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Emgality ® (galcanezumab)
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Can Emgality® (galcanezumab) be used in patients with a history of CNS vascular events?
The phase 3 studies included patients with a history of CNS vascular events. No reports of CNS vascular TEAEs in the patients with a history of CNS vascular events were observed.
Content overview
- Information from the label
- Evaluation of CNS vascular events in phase 3 migraine prevention clinical trials
- What were the baseline CNS vascular disorder characteristics of patients included in clinical studies?
- What CNS vascular disorder treatment-emergent adverse events were reported in patients?
- Is the incidence and prevalence of TIA and ischemic stroke increased in people with migraine?
- Description of analysis set in patients with CNS vascular disorders in the galcanezumab phase 3 migraine prevention clinical trials
- Postmarketing spontaneous reports related to CNS vascular disorders
- References
- Appendix
Information from the label
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
Evaluation of CNS vascular events in phase 3 migraine prevention clinical trials
Patients who had baseline cardiovascular disease were not excluded from participation in the migraine prevention studies.2
Additional details discussing:
- A description of analysis set in patients with CNS vascular disorders in the galcanezumab phase 3 migraine prevention trials is available Description of analysis set in patients with CNS vascular disorders in the galcanezumab phase 3 migraine prevention clinical trials.
- An overview of migraine prevention studies can be found in the section in Appendix Overview of galcanezumab phase 3 migraine prevention studies.
What were the baseline CNS vascular disorder characteristics of patients included in clinical studies?
CNS vascular disorder exclusion criteria
Patients were excluded from the phase 3 migraine prevention clinical trials if they had
- a stroke within 6 months of screening (EVOLVE-1, CGAJ, and CONQUER)
- a lifetime history of stroke (EVOLVE-2 and REGAIN), or
- a history or presence of any other medical illness, including, but not limited to cardiovascular, or any clinically significant laboratory abnormality, that in the judgment of the investigator indicates a medical problem that would preclude study participation.2,3
CNS vascular disorders at baseline
Between 17% and 19% of all patients across the galcanezumab and placebo treatment groups in EVOLVE-1, EVOLVE-2, and REGAIN were in the cardiovascular disease risk "yes" subgroup, or had a comorbid cardiovascular condition or risk factor at baseline.3
The definition of cardiovascular risk is available in the section in Appendix: Definition of a baseline cardiovascular disease risk.
provides baseline CNS vascular disorders among patients in the cardiovascular disease risk "yes" group.2
CNS Vascular Disorders (SMQ) |
PBO |
GMB 120 mg |
GMB 240 mg |
GMB Pooled |
Carotid arteriosclerosisa |
0 (0.0) |
1 (0.81) |
0 (0.0) |
1 (0.40) |
Carotid artery diseasea |
0 (0.0) |
0 (0.0) |
1 (0.81) |
1 (0.40) |
Carotid artery stenosisa |
1 (0.37) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Cerebral artery stenosisa |
0 (0.0) |
1 (0.81) |
0 (0.0) |
1 (0.40) |
Cerebral infarctiona |
1 (0.37) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
CVAa |
2 (0.74) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Ischemic strokea |
0 (0.0) |
0 (0.0) |
1 (0.81) |
1 (0.40) |
TIAa |
5 (1.86) |
0 (0.0) |
1 (0.81) |
1 (0.40) |
Abbreviations: CNS = central nervous system; CVA = cerebrovascular accident; GMB = galcanezumab; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; SMQ = standardized MedDRA query; TIA = transient ischemic attack.
aNarrow scope preferred term.
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What CNS vascular disorder treatment-emergent adverse events were reported in patients?
Two galcanezumab-treated patients reported serious CNS vascular disorder treatment-emergent adverse events (TEAEs) in EVOLVE-1, EVOLVE-2, REGAIN, and CGAJ
- one patient reported a transient ischemic attack (TIA)
- second patient reported intracranial aneurysm.2,3
Both patients were in the baseline cardiovascular disease risk "no" subgroup.2
Both events resolved and the events were deemed not to be related to galcanezumab by the primary investigators because of
Exposure-adjusted incidence rates in CNS vascular disorder TEAEs
Exposure-adjusted incidence rates (EAIRs) are a measure of whether TEAEs occur at an increased frequency with increased treatment duration.2
In the phase 3 double-blind, placebo-controlled migraine prevention clinical trials, there were no significant differences between galcanezumab treatment groups and placebo in EAIRs of CNS vascular disorder TEAEs (galcanezumab pooled 0.19; placebo 0.0).2
No increase was observed in the EAIRs for CNS vascular disorder TEAEs in the longer-term analysis sets up to 12 months.2
The EAIR is equal to 100 times the number of patients experiencing the event divided by event-specific total patient year-at-risk.2
Is the incidence and prevalence of TIA and ischemic stroke increased in people with migraine?
