Q&A: Extended-release sodium oxybate improves sleep continuity, quality in narcolepsy

The REST-ON trial, a phase 3 study of a sodium oxybate formulation for narcolepsy, demonstrated “significant consolidation of sleep” compared with placebo as well as improvements in sleep quality and narcolepsy symptoms.

Specifically, the sodium oxybate formulation — FT218 (Avadel Pharmaceuticals) — improved sleep quality/refreshing nature of sleep as well as sleep paralysis and was well tolerated, with adverse reactions that are known to occur with sodium oxybate, according to the study results. Researchers presented the findings from two analyses of the REST-ON trial at the American Academy of Neurology annual meeting, which was held virtually.

“A mainstay of narcolepsy treatment for nearly 20 years has been sodium oxybate,” Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore Medical Center and professor of neurology at Albert Einstein College of Medicine, told Healio Neurology. “However, because it is immediate release with a short half-life, it has necessitated that patients take a dose before bed and then awaken to take the second dose 2.5 to 4 hours later.”

FT218 is an extended-release oral suspension formulation of sodium oxybate, according to Thorpy. The REST-ON trial evaluated FT218 in 212 adults with narcolepsy. Healio Neurology spoke with Thorpy about the study results presented during the AAN annual meeting and the potential impact FT218 could have in clinical practice.

Healio Neurology: How does FT218 work to treat narcolepsy?

Thorpy: Sodium oxybate is a central nervous system depressant and the sodium salt of gamma-hydroxybutyrate (GHB), which occurs naturally in the brain. Sodium oxybate’s therapeutic action is thought to be mediated via GABAB actions at noradrenergic, dopaminergic and thalamocortical neurons. The American Academy of Sleep Medicine recognizes that sodium oxybate is a standard treatment for excessive daytime sleepiness, cataplexy and disrupted nighttime sleep. While sodium oxybate is recognized to be effective, only immediate-release forms have been available.

FT218 is an investigational, once-nightly sodium oxybate (ON-SXB), which is a proprietary formulation of immediate-release and controlled-release microparticles designed to deliver a full night's dose of medication in a single, extended-release formulation.

Healio Neurology: What did the presentations on FT218 examine?

Thorpy: There were two posters presented at AAN, both of which were pre-specified secondary endpoint data from the pivotal REST-ON phase 3 trial, a randomized, double-blind, placebo-controlled, multicenter, parallel-group study in patients with narcolepsy aged 16 years and older. Three doses of FT218 — 6 g, 7.5 g and 9 g — were evaluated for efficacy and safety. All three coprimary endpoints were highly statistically significant, with P values for all three doses of less than .001 compared with placebo.

In addition to the primary endpoints, the REST-ON trial had several secondary endpoints evaluating additional aspects of narcolepsy.

The first poster looked at polysomnographic measures of sleep continuity in patients with narcolepsy. Disrupted nighttime sleep (DNS) is inherent to narcolepsy and is characterized by fragmented sleep, including frequent, brief nightly arousals and awakenings, as well as shifts from deeper to lighter stages of sleep. These secondary endpoints evaluated the efficacy of FT218 on polysomnographic measures of DNS, including the number of arousals, in patients with narcolepsy.

The second poster examined daytime sleepiness, sleep quality, hallucinations and sleep paralysis in patients with narcolepsy. These secondary endpoints evaluated the efficacy of FT218 on excessive daytime sleepiness (EDS), self-reported sleep quality and refreshing nature of sleep, sleep paralysis and hypnagogic hallucinations.

Healio Neurology: What did the results of each study demonstrate?

Thorpy: What was presented at AAN was evidence of some of the additional clinical benefits of FT218 — specifically, the improvement in disrupted nighttime sleep, both the quality of sleep and refreshing nature of sleep and improvement in excessive daytime sleepiness via patient-reported outcomes.

In the first poster on polysomnographic measures of sleep continuity, FT218 demonstrated a significant consolidation of sleep on polysomnography compared with placebo. Data showed that the mean difference between FT218 and placebo for DNS, or shifts from deeper to lighter stages of sleep and wake, was statistically significant (P < .001) at all doses tested.

In the second poster on daytime sleepiness, sleep quality, hallucinations and sleep paralysis, FT218 demonstrated significant (P < .001) improvement in the Epworth Sleepiness Scale vs. placebo at all doses tested. FT218 also showed a statistically significant (P < .001) improvement compared with placebo for sleep quality and refreshing nature of sleep on a visual analogue scale and for sleep paralysis on a sleep symptom diary, representing an improvement on important narcolepsy symptoms.

FT218 was generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.

Healio Neurology: What do the overall results of these two studies indicate about FT218?

Thorpy: These data further bolster the positive topline results previously disclosed from the REST-ON trial regarding the three co-primary endpoints at all three doses (6 g, 7.5 g, and 9 g doses), demonstrating highly significant, clinically meaningful improvements on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement and mean weekly cataplexy attacks.

The consistency with which FT218 improved both subjective and objective symptoms of narcolepsy, including disrupted nighttime sleep, represent the promise of a potential new treatment strategy for physicians and patients.

Healio Neurology: What are the next steps for FT218?

Thorpy: More FT218 data will be presented at the SLEEP annual meeting in June. Additionally, FT218 is currently under review by the FDA, with a PDUFA target date of October 15, 2021. If approved, FT218 will be the first once nightly oxybate product and will represent a significant advance for patients living with the chronic condition of narcolepsy.

References:

Dauvilliers Y, et al. Polysomnographic measures of sleep continuity in patients with narcolepsy: Results from the REST-ON trial, a pivotal phase 3 study of FT218, a once-nightly sodium oxybate formulation. Presented at: American Academy of Neurology Annual Meeting; April 17-22, 2021 (virtual meeting).

Thorpy M, et al. Daytime sleepiness, sleep quality, hallucinations, and sleep paralysis in patients with narcolepsy: Results from the REST-ON trial, a pivotal phase 3 study of FT218, a once-nightly sodium oxybate formulation. Presented at: American Academy of Neurology Annual Meeting; April 17-22, 2021 (virtual meeting).