Emgality® ▼ (galcanezumab): Respons efter fortsatt behandling hos primära non-responders

Information from the label

The treatment benefit should be assessed within 3 months after initiation of treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter.¹

Description of Analysis

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)^2,3

• chronic migraine (REGAIN),⁴ and

• episodic or chronic migraine that has not benefited from 2 to 4 previous migraine prevention medication categories (CONQUER).⁵

The galcanezumab doses used and duration of the migraine prevention studies are summarized in Table 1.

Table 1. Summary of Study Design in the Migraine Prevention Studies

	GMB Doses Studied	Treatment Duration
EVOLVE studies2,3	120 mg monthlya or 240 mg monthly	6 months double-blind
REGAIN4	120 mg monthlya or 240 mg monthly	3 months double-blind, with optional 9-month open-label extension
CONQUER5	120 mg monthlya	3 months double-blind, with optional 3-month open-label extension

Abbreviation: GMB = galcanezumab.

^a The initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120 mg.

The recommended dose of galcanezumab is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.¹ 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.

Post hoc analyses were conducted to evaluate response with continued galcanezumab treatment in patients who did not meet response definitions after the first 1 or 2 months in the

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

• CONQUER study.⁷

The results are summarized separately in the sections that follow.

The decision to discontinue treatment with galcanezumab in a patient who is not responding well must be based on the clinical judgment of the prescribing healthcare practitioner. As discussed below, factors contributing to galcanezumab treatment response or nonresponse are yet to be elucidated. Reduction in migraine headache days is only one measure of response and there may be other benefits to treatment, determined between the patient and clinician, that justify continued treatment despite not reaching a threshold reduction in migraine headache days.⁶

Analysis of Initial Nonresponders to Galcanezumab in the EVOLVE-1, EVOLVE-2, REGAIN Studies

A post hoc analysis examined response after continued galcanezumab treatment in patients who did not achieve "good" early improvement after 1 or 2 months of randomized, double-blind treatment in the EVOLVE-1, EVOLVE-2, and REGAIN studies.⁶

Good early improvement was defined as reduction from baseline in migraine headache days of

• ≥50% in the episodic migraine studies (EVOLVE-1 and EVOLVE-2), and

• ≥30% in the chronic migraine study (REGAIN).⁶

A ≥30% reduction from baseline in migraine headache days for chronic migraine can be clinically meaningful and was adopted for this analysis.⁶

This analysis included

• 879 galcanezumab-treated patients from the EVOLVE-1 and EVOLVE-2 studies (pooled 120-mg and 240-mg doses), and

• 555 galcanezumab-treated patients from the REGAIN study (pooled 120-mg and 240-mg doses).⁶

Additional information about the design of this post hoc analysis is available in the publication.⁶

Early Improvement Categories

Responses of patients who did not achieve "good" early improvement were subcategorized based on the response a patient indicated within the first or second month of treatment (Table 2).⁶

Table 2. Early Improvement Categories in Patients Who Did Not Achieve Good Early Improvement⁶

Category	Episodic Migraine	Chronic Migraine
Modest early improvement	>30% to <50% fewer migraine headache days	>10% to <30% fewer migraine headache days
Limited early improvement	>10% to ≤30% fewer migraine headache days	N/A
Minimal or no early improvement	≤10% fewer to ≤10% more migraine headache days	≤10% fewer to ≤10% more migraine headache days
Worsening	>10% more migraine headache days	>10% more migraine headache days

Abbreviations: N/A = not applicable.

Outcomes With Continued Treatment in Patients who did not Achieve Good Response After Months 1 or 2

Outcome definitions after continued treatment with galcanezumab through the double-blind treatment period are included below (Table 3).⁶

Table 3. Continued Treatment Outcome Definitions⁶

Category	Episodic Migraine	Chronic Migraine
Better response	≥75% fewer migraine headache days	≥50% fewer migraine headache days
Good response	≥50% fewer migraine headache days	≥30% fewer migraine headache days
Little-to-no response	≤10% fewer migraine headache days	≤10% fewer migraine headache days

Results

In the episodic migraine studies, 48.7% and 67.0% of patients met protocol-defined response at months 1 and 2, respectively. In the chronic migraine study, 44.9% and 56.8% of patients met protocol-defined response at months 1 and 2, respectively. This analysis included only patients who did not meet protocol-defined response at month 1, and month 1 or month 2. The percentages of patients with episodic or chronic migraine by improvement after 1 and 2 months of galcanezumab treatment are provided below: Table 4.⁶ 

Table 4. Percentage of Patients With Episodic or Chronic Migraine by Improvement After 1 Month and 2 Months of Galcanezumab Treatment⁶ 

	EVOLVE-1 and EVOLVE-2 N=878a	REGAIN N=555
NR-1
Protocol-defined Responseb	48.7%	44.9%
Modest Improvement	17.7%	20.9%
Limited Improvement	12.3%	---
Minimal/no improvement	9.7%	24.0%
Worsening	11.6%	10.3%
NR-2
Protocol-defined Responseb	67.0%	56.8%
Modest Improvement	5.7%	12.8%
Limited Improvement	11.2%	---
Minimal/no improvement	7.6%	21.8%
Worsening	8.5%	8.6%

Abbreviations: MHD = migraine headache day; NR-1 = patients without response after month 1 of galcanezumab treatment; NR-2 = patients without response after month 1 or month 2 of galcanezumab treatment.

