Emgality® (Galcanezumab)

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Galcanezumab: Efficacy and Safety by Age in Migraine Prevention Trials

Galcanezumab efficacy and safety in elderly patients 65-75 years of age including those with treatment-resistant migraine were comparable across age groups.

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The information contained in this letter may not completely match the current local labeling for GALCANEZUMAB. Please see local labeling approved in your country. If you require the local labeling, please request it through your Sales Representative.

Description of Clinical Trials

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)1,2
  • chronic migraine (REGAIN),3 and
  • episodic or chronic migraine that has not benefited from 2 to 4 previous migraine prevention medication categories (CONQUER).4

The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days over

  • 6 months for the EVOLVE-1 and EVOLVE-2 studies,1,2 and
  • 3 months for the REGAIN and CONQUER studies.3,4

Galcanezumab has also been studied in a phase 3, open-label, 12-month safety study for the prevention of episodic or chronic migraine.5

In the 12-month, open-label, safety study, the primary endpoint was the long-term safety and tolerability of galcanezumab for up to 12 months of treatment.5

The galcanezumab doses used and duration of the migraine prevention studies are summarized in Summary of Study Design in the Migraine Prevention Studies.

Summary of Study Design in the Migraine Prevention Studiesa

 

GMB Doses Studied

Study Duration

EVOLVE Studies1,2

120 mg monthlyb
or
240 mg monthly

6 months double-blind

REGAIN3

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

CGAJ5

120 mg monthlyb
or
240 mg monthly

12 months open-label

Abbreviation: GMB = galcanezumab.

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.

Patients in EVOLVE-1, EVOLVE-2, REGAIN and CGAJ studies were required to be between the ages of 18 to 65 years, inclusive, at the time of screening.1-3,5 The study population in CONQUER included patients between 18 and 75 years of age.4

Analysis of Effect by Age

Description of Effect by Age Analyses

In an analysis of effect by age, efficacy outcomes were based on the phase 3, double-blind studies EVOLVE-1, EVOLVE-2, and REGAIN.6

Safety outcomes were analyzed using 2 populations

  • the phase 3 pooled population, which included both galcanezumab- and placebo-treated patients from the double-blind EVOLVE-1, EVOLVE-2, and REGAIN studies, and
  • all galcanezumab exposure population, which included only galcanezumab-treated patients from the phase 3 studies EVOLVE-1, EVOLVE-2, and REGAIN (including the open-label extension), the phase 2 placebo-controlled study CGAB, the phase 2 placebo-controlled study ART-01, and the phase 3, open-label safety study CGAJ.6

The CONQUER study was not included in this analysis, but data from the CONQUER study will be included separately to supplement safety findings in patients older than 65 years of age.

Efficacy by Age Analysis

The efficacy of galcanezumab was evaluated across 4 age categories (years) including

  • ≤40
  • >40 to ≤50
  • >50 to ≤55, and
  • >55 to ≤65.6

No pattern suggesting that frequency of monthly migraine headache days increases with age was observed.6 The number of baseline migraine headache days across age groups was similar, with

  • about 9 monthly mean migraine headache days in episodic migraine, and
  • about 19 monthly mean migraine headache days in chronic migraine.6

Overall, findings demonstrated that age, up to 65 years, did not have an effect on

Age was not a stratification factor in the phase 3 migraine prevention studies, resulting in some imbalances of age subgroups across the treatment arms in the pooled analysis of EVOLVE-1 and EVOLVE-2. However, the subgroup analysis appropriately accounts for the age main effect in the model to adjust for potential confounding.6

The only statistically significant treatment-by-subgroup interaction was change from baseline in migraine headache days with acute medication use in the episodic migraine studies, for which older patients appeared to have a larger reduction than younger patients (Efficacy Endpoints and Response by Age - EVOLVE-1 and EVOLVE-2 (Episodic Migraine)).6

Safety by Age Analysis

The safety of galcanezumab was evaluated across 4 age categories (years), including

  • <42
  • 42 to <50
  • 50 to <60, and
  • 60 to ≤65.6

Data do not indicate an increased frequency in galcanezumab-treated patients 60 to ≤65 years of age in

