14 CLINICAL STUDIES

The efficacy of AIMOVIG was evaluated as a preventive treatment of episodic or chronic migraine in three randomized, double-blind, placebo-controlled studies: two studies in patients with episodic migraine (4 to 14 migraine days per month) (Study 1 and Study 2) and one study in patients with chronic migraine (≥ 15 headache days per month with ≥ 8 migraine days per month) (Study 3). The studies enrolled patients with a history of migraine, with or without aura, according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.

Episodic Migraine

Study 1 (NCT 02456740) was a randomized, multi-center, 6-month, placebo-controlled, double-blind study evaluating AIMOVIG for the preventive treatment of episodic migraine. A total of 955 patients with a history of episodic migraine were randomized to receive either AIMOVIG 70 mg (N = 317), AIMOVIG 140 mg (N = 319), or placebo (N = 319) by subcutaneous injection once monthly (QM) for 6 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.

The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.

The primary efficacy endpoint was the change from baseline in mean monthly migraine days over months 4 to 6. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in mean monthly migraine days over months 4 to 6 ("≥ 50% MMD responders"), the change from baseline in mean monthly acute migraine-specific medication days over months 4 to 6, and the change from baseline in mean Migraine Physical Function Impact Diary (MPFID) over months 4 to 6. The MPFID measures the impact of migraine on everyday activities (EA) and physical impairment (PI) using an electronic diary administered daily. Monthly MPFID scores are averaged over 28 days, including days with and without migraine; scores are scaled from 0 to 100. Higher scores indicate worse impact on EA and PI. Reductions from baseline in MPFID scores indicate improvement.

A total of 858 (90%) patients completed the 6-month double-blind study. Patients had a median age of 42 years (range: 18 to 65 years), 85% were female, and 89% were white. Three percent of patients were taking concomitant preventive treatments for migraine. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups.

AIMOVIG treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 3.

Table 3: Efficacy Endpoints Over Months 4 to 6 in Study 1
	AIMOVIG 70 mg Once Monthly	AIMOVIG 140 mg Once Monthly	Placebo
	N = 312	N = 318	N = 316
Monthly Migraine Days (MMD)
Change from baseline	−3.2	−3.7	−1.8
Difference from placebo	−1.4	−1.9
p-value	< 0.001	< 0.001
≥ 50% MMD responders
% Responders	43.3%	50.0%	26.6%
Difference from placebo	16.7%	23.4%
Odds ratio relative to placebo	2.1	2.8
p-value	< 0.001	< 0.001
Monthly acute migraine-specific medication days
Change from baseline	−1.1	−1.6	−0.2
Difference from placebo	−0.9	−1.4
p-value	< 0.001	< 0.001

Figure 1: Change from Baseline in Monthly Migraine Days in Study 1*
* Least-square means and 95% confidence intervals are presented.

Figure 2 shows the distribution of change from baseline in mean monthly migraine days over months 4 to 6 in bins of 2 days by treatment group. A treatment benefit over placebo for both doses of AIMOVIG is seen across a range of changes from baseline in monthly migraine days.

Figure 2: Distribution of Change from Baseline in Mean Monthly Migraine Days Over Months 4 to 6 by Treatment Group in Study 1
Figure excludes patients with missing data.

Compared to placebo, patients treated with AIMOVIG 70 mg once monthly and 140 mg once monthly showed greater reductions from baseline in mean monthly MPFID everyday activity scores averaged over months 4 to 6 [difference from placebo: −2.2 for AIMOVIG 70 mg and −2.6 for AIMOVIG 140 mg; p-value < 0.001 for both], and in mean monthly MPFID physical impairment scores averaged over months 4 to 6 [difference from placebo: −1.9 for AIMOVIG 70 mg and −2.4 for AIMOVIG 140 mg; p-value < 0.001 for both].

Study 2 (NCT 02483585) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating AIMOVIG for the preventive treatment of episodic migraine. A total of 577 patients with a history of episodic migraine were randomized to receive either AIMOVIG 70 mg (N = 286) or placebo (N = 291) by subcutaneous injection once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.

The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.