^a One patient in the episodic group was excluded because of missing month 1 monthly headache day values.

^b Defined as reduction from baseline in monthly MHD of ≥50% for episodic migraine studies, or ≥30% in the chronic migraine study. These patients were not subject to further post hoc analysis.

In the episodic migraine studies, of the patients reporting "modest" early improvement after month 1 of galcanezumab treatment (ie, did not have a protocol-defined response),

• 62% achieved “good”, and

• 20% achieved “better” responses with continued treatment: Table 5.⁶

A percentage of patients with “limited” (43%) or “minimal/no” (34%) early improvement, or “worsening” (20%) achieved a “good” response after continued treatment.⁶

In the chronic migraine study, of the patients reporting "modest" early improvement after month 1 of galcanezumab treatment (ie, did not have a protocol-defined response),

• 38% achieved "good", and

• 13% achieved "better" responses with continued treatment: Table 6.⁶

A good response was achieved after continued treatment for a percentage of patients with "minimal/no" early improvement (17%), or "worsening" early response (11%).

Similar patterns were observed for the patients without response after month 1 or month 2 of galcanezumab treatment in episodic migraine (Table 5) and chronic migraine (Table 6); however, the percentages were lower than in the patients without a response at month 1.⁶

Table 5. Response Outcomes in Initial Nonresponders^a: Galcanezumab-Treated Patients With Episodic Migraine⁶

Response Outcome Categoriesb	Modest (>30% to <50% Fewer Migraine Headache Days)	Limited (>10% to ≤30% Fewer Migraine Headache Days)	Minimal/No (≤10% Fewer to ≤10% More Migraine Headache Days)	Worsening (>10% More Migraine Headache Days)
Subsequent response in NR-1c
Betterd	31/155 (20)	13/108 (12)	11/85 (13)	8/102 (8)
Goode	96/155 (62)	46/108 (43)	29/85 (34)	20/102 (20)
Little-to-nof	10/155 (7)	17/108 (16)	17/85 (20)	48/102 (47)
Subsequent response in NR-2c
Betterd	6/50 (12)	14/98 (14)	3/67 (5)	1/75 (1)
Goode	25/50 (50)	40/98 (41)	12/67 (18)	7/75 (9)
Little-to-nof	2/50 (4)	14/98 (14)	20/67 (30)	49/75 (65)

Abbreviations: NR-1 = patients without response after month 1 of galcanezumab treatment; NR-2 = patients without response after month 1 or month 2 of galcanezumab treatment.

^a An initial nonresponder is defined as a patient who does not achieve ≥50% reduction from baseline in migraine headache days.

^b Data shown as number of patients achieving subsequent response/number of patients in initial response category (%).

^c Response outcome across the remaining months 2 through 6 with continued galcanezumab treatment; data pooled across galcanezumab 120-mg and 240-mg doses.

^d Defined as ≥75% fewer migraine headache days following initial nonresponse.

^e Defined as ≥50% fewer migraine headache days following initial nonresponse.

^f Defined as ≤10% fewer migraine headache days following initial nonresponse.

 

Table 6. Response Outcomes in Initial Nonresponders^a: Galcanezumab-Treated Patients with Chronic Migraine⁶

Response Outcomes Categoriesb	Modest (>10% to <30% Fewer Migraine Headache Days)	Minimal/No (≤10% Fewer to ≤10% More Migraine Headache Days)	Worsening (>10% More Migraine Headache Days)
Subsequent response in NR-1c
Betterd	15/116 (13)	6/133 (5)	2/57 (4)
Goode	44/116 (38)	23/133 (17)	6/57 (11)
Little-to-nof	35/116 (30)	71/133 (53)	42/57 (74)
Subsequent response in NR-2c
Betterd	12/71 (17)	7/121 (6)	1/48 (2)
Goode	25/71 (35)	16/121 (13)	5/48 (10)
Little-to-nof	20/71 (28)	74/121 (61)	41/48 (85)

Abbreviations: NR-1 = patients without response after month 1 of galcanezumab treatment; NR-2 = patients without response after month 1 or month 2 of galcanezumab treatment.

^a An initial nonresponder is defined as a patient who does not achieve ≥30% reduction from baseline in migraine headache days.

^b Data shown as number of patients achieving subsequent response/number of patients in initial response category (%).

^c Response outcome across the remaining months 2 through 3 with continued galcanezumab treatment; data pooled across galcanezumab 120-mg and 240-mg doses.

^d Defined as ≥50% fewer migraine headache days following initial nonresponse.

^e Defined as ≥30% fewer migraine headache days following initial nonresponse.

^f Defined as ≤10% fewer migraine headache days following initial nonresponse.

