Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Användning hos patienter med comorbid depression och ångest

Galcanezumabbehandlade patienter med behandlingsresistent migrän rapporterade signifikant minskade symtom på depression och en minskning av symtom på ångest jämfört med placebo.

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Criteria for Participation in Galcanezumab Phase 3 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 galcanezumab doses studied in 

  • EVOLVE-1, EVOLVE-2, and REGAIN were 120 mg monthly (with a 240-mg loading dose) or 240 mg monthly,1-3 and
  • CONQUER was 120 mg monthly (with a loading dose of 240 mg).4

Note: The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.5 Any other dose described here is not approved and therefore is not recommended.

Patients with depression and/or anxiety were considered for inclusion in these studies. Post hoc analyses have been conducted on the subpopulations with comorbid depression and/or anxiety.6,7

One post hoc analysis evaluated whether comorbid depression and/or anxiety affected the efficacy of galcanezumab using data from the EVOLVE-1, EVOLVE-2, and REGAIN studies. The other post hoc analysis evaluated the effect of galcanezumab treatment on changes in measures of depression and anxiety using data from the CONQUER study.6,7 These results are summarized below. 

Post Hoc Analysis of Patients With Comorbid Anxiety and/or Depression in EVOLVE-1, EVOLVE-2, and REGAIN

Patients with MDD or GAD were considered for inclusion if

  • they were not on excluded medications, and
  • the investigator considered their disease to be stable and expected to remain stable throughout the course of the study.8

Clinical trial exclusion criteria included evidence of significant active or unstable psychiatric disease by medical history, such as

  • bipolar disorder
  • schizophrenia
  • personality disorders, or
  • other serious mood or anxiety disorders.8

Patients were also excluded if

  • in the clinician’s judgment, they were actively suicidal and therefore deemed to be at significant risk for suicide, or
  • they answered “yes” to any of the select items in the  Columbia Suicide Severity Rating Scale, and the ideation or behavior occurred within the past month.8

Select Columbia Suicide Severity Rating Scale Items provides more detailed information regarding the select items from the Columbia Suicide Severity Rating Scale.

A post hoc analysis evaluated the efficacy of galcanezumab for the prevention of migraine in patients with and without a current or past medical history of

  • depression
  • anxiety, or
  • both.

In this analysis, data from the episodic migraine prevention studies, EVOLVE-1 and EVOLVE-2, were pooled and analyzed separately from the chronic migraine prevention study, REGAIN.6 Efficacy of galcanezumab was evaluated both within and between the subgroups of patients who had comorbid depression and/or anxiety and those who did not.6

Baseline Characteristics of Patients With Anxiety and/or Depression in EVOLVE-1, EVOLVE-2, and REGAIN

At baseline, comorbid depression and/or anxiety was reported in 26.0% of patients with episodic migraine, and 28.4% of patients with chronic migraine.6 The majority of these patients reported "current" depression and/or anxiety including

  • 77% of patients with episodic migraine, and
  • 81% of patients with chronic migraine.6

The remaining patients reported a history of comorbid depression and/or anxiety that had resolved prior to study enrollment.6

In the EVOLVE studies and the REGAIN study, compared with patients without comorbid depression and/or anxiety, patients with comorbid depression and/or anxiety had significantly greater baseline

  • number of comorbid conditions (p<.001)
  • functional impairment, represented by a lower MSQ Role Function Restrictive domain score (p<.05)
  • migraine-related disability, represented by a higher MIDAS total score (p<.05), and
  • number of migraine headache days (p<.05).6


In comparison to patients who did not have comorbid depression and/or anxiety, patients with episodic migraine and comorbid depression and/or anxiety

  • had a significantly higher number of migraine headache days with acute medication use (p<.013), and
  • were slightly older (p<.044).6

There were no significant differences in the number of failed migraine preventive treatments between the subgroups with comorbid depression and/or anxiety versus those without in

  • EVOLVE-1, EVOLVE-2, and
  • REGAIN.6

Results of Post Hoc Analysis of Patients With Comorbid Anxiety and/or Depression

In the episodic migraine studies, both doses of galcanezumab showed statistically significant improvements compared to placebo regardless of comorbid depression and/or anxiety subgroup on overall and monthly

  • reduction in migraine headache days
  • reduction in migraine headache days with acute medication use
  • improvement in the MSQ Role Function-Restrictive Score, or
  • 50%, 75%, or 100% response rates.6

In patients without comorbid depression and/or anxiety in the chronic migraine study (REGAIN), both doses of galcanezumab showed statistically significant improvements compared with placebo on overall

  • reduction in migraine headache days
  • reduction in migraine headache days with acute medication use
  • the MSQ Role Function-Restrictive Score, and
  • proportion of patients achieving 50% and 75% response rates.6

In patients with comorbid depression and/or anxiety in the REGAIN study, statistically significant improvement compared with placebo was seen on overall

  • reduction in migraine headache days for galcanezumab 240 mg dose
  • reduction in migraine headache days with acute medication use for both galcanezumab doses, and
  • proportion of patients achieving 50% and 75% response rates for the galcanezumab 240 mg dose.6

In patients with comorbid depression and/or anxiety in the REGAIN study, neither galcanezumab dose showed statistical significance compared with placebo in overall

  • change from baseline in MSQ Role-Function Restrictive Domain Score, and
  • proportion of patients achieving 100% response rates.6

In this post hoc analysis, concomitant medication indications were not collected, therefore it was not determined if patients were being treated for depression and/or anxiety.6

CONQUER Study in Patients With Treatment-Resistant Migraine

Changes in measures of depression and anxiety were evaluated in the CONQUER study and are summarized below.

