Orexin receptor 2 agonist reduces symptoms of narcolepsy type 1

1. In this randomized controlled trial, an oral orexin receptor 2 (OX2R) agonist (TAK-994) was associated with improvements in wakefulness, sleepiness, and cataplexy incidence among patients with narcolepsy type 1.

2. TAK-994 was also associated with liver enzyme elevation and drug-induced hepatotoxicity.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Narcolepsy is a rare chronic disorder of the central nervous system resulting in excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy. Narcolepsy type 1 is specifically characterized by cataplexy and a loss of orexin-releasing neurons in the hypothalamus. Existing medications are only partially effective in managing symptoms of narcolepsy. TAK-994 is an oral selective agonist of OX2R which plays a key role in regulating wakefulness and sleep. This was a phase two study assessing the efficacy and safety of TAK-994 among patients with narcolepsy type 1. Compared to placebo, TAK-994 showed dose-dependent improvements in sleep latency in the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) score by eight weeks. It also reduced the incidence of cataplexy. TAK-994, however, was also associated with clinically important elevations in liver enzymes and drug-induced liver injury. The trial was, therefore, terminated early. Despite its small sample size and early termination, these results demonstrated that OX2R agonism might be beneficial in treating narcolepsy type 1.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: The current study was a phase two randomized placebo-controlled trial investigating TAK-994 for patients with narcolepsy type 1. Adult patients 18 to 65 years of age diagnosed with narcolepsy type 1 as assessed using nocturnal polysomnography and sleep latency tests, who had an ESS score of 10 or greater, and at least four cataplexy episodes were eligible for inclusion. Overall, 73 patients were randomized 1:1:1:1 to receive TAK-994 at doses of 30mg, 90mg, or 180mg, or a placebo twice daily. The primary outcome was sleep latency as measured in the MWT. Secondary outcomes included the ESS score and the incidence of cataplexy. By eight weeks, the least-squares mean changes from baseline in sleep latency in the MWT were 23.9 minutes in the TAK-994 30mg group, 27.4 minutes in the 90mg group, 32.6 minutes in the 180mg group, and -2.5 minutes in the placebo group. This translated to the least-square mean differences compared to placebo of 26.4 minutes (95% Confidence Interval [CI] 20.1 to 32.7) in the TAK-994 30mg group, 29.9 minutes (95% CI, 23.7 to 36.1) in the 90mg group, and 35.0 minutes (95% CI, 28.7 to 41.3) in the 180mg group (p<0.001). Similarly, compared to placebo, the least-squares mean differences in change from baseline in ESS score were -10.1 (95% CI, -14.1 to -6.2) in the 30mg group, -11.4 (95% CI, -15.2 to -7.6) in the 90mg, and -13.0 (95% CI, -17.0 to -9.1) in the 180mg group (p<0.001). In total, 79% of TAK-994 recipients reported adverse events, compared to 24% among the placebo group, the most common being urinary symptoms. Five patients who received TAK-994 had elevations in liver enzymes and three TAK-994 recipients met the criteria for drug-induced liver injury. Due to these findings of hepatotoxicity, the trial was terminated early, resulting in significant missing data. Despite these limitations, these results provided proof of concept that OX2R agonism could be a potential therapeutic target for the treatment of narcolepsy type 1.

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