It was concluded that galcanezumab-treated patients with episodic or chronic migraine who did not respond following 1 or 2 months of treatment

• have a reasonable likelihood of experiencing improvement with continued improvement in the months following initial treatment, and

• were more likely to achieve improved responses with continued treatment if they experienced greater early improvement.⁶

Only a small percentage of patients with episodic or chronic migraine who experienced worsening migraine headache days following initial treatment responded with continued dosing; most patients did not show substantial response with continued treatment.⁶

More information on the analysis and results are included in the open-access article.⁶

Analysis of Initial Nonresponders to Galcanezumab in the CONQUER Study

A similar post hoc analysis was conducted to evaluate response after continued galcanezumab treatment in patients who did not achieve the response threshold after 1 or 2 months of randomized, double-blind treatment in the CONQUER study.⁷

This study enrolled

• 137 patients with episodic migraine, and

• 95 patients with chronic migraine.^5,7

In this analysis, response was defined as reduction from baseline in monthly migraine headache days of

• ≥50% for episodic migraine, and

• ≥30% for chronic migraine.⁷

In the episodic migraine subgroup, 44% and 55% of patients met protocol-defined response at months 1 and 2, respectively.⁷ In the chronic migraine subgroup, 54% and 65% of patients met protocol-defined response at months 1 and 2, respectively.

Nonresponse was further categorized by reduction in migraine headache days at month 1, or months 1 and 2.⁷ The likelihood of subsequent response in these initial nonresponders is summarized for the episodic migraine subgroup (Table 7) and chronic migraine subgroup (Table 8).

Table 7. CONQUER Study: Likelihood of Subsequent Response in Episodic Migraine Subgroup⁷

Response Outcome Categories	≥30% to <50% Fewer Migraine Headache Days	≥10% to <30% Fewer Migraine Headache Days	<10% Fewer to ≤10% More Migraine Headache Days	>10% More Migraine Headache Days
Nonresponse in month 1
Patientsa	23/137 (17)	19/137(14)	19/137 (14)	16/137 (12)
Patients with subsequent responseb over months 2 and 3c	6/23 (26)	2/19 (11)	2/19 (11)	2/16 (13)
Nonresponse in months 1 and 2
Patientsa	9/137 (7)	23/137 (17)	18/137 (13)	11/137 (8)
Patients with subsequent responseb in month 3c	3/9 (33)	5/23 (22)	4/18 (22)	0/11 (0)

^a Represented as number of patients in the initial nonresponse category/number of patients with episodic migraine treated with galcanezumab (%).

^b Response is defined as ≥50% reduction in monthly migraine headache days following initial nonresponse.

^c Represented as number of patients achieving subsequent response/number of patients in initial response category (%).

Table 8. CONQUER Study: Likelihood of Subsequent Response in Chronic Migraine Subgroup⁷

Response Outcome Categories	≥10% to <30% Fewer Migraine Headache Days	<10% Fewer to ≤10% More Migraine Headache Days	>10% More Migraine Headache Days
Nonresponse in month 1
Patientsa	17/95 (18)	14/95 (15)	13/95 (14)
Patients with subsequent responseb over months 2 and 3c	9/17 (53)	4/14 (29)	0/13 (0)
Nonresponse in months 1 and 2
Patientsa	7/95 (7)	16/95 (17)	10/95 (11)
Patients with subsequent responseb in month 3c	2/7 (29)	1/16 (6)	0/10 (0)

^a Represented as number of patients the initial nonresponse category/number of patients with chronic migraine treated with galcanezumab (%).

^b Defined as ≥30% reduction in monthly migraine headache days following initial nonresponse.

^c Represented as number of patients achieving subsequent response/number of patients in initial response category (%).

In this analysis from the CONQUER study,

• 16% of patients in the episodic migraine subgroup with initial nonresponse at month 1 achieved response over months 2 and 3

• 20% of patients in the episodic migraine subgroup with initial nonresponse at months 1 and 2 achieved response at month 3

• 30% of patients in the chronic migraine subgroup with initial nonresponse at month 1 achieved response over months 2 and 3, and

• 9% of patients in the chronic migraine subgroup with initial nonresponse at months 1 and 2 achieved response at month 3.⁷

Patients with greater initial reduction from baseline in migraine headache days were more likely to experience a response with continued treatment.⁷

Therapeutic Indication

Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.¹

References

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

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. Mulleners 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

6. Nichols R, Doty E, Sacco S, et al. Analysis of initial nonresponders to galcanezumab in patients with episodic or chronic migraine: results from the EVOLVE-1, EVOLVE-2, and REGAIN randomized, double-blind, placebo-controlled studies. Headache. 2019;59(2):192-204. http://dx.doi.org/10.1111/head.13443

7. Nichols RM, Ahmed Z, McVige J, et al. Analysis of initial non-response to galcanezumab in patients with treatment-resistant migraine: results from the CONQUER trial. Headache. 2020;60(S1):99. 62nd Annual Scientific Meeting American Headache Society abstract. https://doi.org/10.1111/head.13854

▼ 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.