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An investigational oral selective orexin receptor 2 agonist (oveporexton, Takeda) demonstrated significantly improved measures of wakefulness, sleepiness, and cataplexy in a phase 2b study of adults with narcolepsy type 1 (NT1).

NT1 is a chronic disorder caused by loss of orexin neurons, resulting in low orexin levels in the brain. Hallmarks of the disorder include excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, and sleep paralysis, leading to reduced quality of life.

Current treatments primarily aim to improve wakefulness and control cataplexy but do not address the underlying pathophysiology. Oveporexton (also known as TAK-861) is designed to directly address the orexin deficiency in NT1 by selectively stimulating the orexin receptor 2.

“These data suggest that restoring orexin signaling has the potential to help people with narcolepsy type 1 achieve near normal ranges of wakefulness as seen in healthy individuals while also positively impacting the broader spectrum of the disease,” study co-author Sarah Sheikh, MD, MSc, BM BCh, head of the Neuroscience Therapeutic Area Unit and Global Development at Takeda, told Medscape Medical News.

Results of the phase 2b results, with first author Yves Dauvilliers, MD, with the Sleep and Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France, were published online on May 15 in The New England Journal of Medicine.

New Hope

The randomized, placebo-controlled trial enrolled 112 adults (mean age, 34 years; 52% women) with NT1 confirmed via polysomnography and multiple sleep latency testing. Participants had baseline Epworth Sleepiness Scale (ESS) total score > 12 (normal ≤ 10) and four or more episodes of cataplexy per week during screening.

Participants received either once- or twice-daily oveporexton at doses of 0.5 mg, 2 mg, 2 mg titrated to 5 mg, 7 mg once daily, or matching placebo for 8 weeks.

The primary outcome was the change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (MWT). Secondary endpoints included changes from baseline to week 8 in the ESS total score, weekly cataplexy rate, and the occurrence of adverse events.

Across oveporexton doses, average sleep latency on the MWT increased from 3.6 to 5.6 minutes at baseline to 16.5 to 30.7 minutes at week 8 compared with a change from 6.1 minutes at baseline to 4.7 minutes at week 8 with placebo.

Oveporexton led to dose-dependent improvements of nearly 14-27 minutes in average sleep latency — “markedly greater than mean improvements of 2-12 minutes observed with currently available narcolepsy medications,” the investigators reported.

At 8 weeks, 37%-81% of oveporexton-treated patients had an average sleep latency of 20 minutes or more, on par with healthy individuals, they noted.

Improvements in ESS total scores were also greater than those observed with currently available narcolepsy medications, with 79% of participants who received oveporexton (95% who received 2 mg twice daily) having scores at or below the normative threshold of 10 points at week 8. 

Mean ESS total scores decreased from 18 to 19 at baseline to 4.8 to 8.9 at week 8 compared with a change from 18.6 at baseline to 16.0 at week 8 with placebo.

The average weekly cataplexy rate decreased from about 15 to 31 episodes at baseline to 2 to 10 episodes at week 8 compared with 23 episodes at baseline to 9 episodes at week 8 with placebo.

Decreases in cataplexy frequency were observed with all oveporexton doses, reaching significance with the 2 mg twice daily dose and the 2 mg followed by 5 mg daily dose, as compared with placebo at week 8 (adjusted P <.05 vs placebo).

“Clinically meaningful” improvements in quality of life on the Short Form-36 mental and physical component summary scores were noted across all oveporexton dose groups.

Unsurprisingly, the most common adverse effect with oveporexton was insomnia, which improved over the duration of the study. Notably, there were no liver adverse effects or changes in blood pressure.

The US Food and Drug Administration has granted breakthrough therapy designation for oveporexton (TAK-861) for the treatment of excessive daytime sleepiness in NT1. Global phase 3 trials of oveporexton are currently underway.

Impressive Results

Commenting on the findings for Medscape Medical News, Thomas Scammell, MD, professor of neurology, Harvard Medical School, Boston, said the fact that performance on the wakefulness test was “well into the normal range” with oveporexton is “pretty impressive and something that we very infrequently see with current medicines.” 

Likewise, ESS scores “shifted into normative ranges” with oveporexton. By contrast, “existing narcolepsy medications still leave many symptomatic,” said Scammell, who wasn’t involved in the study.

“I take care of a lot of narcolepsy patients, and we have a variety of medications. On average, they are pretty good, but there’s definitely room for improvement, so this could be a real game changer,” he said.

Scammell noted that a number of companies are developing orexin agonists. “It’s quite likely that a few years from now, when these drugs are clinically available, we’re going to see a shift from some of our currently use drugs towards this new class of drugs for narcolepsy,” he said.

Also weighing in for Medscape Medical News, Andrew Spector, MD, professor of neurology, Duke University School of Medicine, Durham, North Carolina said, “Orexin agonists are an entirely novel way to treat narcolepsy type 1. We currently have no equivalent options.”

“Like levodopa for Parkinson’s disease, orexin agonists can specifically compensate for the lack of orexin that defines this disease. All existing drugs for narcolepsy use alternative neurotransmitter pathways to circumvent the missing orexin. The prospect of adding an additional treatment option for this patient population is exciting,” said Spector, who wasn’t involved in the study.

This study was supported by Takeda. Several authors have disclosed relationships with Takeda. Scammell has consulted for and received research grants from Takeda. Spector had no relevant disclosures.