Calcitonin gene-related peptide (CGRP) is a potent microvascular vasodilator found throughout the body that is hypothesized to play a protective role in cardiovascular health.4
Epidemiology studies report that cardiovascular comorbidities and risk factors for cardiovascular disease vary with
- age
- migraine severity, and
- migraine type.5-7
Observational studies have reported increased relative risks for cardiovascular events, including ischemic stroke and TIA, in the migraine population compared to the non-migraine population.5,8-12
shows the incidence and prevalence of ischemic stroke and TIA reported in epidemiology studies of people with migraine.
TIA |
Ischemic Stroke |
|
Incidence |
0.93 per 1000 patient-years5 |
1.10 per 1000 person-years (any stroke)5 |
In men (average age 51 years), crude incidence per 1000 person-years: |
||
In women ≥45 years, the age-adjusted incidence of ischemic stroke per 1000 person-years: |
||
1.17 |
||
Prevalence |
2.8% of women and 2.5% of men6 |
2.0% of women and 1.6% of men (any stroke)6 |
Abbreviation: TIA = transient ischemic attack.
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Description of analysis set in patients with CNS vascular disorders in the galcanezumab phase 3 migraine prevention clinical trials
The EVOLVE-1, EVOLVE-2, and REGAIN studies were the pivotal studies and safety results have been integrated resulting in a pooled analysis of 2886 adult patients.14
A total of 1435 patients received monthly doses of galcanezumab (120 mg or 240 mg) administered subcutaneously.14
Results from the phase 3 open-label safety study (CGAJ) are provided to supplement the primary integrated safety analysis from the phase 3 migraine prevention clinical trials.
Evaluation of safety by baseline cardiovascular risk was not completed in the CONQUER study; however, information is provided regarding central nervous system (CNS) vascular disorders where relevant.
In the 12-month open-label safety study (CGAJ), a total of 270 adult patients received monthly doses of galcanezumab (120 or 240 mg).15
In the CONQUER study, 462 adult patients were enrolled, 232 patients receiving monthly doses of galcanezumab 120 mg.16
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Postmarketing spontaneous reports related to CNS vascular disorders
Cerebrovascular events that have been reported in the Eli Lilly and Company spontaneous adverse event database through September 27, 2022 can be found in .
Very Rarely Reported (<0.01%) |
cerebellar artery thrombosis, cerebellar infarction, cerebral artery occlusion, cerebral artery stenosis, cerebral cavernous malformation, cerebral hemorrhage, cerebral infarction, cerebral microangiopathy, cerebral small vessel ischemic disease, cerebral thrombosis, cerebral vasoconstriction, cerebrovascular accident, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intracranial aneurysm, ischemic stroke, lacunar infarction, lacunar stroke, subarachnoid hemorrhage, transient ischemic attack, and vasogenic cerebral edema. |
Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
aMedDRA preferred terms.
