Clete A. Kushida, MD, PhD, Neurologist and Division Chief and Medical Director of Stanford Sleep Medicine Center, discusses the REST-ON clinical trial of FT218 for the treatment of narcolepsy.

Narcolepsy is a rare neurological disorder characterized by excessive sleepiness during the day, often with periods of brief involuntary sleep and/or cataplexy.

As Dr. Kushida explains, FT218 is a long-acting form of sodium oxybate which allows it to be given once a day. This is an improvement on previous treatments which required doses to be given twice a night. Narcolepsy patients aged ≥16 years were randomized 1:1 to up titration of FT218 (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105).

In March 2020, the REST-ON study (a double-blind, randomized, placebo-controlled phase 3 trial assessing the efficacy and safety of FT218 in the treatment of excessive daytime sleepiness and cataplexy in patients suffering from narcolepsy) was completed. In December 2020, Avadel submitted a New Drug Application (NDA) to the Food and Drug Administration (FDA) for FT218. This NDA was accepted by the FDA in February 2021 and assigned a Prescription Drug User Fee Act (PDUFA) target action date of October 15, 2021. 

As Dr. Kushida notes, at the SLEEP 2021 conference, post hoc analyses data from the REST-ON study were presented which further demonstrated the efficacy and safety of FT218. As outlined in a Avadel press release, this data included post-hoc analyses related to subtype of narcolepsy, stimulant-use, and weight loss. 

FT218 demonstrated statistically significant improvement in excessive daytime sleepiness (EDS) at all evaluated doses in patients with both narcolepsy subtypes 1 (NT1, with cataplexy) and 2 (NT2, without cataplexy), with greater improvement in measures of EDS, including mean sleep latency on maintenance of wakefulness test (MWT) and Clinical Global Impression-Improvement (CGI-I) in overall condition, compared to placebo. Additionally, a significantly greater percentage of patients with NT1 receiving FT218 were rated as much or very much improved on the CGI-I compared to placebo: 75.5% vs. 35.9% at 9 g, 66.9% vs. 27.9% at 7.5 g, and 39.9% vs. 7.8% at 6 g (all p<0.001). A greater percentage of NT2 patients receiving FT218 were rated as much/very much improved at all three doses compared to placebo.

With regard to the use of stimulants in this patient population, FT218 demonstrated statistically significant improvement in EDS at all evaluated doses in narcolepsy patients with or without stimulant use, with improvement over placebo on MWT and CGI-I. More patients receiving FT218 were rated “much/very much improved” on CGI-I compared to placebo: 80.5% vs. 35.3% at 9 g, 66.3% vs. 26.5% at 7.5 g, and 39.8% vs. 4.4% at 6 g for patients with stimulant use (all p<0.001); 55.1% vs. 27.2% at 9 g (p<0.05), 54.5% vs. 17.5% at 7.5 g (p=0.006), and 40.0% vs. 7.7% at 6 g (p<0.01) for patients without stimulant use.

Finally, as weight gain around time of symptom onset is a concern for many narcolepsy patients, a post-hoc analysis was done on the impact FT218 may have on weight. It was found that patients receiving FT218 experienced a significantly greater decrease in weight and body mass index (BMI) from baseline to study end (week 13) compared to placebo. At the end of the study, the mean (SD) change in weight from baseline was –1.3 (3.6) kg for patients receiving FT218 compared to 0.2 (2.6) kg for patients receiving placebo. Overall, 17.8% of patients receiving FT218 compared to 3.8% of patients receiving placebo experienced ≥5% weight loss.

To learn more about narcolepsy and other rare neurological conditions, go to checkrare.com/diseases/neurology

Reference

Kushida, C., Shapiro, C. M., Roth, T., Thorpy, M. J., Corser, B. C., Ajayi, A. O., Rosenberg, R., Roy, A., Seiden, D., Dubow, J., Dauvilliers, Y. (2021). Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. Sleep. 1-11. Retrieved from: https://doi.org/10.1093/sleep/zsab200