Exposure-adjusted incidence rates are a measure of whether TEAEs occur at an increased frequency with increased treatment duration.7

In EVOLVE-1, EVOLVE-2, and REGAIN, no treatment-by-age subgroup interaction was observed for EAIRs for TEAEs. When compared with a larger pool of galcanezumab-treated patients from phase 2 and phase 3 studies, the EAIRs for TEAEs were consistent across age groups and there was no trend of an increase with increased treatment duration.6,7

Cardiovascular Safety

No galcanezumab-treated patient in the 60 to ≤65 years age group

  • experienced a CV SAE, or
  • discontinued due to an AE likely to be CV in nature.6,7

Increasing age among patients treated with galcanezumab versus placebo was not associated with greater frequencies of hypertension or high blood pressure: Frequency of High Blood Pressure and Hypertension During Double-Blind Treatment - EVOLVE-1, EVOLVE-2, and REGAIN.6

There was no significant treatment-by-age subgroup interaction for TEAEs likely to be CV in nature in EVOLVE-1, EVOLVE-2, and REGAIN. When compared with a larger pool of galcanezumab-treated patients from phase 2 and phase 3 studies, the EAIRs for each age subgroup were consistent with or slightly less than the respective incidence rates for the age groups in EVOLVE-1, EVOLVE-2, and REGAIN.7

There were no significant treatment-by-age subgroup interactions for increase in

  • systolic blood pressure (any postbaseline measurement ≥140 mmHg and ≥20 mmHg increase from baseline), or
  • diastolic blood pressure (any postbaseline measurement ≥90 mmHg and ≥10 mmHg increase from baseline).6

Pharmacokinetics by Age

Pharmacokinetic data were obtained from patients in

  • EVOLVE-1 (N=422)
  • EVOLVE-2 (N=447)
  • REGAIN (N=545),  and
  • a phase 2 study, CGAB (N=266).8

Age (18-65 years) had a minimal effect on galcanezumab clearance (CL/F) in patients with migraine.6

Elderly Subpopulation From CONQUER

In the CONQUER study

  • patients were required to be between the ages of 18 to 75 years, inclusive, at the time of screening, and
  • the mean age was 45.8 years.4

The study enrolled a total of 462 patients, of whom 29 (6.3%) were 65 to 75 years of age (galcanezumab, n=13; placebo, n=16).7

No safety signals were identified based on the data from the 29 patients who were 65 to 75 years of age at time of study entry.7 There were no clinically meaningful differences between the galcanezumab- and placebo-treated patients on

  • TEAEs
  • labs
  • vital signs, and
  • ECGs.7

References

1Stauffer 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

2Skljarevski 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

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

4Mulleners 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

5Camporeale 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

6Stauffer VL, Turner I, Kemmer P, et al. Effect of age on pharmacokinetics, efficacy, and safety of galcanezumab treatment in adult patients with migraine: results from six phase 2 and phase 3 randomized clinical trials. J Headache Pain. 2020:21(1):79. https://doi.org/10.1186/s10194-020-01148-9

7Data on file, Eli Lilly and Company and/or one of its subsidiaries.

8Stauffer VL, Turner I, Kemmer P, et al. Effect of age on efficacy and safety of galcanezumab treatment in adult patients with migraine. Poster presented at: 71st Annual Meeting of the American Academy of Neurology (AAN); May 4-10, 2019; Philadelphia, PA.

Glossary

AE = adverse event

CL/F = apparent clearance

CV = cardiovascular

EAIR = exposure-adjusted incidence rate

ECG = electrocardiogram

SAE = serious adverse event

TEAE = treatment-emergent adverse event

Appendix

Efficacy Endpoints and Response by Age in the Pivotal Clinical Trials for Migraine Prevention

Efficacy Endpoints and Response by Agea - EVOLVE-1 and EVOLVE-2 (Episodic Migraine)6,7

Age group 

Tx

N

Migraine Headache Daysb
LS Mean Change

Migraine Headache Days With Acute Med Use
LS Mean Changec

50% Response
Est Rate (OR)

