14 CLINICAL STUDIES

14.1 Excessive Daytime Sleepiness (EDS) in Patients with Narcolepsy

Adult Patients with Narcolepsy

The efficacy of WAKIX for the treatment of excessive daytime sleepiness in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 1; NCT01067222 and Study 2; NCT01638403). Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy (with or without cataplexy) and who had an Epworth Sleepiness Scale (ESS) score ≥14 were eligible to enroll in the studies. EDS was assessed using the ESS, an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Each of the 8 items on the ESS is rated from 0 (would never doze) to 3 (high chance of dozing); the maximum score is 24. Study 1 and Study 2 included an 8-week treatment period: a 3-week dose titration phase followed by a 5-week stable dose phase. These studies compared WAKIX to both a placebo and an active control.

In Study 1, 95 patients were randomized to receive WAKIX, placebo, or active control. The dose of WAKIX was initiated at 8.9 mg once daily and could be increased at weekly intervals to 17.8 mg or 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable dose phase. 61% of patients reached a stable dose of 35.6 mg. Median age in the study was 37 years. More than 90% of patients in the WAKIX and placebo groups were Caucasian and 54% were male. Approximately 80% of the population had a history of cataplexy.

WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo (Table 3).

In Study 2, 166 patients were randomized to receive WAKIX, placebo, or active control. The dose of WAKIX was initiated at 4.45 mg and could be increased at weekly intervals to 8.9 mg or 17.8 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable-dose phase. 76% of patients reached a stable dose of 17.8 mg. Median age in the study was 40 years. In the WAKIX and placebo groups, approximately 50% of patients were male, 90% of patients were Caucasian, and 75% of patients had a history of cataplexy.

WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo (Table 3).

Examination of demographic subgroups by sex did not suggest differences in response.

The efficacy results from Study 1 and Study 2 are shown in Table 3.

Table 3: Efficacy Results for Epworth Sleepiness Scale in Adult Patients with Narcolepsy (Study 1 and Study 2)
CI = confidence interval; LS Mean = least square mean; SD = standard deviation; SE = standard error aMaximum dose randomized to was 35.6 mg bMaximum dose randomized to was 17.8 mg cA lower score on the ESS represents improvement; scores range from 0 (no symptoms) to 24 (worst symptoms) dA negative value for the placebo subtracted difference represents improvement
Study	Treatment Group (N)	Baseline ESS Score Mean (SD)	Final ESS Scorec LS Mean at Week 8 (SE)	Placebo Subtracted Difference [95% CI] at Week 8d
Study 1a	WAKIX (n=31)	17.8 (2.5)	12.4 (1.01)	-3.1 [-5.73; -0.46]
Study 1a	Placebo (n=30)	18.9 (2.5)	15.5 (1.03)	-3.1 [-5.73; -0.46]
Study 2b	WAKIX (n=66)	18.3 (2.4)	13.3 (1.19)	-2.2 [-4.17; -0.22]
Study 2b	Placebo (n=32)	18.2 (2.3)	15.5 (1.32)	-2.2 [-4.17; -0.22]

Figure 6 shows the ESS score from baseline to Week 8 in Study 1.

Figure 6: Epworth Sleepiness Scale Score (mean ± SEM) from Baseline to Week 8 in Study 1

SEM = standard error of the mean (raw mean scores)
ESS scores range from 0 to 24, with 0 being the best score and 24 being the worst score

Pediatric Patients (6 years of age and older) with Narcolepsy

The efficacy of WAKIX for the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy was evaluated in one multicenter, randomized, double-blind, placebo-controlled study (Study 4; NCT02611687). Pediatric patients 6 to 17 years who met the International Classification of Sleep Disorders (ICSD-3) criteria for narcolepsy (with or without cataplexy) and who had a Pediatric Daytime Sleepiness Scale (PDSS) score ≥15 were eligible to enroll in the study. EDS was assessed with the PDSS, an 8-item questionnaire in which patients report their frequency of EDS-related symptoms. Each of the 8 items on the PDSS is rated from 0 (never) to 4 (very often, always); the maximum score is 32, with higher scores representing greater severity of symptoms. The study included an 8-week treatment period: a 4-week dose titration phase followed by a 4-week stable dose phase.

