DUET boosts LXB potential in narcolepsy or idiopathic hypersomnia

Data from the phase IV DUET* study presented at AAN 2025 reinforce the potential of low-sodium oxybate (LXB) for the treatment of narcolepsy or idiopathic hypersomnia (IH).

The safety analysis set comprised participants who took their prescribed LXB regimen (twice nightly [narcolepsy] and once or twice nightly per investigator’s discretion [IH cohort]) for ≥1 night after the 8-day baseline (BL) period: 55 (mean age 33.4 years, 72.7 percent women) and 46 (mean age 38.1 years, 80.4 percent women), respectively. About 80 percent of participants were oxybate-naïve.

Daytime, nighttime-related symptoms

The mean ESS** scores dropped significantly from BL to end-of-treatment (EOT) in both narcolepsy (from 16.3 to 8.6; p<0.0001) and IH cohorts (from 16.5 to 8.1; p<0.0001). An ESS score >10 equates to excessive daytime sleepiness (EDS), while a score ≤10 denotes normal DS. [AAN 2025, poster 008]

In the IH cohort, the mean BL IH Severity Scale total score of 32.9 dropped to 17.7 by EOT, yielding a least-squares mean (LSM) change of -15.5 (p<0.0001). The EOT score fell below the optimal cutoff (ie, 22) for differentiating between untreated individuals with IH and community-dwelling controls.

For those with narcolepsy, from BL to EOT, LXB reduced the mean total number of shifts from deeper to lighter sleep stages*** (from 54.6 to 41.6; p<0.0001) and number of awakenings (from 13.9 to 10.8; p=0.0015) and increased the mean stage N3 sleep duration signifying prolonged duration of deep sleep (from 61.1 to 106.1 min; p<0.0001). “[The] fewer shifts from deeper to lighter stages of sleep [denoted] less disrupted nighttime sleep,” the researchers said.

Furthermore, 76.6 percent of individuals with narcolepsy and 70.3 percent of those with IH reported very much/much improvement on the PGI-C^#. About 62 percent of participants with IH also reported very much/much improvement on the PGI-C for sleep inertia.

The overall incidence of treatment-emergent adverse events (TEAEs) was 61.8 percent in the narcolepsy cohort and 73.9 percent in the IH cohort, but most were mild or moderate in severity. The most common TEAE was nausea (21.8 percent and 19.6 percent, respectively). Treatment discontinuations due to a TEAE were rare (n=4 and 1). “Overall, the TEAEs were consistent with the known safety profile of LXB,” said the researchers.

Cognitive, work-related improvements

There were also improvements in overall cognitive function, as reflected by the reductions in mean BC-CCI^## total scores in both narcolepsy and IH cohorts (mean changes, -4.2 and -4.8). From BL to EOT, the mean BC-CCI total score dropped from ‘moderate’ (9–14) to ‘mild’ (5–8), signifying reductions in the severity of cognitive complaints. [AAN 2025, poster 002]

Of note, half of those with narcolepsy reported moderate-to-severe cognitive complaints at BL; by EOT, this dropped to 14.7 percent. The corresponding BL rate in the IH cohort was 57.5 percent, dropping to 17.5 percent by EOT.

“From BL to EOT, the proportion of participants reporting that cognitive symptoms made it difficult to work, have relationships, or enjoy activities decreased in both [cohorts],” added the researchers.

Absenteeism (work time missed) dropped from BL to EOT in both narcolepsy (mean percentage impairment dropped from 16.4 to 2.8) and IH cohorts (from 8.2 to 4.5). Comparisons between time points yielded mean changes of -12.5 and -4.6, respectively.

Among employed participants in the narcolepsy and IH cohorts, LXB treatment reduced presenteeism (impairment while working; mean changes, -33 and -30.7) and overall work impairment (absenteeism + presenteeism; mean changes, -36.1 and -32.4).

“In our study, participants with narcolepsy or IH taking open-label LXB showed improvements in cognitive complaints and related functional impacts, work productivity, and daily activities. The reductions in moderate-to-severe cognitive complaints and absenteeism were substantial,” the researchers said.

Despite the potential limitations of a single-arm, open-label study design, the findings reinforce the symptom burden among individuals with narcolepsy and IH and further support LXB as an effective treatment for these conditions, they added.