After coming up short in trials with two orexin type 2 receptor (OX2R) selective agonists, Takeda has scored with oveporexton, gaining FDA approval for the first-in-class, twice-daily tablet as a treatment for adults with narcolepsy type 1 (NT1).
Rather than addressing the symptoms of narcolepsy, Orzeyful—as it will be known commercially—becomes the first medicine to address its root cause, doing so by mimicking the body’s orexin cycle. Orexin is a neuropeptide lacking in patients with narcolepsy that helps regulate waking, wakefulness, appetite and energy.
“The FDA approval of Orzeyful marks a new chapter for the narcolepsy type 1 community, as we introduce an entirely new class of medicine that will potentially redefine how this disease is managed and how people feel on treatment,” Takeda CEO Julie Kim said in a statement.
Takeda has a lot riding on Orzeyful, pegging its peak sales at between $2 billion and $3 billion. It is one of three potential blockbusters the Japanese company is counting on as it faces biosimilar competition for its top-selling product Entyvio.
NT1 is a neurological condition driven by the loss of orexin, affecting roughly 120,000 people in the U.S., many of whom remain undiagnosed. NT1 causes daytime sleepiness, cataplexy (sudden loss of muscle tone), cognitive symptoms, disrupted nighttime sleep and hallucinations.
Julie Flygare, who is the CEO at Project Sleep and an NT1 patient, called the approval “a historic moment,” as it “expands our treatment choices.”
The approval is backed by two phase 3 studies which showed that Orzeyful, compared to placebo, provides statistically significant improvements in daytime sleepiness, cataplexy and health-related quality of life measures.
No serious treatment-related adverse events were reported in the trials. The most common side effects were insomnia and urinary urgency and frequency.
Takeda will launch Orzeyful after the Drug Enforcement Administration (DEA) completes its controlled substance classification review, which is expected within the next 90 days. The company added that it does not expect Orzeyful sales to significantly impact its revenue forecast for the fiscal year, which ends on March 31, 2027.
The success of Orzeyful comes after the company’s first attempt in the indication with an OX2R agonist, TAK-994, was halted five years ago in two phase 2 trials because of liver toxicity issues. Then, two years ago, Takeda grounded OX2R agonist danavorexton (TAK-925) because of slow enrollment in a phase 2 trial testing the intravenous treatment in post-surgical patients with obstructive sleep apnea.
"Orzeyful is just the beginning. With orexin emerging as a powerful therapeutic pathway, Takeda is unlocking the potential of this new class of medicine for patients across a range of disorders," Andy Plump, M.D., Ph.D., Takeda's R&D chief, said in the release.
Takeda hopes to gain FDA approval for another first-in-class treatment later in this quarter as rusfertide is under review for the blood disorder polycythemia vera. The injected hepcidin mimetic peptide, which was acquired in a $300 million licensing deal with Protagonist Therapeutics in 2024, scored in a phase 3 trial last year. Takeda expects that rusfertide has the potential to bring between $1 billion and $2 billion in peak sales.
Takeda’s highest hopes in its pipeline are for Entyvio follow-on zasocitinib. The TYK2 inhibitor, which was secured in a $4 billion upfront deal with Nimbus Therapeutics four years ago, has the potential to become the top oral drug in the in psoriasis and psoriatic arthritis, according to Takeda, drawing a peak sales forecast of between $3 billion and $6 billion. Last month, the company unveiled additional data from a successful phase 3 study of zasocitinib.