14 CLINICAL STUDIES

14.1 Cataplexy and Excessive Daytime Sleepiness (EDS) in Adult Narcolepsy

Efficacy of XYWAV for the treatment of cataplexy and excessive daytime sleepiness in adult patients with narcolepsy was established in a double‑blind, placebo‑controlled, randomized‑withdrawal study (Study 1; NCT03030599). This study had two parts, consisting of the main study, followed by an optional 24-week open‑label extension (OLE). The main study consisted of a 12‑week open-label optimized treatment and titration period (OL OTTP), followed by a 2-week stable-dose period (SDP), and finally a 2‑week double-blind randomized-withdrawal period (DB RWP).

Study 1 enrolled 201 patients with narcolepsy with cataplexy, 18 to 70 years of age, with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 201 patients, 134 were randomized 1:1 to continue treatment with XYWAV or to placebo in the 2‑week DB RWP. In the safety population, overall, the median age was 36.0 years (range: 18 to 70). The majority of subjects were female (61%), and most were white (88%) and not Hispanic or Latino (84%).

Patients entering the study were taking a stable dosage of 1) Xyrem only, 2) Xyrem + another anticataplectic, 3) a non-Xyrem anticataplectic, or 4) were cataplexy‑treatment naïve. Patients taking Xyrem at study entry were switched (at a gram for gram dose) from Xyrem to XYWAV for a minimum of 2 weeks and titrated, if needed, to a stable, tolerable, and effective dosage over 8 weeks. Most patients who switched from Xyrem to XYWAV (41/59; 69%) had no change in dosage from study entry to the stable dose period; 27% (16/59) had an increase in dosage, and 3% (2/59) had a decrease in dosage. Among patients whose dosage was changed, most changes were within one titration step (≤1.5 g). Patients not taking Xyrem at study entry were initiated at 4.5 g/night of XYWAV and titrated at a rate of 1 or 1.5 g/night/week to a tolerable dose of XYWAV. Patients taking an anticataplectic other than Xyrem were tapered off the non-Xyrem anticataplectic over 2 to 8 weeks. All patients continued to receive XYWAV only, for the treatment of cataplexy during the last 2 weeks of the OL OTTP.

CNS stimulants were allowed at entry, and approximately 59% of patients continued taking a stable dose of stimulant throughout the SDP and DB RWP.

The total nightly dose of XYWAV was administered in two equally divided doses in 90% (62/69) of patients. Unequal doses were administered in 10% (7/69) of patients treated with XYWAV.

The primary efficacy endpoint was the change in frequency of cataplexy attacks from the 2 weeks of the SDP to the 2 weeks of the DB RWP. The key secondary endpoint was the change in the Epworth Sleepiness Scale (ESS) score, as a measure of reduction in EDS from the end of the SDP to the end of the DB RWP.

Patients taking stable doses of XYWAV who discontinued XYWAV treatment and were randomized to placebo during the DB RWP experienced a significant worsening in the average weekly number of cataplexy attacks and in ESS score, compared with patients randomized to continue treatment with XYWAV (see Table 6).

Table 6: Mean and Median Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (ESS)
	Average Weekly Number of Cataplexy Attacks		ESS SCORE
	Placebo (N=65)	XYWAV (N=69)	Placebo (N=65)	XYWAV (N=69)
Baseline (2 Weeks of the Stable Dose Period)
Mean (SD)	7.2 (14.4)	8.9 (16.8)	12.6 (5.5)	13.6 (5.3)
Median	1.0	1.1	13.0	14.0
Change from Baseline (2 Weeks of the Stable Dose Period) to the 2 Weeks of the DB RWP			Change from End of Stable Dose Period to End of DB RWP
Mean (SD)	11.5 (24.8)	0.1 (5.8)	3.0 (4.7)	0.0 (2.9)
Median	2.4	0.0	2.0	0.0
p-value	<0.0001		<0.0001

DB RWP=Double‑blind Randomized-withdrawal Period; SD=standard deviation

14.2 Cataplexy and Excessive Daytime Sleepiness in Pediatric Narcolepsy

The effectiveness of XYWAV in pediatric patients is based upon a clinical study in patients treated with Xyrem, as described below, and additional pharmacokinetic information [see Use in Specific Populations (8.4)].

The effectiveness of Xyrem in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study (NCT02221869). The study was conducted in 106 pediatric patients (median age: 12 years; range: 7 to 17 years) with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 106 patients, 2 did not receive study drug and 63 patients were randomized 1:1 either to continued treatment with Xyrem or to placebo. Randomization to placebo was stopped early as the efficacy criterion was met at the pre-planned interim analysis.

