Evaluation
of Cardiovascular Safety in Phase 3 Migraine Prevention Clinical
Trials
Description
of Analysis Set
The
CV safety profile of galcanezumab was evaluated1
in phase 3 randomized, double-blind, placebo-controlled studies in
adult patients for the prevention of
episodic
migraine (EVOLVE-1 and EVOLVE-2; 6 months),2,3 and
chronic
migraine (REGAIN; 3 months).4
Patients
were excluded from study enrollment if they met any of the following
criteria at screening:
ECGs
showing abnormalities compatible with acute cardiovascular events or
serious cardiovascular risk, including but not limited to a
corrected QT (QTcB [Bazett's]) interval > 470 msec for women
and >450 for men
history
of myocardial infarction, unstable angina, percutaneous coronary
intervention, coronary artery bypass graft, or deep vein
thrombosis/pulmonary embolism within 6 months of screening
planned
cardiovascular surgery or percutaneous coronary angioplasty
stroke
within 6 months of screening (EVOLVE-1 and CGAJ)
a
lifetime history of stroke (EVOLVE-2 and REGAIN).1
A
total of 17.21% of patients were identified to be in the CV
disease risk "yes" subgroup across galcanezumab treatment
groups Table 1.1
Table
1. CV Disease Risk Group - Phase 3 Double-Blind, Placebo-Controlled
Migraine Prevention Studies1
CV
Disease Risk Group
|
PBO
N=1451
n
(%)
|
GMB
120 mg
N=705
n (%)
|
GMB
240 mg
N=730
n (%)
|
GMB
Pooled
N=1435
n (%)
|
Yes
|
269
(18.54)
|
123
(17.45)
|
124
(16.99)
|
247
(17.21)
|
No
|
1182
(81.46)
|
582
(82.55)
|
606
(83.01)
|
1188
(82.79)
|
Abbreviations:
CV = cardiovascular; GMB = galcanezumab; GMB_Pooled = GMB 120 mg and
GMB 240 mg pooled; PBO = placebo.
The
most common conditions in the CV risk "yes" subgroup for
this pooled analysis set (galcanezumab pooled and placebo,
respectively) were
hypertension
(41.7% versus 50.2%)
hypercholesterolemia
(25.9% versus 14.1%)
hyperlipidemia
(19.0% versus 19.0%)
type
2 diabetes (7.3% versus 7.4%)
cholesterol
increased (6.5% versus 4.5%), and
dyslipidemia
(4.9% versus 8.2%).1
Note:
The recommended dose is 120 mg galcanezumab injected subcutaneously
once monthly, with a 240 mg loading dose as the initial dose .5
The results of a maintenance dose of galcanezumab 240 mg once monthly
are also described here. Even though this dose has been tested in
pivotal studies, it has not been approved and therefore is not
recommended.
SAEs
and Discontinuations Due to CV TEAS
There
were no significant differences between galcanezumab and placebo in
the frequency of CV SAEs or discontinuations due to CV TEAEs.1,6,7
There
were 3 CV SAEs each in the
galcanezumab
240 mg (acute myocardial infarction, transient ischemic attack,
pulmonary embolism), and
placebo
(pulmonary embolism, deep vein thromboembolism, myocardial
infarction) groups.6,7
All
of the CV SAEs in the galcanezumab-treated patients resolved.7
Based on similarities in the type, frequency, and time of onset from
study treatment between galcanezumab-treated patients and placebo for
these events, the events were not considered to be related to
galcanezumab treatment.1,6
The
3 patients with CV SAEs in the galcanezumab 240-mg group were in the
"no" CV disease-risk group.1
Of
the 3 patients in the placebo group with CV SAEs, the patients who
reported myocardial infarction and deep vein thrombosis were in the
CV disease-risk "yes" subgroup, and the patient who
reported pulmonary embolism was in the CV disease-risk "no"
subgroup.1
Cardiovascular
TEAEs leading to discontinuation in placebo-treated patients were
myocardial infarction, deep vein thrombosis, and hypertension. One
galcanezumab-treated patient discontinued due to a transient ischemic
attack (CV disease-risk "no" subgroup).6,7
Changes
in Use of CV Concomitant Medications
There
was no difference in the increase of concomitant CV medications
between CV disease risk subgroups.1
Table
2 summarizes the increase in CV concomitant medications
during the double-blind treatment phase by CV disease risk group.6
Table
2. Dose Increase or New Start of CV Concomitant Medications - Phase
3, Placebo-Controlled, Migraine Prevention Analysis Set1,6
Medication
Group
|
All
Patients PBO (%)
|
All
Patients
GMB Pooled (%)
|
CV
Disease Risk "Yes" Group PBO (%)
|
CV
Disease Risk "Yes" Group GMB Pooled (%)
|
CV
Disease Risk Group "No" PBO (%)
|
CV
Disease Risk "No" Group GMB Pooled (%)
|
Antihypertensivesa
|
2.3
|
1.6
|
7.8
|
4.1
|
1.1
|
1.1
|
Antiarrhythmics
|
0.6
|
0.1
|
1.9
|
0.0
|
0.3
|
0.2
|
Antianginals
|
0.2
|
0.0
|
0.7
|
0.0
|
0.1
|
0.0
|
Antithrombotics
|
1.3
|
1.4
|
1.5
|
1.2
|
1.3
|
1.4
|
Abbreviations:
CV = cardiovascular; GMB = galcanezumab; GMB Pooled = GMB 120 mg and
GMB 240 mg pooled; PBO = placebo.
a
Anti-hypertensives were not allowed for the acute
treatment of migraine headaches during the phase 3 migraine
prevention studies. Migraine preventives were not allowed at any time
in EVOLVE-1 and EVOLVE-2; in REGAIN, up to 1/3 of enrolled patients
were allowed to continue migraine prophylactic treatment with
propranolol if the patient had been on a stable dose for at least 2
months prior to baseline and the dosing remained stable throughout
the double-blind treatment period.
Note:
The recommended dose is 120 mg galcanezumab injected subcutaneously
once monthly, with a 240 mg loading dose as the initial dose .5
The results of a maintenance dose of galcanezumab 240 mg once monthly
are also described here. Even though this dose has been tested in
pivotal studies, it has not been approved and therefore is not
recommended.
Exposure-Adjusted
Incidence Rates
Exposure-adjusted
incidence rates are a measure of whether TEAEs occur at an increased
frequency with increased treatment duration.1
There
were no significant differences between any galcanezumab dose group
and placebo in the EAIRs across the 9 MedDRA SMQs and associated PTs
that were used to assess baseline CV risk.1
Therapeutic
Indication
Galcanezumab
is indicated for the prophylaxis of migraine in adults who have at
least 4 migraine days per month.5
The
recommended dose is 120 mg galcanezumab injected subcutaneously once
monthly, with a 240 mg loading dose as the initial dose.5
References
1.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
2.
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
3.
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
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.
Emgality [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
6.
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
7.
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
Glossary
AE =
adverse event
CV =
cardiovascular
EAIR
= exposure-adjusted incidence rate
ECG
= electrocardiogram
FRS
= Framingham Risk Score
MedDRA
= Medical Dictionary for Regulatory Activities
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.