In Study 4, 110 pediatric patients 6 to 17 years were randomized to receive WAKIX or placebo. The dose of WAKIX was initiated at 4.45 mg once daily and could be increased at weekly intervals to 17.8 mg for patients weighing <40 kg or 35.6 mg for patients weighing≥40 kg, based on clinical response and tolerability. No dose adjustments were permitted during the 4-week stable dose phase. 69% of patients weighing <40 kg reached a stable dose of 17.8 mg and 72% of patients weighing ≥40 kg reached a stable dose of 35.6 mg. Median age in the study was 13 years, 56% of the patients were male, and 82% of the population had a history of cataplexy. Race and ethnicity were not collected in this study.

WAKIX demonstrated statistically significantly greater improvement on the least square mean change from baseline to the end of treatment in final PDSS total score compared to placebo, of -3.41 points (95% CI: -5.52, -1.31). Study 4 included global assessments, which showed positive trends supporting PDSS total score of improvement in favor of WAKIX.

14.2 Cataplexy in Adult Patients with Narcolepsy

The efficacy of WAKIX for the treatment of cataplexy in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 3; NCT01800045 and Study 1; NCT01067222). Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy with cataplexy with at least 3 cataplexy attacks per week and an ESS score of ≥12 were eligible to enroll in Study 3; patients meeting the ICSD-2 criteria for narcolepsy (with or without cataplexy) and an ESS score of ≥14 were eligible to enroll in Study 1.

Study 3 included a 7-week treatment period: a 3-week dose titration phase followed by a 4-week stable dose phase. 105 patients were randomized to receive WAKIX or placebo. The dose of WAKIX was initiated at 4.45 mg once daily for the first week, increased to 8.9 mg for the second week, and could remain the same or be decreased or increased at the next two weekly intervals to a maximum of 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 4-week stable dose phase. 65% of patients reached a stable dose of 35.6 mg. Median age in the study was 37 years and 51% of the patients were male. Race was not collected in this study.

WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the change in geometric mean number of cataplexy attacks per week from baseline to the average of the 4 week stable dosing period for WAKIX compared to placebo (Table 4).

Study 1 was described in Section 14.1. In the subset of patients with a history of cataplexy (n=49), WAKIX demonstrated statistically significantly greater improvement on the secondary endpoint, the change from baseline in geometric mean daily rate of cataplexy at Week 8 for WAKIX compared to placebo (Table 4).

In both Study 3 and Study 1, examination of demographic subgroups by sex did not suggest differences in response.

Table 4: Efficacy Results for Cataplexy in Adult Patients with Narcolepsy (Study 3 and Study 1)
Study	Endpoint	Treatment Group (N)	Baseline Rate Meana (SD) [95% CI]	Final Rate Meana (SD) [95% CI]	Rate Ratiob (WAKIX to placebo) [95% CI]
CI = confidence interval; SD = standard deviation a The mean refers to geometric mean, which was used because values for weekly rate of cataplexy were not normally distributed; the geometric mean takes the average of the logs of the individual values and exponentiates that average back to an arithmetic scale. b The rate ratio is derived from a Poisson regression model. c Patients with a history of cataplexy.
Study 3	Final Mean Weekly Rate of Cataplexy Over 4-Week Stable Dosing Period (primary endpoint)	WAKIX (n=54)	9.1 (2.0) [7.6, 11.0]	2.3 (4.4) [1.5, 3.4]	0.51 [0.44, 0.60]
Study 3		Placebo (n=51)	7.3 (2.0) [6.0, 8.9]	4.5 (4.8) [2.9, 7.0]	0.51 [0.44, 0.60]
Study 1	Final Mean Daily Rate of Cataplexy at Week 8 (secondary endpoint)	WAKIX (n=25)c	0.4 (4.0) [0.2, 0.7]	0.1 (2.8) [0.1, 0.2]	0.07 [0.01, 0.36]
Study 1		Placebo (n=24) c	0.3 (3.6) [0.1, 0.4]	0.2 (4.3) [0.1, 0.5]	0.07 [0.01, 0.36]