Patients entered the study either taking a stable dosage of Xyrem or were Xyrem-naïve. CNS stimulants were allowed at entry, and approximately 50% of patients continued taking a stable dose of stimulant throughout the stable-dose and double-blind periods. Xyrem-naïve patients were initiated and titrated based on body weight over a period of up to 10 weeks. The total nightly dose was administered in two divided doses, with the first dose given at nighttime and the second given 2.5 to 4 hours later [see Dosage and Administration (2.2)]. Once a stable dosage of Xyrem had been achieved, these patients entered the 2-week stable-dose period; patients on a stable dosage of Xyrem at study entry remained on this dosage for 3 weeks prior to randomization. Efficacy was established at dosages ranging from 3 g to 9 g of Xyrem per night.

The primary efficacy measure was the change in frequency of cataplexy attacks. In addition, change in cataplexy severity was evaluated with the Clinical Global Impression of Change for cataplexy severity. The efficacy of Xyrem in the treatment of excessive daytime sleepiness in pediatric patients with narcolepsy was evaluated with the change in the Epworth Sleepiness Scale (Child and Adolescent) score. The Epworth Sleepiness Scale (Child and Adolescent) is a modified version of the scale used in the adult clinical trial described above. The overall change in narcolepsy condition was assessed by the Clinical Global Impression of Change for narcolepsy overall. Efficacy was assessed during or at the end of the 2-week double-blind treatment period, relative to the last 2 weeks or end of the stable-dose period (see Tables 7 and 8).

Pediatric patients taking stable dosages of Xyrem who discontinued Xyrem treatment and were randomized to placebo during the double-blind treatment period experienced a statistically significant increase in weekly cataplexy attacks compared with patients who were randomized to continue treatment with Xyrem. Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of EDS compared with patients randomized to continue receiving Xyrem (see Table 7).

Table 7: Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (Child and Adolescent) Score
Treatment Group	Baseline*,†	Double-blind Treatment Period‡,§	Median Change from Baseline	Comparison to Placebo (p-value¶)
Median Number of Cataplexy Attacks (attacks/week)
Placebo (n=32)	4.7	21.3	12.7	-
Xyrem (n=31)	3.5	3.8	0.3	<0.0001
Median Epworth Sleepiness Scale (Child and Adolescent) Score
Placebo (n=31**)	11	12	3	-
Xyrem (n=30**)	8	9	0	0.0004

* For weekly number of cataplexy attacks, baseline value is calculated from the last 14 days of the stable-dose period.
† For Epworth Sleepiness Scale score, baseline value is collected at the end of stable-dose period.
‡ Weekly number of cataplexy attacks is calculated from all days within the double-blind treatment period.
§ For Epworth Sleepiness Scale, value is collected at the end of the double-blind treatment period.
¶ P-value from rank-based analysis of covariance (ANCOVA) with treatment as a factor and rank baseline value as a covariate.
** One patient in each of the treatment groups did not have baseline ESS score available and were not included in this analysis.

Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of cataplexy severity and narcolepsy overall according to the clinician’s assessment compared with patients randomized to continue receiving Xyrem (see Table 8).

Table 8: Clinical Global Impression of Change (CGIc) for Cataplexy Severity and Narcolepsy Overall
Worsened, %†	CGIc Cataplexy Severity*		CGIc Narcolepsy Overall*
	Placebo (n=32)	Xyrem (n=29)‡	Placebo (n=32)	Xyrem (n=29)‡
Much worse or very much worse	66%	17%	59%	10%
p-value§	0.0001		<0.0001

* Responses indicate change of severity or symptoms relative to receiving Xyrem treatment at baseline.
† Percentages based on total number of observed values.
‡ Two patients randomized to Xyrem did not have the CGIc assessments completed and were excluded from the analysis.
§ P-value from Pearson’s chi-square test.

14.3 Idiopathic Hypersomnia (IH) in Adults

Efficacy of XYWAV for the treatment of IH in adult patients as a once or twice nightly regimen was established in a double-blind, placebo-controlled, randomized-withdrawal, study (Study 2, NCT03533114). Study 2 consisted of a minimum of 10‑week open‑label treatment titration and optimization period (OL OTTP), (with up to 4 additional weeks) to allow for an optimally effective and tolerable dose and regimen followed by a 2‑week stable dose period (SDP), a 2‑week double-blind, randomized withdrawal period (DB RWP), and a 24‑week open label safety extension period (OLE).

