Emgality® (Galcanezumab)

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What is the cardiovascular safety profile of galcanezumab?

There were no significant differences between galcanezumab and placebo in CV TEAEs, CV SAEs, or discontinuations due to CV TEAEs in the phase 3 placebo-controlled clinical trials for migraine prevention or episodic cluster headache.

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Additional Information

Galcanezumab has been studied in migraine prevention and cluster headache.1-5 The CV safety profile summary for each indication is summarized separately below.

Additionally, postmarketing reports are summarized separately in the Postmarketing Spontaneous Reports section.

Cardiovascular Safety Migraine

Description of Pooled Analysis and Summary of Exposure

The CV safety profile of galcanezumab was evaluated in phase 3 randomized, double-blind, placebo-controlled studies in adult patients for the prevention of

  • episodic migraine (EVOLVE-1 and EVOLVE-2),1,2 and
  • chronic migraine (REGAIN).3

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

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

Additional results are provided when relevant from

  • a phase 3 open-label, 12-month safety study of galcanezumab (120 mg or 240 mg) in 270 patients with episodic and chronic migraine (study CGAJ)7
  • a phase 3 double-blind, placebo-controlled study of galcanezumab 120 mg in 462 patients with treatment resistant migraine,8 or
  • a pooled analysis of 2586 galcanezumab-treated patients from phase 2 and phase 3 migraine prevention clinical trials.9

Evaluation of Cardiovascular Safety

Blood Pressure and Pulse Changes

Treatment with galcanezumab did not result in hemodynamic changes consistent with vasoconstriction.10

Mean changes in blood pressure and pulse were small, with no clinically significant changes.6,10

There were no significant differences between galcanezumab and placebo in the frequency of

  • treatment-emergent high, or
  • sustained blood pressure elevation.6,9,10

Furthermore, there were no differences in TEAEs between the pooled galcanezumab (1.11%) and placebo (1.24%) groups in the proportion of patients with at least 1 narrow scope preferred term in the Hypertension SMQ.9,10

The percentages of patients with a categorical increase in systolic blood pressure, diastolic blood pressure, or pulse rate at any time post baseline were similar between treatment groups. The difference in the percentage of patients between placebo and either galcanezumab treatment group was less than 1%.10

Electrocardiogram Changes

There were no clinically important differences between galcanezumab and placebo in ECG parameters including QTcF or in any qualitative findings. No patient experienced a QTcF >500 msec.6,9,10

There were significantly more galcanezumab-treated patients (n=8; 0.6%) who met criteria for high QRS interval (≥120 msec) compared with placebo (n=1; 0.2%; p≤.05).9,10 Of the 8 galcanezumab-treated patients,

  • 6 had a preexisting condition of complete or incomplete bundle branch block at study entry, of whom 5 had a QRS ≥120 msec prior to dosing, and
  • 1 patient discontinued treatment due to mild dyspepsia.9,10

No patient discontinued due to high QRS interval.9

Blood Pressure and Electrocardiogram Changes in Patients With Treatment Resistant Migraine: CONQUER Study

CONQUER was a phase 3 randomized double-blind, placebo-controlled study in adult patients that assessed galcanezumab efficacy and safety in patients with episodic migraine or chronic migraine who had not benefited from multiple previous migraine preventive treatments.8

There were no meaningful differences between the galcanezumab- and placebo-treated patients on pulse and ECG parameters.9

Changes in Vital Signs and Electrocardiograms in Elderly Patients: CONQUER Study

In patients who were older than 65 years at study entry, there were no clinically meaningful differences between the galcanezumab- and placebo-treated patients on vital signs and ECGs.9

There were no treatment-emergent abnormal changes in vital signs in the elderly patients during the double-blind treatment phase except for

  • 1 placebo-treated patient with treatment-emergent high systolic blood pressure at visit 4 (150 mm Hg), and
  • 1 galcanezumab-treated patient with treatment-emergent high diastolic blood pressure at visit 6 (92 mm Hg). This patient was noted as having preexisting hypertension, with a diastolic blood pressure of 91 mm Hg at the screening visit.9

During the open-label treatment phase, there were 3 elderly patients who were previously randomized to placebo with treatment-emergent high diastolic blood pressure.9 

There were no treatment-emergent abnormal changes in qualitative or quantitative ECG parameters in the elderly patients except for

  • qualitative changes in 1 placebo-treated patient in the double-blind phase, and
  • 1 prior galcanezumab-treated patient in the open-label phase with sinus bradycardia at visit 9 who had sinus bradycardia at screening.9

Cardiovascular TEAEs and SAEs

Evaluation of CV TEAEs did not reveal any clinically important differences compared to placebo (Migraine Prevention: CV TEAEs - Phase 3, Placebo-Controlled Analysis Set).10 A low proportion of galcanezumab-treated patients and placebo-treated patients reported CV TEAEs across all 9 SMQs, with the highest frequency reported in the Hypertension SMQ. No statistically significant differences were observed between both galcanezumab dose groups and placebo in any SMQ based on the narrow scope preferred terms.

