FT218 Continues to Show Potential for Narcolepsy Treatment

Clete A. Kushida, MD, PhD

Avadel Pharmaceuticals’ FT218, an investigational once-nightly sodium oxybate formulation, continues to show positive data from the phase 3 REST-ON study (NCT02720744), with newly published analysis showing a significant improvement of narcolepsy symptoms and retention of a safety profile consistent with sodium oxybate.

A total of 222 patients with narcolepsy aged 16 years or older were randomized 1:1 to uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g FT218 or placebo across a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period. Lead author Clete A. Kushida, MD, PhD, director, Stanford Center for Human Sleep Research, and colleagues used change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement (CGI-I), and weekly cataplexy attacks within the 6-, 7.5-, and 9-g groups as primary end points. Randomization was stratified by narcolepsy type 1 or type 2 (NT1; NT2).

Treatment with FT218 vs placebo resulted in a significantly greater increase in sleep latency at week 3 for the 6-g dose group (8.1 vs 3.1 min, respectively; least squares mean change from baseline [LSMD], 4.98 [95% CI, 2.90-7.05]; P <.001); at week 8 for the 7.5-g dose group (9.6 vs 3.3 min, respectively; LSMD, 6.21 [95% CI, 3.84-8.58]; P <.001); and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min, respectively; LSMD, 6.13 [95% CI, 3.52-8.75]; P <.001).

FT218 is currently under review by the FDA after the agency accepted its new drug application in March. With a Prescription Drug User Fee Act (PDUFA) action date of October 15, 2021, the study authors noted that, "if approved, FT218 may represent a major advance for patients experiencing the burdensome symptoms of narcolepsy and for physicians who manage their patients with this chronic, debilitating sleep disorder."

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Participants from both treatment groups were markedly impaired, demonstrated by a mean baseline CGI-Severity score of 5.1. Investigators found a significantly greater proportion of patients in the FT218 treatment arm compared with placebo were rated much or very much improved on the CGI-I at week 3 for the 6-g dose (40.1% vs 6.1%, respectively; OR, 10.29 [95% CI, 3.93-26.92]; P <.001); at week 8 for the 7.5-g dose (62.6% vs 22.8%, respectively; OR, 5.67 [95% CI, 2.82-11.40]; P <.001); and at week 13 for the 9-g dose (72% vs 31.6%, respectively; OR, 5.56 [95% CI, 2.76-11.23]; P <.001).

At week 3, patients treated with FT218 6-g had a decrease of 7.4 weekly cataplexy attacks compared to 2.6 for those on placebo (LSMD, –4.83 [95% CI, –7.04 to –2.62]; P <.001). This trend continues at week 8 for the 7.5-g dose group (–10 vs –3.7, respectively; LSMD, –6.27 [95% CI, –8.74 to –3.81]; P <.001), and at week 13 for the 9-g dose group (–11.5 vs –4.9, respectively; LSMD, –6.65 [95% CI, –9.32 to –3.98]; P <.001).

In total, 83 (77.6%) and 49 (46.7%) participants in the FT218 and placebo groups, respectively, had treatment-emergent adverse events (TEAEs), most of which were considered mild or moderate in severity. Nausea (22.4%), headache (18.7%), vomiting (17.8%), dizziness (15.9%), enuresis (15.9%), decreased appetite (12.1%), anxiety (7.5%), hyperhidrosis (5.6%) and decreased weight (5.6%) were all frequently reported TEAEs for the FT218 group. No participants in the FT218 group and 1 participant in the placebo arm discontinued due to a TEAE of worsening sleep apnea.

Seven participants, 5 in the FT218 treatment arm and 2 in the placebo group, reported serious TEAEs. Only the SAE in the 9-g dose group (suicidal ideation) was considered treatment-related. This participant had a history of depression and anxiety, discontinued treatment and spent 2 nights in a psychiatric ward where they were treated with lorazepam and then discharged with a lorazepam prescription. A week later after reporting suicidal ideation, the participant was evaluated by an investigator, was found to have a negative Columbia Suicide Severity Rating Scale score, and thus the SAE was considered resolved.

Adverse drug reactions (ADRs) occurred in 61 (57%) participants in the FT218 arm and 17 (16.2%) participants in the placebo arm. Overall, 17 (15.9%) participants in the treatment arm and 2 (1.9%) participants in the placebo group discontinued owing to ADRs. Notably, there were no clinically meaningful changes from baseline in clinical laboratory values, blood pressure, or heart rate for FT218 or clinically meaningful differences compared to placebo.

Trial investigator Asim Roy, MD, medical director, Ohio State Sleep Medicine Institute, presented additional analyses from REST-ON at the 2021 SLEEP Virtual Annual Meeting, June 10-13. The findings confirmed FT218’s impact on reduced sleep latency, as well as its ability to produce greater decreases in weight and body mass index. Watch his commentary below as he discussed the effect the investigational agent has in treating narcolepsy regardless of stimulant use.

REFERENCES

1. Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvements of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. SLEEP. Published online August 6, 2021. doi: 10.1093/sleep/zsab200.

2. Avadel presents new clinical data from pivotal phase 3 REST-ON trial supporting clinical benefit of FT218 in patients with narcolepsy at SLEEP 2021. News release. Avadel Pharmaceuticals. June 9, 2021. Accessed August 10, 2021. https://www.globenewswire.com/news-release/2021/06/09/2244435/0/en/Avadel-Presents-New-Clinical-Data-from-Pivotal-Phase-3-REST-ON-Trial-Supporting-Clinical-Benefit-of-FT218-in-Patients-with-Narcolepsy-at-SLEEP-2021.html