While associated with hepatotoxic effects that led to early trial termination, the oral orexin receptor 2 agonist TAK-994 improved sleepiness and cataplexy in patients with narcolepsy type 1 over a period of 8 weeks. “Although the phase 2 trial was not designed to compare the efficacy of TAK-994 with that of other narcolepsy medications, the improvements of 25 to 35 minutes in average sleep latency on the MWT were of greater magnitude than improvements of 2 to 12 minutes observed with currently available agents,” the authors write.
Patients with confirmed narcolepsy type 1 were randomized to twice-daily placebo or oral TAK-994 in doses of 30 mg, 90 mg, or 180 mg. The primary endpoint was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes).
“Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo,” the authors write. “The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and −2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P <0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were −12.2 in the 30-mg group, −13.5 in the 90-mg group, −15.1 in the 180-mg group, and −2.1 in the placebo group (difference vs. placebo, −10.1 in the 30-mg group, −11.4 in the 90-mg group, and −13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy’s law criteria occurred in 3 patients.”
Editorial: “Despite the halt in the development of TAK-994, there is a strong rationale to pursue the use of orexin agonists for the treatment of narcolepsy type 1 and perhaps other disorders of hypersomnolence or circadian dislocation, such as shift-work sleep disorder or jet lag, for which trials are being undertaken,” editorialists write. “The outcomes described in the current report may be seen as a backward step because of the decision to terminate the trial. However, the impressive efficacy is a major step forward in helping patients with narcolepsy type 1.”