated preferred
terms in the phase 3, placebo-controlled analysis set.9
In
the longer-term analysis sets up to 12 months, there were no
increases in the EAIRs with longer treatment duration for
treatment-emergent
high systolic or diastolic blood pressure,5
and
CV
TEAEs.9
Postmarketing
Spontaneous Reports
Through
27 September 2019, CV and cerebrovascular events have been reported
"rarely" or "very rarely" in the Lilly
spontaneous AE database. Rarely reported is defined as an AE that has
been reported at an estimated rate of ≥.01% and <0.1% according
to the reporting system information. Very rarely reported is defined
as an AE that has been reported at an estimated rate of <.01%
according to the reporting system information.9
Postmarketing
data do not necessarily represent the rate of occurrence of an AE in
a treated population, but they represent a reporting rate of a
particular AE to the company. Spontaneous reporting of AEs can be
highly variable and is not appropriately controlled clinical
information on which to base an assessment of whether a particular
drug product is the causal agent of an event.11
Spontaneous
reporting has limited use due to
lack
of control population
under-reporting
or reporting bias, and
missing
or incomplete information regarding medical history or concomitant
medications.11
References
1.
Emgality [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety of
galcanezumab for the prevention of episodic migraine: results of the
EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia.
2018;38(8):1442-1454. http://dx.doi.org/10.1177/0333102418779543
3.
Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab
for the prevention of episodic migraine: the EVOLVE-1 randomized
clinical trial. JAMA Neurol. 2018;75(9):1080-1088.
http://dx.doi.org/10.1001/jamaneurol.2018.1212
4.
Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic
migraine: the randomized, double-blind, placebo-controlled REGAIN
study. Neurology. 2018;91(24):e2211-e2221.
http://dx.doi.org/10.1212/WNL.0000000000006640
5.
Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of
monthly galcanezumab injections in patients with migraine: integrated
results from migraine studies. BMC Neurology. 2020;20(1):25.
http://dx.doi.org/10.1186/s12883-020-1609-7.
Published correction appears in BMC Neurology. 2020;20(1):90.
http://dx.doi.org/10.1186/s12883-020-01675-7
6.
Stauffer VL, Wang S, Bangs M, et al. Phase 3 safety data from
studies comparing galcanezumab and placebo in patients with episodic
and chronic migraine. Poster presented at: European Academy of
Neurology (EAN) – 4th
Congress; June 16-19, 2018; Lisbon, Portugal.
7.
Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term,
open-label safety study of galcanezumab in patients with migraine.
BMC Neurology. 2018;18(1):188.
http://dx.doi.org/10.1186/s12883-018-1193-2
8.
Mulleners WM, Kim B, Láinez MJA, et al. A phase 3,
placebo-controlled study of galcanezumab in patients with
treatment-resistant migraine: results from the 3-month, double-blind
treatment phase of the CONQUER study. Poster presented at: 24th World
Congress of Neurology (WCN); October 27-31, 2019; Dubai, United Arab
Emirates.
9.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
10.
Oakes TM, Kovacs R, Rosen N, et al. Evaluation of cardiovascular
outcomes in adult patients with episodic or chronic migraine treated
with galcanezumab: data from three phase 3 randomized, double-blind,
placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies. Headache.
2020;60(1):110-123. http://dx.doi.org/10.1111/head.13684
11.
Goldman SA. Limitations and strengths of spontaneous reports data.
Clin Ther. 1998;20(suppl 3):C40-44.
http://dx.doi.org/10.1016/S0149-2918(98)80007-6
Glossary
CV =
cardiovascular
EAIR
= exposure-adjusted incidence rate
ECG
= electrocardiogram
QTcF
= Fridericia's corrected QT interval
SAE
= serious adverse event
SMQ
= standard MedDRA query
TEAE
= treatment-emergent adverse event
▼ This
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.