14 CLINICAL STUDIES

The efficacy of VYEPTI was evaluated as a preventive treatment of episodic and chronic migraine in two randomized, multicenter, placebo-controlled studies, both with 6-month double-blind periods: one study in patients with episodic migraine (Study 1) and one study in patients with chronic migraine (Study 2). VYEPTI was administered by intravenous infusion every 3 months in both studies; however, the primary endpoint was measured at 12 weeks.

Study 1: Episodic Migraine

Study 1 (NCT02559895) included adults with a history of episodic migraine (4 to 14 headache days per month, of which at least 4 were migraine days). A total of 665 patients were randomized to receive placebo (N=222), 100 mg VYEPTI (N=221), or 300 mg VYEPTI (N=222) every 3 months for 12 months. Patients were allowed to use concurrent acute migraine or headache medications, including migraine-specific medications (i.e., triptans, ergotamine derivatives), during the trial.

The study excluded patients with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease.

The primary efficacy endpoint was the change from baseline in mean monthly migraine days over Months 1-3. Secondary endpoints included the percentages of patients with 50% or greater, and 75% or greater reductions from baseline in monthly migraine days over Months 1-3.

Patients had a median age of 39 years (range: 18 to 71 years), 84% were female, and 84% were white. The mean migraine frequency at baseline was approximately 8.6 migraine days per month and was similar across treatment groups.

VYEPTI treatment demonstrated statistically significant improvements compared to placebo for the primary efficacy endpoint, as shown in Table 2; secondary endpoints are also summarized in Table 2.

Table 2. Efficacy Endpoint Results in Study 1

	VYEPTI100 mg N=221	VYEPTI300 mgN=222	PlaceboN=222
Monthly Migraine Days (MMD) – Months 1-3
Change from baseline	-3.9	-4.3	-3.2
Difference from placebo	-0.7	-1.1
p-value	0.018	<0.001
≥50% MMD responders – Months 1-3
% Responders	49.8%	56.3%	37.4%
Difference from placebo	12.4%	18.9%
p-value	0.009*	<0.001
≥75% MMD responders – Months 1-3
% Responders	22.2%	29.7%	16.2%
Difference from placebo	6.0%	13.5%
p-value	NS**	<0.001

* Nominal statistical significance

** NS = Not statistically significant

Figure 1 shows the mean change from baseline in average monthly migraine days in Study 1. Patients treated with VYEPTI at both doses had greater mean decreases from baseline in mean monthly migraine days over Months 1-3 compared to placebo-treated patients.

Figure 1. Change from Baseline in Monthly Migraine Days in Study 1

Figure 1. Change from Baseline in Monthly Migraine Days in Study 1

Figure 2 shows the distribution of change from baseline in mean monthly migraine days through Month 3 by treatment group in 2-day increments.

Figure 2. Distribution of Change from Baseline in Mean Monthly Migraine Days over Months 1 to 3 by Treatment Group in Study 1

Figure 2. Distribution of Change from Baseline in Mean Monthly Migraine Days over Months 1 to 3 by Treatment Group in Study 1

Figure 3 demonstrates that greater percentages of placebo-treated patients had migraines on most days during the first 7 days of treatment compared to VYEPTI-treated patients in Study 1.

Figure 3. Percentage of Patients with a Migraine from Day -1 (Day Prior to Infusion) to Day 7 in Study 1

Figure 3. Percentage of Patients with a Migraine from Day -1 (Day Prior to Infusion) to Day 7 in Study 1

Study 2: Chronic Migraine

Study 2 (NCT02974153) included adults with a history of chronic migraine (15 to 26 headache days per month, of which at least 8 were migraine days). A total of 1072 patients were randomized and received placebo (N=366), 100 mg VYEPTI (N=356), or 300 mg VYEPTI (N=350) every 3 months for 6 months. Patients were allowed to use and to continue an established stable regimen of acute migraine or headache preventive medication (except onabotulinumtoxinA). Patients with a dual diagnosis of chronic migraine and medication overuse headache attributable to acute medication overuse (triptans, ergotamine, or combination analgesics greater than 10 days per month) were included in the study population. Patients using opioids or butalbital-containing products greater than 4 days per month were not allowed.

The study excluded patients with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease.

The primary efficacy endpoint was the change from baseline in mean monthly migraine days over Months 1-3. Secondary endpoints included the percentages of patients with 50% or greater and 75% or greater reductions from baseline in monthly migraine days over Months 1-3.

Patients had a median age of 41 years (range: 18 to 65 years), 88% were female, and 91% were white. Forty-one percent of patients were taking concomitant preventive medication for migraine. The mean migraine frequency at baseline was approximately 16.1 migraine days per month and was similar across treatment groups.

VYEPTI treatment demonstrated statistically significant improvements compared to placebo for the primary efficacy endpoint, as shown in Table 3; secondary endpoints are also summarized in Table 3.

Table 3. Efficacy Endpoint Results in Study 2

	VYEPTI100 mg N=356	VYEPTI300 mgN=350	PlaceboN=366
Monthly Migraine Days (MMD) – Months 1-3
Change from baseline	-7.7	-8.2	-5.6
Difference from placebo	-2.0	-2.6
p-value	<0.001	<0.001
≥50% MMD responders –Months 1-3
% Responders	57.6%	61.4%	39.3%
Difference from placebo	18.2%	22.1%
p-value	<0.001	<0.001
≥75% MMD responders –Months 1-3
% Responders	26.7%	33.1%	15.0%
Difference from placebo	11.7%	18.1%
p-value	<0.001	<0.001

Figure 4 shows the mean change from baseline in average monthly migraine days for Study 2. Patients treated with VYEPTI at both doses had greater mean decreases from baseline in mean monthly migraine days over Month 1-3 compared to placebo-treated patients.

Figure 4. Change from Baseline in Monthly Migraine Days in Study 2

Figure 4. Change from Baseline in Monthly Migraine Days in Study 2

Figure 5 shows the distribution of change from baseline in mean monthly migraine days through Month 3 by treatment group in 3-day increments.

Figure 5. Distribution of Change from Baseline in Mean Monthly Migraine Days over Months 1-3 by Treatment Group in Study 2

Figure 5. Distribution of Change from Baseline in Mean Monthly Migraine Days over Months 1-3 by Treatment Group in Study 2

Figure 6 demonstrates that greater percentages of placebo-treated patients had migraines on individual days during the first 7 days of treatment compared to VYEPTI-treated patients in Study 2.

Figure 6. Percentage of Patients with a Migraine from Day -1 (Day Prior to Infusion) to Day 7 in Study 2

Figure 6. Percentage of Patients with a Migraine from Day -1 (Day Prior to Infusion) to Day 7 in Study 2