Certain antidepressants or anxiolytics such as SNRIs, SSRIs, or benzodiazepines were allowed if patients

  • were on a stable dose for ≥2 months prior to the prospective baseline period, and
  • would stay on that same dose throughout the double-blind treatment period.7

Starting a new medication or changing the dose of an existing one was not allowed during the baseline or treatment period.7

Patients with evidence of significant active or unstable psychiatric disease were excluded. However, patients with MDD or GAD whose disease state was considered stable were eligible for enrollment.7

Subgroup Analysis: Changes in Anxiety and Depression

Subgroup analysis of changes in measures of depression and anxiety after 3 months of treatment with galcanezumab or placebo in patients with multiple prior migraine preventive treatment failures was conducted.7

Patients with MDD were identified using the PHQ-9 for assessing depressive symptoms and severity over the past 2 weeks. 7

Patients with GAD were identified using the GAD-7 scale for assessing anxiety symptoms and severity over the past 2 weeks.7

Detailed information about the  and the   is provided in the Appendix.

The study enrolled a total of 462 patients. At baseline, 

  • 14.3% of patients met PHQ-9 criteria for MDD (8.6% with episodic migraine, 22.3% with chronic migraine), and
  • 14.7% met the GAD-7 criteria for GAD (11.5% with episodic migraine, 19.2% with chronic migraine).7

The mean PHQ-9 score at baseline was 7.7 for galcanezumab-treated patients, and 7.8 for the placebo group, corresponding to mild levels of MDD severity.7

The mean GAD-7 score at baseline was 4.8 for galcanezumab-treated patients, and 4.9 for the placebo group, corresponding to mild levels of GAD severity.7

The percentage of patients being actively treated for depression or anxiety at baseline was not analyzed.7

Galcanezumab Reduced Symptoms of Depression and Anxiety Compared With Placebo

Patients treated with galcanezumab had a significant reduction in symptoms of depression compared with placebo as demonstrated by lower PHQ-9 scores at month 3 (Reduction in Symptoms of Depression From Baseline to Month 3).7

Reduction in Symptoms of Depression From Baseline to Month 37

Abbreviations: GMB = galcanezumab; LS = least squares; PBO = placebo; PHQ-9 = Patient Health Questionnaire-9.
*p=.009 vs placebo.

Ratings of anxiety were also lower for galcanezumab-treated patients at month 3, but statistical separation of galcanezumab from placebo in the reduction of anxiety symptoms was not observed (Reduction in Symptoms of Anxiety From Baseline to Month 3).7

Reduction in Symptoms of Anxiety From Baseline to Month 37

Abbreviations: GAD-7 = 7-Item Generalized Anxiety Disorder scale; GMB = galcanezumab; LS = least squares; NS = not significant; PBO = placebo.
*p=0.07 vs placebo.

Categorical shift of severity levels of symptoms of depression and anxiety based on PHQ-9 and GAD-7 total scores was also evaluated.7

After 3 months of treatment, galcanezumab-treated patients were statistically significantly more likely to  be in the "minimal" severity level of depression compared to placebo (p=.020). In contrast, the categorical levels of severity of anxiety were not  statistically significantly different between galcanezumab and placebo.7

On the individual PHQ-9 items, a higher proportion of galcanezumab-treated patients than placebo-treated patients at month 3

  • reported "Not at All" score, and
  • showed improved scores from baseline.7

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

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

5Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

6Smitherman TA, Tietjen GE, Schuh K, et al. Efficacy of galcanezumab for migraine prevention in patients with a medical history of anxiety and/or depression: a post hoc analysis of the phase 3, randomized, double-blind, placebo-controlled REGAIN, and pooled EVOLVE-1 and EVOLVE-2 studies. Headache. 2020;60(10):2202-2219. https://doi.org/10.1111/head.13970

7Maizels M, Buse D, Jedynak JP, et al. Assessment of anxiety and depression in a randomized, double-blind, placebo-controlled study of galcanezumab in adults with treatment-resistant migraine: results from the CONQUER study. Poster presented at: 24th World Congress of Neurology (WCN); October 27-31, 2019; Dubai, United Arab Emirates.

8Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Appendix

Select Columbia Suicide Severity Rating Scale Items

Select Columbia Suicide Severity Rating Scale Items8

Domain Evaluated

Description

Suicidal Ideation

Question 4 - Active suicidal ideation with some intent to act, without specific plan

Question 5 - Active suicidal ideation with specific plan and intent

Suicidal Behavior

actual attempt

interrupted attempt

aborted attempt

preparatory act or behavior

PHQ-9 Scale 

 In the PHQ-9, symptoms are rated using 9 questions on a 4-point scale in which

  • 0=not at all
  • 1=several days
  • 2=more than half the time, and
  • 3=nearly every day.7

Total score for the PHQ-9 ranges from 0 to 27, with levels of depression severity defined as

  • 0-4=minimal
  • 5-9=mild
  • 10-14=moderate
  • 15-19=moderately severe, and 
  • 20-27=severe.7

GAD-7 Scale

 In the GAD-7, symptoms are rated using 7 questions on a 4-point scale in which

  • 0=not at all
  • 1=several days
  • 2=more than half the days, and
  • 3=nearly every day.7

Total score for the GAD-7 ranges from 0-21, with levels of anxiety severity defined as

  • 0-4=minimal
  • 5-9=mild
  • 10-14=moderate, and
  • 15-21=severe.7

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 January 20, 2021


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