Jazz Pharmaceuticals plc announced positive data from the Phase 3 multicenter, placebo-controlled, double-blind, randomized withdrawal study of Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution for the treatment of adults with idiopathic hypersomnia were published online in The Lancet Neurology. The results of the Phase 3 clinical trial showed clinically meaningful and statistically significant differences with Xywav compared to placebo in the primary endpoint of change in the Epworth Sleepiness Scale (ESS) score and key secondary endpoints, which included measures that assessed patients' perceptions of the changes in their idiopathic hypersomnia overall (PGIc), symptom severity, including excessive daytime sleepiness (EDS), sleep inertia and prolonged sleep duration (Idiopathic Hypersomnia Severity Scale), and improved daytime performance.1  In August 2021, Xywav became the first and only drug approved for patients with idiopathic hypersomnia by the U.S. Food and Drug Administration (FDA).Xywav for idiopathic hypersomnia was made commercially available in November 2021.  Phase 3 Trial Results: In the trial (NCT03533114), investigators at 50 centers in seven countries enrolled a total of 154 adults aged 19 to 75 diagnosed with idiopathic hypersomnia. Following a screening period, the study had three dosing periods.

First, participants received open-label Xywav for 10 to 14 weeks, until their individual doses were optimized. Optimized dose ranged from 2.5 to 9.0 grams per night. Patients then received stable, optimized doses for two weeks, with median doses of 4.5 ((interquartile range [IQR], (3.0 to 5.0) grams nightly (one dose regimen, 21 patients) and 7.5 (IQR 6.5 to 8.1) grams nightly (two-dose regimen, 93 patients), with 40 patients changing dosing regiments once or more times.

During a double-blind randomized withdrawal period (DBRWP), patients received either the optimized stable dose of Xywav or a placebo for two weeks. Participants entered the study with a mean (SD) ESS score of 16.1 (3.6), indicating substantial excessive daytime sleepiness. During the Xywav open-label titration and optimization period, ESS scores decreased, indicating improvement, which was maintained during the stable dose period (SDP).

The study's primary endpoint was change in the ESS scores as measured from the end of the SDP to the end of the DBRWP. Participants randomized to continue Xywav had stable mean (SD) ESS scores [from 6.3 (4.3) to 7.0 (5.0)], in contrast to those randomized to placebo whose mean (SD) ESS scores increased from 5.8 (3.7) to 13.3 (4.1) points, indicating worsening. The differences between the two group's mean ESS scores, [5.8 (3.7) to 13.3 (4.1)] were statistically significant, [95% Cl: -6.5 points (-8.0, -5.0), P<0.0001].

An ESS score of below 10 is considered normal among those without a sleep disorder. Participants entered the study with a mean (SD) IHSS score of 32.1 (8.0) indicating severe disease. During the Xywav open-label titration and optimization period, IHSS scores decreased, indicating improvement, which was maintained during the SDP.

On the key secondary endpoint, participants randomized to continue Xywav had stable mean IHSS scores (15.5 [9.2] to 16.9 [8.1]), in contrast to those randomized to placebo whose mean (SD) IHSS scores increased from (15.2 [7.8] to 28.5 [9.0]), indicating worsening. The difference in change in IHSS score was statistically significant (estimated median difference [95% CI: -12.0 (-15.0, -8.0); P<0.0001]. A score of 22 or below is considered the best cutoff to differentiate individuals with untreated idiopathic hypersomnia from a control population without sleepiness.

Xywav also demonstrated clinically meaningful differences compared to placebo on the Patient Global Impression of Change (PGIc) [difference in proportion worsened, 95% CI: -67 (-80%, -53%; P<0.0001],1 as well as four other secondary endpoints that documented the benefits of Xywav vs. placebo, including the Clinical Global Impression of Change (CGIc), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), the visual analog scale for sleep inertia (VAS-SI) and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). The distribution of ratings by investigators using the CGIc scale demonstrated worsening in symptoms among fewer participants randomized to Xywav compared to those on placebo, indicating clinical satisfaction with the treatment.

Also, a difference in the median scores were observed in the Xywav group vs. the placebo group, on the FOSQ-10 [95% CI: 3.7 (2.5, 5.0), nominal P<0.0001]. Participants' VAS-SI scores decreased, indicating an improvement, from the last week of screening to the end of the SDP, then remained stable during DBRWP in the group randomized to Xywav and increased in the placebo group [least squares mean difference 95% CI: -22.2 (-29.7, -14.8), nominal P<0.0001].

On the WPAI:SHP, significant differences between the groups from end of SDP to end of DBRWP were observed with estimated median differences of [95% CI: 0.0 (-3.2, 0), P=0.0092] for absenteeism, [95% CI: -27.5 (-37.1, -17.9, P<0.0001] for presenteeism, [95% CI: -30.8 (-39.9, -21.7), P<0.001] for overall work impairment, and [95% CI: -31.7 (-40.0, -23.5), P<0.0001] for overall activity impairment.