Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Användning hos patienter med tidigare kärlsjukdom i CNS

Patienter som nyligen drabbats av stroke uteslöts från kliniska prövningar.

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

Description of Analysis Set and Summary of Exposure

Central nervous system vascular events were evaluated in phase 3 galcanezumab studies including

  • 2 randomized, double-blind, placebo-controlled, 6-month episodic migraine prevention studies (EVOLVE-1 and EVOLVE-2)2,3

  • 1 randomized, double-blind, placebo-controlled, 3-month chronic migraine prevention study with an optional 9-month open-label extension phase (REGAIN), and4

  • one 12-month, open-label safety study in patients with episodic or chronic migraine (CGAJ).5

This pooled analysis of 2886 adult patients included a total of 1435 patients that received galcanezumab (120 mg or 240 mg) subcutaneously.6

  • The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.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.

The majority of patients were female (>80%) and Caucasian (>75%), with a mean age of 41-42 years.6

The summary of exposure for this dataset is described in Table 1.

Additional results are provided when relevant from study CGAJ, the phase 3 open-label, 12-month safety study of galcanezumab (120 mg or 240 mg) in 270 patients with episodic or chronic migraine.5

Table 1. Migraine Prevention: Phase 3 Placebo-Controlled Integrated Analysis Dataset - Summary of Exposure7,8

Treatment

N

Median Patient Days of Exposure

Total Patient Years

Placebo

1451

169

532.66

GMB 120 mg

705

169

267.65

GMB 240 mg

730

168

268.69

GMB Pooled

1435

169

536.34

Abbreviation: GMB = galcanezumab.

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 and CGAJ)

  • 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.7,9

Cardiovascular Disease Risk

At baseline, patients with comorbid cardiovascular disease and risk were grouped into a cardiovascular disease risk group (yes or no) based on reported medical history or preexisting conditions.9

Between 17.0% and 19.0% of patients were identified to be in the cardiovascular disease risk "yes" subgroup across treatment groups in EVOLVE-1, EVOLVE-2, and REGAIN.7,9

Baseline CNS Vascular Disorders

Baseline CNS vascular disorders among patients in the cardiovascular disease risk "yes" group are presented below, Table 2.7

Table 2. Baseline CNS Vascular Disorders Among Patients in the Cardiovascular Disease Risk "Yes" Group - Phase 3 Double-Blind, Placebo-Controlled Migraine Prevention Trials7

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; PBO = placebo; SMQ = standardized MedDRA query; TIA = transient ischemic attack.

a Narrow scope preferred term.

CNS Vascular Disorder TEAEs

In the phase 3 migraine prevention clinical trials, 2 galcanezumab-treated patients reported a serious CNS vascular disorder TEAE.7

Both patients were in the baseline cardiovascular disease risk "no" subgroup.7

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

  • other potential contributing factors, and

  • insufficient evidence to substantiate a reasonable association between galcanezumab and the TEAEs.7

Exposure-Adjusted Incidence Rates

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.7

The EAIR is equal to 100 times the number of patients experiencing the event divided by event-specific total patient year-at-risk.7

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.10

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

  • age

  • migraine severity, and

  • migraine type.11-13

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.11,14-16 The incidence and prevalence of ischemic stroke and TIA reported in epidemiology studies of people with migraine are shown in Table 3.

Table 3. Incidence and Prevalence of TIA and Ischemic Stroke in People With Migraine11,12,14,17


TIA

Ischemic Stroke

Incidence

0.93 per 1000 patient-years11

1.40 in men; 0.73 in women

1.10 per 1000 person-years (any stroke)11

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 2.3117

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 aura14 

Prevalence

2.8% of women and 2.5% of men12

2.0% of women and 1.6% of men (any stroke)12 

Abbreviation: TIA = transient ischemic attack.

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. 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. 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

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

8. 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 Neurol. 2020;20(1):25. http://dx.doi.org/10.1186/s12883-020-1609-7. Published correction appears in BMC Neurol. 2020;20(1):90. http://dx.doi.org/10.1186/s12883-020-01675-7

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

Glossary

CGRP = calcitonin gene-related peptide

CNS = central nervous system

EAIR = exposure-adjusted incidence rate

TEAE = treatment-emergent adverse event

TIA = transient ischemic attack

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.

Datum fӧr senaste ӧversyn 2019 M04 03


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