Information
from the Label
In
the clinical studies, the incidence of anti-drug antibody development
during the double-blind treatment phase was 4.8 % in patients
receiving galcanezumab once monthly (all but one of whom had in
vitro neutralizing activity). With 12 months of treatment, up to
12.5 % of galcanezumab-treated patients developed anti-drug
antibodies, most of which were of low titre and tested positive for
neutralising activity in vitro. However, the presence of
anti-drug antibodies did not affect the pharmacokinetics, efficacy,
or safety of galcanezumab.1
Galcanezumab
is contraindicated in patients with hypersensitivity to the active
substance or to any of the excipients (L-histidine, L-histidine
hydrochloride monohydrate, Polysorbate 80, Sodium chloride, Water for
injections).1
Immunogenicity
in Phase 3 Studies Migraine Prevention Studies
Galcanezumab
is a humanized monoclonal IgG4 antibody. Because the possibility for
an immunogenic response exists with any monoclonal antibody, subjects
in all galcanezumab clinical studies were tested for the presence of
ADA. An integrated assessment of immunogenicity was completed to
evaluate any potential clinically relevant correlations with
immunogenicity.2
This
integrated assessment3
included the
baseline
and double-blind, placebo-controlled phases of the EVOLVE-1,
EVOLVE-2, and REGAIN studies,4-6
and
baseline
and open-label phases of the open-label safety study CGAJ.7
See
Overview of Phase 3 Migraine
Prevention Programfor an overview of these studies.
Migraine
Prevention: Incidence of ADA at Baseline, TE ADA, and NAb
Patients
were considered to have developed TE ADA if
ADA
was not present at baseline and they have at least one postbaseline
sample with ADA detected at titer ≥1:20, or
ADA
present at baseline and they have at least one postbaseline sample
with ADA detected at titer ≥4-fold greater than baseline
titer.2
In
double-blind placebo-controlled studies, EVOLVE-1, EVOLVE-2, and
REGAIN, up to 9.4% of patients treated with galcanezumab developed TE
ADA. In the 12-month open-label study CGAJ, up to 12.4% of
patients treated with galcanezumab developed TE ADA during the
treatment phase.2
The
majority of patients who developed TE ADA with galcanezumab
treatment did not have pre-existing ADA.2
For
details, see Table 1.
Table
1. Anti-Drug and Neutralizing Antibody Findings Across the Phase 3
Galcanezumab Studies2
|
PBO
n
(%)
|
GMB
120mg
n (%)
|
GMB
240mg
n (%)
|
GMB
Pooled
n (%)
|
REGAIN
|
Evaluable
subjectsa
|
535
|
264
|
272
|
536
|
ADA
present at BL
|
33
(6.2)
|
22
(8.3)
|
27
(9.9)
|
49
(9.1)
|
NAb
present
|
26
(4.9)
|
15
(5.7)
|
18
(6.6)
|
33
(6.2)
|
TE
ADA+b
|
8
(1.5)
|
7
(2.7)
|
7
(2.6)
|
14
(2.6)
|
NAb
presentc
|
3
(0.6)
|
6
(2.3)d
|
4
(1.5)
|
10
(1.9)
|
EVOLVE-1
|
Evaluable
subjectse
|
422
|
202
|
213
|
415
|
ADA
present at BL
|
25
(5.9)
|
18
(8.9)
|
23
(10.8)
|
41
(9.9)
|
NAb
present
|
11
(2.6)
|
10
(5.0)
|
17
(8.0)
|
27
(6.5)
|
TE
ADA+b
|
7
(1.7)
|
9
(4.5)
|
11
(5.2)d
|
20
(4.8)d
|
NAb
presentc
|
6
(1.4)
|
9
(4.5)
|
11
(5.2)d
|
20
(4.8)d
|
EVOLVE-2
|
Evaluable
subjectse
|
443
|
223
|
214
|
437
|
ADA
present at BL
|
37
(8.4)
|
18
(8.1)
|
24
(11.2)
|
42
(9.6)
|
NAb
present
|
19
(4.3)
|
10
(4.5)
|
13
(6.1)
|
23
(5.3)
|
TE
ADA+b
|
2
(0.5)
|
21
(9.4)f
|
11
(5.1)f
|
32
(7.3)f
|
NAb
presentc
|
1
(0.2)
|
21
(9.4)f
|
9
(4.2)f
|
30
(6.9)f
|
Study
CGAJ
|
Evaluable
subjectsg
|
---
|
129
|
137
|
266
|
ADA
present at BL
|
---
|
8
(6.2)
|
12
(8.8)
|
20
(7.5)
|
NAb
present
|
---
|
8
(6.2)
|
6
(4.4)
|
14
(5.3)
|
TE
ADA+b
|
---
|
16
(12.4)
|
10
(7.3)
|
26
(9.8)
|
NAb
presentc
|
---
|
16
(12.4)
|
10
(7.3)
|
26
(9.8)
|
Abbreviations:
ADA = anti-drug antibody; BL = baseline; GMB = galcanezumab; NAb =
neutralizing antibody; PBO = placebo; TE = treatment-emergent.
a
During the 3-month, double-blind treatment phase.
b
Defined as patients without ADA present at baseline and
at least one postbaseline sample with ADA detected at titer ≥1:20,
or patients with ADA present at baseline and at least one
postbaseline sample with ADA titer ≥4-fold greater than
baseline titer.
c
In the treatment period, NAb present refers to patients
who were TE ADA+ and had NAb detected at least once. Analyses were
conducted on TE ADA evaluable patients in the safety population using
modal dose.
d
p<.05 vs placebo.
e
During the 6-month, double-blind treatment phase.
f
p<.001 vs placebo.
g
During the 12-month, open-label treatment phase.