The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days ("≥ 50% MMD responders"), the change from baseline in monthly acute migraine-specific medication days at month 3, and the proportion of patients with at least a 5-point score reduction from baseline in MPFID at month 3.

A total of 546 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 65 years), 85% were female, and 90% were white. Six to seven percent of patients were taking concomitant preventive migraine treatment. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar between treatment groups.

AIMOVIG treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 4.

Table 4: Efficacy Endpoints at Month 3 for Study 2
	AIMOVIG 70 mg Once Monthly	Placebo
	N = 282	N = 288
Monthly Migraine Days (MMD)
Change from baseline	−2.9	−1.8
Difference from placebo	−1.0
p-value	< 0.001
≥ 50% MMD responders
% Responders	39.7%	29.5%
Difference from placebo	10.2%
Odds ratio relative to placebo	1.6
p-value	0.010
Monthly acute migraine-specific medication days
Change from baseline	−1.2	−0.6
Difference from placebo	−0.6
p-value	0.002

Figure 3: Change from Baseline in Monthly Migraine Days in Study 2*
* Least-square means and 95% confidence intervals are presented.

Figure 4 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 2 days by treatment group. A treatment benefit over placebo for AIMOVIG is seen across a range of changes from baseline in monthly migraine days.

Figure 4: Distribution of Change from Baseline in Monthly Migraine Days at Month 3 by Treatment Group in Study 2
Figure excludes patients with missing data.

The pre-specified analysis for the MPFID was based on at least a 5-point reduction within-patient responder definition. AIMOVIG 70 mg once monthly was not significantly better than placebo for the proportion of responders for everyday activity [difference from placebo: 4.7%; odds ratio = 1.2; p-value = 0.26] and physical impairment [difference from placebo: 5.9%; odds ratio = 1.3; p-value = 0.13]. In an exploratory analysis of the change from baseline in the mean MPFID scores at month 3, patients treated with AIMOVIG 70 mg, as compared to placebo, showed nominally greater reductions of physical impairment scores [difference from placebo: -1.3; p-value = 0.021], but not of everyday activities scores [difference from placebo: -1.1; p-value = 0.061].

Chronic Migraine

Study 3 (NCT 02066415) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating AIMOVIG as a preventive treatment of chronic migraine. A total of 667 patients with a history of chronic migraine with or without aura were randomized to receive AIMOVIG 70 mg (N = 191), AIMOVIG 140 mg (N = 190), or placebo (N = 286) by subcutaneous injections once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.

The study excluded patients with medication overuse headache caused by opiate overuse and patients with concurrent use of migraine preventive treatments. Patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening were also excluded.

The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days ("≥ 50% MMD responders") and change from baseline in monthly acute migraine-specific medication days at month 3.

A total of 631 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 66 years), 83% were female, and 94% were white. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups.

AIMOVIG treatment demonstrated statistically significant improvements for key efficacy outcomes compared to placebo, as summarized in Table 5.

Table 5: Efficacy Endpoints at Month 3 in Study 3
	AIMOVIG 70 mg Once Monthly	AIMOVIG 140 mg Once Monthly	Placebo
	N = 188	N = 187	N = 281
Monthly Migraine Days (MMD)
Change from baseline	−6.6	−6.6	−4.2
Difference from placebo	−2.5	−2.5
p-value	< 0.001	< 0.001
≥ 50% MMD responders
% Responders	39.9%	41.2%	23.5%
Difference from placebo	16.4%	17.7%
Odds ratio relative to placebo	2.2	2.3
p-value	< 0.001	< 0.001
Monthly acute migraine-specific medication days
Change from baseline	−3.5	−4.1	−1.6
Difference from placebo	−1.9	−2.6
p-value	< 0.001	< 0.001

Figure 5: Change from Baseline in Monthly Migraine Days in Study 3*
* Least-square means and 95% confidence intervals are presented.

Figure 6 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 3 days by treatment group. A treatment benefit over placebo for both doses of AIMOVIG is seen across a range of changes from baseline in migraine days.

Figure 6: Distribution of Change from Baseline in Monthly Migraine Days at Month 3 by Treatment Group in Study 3
Figure excludes patients with missing data.