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.17
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.17
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References
1Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Oakes 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
4Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099-1142. http://dx.doi.org/10.1152/physrev.00034.2013
5Becker C, Brobert GP, Almqvist PM, et al. Migraine and the risk of stroke, TIA, or death in the UK (CME). Headache. 2007;47(10):1374-1384. http://dx.doi.org/10.1111/j.1526-4610.2007.00937.x
6Buse DC, Reed ML, Fanning KM, et al. Cardiovascular events, conditions, and procedures among people with episodic migraine in the US population: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2017;57(1):31-44. http://dx.doi.org/10.1111/head.12962
7Le H, Tfelt-Hansen P, Russell MB, et al. Co-morbidity of migraine with somatic disease in a large population-based study. Cephalalgia. 2011;31(1):43-64. http://dx.doi.org/10.1177/0333102410373159
8Kurth T, Gaziano JM, Cook NR, et al. Migraine and risk of cardiovascular disease in women. JAMA. 2006;296(3):283-291. http://dx.doi.org/10.1001/jama.296.3.283
9Sacco S, Ornello R, Ripa P, et al. Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies. Eur J Neurol. 2015;22(6):1001-1011. http://dx.doi.org/10.1111/ene.12701
10Peng KP, Chen YT, Fuh JL, et al. Migraine and incidence of ischemic stroke: a nationwide population-based study. Cephalalgia. 2017;37(4):327-335. http://dx.doi.org/10.1177/0333102416642602
11Lee SY, Lim JS, Oh DJ, et al. Risk of ischaemic stroke in patients with migraine: a longitudinal follow-up study using a national sample cohort in South Korea. BMJ Open. 2019;9(4):e027701. http://dx.doi.org/10.1136/bmjopen-2018-027701
12Adelborg K, Szepligeti SK, Holland-Bill L, et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018;360:k96. http://dx.doi.org/10.1136/bmj.k96
13Buring JE, Hebert P, Romero J, et al. Migraine and subsequent risk of stroke in the Physicians' Health Study. Arch Neurol. 1995;52(2):129-134. http://dx.doi.org/10.1001/archneur.1995.00540260031012
14Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies. BMC Neurol. 2020;20(1):25. https://doi.org/10.1186/s12883-020-1609-7
15Camporeale 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
16Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-825. http://dx.doi.org/10.1016/S1474-4422(20)30279-9
17Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6
18Stauffer 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
19Skljarevski 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
20Detke 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
21Pozo-Rosich P, Detke HC, Wang S, et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022;38(5):731-742. https://doi.org/10.1080/03007995.2022.2059975
22Reuter U, Lucas C, Dolezil D, et al. Galcanezumab in patients with multiple previous migraine preventive medication category failures: results from the open-label period of the CONQUER trial. Adv Ther. 2021;38:5465-5483. http://dx.doi.org/10.1007/s12325-021-01911-7
Appendix
Overview of galcanezumab phase 3 migraine prevention studies
Galcanezumab has been studied in phase 3, randomized, double-blind, placebo-controlled studies in adult patients for the prevention of
Galcanezumab has also been studied in a phase 3, open-label, 12-month safety study (CGAJ) for the prevention of episodic or chronic migraine.15
|
GMB Doses Studied |
Study Duration |
120 mg monthlyb |
6 months double-blind |
|
120 mg monthlyc |
3 months double-blind, |
|
120 mg monthlyb |
3 months double-blind, |
|
CGAJ15 |
120 mg monthlyb |
12 months open-label |
Abbreviations: GMB = galcanezumab; OLE = open-label extension.
aWith the exception of study CGAJ, all studies were randomized, double-blind, and placebo-controlled.
bThe initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120 mg.
cThe initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120 mg during double-blind treatment.
dThe dosing regimen for the OLE started all patients on a 240-mg galcanezumab loading dose (2 injections of 120 mg each) after completing double-blind treatment at month 3. At month 4, all patients then received a maintenance dose of 120 mg galcanezumab (single injection) in order to encourage the use of the lowest possible monthly maintenance dose. However, starting at month 5, dosing was flexible such that patients could receive 1 injection (120 mg) or 2 injections (a total of 240 mg) per month at the investigators’ clinical discretion.
eDosing in the OLE was 120 mg per month galcanezumab, with a blinded loading dose of 240 mg for previous-placebo patients. Thus, all patients received two injections at their first open-label dose visit (either two 120-mg galcanezumab injections or one 120-mg galcanezumab injection plus one placebo injection) and a single injection of galcanezumab 120 mg at all subsequent monthly dosing visits.
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Definition of a baseline cardiovascular disease risk
Patients had a baseline cardiovascular disease risk of
- "yes" if they had 1 or more conditions that were part of the patients’ medical history or preexisting conditions using narrow terms from Medical Dictionary for Regulatory Activities (MedDRA) standard MedDRA queries (SMQs), and
- "no" if they did not have any of the preferred terms (PTs) in the MedDRA SMQs as a preexisting condition or medical history event.2,3
The MedDRA SMQs included the following:
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Date of Last Review: 08 November 2023