Oveporexton improves symptoms in patients with narcolepsy type 1

1. In this randomized controlled trial, oveporexton use significantly improved symptoms of narcolepsy over eight weeks. 

2. Adverse events were more frequent with oveporexton use than placebo, and the frequency of adverse events increased with greater exposure to oveporexton.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Narcolepsy type 1 is a hypersomnolence disorder that is characterized by excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hallucinations, sleep paralysis, and markedly reduced quality of life. This disorder results from a loss of hypothalamic orexin-producing neurons, leading to low to absent orexin levels in the cerebrospinal fluid (CSF). Orexin acts on G protein-coupled receptors, with the OX2 receptor (OX2R) having functions in wakefulness, REM sleep, and prevention of cataplexy in animal models. Previous studies support the usage of OX2R agonists as treatment for narcolepsy. Oveporexton is a highly selective oral OX2R agonist that crosses the blood-brain barrier and has been shown to improve wakefulness in preclinical models. This phase two, randomized controlled trial investigated the efficacy and safety of oveporexton for the treatment of narcolepsy type 1. The primary endpoint of this study was the mean change from baseline to week eight in average sleep latency on the Maintenance of Wakefulness Test (MWT). Secondary endpoints included change from baseline to week eight in the Epworth Sleepiness Scale (ESS), the weekly cataplexy rate at week 8, and the occurrence of adverse events. The results from this study found that oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over an eight-week period. There were more frequent adverse events with the usage of oveporexton than placebo.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This randomized controlled trial evaluated the efficacy and safety of oveporexton for the treatment of narcolepsy type 1. Adult patients aged 18 to 70 with a confirmed diagnosis of narcolepsy type 1, an ESS score of >12, at least four episodes of partial or complete cataplexy per week, and either a CSF orexin A or hypocretin-1 concentration of <110 pg/mL or a positive HLA genotype HLA-DQB1*06:02 were eligible for this study. The primary endpoint was the mean change from baseline in average sleep latency on the MWT. Secondary endpoints included change from baseline to week eight in the ESS, the weekly cataplexy rate at week eight, and the occurrence of adverse events.  A total of 112 patients were randomized to receive either oveporexton (n=90) or placebo (n=22). Specifically, 23 participants received 0.5mg twice daily, 21 participants received 2mg twice daily, 23 participants received 2mg followed by 5mg daily, 23 participants received 7mg once daily, and 22 participants received a placebo. The results from this study found that the mean changes from baseline to week 8 in average sleep latency on the MWT were 12.5, 23.5, 25.4, 15.0, and −1.2 minutes, respectively (adjusted p≤0.001 for all comparisons vs. placebo). At week eight, the mean changes in the ESS total score were −8.9, −13.8, −12.8, −11.3, and −2.5, respectively (adjusted p≤0.004 for all comparisons vs. placebo) and the weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, 5.89, and 8.76, respectively (adjusted p<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo). The frequency of adverse events was greater in the oveporexton groups than placebo group, with insomnia, urinary frequency, and urinary urgency being the most common adverse events. In summary, results from this phase two trial found that oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of eight weeks in patients with narcolepsy type 1.

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