Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Leversäkerhet vid migränförebyggande

Data från fas 3 dubbelblinda, placebokontrollerade migränstudier visade ingen kliniskt meningsfull påverkan av galcanezumab på leversäkerhet.

Detailed Information

Description of Analysis Results

Mean Changes in Hepatic Laboratory Measures

There were no clinically meaningful differences between either galcanezumab group and placebo in mean change from baseline in

  • ALT

  • AST

  • ALP

  • bilirubin, and

  • creatine kinase.1

Treatment-Emergent Hepatic Abnormal Laboratory Measures

As shown in Table 1, there were no significant differences between treatment groups in the incidence of abnormal hepatic laboratory results at any time during double-blind treatment for all values except for ALT ≥5X ULN and the frequencies for any of these abnormalities was <1.0%.1

For patients with abnormal hepatic laboratory results, additional data regarding other lab values, medical history, concomitant medications, and TEAEs were reviewed.1 Overall, for patients with abnormal hepatic laboratory results, there were no patterns that would suggest an association with galcanezumab. All of these events were either transient and not clinically significant, or they were likely related to

  • preexisting abnormalities

  • other medical conditions (hepatic steatosis, hepatitis A, musculoskeletal injury), or

  • concomitant medication use including acetaminophen/paracetamol, naproxen, metoclopramide, dexketoprophen, and ibuprofen.

Table 1. Incidence of Abnormal Hepatic Laboratory Measures at Any Time During Double-Blind Treatment1

 

Maximum Post-Baseline Category

Treatment Group

ALT ≥3X ULN

n (%)

ALT ≥5X ULN 

n (%)

ALT ≥10X ULN 

n (%)

AST ≥3X ULN

n (%)

AST ≥5X ULN

n (%)

AST ≥10X ULN

n (%)

ALP ≥2X ULN

n (%)

TBL ≥2X ULN

n (%)

Placebo

7 (0.52)

0 (0)

0 (0)

2 (0.15)

0 (0)

0 (0)

0 (0)

1 (0.07)

GMB 120 mg

4 (0.60)

1 (0.15)

1 (0.15)

1 (0.15)

0 (0)

0 (0)

1 (0.15)

0 (0)

GMB 240 mg

6 (0.88)

3 (0.44)a

0 (0)

4 (0.44)

0 (0)

0 (0)

0 (0)

0 (0)

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GMB = galcanezumab; TBL = total bilirubin; X = times; ULN = upper limit of normal.

a p=.015 vs placebo.

Note: The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose .2 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.

Treatment-Emergent Adverse Events Related to Hepatic Safety

The incidence of hepatic TEAEs was low across all treatment groups (<1.0%) as shown in Table 2.1 All events were non-serious in nature.

Table 2. Incidence of TEAEs Related to Hepatic Injury and Function1

TEAEa

Placebo
n (%)

GMB 120 mg
n (%)

GMB 240 mg
n (%)

ALT increased

1 (0.07)

1 (0.14)

3 (0.41)

ALP increasedb

0 (0)

2 (0.28)c

0 (0)

Ascites

0 (0)

0 (0)

1 (0.14)

AST increased

0 (0)

1 (0.14)

1 (0.14)

Hepatic enzyme increased

1 (0.07)

1 (0.14)

2 (0.27)

Hepatic steatosis

2 (0.14)

0 (0)

0 (0)

International normalized ratio increased

0 (0)

0 (0)

1 (0.14)

Liver function test abnormal

1 (0.07)

0 (0)

0 (0)

Liver function test increasedb

1 (0.07)

0 (0)

0 (0)

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GMB = galcanezumab; TEAE = treatment-emergent adverse event.

a Narrow Scope Preferred Term unless otherwise specified.

b Broad Scope Preferred Term.

c p=.043 vs placebo.

Note: The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose .2 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.

Serious Adverse Events Related to Hepatic Safety

There were no SAEs related to hepatic laboratory values or hepatic safety during double-blind treatment in the phase 3, placebo-controlled galcanezumab migraine prevention clinical trials.1

Discontinuations Due to AEs Related to Hepatic Safety

In the phase 3, placebo-controlled migraine prevention clinical trials, 2 patients receiving galcanezumab 240 mg discontinued due to AEs related to hepatic safety (hepatic enzyme increased).1 

Three additional galcanezumab-treated patients discontinued due to hepatic related AEs during open-label galcanezumab 120 mg treatment in the REGAIN study. The patients discontinued due to the hepatic adverse events of

  • hepatic enzyme increased (n=2), and

  • ALT increased (n=1).1

Evaluation of Drug-Induced Serious Hepatotoxicity

Hy's law evaluation was completed in an analysis set that included phase 2 and phase 3 clinical trials. Hy's law is defined as the combination of drug related elevation of ALT ≥3X ULN and TBL ≥2X ULN, in the absence of significant cholestasis, ALP <2X ULN, and in the absence of other causes of liver injury.1

No galcanezumab or placebo treated patients had hepatic laboratory values that met the criteria for Hy's law.1 

Description of Analysis Set

The hepatic 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),3,4 and

  • chronic migraine (REGAIN; 3 months).5

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 studies had a duration of

  • 6 months for prevention of episodic migraine,3,4 and

  • 3 months for prevention of chronic migraine, with an optional 9-month open-label extension phase.5 

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

Renal or Hepatic Impairment

No dose adjustment is required in patients with mild to moderate renal impairment or hepatic impairment.2

Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the PK of galcanezumab have not been conducted.2

Renal elimination of IgG monoclonal antibody is low. Similarly, IgG monoclonal antibodies are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence the clearance of galcanezumab.2

Based on a population PK analysis, bilirubin concentration or Cockcroft-Gault creatinine clearance (range: 24 to 308 mL/min) did not significantly influence the apparent clearance of galcanezumab.2

Therapeutic Indication

Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.2

The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.2

References

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

2. Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

3. 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

4. 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

5. 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

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.

Glossary

AE = adverse event

ALP = alkaline phosphatase

ALT = alanine aminotransferase

AST = aspartate aminotransferase

SAE = serious adverse event

TBL = total bilirubin

TEAE = treatment-emergent adverse event

ULN = upper limit of normal

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 M02 13

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