Emgality® ▼ (galcanezumab): Use in Patients With Comorbid Heart Disease

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 Set^1,6

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.