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HOUSTON -- An investigational oral drug targeting the lack of brain orexin neuropeptides that characterizes narcolepsy type 1 demonstrated safety and effectiveness for the condition in a phase IIb trial.

At all four doses of TAK-861 evaluated, the primary endpoint showed a statistically significant and clinically meaningful increase on the Maintenance of Wakefulness Test (MWT), with mean sleep latency increases at week 8 ranging from 16.5 to 30.7 minutes versus placebo (P≤0.001), Yves Dauvilliers, MD, PhD, of the University of Montpellier in France, reported here.

The orexin receptor 2 agonist, also demonstrated significant improvements in subjective measures of sleepiness and weekly cataplexy rates, according to findings presented at the annual SLEEP meeting, jointly hosted by the American Academy of Sleep Medicine and the Sleep Research Society.

In his presentation, Dauvilliers said that based on the results, "TAK-861 has the potential to provide transformative efficacy in addressing the overall disease burden in people with [narcolepsy type 1]." Phase III trials are being planned, .

Importantly, there were no serious treatment-related adverse events (AEs) with the drug or AEs leading to drug discontinuation, Dauvilliers reported, with insomnia and urinary urgency being the most common events.

Development of a similar orexin receptor 2 agonist (TAK-994, also by Takeda) was terminated despite showing major efficacy in narcolepsy type 1 after some patients had drug-induced liver injury that met criteria, which predicts the risk of fatal liver events.

Narcolepsy type 1 is a rare, chronic central nervous system disorder defined by a loss of orexin neurons, with common symptoms including excessive daytime sleepiness, sleep paralysis, disrupted nighttime sleep, cataplexy, and hypnagogic or hypnopompic hallucinations.

With current medications, which are often used in polypharmacy, sleep latency times typically improve by about 2 to 12 minutes.

Lucie Barateau, MD, PhD, also of the University of Montpellier, presented exploratory findings of the study at SLEEP showing that TAK-861 reduced narcolepsy severity and was associated with improvements in physician- and patient-reported measures of treatment experience.

She highlighted the fact that none of the available treatments target the underlying pathophysiology of narcolepsy type 1.

"That could explain, at least in part, why even with medication the patients are rarely normalized," said Barateau. "They often have residual symptoms."

Dauvilliers presented the primary analysis of a testing TAK-861 in 112 patients with narcolepsy type 1. Patients were randomly assigned to one of four different treatment arms of TAK-861 (0.5 mg twice daily; 2 mg twice daily; 2 mg followed by 5 mg later in the day; and 7 mg once daily) or placebo.

The primary endpoint was change in MWT (range, 0 to 40 minutes, with ≥20 minutes representing a normal ability to stay awake). Secondary endpoints included changes in the Epworth Sleepiness Scale (ESS; range, 0 to 24, with higher scores indicating greater daytime sleepiness; with a normal score being below 10) and in weekly cataplexy rates.

Main inclusion criteria were an ESS score above 12 and at least four weekly cataplexy episodes. Main exclusion criteria were a separate medical disorder associated with excessive daytime sleepiness, medically significant hepatic or thyroid disease, and any gastrointestinal disease affecting drug absorption.

Patients had an average age of 34 years (range 16-70), and 51.8% were females. Most were white (85.7%), with 7.1% Asian and 5.4% Black. At baseline, mean sleep latency on the MWT ranged from 3.6 to 6.1 minutes across arms, average ESS scores ranged from 18.3 to 19.0, and average cataplexy events per week ranged from 15.7 to 31.1.

At week 4, the MWT showed that sleep latency was normalized with all four doses of TAK-861, though by week 8 only the patients assigned to the 2-mg twice-daily dosing and the 2 mg/5 mg strategy stayed above that 20-minute threshold on average.

Regardless, at week 8, significant least squares mean differences were observed with all four doses of the drug versus placebo (P≤0.001):

• 0.5 mg: mean difference 13.65 minutes (95% CI 7.74-19.57)
• 2 mg: mean difference 24.67 minutes (95% CI 18.87-30.46)
• 2 mg/5 mg: mean difference 26.58 minutes (95% CI 20.81-32.35)
• 7 mg: mean difference 16.13 minutes (95% CI 10.49-21.76)

Most of the TAK-861-treated patients in the trial achieved an ESS score ≤10 after 8 weeks of treatment: 66.7% at the lowest dose, 95.2% with the 2-mg twice-daily dose, 81.8% with the 2 mg/5 mg dosing, and 73.9% with the 7-mg once-daily dose, as compared with 19% with placebo.

At 8 weeks, two different doses led to significant changes in weekly cataplexy rate, with incidence rates declining from 11 to 1.4 per week with the 2-mg twice-daily dose (incidence rate ratio [IRR] 0.36 versus placebo, 95% CI 0.16-0.79, P=0.034) and from 11.3 to 0.7 per week with the 2 mg/5 mg dosing (IRR 0.28, 95% CI 0.13-0.60, P=0.003).

As noted, there were no serious treatment-related AEs associated with TAK-861. Overall, AEs of any grade considered treatment-related ranged from 52.2% with the lowest TAK-861 dose to 87.0% at the higher doses, versus 13.6% with placebo. Most were mild to moderate.

The most common AEs of any grade associated with the orexin receptor 2 agonist included insomnia (21.7-65.2% vs 4.5% with placebo), micturition urgency (19-52.5% vs 4.5%), micturition frequency (13-52.2% vs 4.5%), and salivary hypersecretion (8.7-26.1% vs 4.5%).

No cases of hepatotoxicity or visual disturbances were reported.

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