There is no biological measure for wakefulness. In a narcolepsy clinical trial, a patient lies down in a dark lab while clinicians count the minutes until sleep comes. The average time in four tests counts as the result. Sarah Sheikh, head of the neuroscience therapeutic area unit and head of global development at Takeda Pharmaceutical, says this maintenance of wakefulness test is perhaps the most boring and artificial of all clinical tests, but it is the standard way of evaluating narcolepsy drugs.
A Takeda drug that could be first in a new class of narcolepsy medicines met the main goal of two Phase 3 clinical trials with statistically significant results showing it helped participants stay awake longer in those darkened rooms. But here’s what it meant for patients in their daily lives: Getting up off of the couch, leaving the house, going to the gym, engaging with family and friends, and returning to school or work.
“In a way, this is bringing people back into society to lead an engaged and productive life,” Sheikh said in an interview.
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The results for the drug, oveporexton, were presented Monday during the World Sleep 2025 Congress in Singapore. Takeda now aims for regulatory submissions for the drug in the U.S. and around the world in the current fiscal year. The pharmaceutical giant estimates the twice-daily pill could achieve peak global revenue between $2 billion and $3 billion.
There are two main forms of narcolepsy. Takeda developed overporexton for narcolepsy type 1, or NT1, a form of the disease accompanied by events of sudden muscle weakness called cataplexy. The rarer NT2 is similar to type one, but without cataplexy.
The narcolepsy drugs currently available are older medications that treat disease symptoms — excessive sleepiness during the day as well as difficulty falling asleep at night. Those drugs do not address the underlying cause of narcolepsy, which is a loss of orexin, a neuropeptide that regulates the sleep/wake cycle. Oveporexton is an oral small molecule designed to stand in for orexin, binding to orexin 2 receptors and activating them to restore the activity lost when levels of native orexin decline.
In a maintenance of wakefulness test, or MWT, the normal range for people who don’t have narcolepsy is staying awake in the dark room for 20 minutes or more. Takeda evaluated oveporexton in two placebo-controlled Phase 3 clinical trials enrolling 273 participants total. In the study that tested a low dose and a high dose of overporexton, the low dose helped patients stay awake an average of 19.3 minutes at 12 weeks; the high dose was better at 21.8 minutes. In the trial that evaluated only the high dose, the result was even better as the study drug helped patients stay awake an average of 24.6 minutes. The placebo results in both studies were all 4.5 minutes or less. Sheikh noted that oveporexton’s results also top currently available narcolepsy drugs, which help patients stay awake for between three and 10 minutes in the MWT.
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Study participants were also evaluated according to a sleepiness scale, in which patients score their levels of sleepiness during the week in a diary — a lower score means less sleepiness. Takeda reported that nearly 85% of participants who received the high dose of oveporexton achieved scores comparable to those of healthy people. On measures of cataplexy, median cataplexy-free days per week increased from zero at baseline to four-five days at week 12. There was no increase in such days reported for the placebo group.
“It’s the first time in this disease that anyone has ever been able to show this magnitude of effect across every single symptom that affects patients with NT1 with high statistical significance,” Sheikh said.
Takeda said oveporexton was well tolerated by patients. The most frequent treatment related adverse events were urinary frequency or urgency as well as insomnia. Both of these side effects started within the first few days of treatment and resolved in about a week. Importantly, there were no signs of liver toxicity. An earlier effort by Takeda to develop an orexin agonist was discontinued due to liver complications.
While Takeda’s NT1 drug could be first in a new class of narcolepsy drugs, competition is coming. Alkermes has reached mid-stage development with an orexin agonist called alixorexton. In a 2024 interview, Chief Operating Officer Blair Jackson said achieving once-daily dosing and a better level of alertness with this brain-penetrating drug could offer best-in-class potential in NT1. But some investors are concerned about blurred vision, which has emerged in testing of the Alkermes pill. In Phase 2 results presented at World Sleep, the Alkermes drug achieved statistically significant MWT results measured at six weeks. Like Takeda’s drug, urinary frequency/urgency and insomnia were commonly reported side effects that resolved within a week. Alkermes said the blurry vision typically resolved within three days.
During a Monday conference call with analysts, Sheikh said Takeda searched for visual disturbances and found that such problems were low and equally balanced between the treatment and placebo arms. She added that vision problems are “absolutely not an issue for us.”
In a note sent to investors, Leerink Partners analyst Marc Goodman said the higher rates of visual disturbances were driven by the higher dose of alixorexton, so the firm believes Alkermes can basically get the same efficacy but lower rates of this complication with the two lower doses of the drug. Efficacy of the Alkermes drug “seems a little better than that of Takeda but not significantly better,” Goodman wrote. But once daily dosing and flexibility of dosing should be an advantage for the Alkermes drug as the company aims to become the second player in the orexin agonist market, he said.
Takeda actually tested once-daily dosing in Phase 2, Sheikh said during the conference call. But twice-daily dosing more closely mimics natural dosing of orexin. Furthermore, a twice-daily pill gives physicians and patients more dosing flexibility, allowing for individualized treatment options, she said. With that flexibility in mind, Takeda will seek regulatory approvals for both doses of oveporexton.
Takeda aims to expand its orexin efforts beyond NT1. Another drug, TAK-360, is in Phase 2 testing for NT2 and idiopathic hypersomnia. Other orexin agonists are in earlier stages of development for other sleep/wake conditions. The company is also developing drugs addressing other physiological processes regulated by orexin receptors such as respiration, mood, and metabolism.
Other companies developing orexin receptor agonists include Centessa Pharmaceuticals, which has advanced ORX750 to Phase 2 testing in NT1, NT2, and idiopathic hypersomnia. Meanwhile, Eisai presented Phase 1 results at World Sleep for its NT1 drug candidate, E2086.
Photo: Roos Koole, Getty Images