Study 2 enrolled 154 patients with idiopathic hypersomnia, 19 to 75 years of age. Of the 154 patients, 115 were evaluable for efficacy data and were randomized 1:1 to continue treatment with XYWAV or to placebo in the 2‑week DB RWP. In the safety population, overall, the median age was 39 years (range: 19 to 75). At baseline, 2% of patients were taking Xyrem only, 4% of patients were taking Xyrem and an additional stimulant or alerting agent, 54% of patients were not currently taking Xyrem but were taking a stimulant or alerting agent, and 41% were treatment naïve. CNS stimulants were allowed at entry, and approximately 57% of patients continued taking a stable dose of stimulant throughout the SDP and DB RWP.

The majority of subjects were female (71%), and most were white (81%) and not Hispanic or Latino (79%).

The XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time. Patients were considered for twice nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later.

Based on clinical response during the OTTP, investigators were permitted to switch patients between twice nightly and once nightly dosing regimens. When patients were switched from a twice nightly to a once nightly dosing regimen, the total nightly dose was initially the same as the first dose of the twice nightly dosing regimen. When patients were switched from a once nightly to a twice nightly dosing regimen, the total nightly dose was no more than 1.5 g higher than the current dose, divided into two doses.

At the start of the DB RWP, 23% (27/115) of patients were taking XYWAV once nightly (median nightly dose 4.5 g), and 77% (88/115) of patients were taking XYWAV twice nightly (median nightly dose 7.5 g). There were no meaningful differences in demographics, baseline characteristics or disease severity between patients receiving XYWAV once nightly vs twice nightly.

The primary efficacy endpoint was the change in Epworth Sleepiness Scale (ESS) score, as a measure of reduction in EDS from the end of the SDP to the end of the DB RWP. The ESS is an 8-item self-reported 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), with a maximum score of 24. Key secondary efficacy endpoints included patient global impression of change (PGIc) and the Idiopathic Hypersomnia Severity Scale (IHSS), both assessed as a change from the end of the SDP to the end of the DB RWP. The IHSS is a 14-item self-reported questionnaire assessing the severity of IH symptoms of excessive sleepiness, prolonged sleep duration, cognitive impairment, and sleep inertia. Total scores can range from 0-50, with higher scores indicating a greater severity or frequency of symptoms.

Change in ESS

Patients in Study 2 taking stable doses of XYWAV who were withdrawn from XYWAV treatment and randomized to placebo during DB RWP experienced significant worsening in ESS score compared with patients randomized to continue treatment with XYWAV (p<0.0001) across all dosing regimens (see Table 9). These two treatment groups had comparable median ESS scores (Placebo=17; XYWAV=16) at entry into the OTTP.

Table 9: Median Change in Epworth Sleepiness Scale (ESS)
ESS Score
	Placebo (N=59)	XYWAV (N=56)
Baseline End of 2-Week SDP
Median	5.0	6.5
End of 2-Week DB RWP
Median	14.0	7.0
Median Change from End of 2-Week SDP to End of 2-Week DB RWP
Median	8.0	0.0
p-value	<0.0001

SDP=Stable Dose Period
DB RWP=Double-blind Randomized-withdrawal Period

PGIc

Patient Global Impression of change (PGIc) ratings showed that patients randomized to placebo experienced a worsening of symptoms of idiopathic hypersomnia overall compared with patients randomized to XYWAV (Table 10). The percentage of patients with worsening PGIc scores for IH overall (defined as scores of Minimally, Much Worse, or Very Much Worse) was greater for patients receiving placebo (88.1%) compared with patients receiving XYWAV (21.4%) (p<0.0001).

Table 10: PGIc* at End of the DB RWP†
	PGIc* IH Overall
Worsened,% ‡†	Placebo (N=59) n (%)	XYWAV (N=56) n (%)
Proportion Worsened (minimally, much, or very much worse)	52 (88.1)	12 (21.4)
p‑value	<0.0001	n/a

*PGIc is a 7‑point patient-reported scale by which patients rated their symptom change from “very much improved” to “very much worse.”
†DB RWP=Double‑blind Randomized-withdrawal Period.
‡At the end of the DB RWP/early termination visit, patients rated the change in their condition since the end of the Open-Label Stable-Dose Period.

IHSS

At end of DB RWP, patients randomized to placebo experienced a worsening in IHSS total score, compared to patients randomized to XYWAV (p<0.0001) (see Table 11). These two treatment groups had comparable median IHSS scores (Placebo=33; XYWAV=33) at entry into the OTTP.

Table 11: Median Changes in IHSS Total Score
Total Score
	Placebo (N=59)	XYWAV (N=56)
Baseline End of 2-Week SDP
Median	14.0	14.0
End of 2-Week DB RWP
Median	29.0	16.0
Median Change from End of 2-Week SDP to End of 2-Week DB RWP
Median	14.0	0.0
p-value	<0.0001

SDP=Stable Dose Period
DB RWP=Double‑blind Randomized-withdrawal Period