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A novel drug to supply the severe lack of brain orexin neuropeptides that characterizes narcolepsy type 1 showed major efficacy in a phase II study, although safety events spelled the end of the road for the trial.

Sleep latency normalized after 8 weeks on the oral OX2R agonist (TAK-994), with Maintenance of Wakefulness Test times rising by 26.4 to 35.0 minutes across doses tested (P<0.001 for all comparisons).

Sleep latency times typically improve by 2 to 12 minutes with the currently available agents that are often used in polypharmacy for this classic type of narcolepsy, reported Christian von Hehn, MD, PhD, of drug developer Takeda in Lexington, Massachusetts, and colleagues.

Cataplexy attacks dropped to around one per week with all the doses compared with 5.8 per week in the placebo group.

"These findings may have implications for quality of life, work productivity, and patient safety (notably, driving risk), but these were not tested in this trial," the researchers wrote in the .

However, 79% of the patients who got TAK-994 had adverse events, most commonly urinary urgency or frequency. The trial was stopped and drug development discontinued after five of the 56 recipients had clinically important elevations in liver-enzyme levels, and three had drug-induced liver injury meeting Hy's law criteria, which predict the risk of fatal drug-induced liver events.

Orexins like TAK-994 increase sleep-wake stability and alertness; levels are low or absent in cerebrospinal fluid in narcolepsy type 1.

Orexin antagonists have been developed to treat insomnia, while orexin agonists (focusing on OX2R) are in development to treat narcolepsy type 1 and possibly other disorders of hypersomnolence, noted an accompanying by Nathaniel S. Marshall, PhD, and Ronald R. Grunstein, MD, PhD, both of the Centre for Integrated Research and Understanding of Sleep at the Woolcock Institute for Medical Research in Sydney.

Altogether, the findings provide 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," they wrote.

There is hope for other orexin agonists to pan out without the safety risks, the researchers suggested.

"The current hypothesis is that TAK-994-associated drug-induced liver injury is caused by reactive metabolites and is unlikely to be an on-target effect of OX2R activation because orexin receptors are not expressed on human hepatocytes or on most immune cells," they noted.

Two randomized controlled trials are underway with another OX2R agonist, TAK-861, for the treatment of narcolepsy and .

While von Hehn's group analyzed data for all the patients treated with at least one dose with the use of linear mixed models, the editorialists pointed out that these models were run on only 56% complete data (41 patients with primary endpoint data). "This degree of incomplete data is a potential source of bias that might slightly overestimate what is otherwise a truly remarkable effect."

The trial randomized 73 patients (mean age 31, 58% women) with confirmed narcolepsy type 1 by clinical criteria to get twice-daily oral TAK-994 at 30 mg, 90 mg, or 180 mg, or placebo. Characteristics were typical for the condition, with an average sleep latency on the Maintenance of Wakefulness Test, which measures ability to stay awake under sleep-inducing conditions in the daytime, of just 5.8 minutes on average, whereas normal for a healthy person is considered 20 to 30 minutes or more. Mean Epworth Sleepiness Scale (ESS) score averaged 17.5 (<10 is considered normal); the mean weekly cataplexy rate was 14.4 episodes.

Improvements from baseline to week 8 appeared dose-dependent: Least-squares mean changes in average sleep latency were gains of 23.9 minutes on 30-mg TAK-994, 27.4 minutes with 90 mg, and 32.6 minutes on 180 mg, compared with a decrease of 2.5 minutes in the placebo group (all P<0.001). Least-squares mean improvements in the ESS score were 12.2, 13.5, 15.1, and 2.1, respectively.

"The outcomes described in the current report may be seen as a backward step because of the decision to terminate the trial," the editorialists concluded. "However, the impressive efficacy is a major step forward in helping patients with narcolepsy type 1."

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