There were no significant differences between galcanezumab and placebo in the frequency of CV SAEs or discontinuations due to CV TEAEs.6,9,10

Migraine Prevention: CV TEAEs - Phase 3, Placebo-Controlled Analysis Set9,10

SMQab

PBO
N=1451

GMB 120 mg
N=705

GMB 240 mg
N=730

GMB Pooled
N=1435

Cardiac arrhythmias, n (%)

6 (0.41)

2 (0.28)

3 (0.41)

5 (0.35)

OR vs PBOc

---

0.68

1.00

0.84

Cardiac failure, n (%)

1 (0.07)

0 (0.00)

0 (0.00)

0 (0.00)

OR vs PBOc

---

0.00

0.00

0.00

Cardiomyopathy, n (%)

0 (0.00)

0 (0.00)

0 (0.00)

0 (0.00)

OR vs PBOc

---

---

---

---

CNS vascular disorder, n (%)

0 (0.00)

0 (0.00)

1 (0.14)

1 (0.07)

OR vs PBOc

---

---

---

---

Embolic and thrombotic events, n (%)

4 (0.28)

0 (0.00)

4 (0.55)

4 (0.28)

OR vs PBOc

---

0.00

1.99

1.01

Hypertension, n (%)

18 (1.24)

9 (1.28)

7 (0.96)

16 (1.11)

OR vs PBOc

---

1.03

0.77

0.90

Ischemic heart disease, n (%)

1 (0.07)

1 (0.14)

1 (0.14)

2 (0.14)

OR vs PBOc

---

2.05

1.99

2.02

Pulmonary hypertension, n (%)

0 (0.00)

0 (0.00)

0 (0.00)

0 (0.00)

OR vs PBOc

---

---

---

---

Torsades de pointes/QT prologation, n (%)

2 (0.14)

1 (0.14)

1 (0.14)

2 (0.14)

OR vs PBOc

---

1.03

0.99

1.01

Abbreviations: CNS = central nervous system; CV = cardiovascular; GMB = galcanezumab; MedDRA = Medical Dictionary for Regulatory Activities; N = number of patients in the analysis population; n = number of patients within each specific category; PBO = placebo; SMQ = Standardized MedDRA Query; TEAE = treatment-emergent adverse event.

aEach preferred term for the SMQ represents the narrow scope terms only.

bMedDRA version 19.1.

cMantel-Haenszel odds ratio stratified by study and 95% CI (CI calculated if ≥ 4 events in numerator and ≥ 1 event in denominator).

Changes in Use of CV Concomitant Medications

Concomitant CV medication usage at baseline was comparable across all treatment groups. At baseline, approximately

  • 6.7% to 8.8% of patients were taking antihypertensives
  • 2.0% to 2.5% were taking antithrombotics
  • 0.8% to 1.3% were taking antiarrhythmics, and
  • 0.1% to 0.3% were taking antianginals.10

During the double-blind treatment phase, dose increases, or a new start of CV medications was comparable across all treatment groups. These findings provide additional evidence that galcanezumab did not have a negative impact on CV function.9,10

Exposure-Adjusted Incidence Rates for Blood Pressure and CV TEAEs

There were no significant differences between any galcanezumab dose group and placebo in the EAIRs for the 9 SMQs and associated preferred terms in the phase 3, placebo-controlled analysis set.9 

In the longer-term analysis sets up to 12 months, there were no increases in the EAIRs with longer treatment duration for

  • treatment-emergent high systolic or diastolic blood pressure,6 and
  • CV TEAEs.9

Cardiovascular Safety Cluster Headache

Description of Pooled Analysis and Exposure

The CV safety profile of galcanezumab was studied in 2 phase 3 randomized, double-blind, placebo-controlled studies in adults with

  • episodic cluster headache (CGAL),4 and
  • chronic cluster headache (CGAM).5

This pooled analysis of 343 adult patients included a total of 166 patients that received galcanezumab 300 mg monthly by subcutaneous injection.9