75% Response
Est Rate (OR)

100% Response
Est Rate (OR)

≤40

PBO

370

-2.63

-1.87

37.6 

17.9 

4.9

GMB 120

212

-4.31d

-3.38d

57.7 (2.26)d

32.4 (2.20)d

13.4 (3.03)d

GMB 240

216

-4.31d

-3.27d

57.8 (2.27)d

34.5 (2.42)d

12.0 (2.67)d

>40 - ≤50

PBO

295

-2.77

-2.37

39.4

19.0

6.0

GMB 120

125

-4.43d

-4.05d

61.4 (2.45)d

35.8 (2.38)d

11.7 (2.06)e

GMB 240

113

-4.22d

-3.84d

58.8 (2.19)d

36.7 (2.47)d

15.5 (2.87)d

>50 - ≤55

PBO

95

-1.91

-1.70

36.7

21.6

8.2

GMB 120

53

-4.77d

-4.25d

66.1 (3.67)d 

43.2 (2.77)d

19.2 (2.66)e

GMB 240

57

-4.20d

-4.01d

58.4 (2.43)d 

40.7 (2.50)e

16.6 (2.24)e

>55 - ≤65

PBO

115

-2.14

-1.86

30.4

16.2

6.3

GMB 120

46

-5.04d

-4.22d

68.5 (4.98)d

43.5 (4.00)d

10.3 (1.71)

GMB 240

42

-4.95d

-4.54d

65.0 (4.25)d

38.5 (3.26)d

18.1 (3.29)e

Abbreviations: Est = estimated using model; GMB = galcanezumab; GMB 120 = galcanezumab 120 mg; GMB 240 = galcanezumab 240 mg; LS Mean = least squares mean; med = medication; PBO = placebo; Tx = treatment.

aAverage of all months.

bPrimary endpoint.

cGMB 240 mg treatment-by-subgroup p=.024. Patients >55 to ≤65 years and treated with GMB 240mg appeared to have a larger reduction than younger patients.

dp<.001 vs placebo.

ep<.05 vs placebo.

Functional Endpoints by Agea - EVOLVE-1 and EVOLVE-2 (Episodic Migraine)7,8

Age group

Tx

N

MSQ Role Function-Restrictive
LS Mean Change

PGI-S
LS Mean Change

≤40

PBO

319

23.55

-1.18

GMB 120

191

30.72b

-1.51b

GMB 240

196

30.79b

-1.46c

>40 - ≤50

PBO

268

23.04

-1.08

GMB 120

117

30.65b

-1.47c

GMB 240

106

28.88b

-1.37c

>50 - ≤55

PBO

87

20.78

-1.14

GMB 120

53

29.60b

-1.11

GMB 240

52

27.95c

-1.05

>55 - ≤65

PBO

99

17.61

-0.85

GMB 120

41

31.41b

-1.12

GMB 240

40

29.84b

-1.31c

Abbreviations: GMB = galcanezumab; GMB 120 = galcanezumab 120 mg; GMB 240 = galcanezumab 240 mg; LS Mean = least squares mean; MSQ = Migraine-Specific Quality of Life Questionnaire; PBO = placebo; PGI-S = Patient Global Impression of Severity; Tx = treatment.

aAverage of months 4 to 6.

bp<.001 vs placebo.

cp<.05 vs placebo.

Efficacy Endpoints and Response by Agea - REGAIN (Chronic Migraine)6,7

Age group

Tx

N

Migraine Headache Daysb
LS Mean Change

Migraine Headache Days With Acute Med Use
LS Mean Change

50% Response
Est Rate (OR)

75% Response
Est Rate (ORc)

100% Response
Est Rate (ORd)

≤40

PBO

238

-3.90

-2.73

21.4

7.7

1.7e

GMB 120

139

-5.38f

-4.44f

31.2 (1.67)f

10.3 (1.38)

0.8e

GMB 240

125

-5.52f

-4.27f

30.6 (1.62)f

13.7 (1.91)f

2.2e

>40 - ≤50

PBO

159

-1.72

-1.94

11.6

4.1

1.0e

GMB 120

75

-4.78g

-5.26g

30.0 (3.28)g

8.3 (2.13)

