The US FDA has approved Orzeyful (oveporexton) for the treatment of narcolepsy type 1 (NT1) in adults, marking the first approval of an orexin receptor agonist for this indication. Takeda (TSE: 4502/NYSE: TAK) said the oral orexin receptor 2 (OX2R) agonist is the first therapy indicated to address the underlying orexin deficiency driving NT1, rather than managing individual symptoms.
The US is the second major market to approve oveporexton after China's NMPA granted approval in July, reflecting China's increasingly prominent role in the global launch sequence for innovative medicines supported by multinational clinical development.
Orzeyful is administered orally at doses of 1 mg or 2 mg twice daily. It is contraindicated with strong CYP3A inhibitors, and the Drug Enforcement Administration (DEA) is expected to complete controlled substance scheduling within 90 days of approval, after which the drug will be distributed through specialty pharmacy. The most common adverse reactions reported in Phase III studies were insomnia, urinary frequency, urinary urgency, and salivary hypersecretion.
The approval rests on two global Phase III studies, FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002), which enrolled adults with NT1. Both trials reported statistically significant improvements versus placebo across excessive daytime sleepiness, cataplexy rate, and health-related quality of life, as previously reported from data presented at SLEEP 2026. Oveporexton was described by Takeda as generally well-tolerated, with a safety profile consistent across studies.
Oveporexton selectively activates OX2R to restore orexinergic signaling, which is near-absent in NT1 due to autoimmune destruction of hypothalamic orexin-producing neurons. This mechanism is distinct from approved NT1 therapies — such as sodium oxybate, which acts via GABA-B receptor agonism, and pitolisant, a histamine H3 receptor antagonist — which address downstream symptoms rather than the orexin deficit directly.