The majority of patients were male (>75%) and Caucasian (>80%), with a mean age of 45 to 46 years.4,5,9

The CGAM study in chronic cluster headache did not meet its primary endpoint.5 However, safety results from the 2 placebo-controlled cluster headache trials were integrated and are the primary analysis set used for evaluation of galcanezumab safety in cluster headache.9

Evaluation of Cardiovascular Safety

Blood Pressure and Pulse Changes

The CV safety profile of galcanezumab in cluster headache was consistent with the established safety profile of galcanezumab. Evaluation of CV parameters in the galcanezumab phase 3, placebo-controlled cluster headache studies showed no clinically meaningful changes compared to placebo in heart rate.9

For both systolic and diastolic blood pressure, a small mean change was observed (<2 mmHg compared to placebo). This difference was not clinically meaningful and potentially due to chance given the smaller sample size of the cluster headache population.9

Electrocardiogram Changes

In the cluster headache placebo-controlled population, the mean changes in ECG parameters relating to PR interval, QRS interval, and QTcF were minimal and not clinically important.4,5,9

A low number of patients (<3%) in either treatment group met treatment-emergent change criteria in these parameters with no clinically important differences between galcanezumab and placebo. No patients experienced a QTcF >500 msec.9

Cardiovascular TEAEs and SAEs

Evaluation of CV TEAEs in the cluster headache placebo-controlled studies did not reveal any clinically important differences in frequency compared to placebo.9

A low percentage of patients (galcanezameb 4.2% and placebo 6.2%) reported TEAEs CV in nature across the 9 SMQs with no significant differences between treatment groups.9

There were no significant or clinically meaningful differences between galcanezumab and placebo in the frequency of

  • CV SAEs, or
  • discontinuations due to CV TEAEs.9

Changes in Use of CV Concomitant Medications

Concomitant CV medication usage at baseline was comparable across treatment groups. At baseline, approximately

  • 9.6% to 11.5% of patients were taking antihypertensives
  • 2.8% to 6.6% of patients were taking antithrombotics
  • 0% to 1.7% of patients were taking antiarrhythmics, and
  • no patients were taking antianginals.9

Overall, low numbers of patients had increases or new starts of concomitant CV medications.9

Exposure-Adjusted Incidence Rates for CV TEAEs

Longer duration of treatment did not lead to an increase in events for the 2 SMQs with preferred terms in the phase 3 placebo-controlled analysis set (Cardiac arrhythmia and Hypertension) when compared to larger analysis sets of

  • phase 3 double-blind, placebo-controlled migraine prevention and cluster headache clinical trials, and
  • galcanezumab treated patients in phase 2 and phase 3 clinical trials.9

The EAIR results are consistent with the established galcanezumab safety profile with the highest EAIRs for both galcanezumab and placebo observed in Cardiac arrhythmia and Hypertension SMQs.9

Postmarketing Spontaneous Reports

Through 27 September 2019, CV and cerebrovascular events have been reported "rarely" or "very rarely" in the Lilly spontaneous AE database. Rarely reported is defined as an AE that has been reported at an estimated rate of ≥.01% and <0.1% according to the reporting system information. Very rarely reported is defined as an AE that has been reported at an estimated rate of <.01% according to the reporting system information.9

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.11

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.11

References

1Skljarevski 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

2Stauffer 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

3Detke 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

4Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141. http://dx.doi.org/10.1056/NEJMoa1813440

5Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment [published online February 12, 2020]. Cephalalgia. http://dx.doi.org/10.1177/0333102420905321

6Bangs 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

7Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term, open-label safety study of galcanezumab in patients with migraine. BMC Neurology. 2018;18(1):188. http://dx.doi.org/10.1186/s12883-018-1193-2

8Mulleners WM, Kim B, Láinez MJA, et al. A phase 3, placebo-controlled study of galcanezumab in patients with treatment-resistant migraine: results from the 3-month, double-blind treatment phase of the CONQUER study. Poster presented at: 24th World Congress of Neurology (WCN); October 27-31, 2019; Dubai, United Arab Emirates.

9Data on file, Eli Lilly and Company and/or one of its subsidiaries.

10Oakes 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

11Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6

Glossary

CV = cardiovascular

EAIR = exposure-adjusted incidence rate

ECG = electrocardiogram

QTcF = Fridericia's corrected QT interval

SAE = serious adverse event

SMQ = standard MedDRA query

TEAE = treatment-emergent adverse event

Fecha de la última revisión: 2020 M01 30


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