2.7e

GMB 240

75

-4.16f

-3.85f

29.2 (3.16)g

8.1 (2.07)

3.7e

>50 - ≤55

PBO

64

-2.65

-2.72

19.3

8.6e

1.6e

GMB 120

31

-3.69

-4.35

26.4 (1.50)

12.0 (NC)e

3.4e

GMB 240

32

-3.73

-4.77

27.9 (1.62)

14.6e

4.7e

>55 - ≤65

PBO

77

-1.70

-1.16

13.2

2.3

1.4e

GMB 120

28

-4.61f

-5.17f

31.8 (3.07)f

10.7 (5.12)

10.7e

GMB 240

42

-4.47f

-5.32g

33.3 (3.28)f

10.6 (5.06)f

0e

Abbreviations: Est = estimated using model; GMB = galcanezumab; GMB 120 = galcanezumab 120 mg; GMB 240 = galcanezumab 240 mg; LS = least squares; Med = medication; NC = not calculable (0 patients responded in ≥1 treatment group for the specific subgroup shown, and none of the models converged); PBO = placebo; Tx = treatment.

aAverage of all months.

bPrimary endpoint.

cTreatment subgroup p value not calculable.

dOdds ratio and treatment subgroup p value not calculable (0 patients responded in ≥1 treatment group for the specific subgroup shown, and none of the models converged).

eWhere the model could not converge due to 0 patients responding in at least 1 treatment group for the specific subgroup for at least 1 month, raw rate was reported rather than model-estimated rate. Odds ratios and treatment-by-subgroup interactions could not be tested in these situations.

fp<.05 vs placebo.

gp<.001 vs placebo.

Functional Endpoints by Agea - REGAIN (Chronic Migraine)7,8

Age group

Tx

N

MSQ Role Function-Restrictive
LS Mean Change

PGI-S
LS Mean Change

≤40

PBO

217

19.89

-0.49

GMB 120

126

22.85

-0.46

GMB 240

113

25.43b

-0.67

>40 - ≤50

PBO

146

15.34

-0.58

GMB 120

73

20.38

-0.84

GMB 240

69

21.94b

-0.90

>50 - ≤55

PBO

60

14.97

-0.89

GMB 120

26

21.79

-0.83

GMB 240

32

23.26

-1.02

>55 - ≤65

PBO

71

15.53

-0.46

GMB 120

27

26.12b

-1.14

GMB 240

39

22.30

-1.18b

Abbreviations: GMB = galcanezumab; GMB 120 = galcanezumab 120 mg; GMB 240 = galcanezumab 240 mg; LS Mean = least squares mean; MSQ = Migraine-Specific Quality of Life Questionnaire; PBO = placebo; PGI-S = Patient Global Impression of Severity; Tx = treatment.

aAt month 3.

bp<.05 vs placebo.

Safety by Age in the Pivotal Clinical Trials for Migraine Prevention

Frequency of TEAEs, SAEs, and DCAEs by Age Group During Double-Blind Treatment - EVOLVE-1, EVOLVE-2, and REGAIN6,7

Abbreviations: DCAE = discontinuation due to adverse event; GMB Pooled = galcanezumab 120 mg and 240 mg pooled; PBO = placebo; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
* There were no significant treatment-by-subgroup interaction for SAEs or DCAEs, calculated using a logistic regression model including study, subgroup, treatment and treatment* subgroup.
^^ p≤.05 vs placebo.

Frequency of High Blood Pressure and Hypertension During Double-Blind Treatment - EVOLVE-1, EVOLVE-2, and REGAIN6

Abbreviations: BP = blood pressure; GMB Pooled = galcanezumab 120 mg and 240 mg pooled; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; SMQ = standard MedDRA query.
† High systolic blood pressure, any post-baseline measurement ≥140 mmHg and ≥20 mmHg increase from baseline.
# High diastolic blood pressure, any post-baseline measurement ≥90 mmHg and ≥10 mmHg increase from baseline.
* SMQ search included only narrow terms.

Fecha de la última revisión: 2020 M12 14


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