Once-Nightly Sodium Oxybate Effective in Both Narcolepsy Type 1 and 2

Jennifer Gudeman

A recently published post-hoc analysis of the phase 3 REST-ON study (NCT02720744) showed that treatment with once-nightly sodium oxybate (ON-SXB; Lumryz; Avadel Pharamaceuticals) was effective in treating excessive daytime sleepiness (EDS) and disrupted nighttime sleep (DNS) regardless of narcolepsy type.¹

REST-ON was a multicenter, randomized, double-blind, placebo-controlled study that served as the supportive data for ON-SXB’s approval earlier this year. In the study, patients with narcolepsy were randomly assigned 1:1 to either ON-SXB or placebo, with randomization stratified by narcolepsy type 1 (NT1) and type 2 (NT2). After a 3-week screening period, patients underwent a 13-week treatment period where they received 4.5 g for 1 week, 6 g during weeks 2-3, 7.5 g during weeks 4-8, and 9 g during weeks 9-13, dosed once nightly at bedtime.

The cohort comprised of 212 patients who took at least 1 dose of the study drug. Of these, 162 (76.4%) had NT1 and 23.6% had NT2. At the conclusion of the 13-week period, the least squares mean (LSM) change in mean sleep latency was 11.1 (SE, 1.1) min for ON-SXB 9 g vs 5.1 (SE, 1.1) min for placebo in participants with NT1 (LSM difference vs placebo, P <.001) and was 9.6 (SE, 1.8) min vs 3.3 (SE, 1.9) min, respectively, for NT2.

"One of the reasons that we felt this was so important is there’s a tendency for some clinicians to reserve the use of sodium oxybate only for patients with type 1 narcolepsy,” senior investigator Jennifer Gudeman, senior vice president of medical and clinical affairs for Avadel, told NeurologyLive^®. "I think it has to do with the fact that initially, the immediate release form of sodium oxybate that’s given twice nightly was approved to treat cataplexy. It was subsequently expanded to include the treatment of excessive daytime sleepiness, but perhaps because there was a little bit of lag in that approval, or perhaps there hadn’t been specific data available in narcolepsy type 2, there is this tendency to maybe not consider a sodium oxybate for type 2."

Additional results showed that a significantly greater percentage of patients with NT1 receiving ON-SXB vs placebo were rated as “much” or "very much improved" on the CGI-I scale at week 3 (6 g; P <.001), week 8 (7.5 g; P <.001), and week 13 (9 g; P <.001). Similarly, a greater percentage of patients with NT2 were considered "much” or "very much improved" on the same scale; however, the GLIMMIX model could not be calculated based on small sample size.

In terms of secondary end points, patients with NT1 and NT2 treated with ON-SXB demonstrated significant reductions in the total number of sleep stage shifts, which included N1, N2, N3, and REM sleep to wake. Furthermore, treatment with ON-SXB resulted in significant reductions of nocturnal arousals, regardless of narcolepsy subtype. Of note, statistically significant improvements in nocturnal arousals in the NT2 group were observed at week 8 (7.5 g; ON-SXB: –37.8 [SE, 4.4] vs placebo: –21.2 [SE, 4.8]) and week 13 (9 g; –45.0 [SE, 5.4] vs –24.6 [SE, 5.7]), but the reduction did not reach statistical significance at week 3 (6 g; –31.9 [SE, 4.3] vs –26.1 [SE, 4.6]).

LISTEN NOW: Episode 104: Effects of Once-Nightly Sodium Oxybate on Narcolepsy Types 1 and 2

Despite having similar baseline patient-reported sleep quality and refreshing nature of sleep, treated patients on ON-SXB began to separate themselves from placebo as early as week 3, with improvements that lasted through the 13-week study. In addition, patients on active treatment saw significant improvements vs placebo in Epworth Sleepiness Scale (ESS), a subjective measure of sleepiness in everyday situations.

The LSM change from baseline in ESS scores was significantly reduced with ON-SXB vs placebo in the NT1 subgroup at week 3 (6 g; –3.5 [SE, 0.5] vs –1.3 [SE, 0.5]; LSM difference vs placebo, P ≤.001), week 8 (7.5 g; –6.0 [SE, 0.6] vs –2.0 [SE, 0.6]; LSM difference vs placebo, P <.001) and week 13 (9 g; –6.8 [SE, 0.7] vs –2.5 [SE, 0.7]; LSM difference vs placebo, P <.001). Participants with NT2 had improved ESS scores from baseline with OX-SXB vs placebo at all 3 doses and time points, but the differences did not reach statistical significance (LSM change from baseline: 6 g; –3.4 [SE, 0.9] vs –1.9 [SE, 1.0]; 7.5 g: –3.6 [SE, 1.1] vs –2.9 [SE, 1.1]; 9 g: –5.8 [SE, 1.1] vs –3.1 [SE, 1.2]).

"When we think about narcolepsy, we tend to focus mostly on the excessive daytime sleepiness, but about two-thirds of people with narcolepsy also experience DNS," Gudeman added. "They fall asleep but their sleep is not restorative, its not satisfactory. They’re constantly moving in and out of different sleep state shifts, they’re experiencing nocturnal arousals. Our published analysis shows that ON-SXB reduces nocturnal arousals, reduces those shifts in sleep stage, and ultimately results in patients reporting better sleep quality, as well as more refreshing sleep. That’s an area that I think is really helpful with the data we have."

REFERENCE
1. Dauvilliers Y, Roth T, Thorpy MJ, et al. Efficacy of once-nightly sodium oxybate (FT218) in narcolepsy type 1 and type 2: post hoc analysis from the phase 3 REST-ON trial. Sleep. 2023;11(46). doi:10.1093/sleep/zsad152