FDA Approves First-in-Class Narcolepsy Drug

The U.S. Food and Drug Administration (FDA) has granted approval to oveporexton (Orzeyful), marking the first-ever drug specifically designed to treat narcolepsy type 1 (narcolepsy with cataplexy) in adults. Announced on Wednesday, this groundbreaking medication represents a significant leap forward in addressing the root cause of this rare sleep disorder, rather than merely alleviating symptoms.

Tiffany Farchione, MD, director of the division of psychiatry at the FDA's Center for Drug Evaluation and Research, highlighted that patients with narcolepsy type 1 have historically relied on treatments that only alleviate certain aspects of the condition, leaving the underlying biology of the disease unaddressed. Orzeyful is poised to change this narrative by targeting the fundamental biology of the disease, offering a comprehensive solution.

Narcolepsy type 1 is a chronic neurological disorder characterized by a loss of brain cells that produce orexin, a neuropeptide crucial for regulating wakefulness, sleep, and muscle tone. Individuals affected by this condition often experience persistent symptoms, including excessive daytime sleepiness, cataplexy (sudden episodes of muscle weakness triggered by strong emotions), cognitive impairments, and disrupted nighttime sleep.

It is estimated that one in every 2,000 people in the United States is affected by narcolepsy type 1.

Oveporexton, an oral orexin receptor 2 agonist, works by restoring the missing orexin signaling pathway in patients with narcolepsy type 1. The drug is available as a tablet that is taken twice daily. Emmanuel Mignot, MD, PhD, the principal U.S. investigator in the phase III program, emphasized that Orzeyful is the first and only approved orexin therapy to treat the full spectrum of the disease, enabling a more holistic approach to treatment in clinical settings.

To support its approval, two phase III randomized, double-blind trials - FirstLight and RadiantLight - were conducted, involving 273 adults with narcolepsy type 1. The results of these studies demonstrated that oveporexton 2 mg taken twice daily significantly improved various aspects of narcolepsy symptoms. These improvements included normalized wakefulness, a substantial reduction in cataplexy episodes, and meaningful enhancements across a wide range of narcolepsy symptoms such as sleep paralysis, hallucinations, and disrupted nighttime sleep.

Common side effects associated with oveporexton treatment included insomnia, urinary urgency and frequency, nasopharyngitis, and excessive saliva. These adverse events, while common, were generally not severe enough to require medical intervention. Interestingly, 11% of patients treated with oveporexton experienced elevated levels of creatine phosphokinase (CPK), a marker for muscle damage, compared to 5% in the placebo group.

Two patients with markedly elevated CPK levels and transaminase levels were required to discontinue treatment. However, none of these cases were linked to myoglobinuria or renal impairment. Patients are advised to report any unexplained muscle pain, weakness, or dark urine, especially when engaging in vigorous physical activity or taking medications that may induce myotoxicity.

Furthermore, oveporexton is contraindicated in patients who are taking strong CYP3A inhibitors. The drug will only become available once the Drug Enforcement Agency (DEA) issues a scheduling decision, anticipated within 90 days of approval. Once the controlled substance classification is determined, the medication will be distributed through a specialty pharmacy, ensuring controlled access to patients who can benefit from this innovative treatment option.