Emgality ® ▼ (galcanezumab)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Emgality Summary of Product Characteristics (SmPC)

Can patients with CNS vascular events history use Emgality® ▼(galcanezumab)?

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.

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

Use in Patients With a History of CNS Vascular Events in 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, composed of a total of 1435 patients who received monthly doses of galcanezumab (120 mg or 240 mg) administered subcutaneously.2

Additional details on the studies are available in the section in appendix: Migraine Prevention Studies.


Definition of the cardiovascular risk is available in the section in appendix: Definition of cardiovascular disease risk.

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 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).3 In the CONQUER study, of 462 adult patients enrolled, with 232 patients received monthly doses of galcanezumab 120 mg.4 

Baseline CNS Vascular Disorder Characteristics

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.5,6

Baseline CNS Vascular Disorders

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.6    

Table 1 provides baseline CNS vascular disorders among patients in the cardiovascular disease risk "yes" group.5

Table 1. Baseline CNS Vascular Disorders Among Patients in the Cardiovascular Disease Risk "Yes" Group - EVOLVE-1, EVOLVE-2, and REGAIN5

CNS Vascular Disorders (SMQ)
Ischemic CNS Vascular Condition (Sub-SMQ)

PBO
N=269
n (%)

GMB 120 mg
N=123
n (%)

GMB 240 mg
N=124
n (%)

GMB Pooled
N=247
n (%)

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.

a Narrow scope preferred term.

CNS Vascular Disorder TEAEs

In EVOLVE-1, EVOLVE-2, REGAIN, and CGAJ, among galcanezumab-treated patients, one patient reported a transient ischemic attack and another reported intracranial aneurysm; both were serious CNS vascular disorder TEAEs.5,6  

Both patients were in the baseline cardiovascular disease risk "no" subgroup.5

Both events resolved and the events were deemed not to be related to galcanezumab by the primary investigators because of

  • other potential contributing factors, and

  • insufficient evidence to substantiate a reasonable association between galcanezumab and the TEAEs.5,6

Exposure-Adjusted Incidence Rates

EAIRs are a measure of whether TEAEs occur at an increased frequency with increased treatment duration.5

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). No increase was observed in the EAIRs for CNS vascular disorder TEAEs in the longer-term analysis sets up to 12 months.5

The EAIR is equal to 100 times the number of patients experiencing the event divided by event-specific total patient year-at-risk.5

Incidence and Prevalence of TIA and Ischemic Stroke in People With Migraine

CGRP is a potent microvascular vasodilator found throughout the body that is hypothesized to play a protective role in cardiovascular health.7

Epidemiology studies report that cardiovascular comorbidities and risk factors for cardiovascular disease vary with

  • age

  • migraine severity, and

  • migraine type.8-10

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.8,11-15 Table 2 shows the incidence and prevalence of ischemic stroke and TIA reported in epidemiology studies of people with migraine.

Table 2. Incidence and Prevalence of TIA and Ischemic Stroke in People With Migraine8,9,11,16


TIA

Ischemic Stroke

Incidence

0.93 per 1000 patient-years8

1.40 in men; 0.73 in women

1.10 per 1000 person-years (any stroke)8

1.74 in men; 0.85 in women

In men (average age 51 years), crude incidence per 1000 person-years:
any stroke 2.59; ischemic stroke 2.3116

In women ≥45 years, the age-adjusted incidence of ischemic stroke per 1000 person-years:
1.31 in those with active migraine with aura; 1.07 in those with active migraine without aura11 

1.17 

Prevalence

2.8% of women and 2.5% of men9

2.0% of women and 1.6% of men (any stroke)9 

Abbreviation: TIA = transient ischemic attack.

Postmarketing Spontaneous Reports

Through September 27, 2020, the following cerebrovascular events have been very rarely reported in the Lilly spontaneous AE database

  • cerebrovascular accident

  • cerebellar artery thrombosis

  • ischemic stroke, and

  • transient ischemic attack.5

Very rarely reported is defined as an AE that has been reported at an estimated rate of <.01% according to the reporting system information.5 Information is not available regarding patient baseline cardiovascular risk for these postmarketing reports.

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

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. Bangs 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

3. 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

4. Mulleners 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

5. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

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. Russell 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

8. Becker 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

9. Buse 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

10. Le 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

11. Kurth 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

12. Sacco 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

13. Peng 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

14. Lee 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

15. Adelborg 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

16. Buring 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

17. Goldman 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

18. 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

19. 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

20. 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

Glossary

CGRP = calcitonin gene-related peptide

CNS = central nervous system

EAIR = exposure-adjusted incidence rate

MedDRA = Medical Dictionary for Regulatory Activities

PT = preferred term

SMQ = standard MedDRA query

TEAE = treatment-emergent adverse event

TIA = transient ischemic attack

Appendix

Migraine Prevention 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)18,19

  • chronic migraine (REGAIN),20 and

  • episodic or chronic migraine that has not benefited from 2 to 4 previous migraine prevention medication categories (CONQUER).4

Galcanezumab has also been studied in a phase 3, open-label, 12-month safety study for the prevention of episodic or chronic migraine.3

Table 3 summarizes the galcanezumab doses used and duration of the migraine prevention studies.

Table 3. Summary of Study Design in the Migraine Prevention Studiesa

 

GMB Doses Studied

Study Duration

EVOLVE Studies18,19

120 mg monthlyb

or
240 mg monthly

6 months, double-blind

REGAIN20

120 mg monthlyb

or
240 mg monthly

3 months, double-blind,
with optional 9-month open-label extension

CONQUER4

120 mg monthlyb

3 months, double-blind, 
with optional 3-month open-label extension

CGAJ3

120 mg monthlyb

or
240 mg monthly

12 months, open-label

Abbreviation: GMB = galcanezumab.

a With the exception of study CGAJ, all studies were randomized, double-blind, and placebo-controlled. 

b The initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120 mg.

Definition of 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 MedDRA SMQs, and 

  • "no" if they did not have any of the PTs in the MedDRA SMQs as a preexisting condition or medical history event.6

The MedDRA SMQs included the following:

  • ischemic heart disease (sub-SMQs: myocardial infarction and other ischemic heart disease)

  • hypertension

  • cardiac failure

  • cardiomyopathy

  • ischemic central nervous system vascular conditions

  • dyslipidemia, and

  • hyperglycemia/new-onset diabetes mellitus.6  

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.

Date of Last Review: February 02, 2021


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