Note:
The recommended dose is 120 mg galcanezumab injected subcutaneously
once monthly, with a 240 mg loading dose as the initial dose .1
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.
Migraine
Prevention: ADA Titer Over Time
Across
all the studies, the majority of patients who developed TE ADA with
galcanezumab treatment
had
a TE ADA+ titer detected at only one assessment during the treatment
phase, and
had
maximum postbaseline titers ≤1:160 that decreased over time (many
no longer had TE ADA titers by their last assessment of the
treatment period).2
Within
the 6-month treatment period in EVOLVE-1and EVOLVE-2, 20.5% of
patients who were TE ADA+ earlier in the study no longer had TE ADA
titers at the final assessment.3
In
the 12-month open-label study CGAJ, a greater proportion of TE
ADA+ patients, 46.2%, had titers that decreased over time and 38.5%
no longer had TE ADA titers at the final assessment.3
Migraine
Prevention: Effect of ADA on Galcanezumab PK and Target Engagement
ADA
had no notable effect on
Migraine
Prevention: Impact of TE ADA on Efficacy
The
range of mean monthly MHD changes in patients who developed TE ADA
was similar to that observed for all galcanezumab-treated patients,
regardless of TE ADA status.2
These findings support a lack of clinically meaningful impact of the
observed immunogenicity on galcanezumab efficacy.
Migraine
Prevention: Impact of TE ADA on Safety
No
PTs were reported exclusively by TE ADA+ patients for
hypersensitivity
events, or
injection
site-related AEs.2
Criteria
for case level review was based on OR and p-value from the
Cochran-Mantel-Haenszel test that compared the proportions of
patients with ≥1 hypersensitivity event preferred term or ≥1
preferred term related to injection sites between TE ADA+ and TE ADA-
patients, stratified by study.2
Events with an OR >2.0 or p≤.05 met flagging criteria for
further review.
For
hypersensitivity events or injection site-related AEs that met
criteria for case level review, no consistent temporal relationship,
or titer response relationship were observed between the presence of
TE ADA and the events. As with any therapeutic antibody, treatment
with galcanezumab can elicit an ADA response in some patients.3
These
analyses from the phase 3 migraine program characterize the
immunogenicity of galcanezumab treatment in patients with episodic
and chronic migraine, and reveal that immunogenicity did not impact
hypersensitivity
events
injection
site-related AEs
galcanezumab
concentrations
CGRP
concentrations, or
the
efficacy profile of galcanezumab.2
Therapeutic
Indication
Galcanezumab
is indicated for the prophylaxis of migraine in adults who have at
least 4 migraine days per month.1
The
recommended dose is 120 mg galcanezumab injected subcutaneously once
monthly, with a 240 mg loading dose as the initial dose.1
References
1.
Emgality [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Martinez JM, Garces S, Anglin G, et al. Immunogenicity findings from
phase 3 galcanezumab trials in patients with episodic or chronic
migraine. Poster presented at: 12th European Headache Federation
Congress; September 28-30, 2018; Florence, Italy.
3.
Martinez JM, Hindiyeh N, Anglin G, et al. Assessment of
immunogenicity from galcanezumab phase 3 trials in patients with
episodic or chronic migraine. Cephalalgia. 2020;40(9):978-989.
https://doi.org/10.1177/0333102420920642
4.
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
5.
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
6.
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
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 Neurol. 2018;18(1):188.
http://dx.doi.org/10.1186/s12883-018-1193-2
Glossary
ADA
= anti-drug antibody
AE =
adverse event
CGRP
= calcitonin gene-related peptide
IgG4
= immunoglobulin G (subclass) 4
MHD
= migraine headache day
NAb
= neutralizing antibody
OR =
odds ratio
PK =
pharmacokinetics
PT =
preferred term
TE
ADA = treatment-emergent anti-drug antibodies
▼ 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.
Appendix
Overview
of Phase 3 Migraine Prevention Program
EVOLVE-1,
EVOLVE-2, and REGAIN Studies
Galcanezumab
has been studied in phase 3 randomized, double-blind,
placebo-controlled studies in adult patients for the prevention of
episodic
migraine (EVOLVE-1 and EVOLVE-2),4,5
and
chronic
migraine (REGAIN).6
The
studies had a duration of
6
months for prevention of episodic migraine,4,5
and
3
months for prevention of chronic migraine, with an optional 9-month
open-label extension phase.6
Patients
were randomized at the beginning of double-blind treatment in a 2:1:1
ratio to receive monthly subcutaneous injections of
placebo
galcanezumab
120 mg with a loading dose of 240 mg, or
galcanezumab
240 mg.4-6
12
Month Open-Label Safety Study
Galcanezumab
has also been studied in a phase 3, open-label, 12-month safety study
for the prevention of episodic or chronic migraine.7
In
this study, patients were randomized to receive 12 monthly
subcutaneous injections of
galcanezumab
120 mg with a loading dose of 240 mg, or
galcanezumab
240 mg.7