The latest

Approved on August 5th, oveporexton marks the first market entry for medicines designed to mimic orexins, neurotransmitters that co-ordinate wakefulness. Takeda’s drug targets narcolepsy, whose type 1 form combines excessive daytime sleepiness with cataplexy, or sudden loss of muscle control. The decision has intensified a pharmaceutical race involving Alkermes and Eli Lilly, although proposed uses in ADHD, addiction and depression still require robust trials.

Details

• Biological target: Orexins are produced by a small group of hypothalamic neurons and bind two receptors, OXR1 and OX2R. OX2R activation co-ordinates wakefulness systems using norepinephrine, serotonin and dopamine; OXR1 is more closely associated with reward and motivation. Loss of orexin-producing neurons underlies type 1 narcolepsy, whose paralysis-like cataplexy can occur while a patient remains conscious.
• Trial findings: Results published in May 2025 showed patients taking oveporexton stayed awake 12.5 to 25 minutes longer in a dark-room Maintenance of Wakefulness test, depending on dose. Cataplexy attacks occurred about one-third as often as among placebo recipients. Reported side-effects included insomnia and an uncomfortable need to urinate in about one-third of patients.
• Treatment contrast: Existing options, including methylphenidate and modafinil, manage symptoms by increasing neurotransmitter activity across multiple brain regions. That can improve alertness but may bring anxiety, raised blood pressure or disrupted sleep; some drugs also carry addiction risk. Orexin agonists instead act upstream to restore signalling that aligns several alertness systems.
• Development setback: Takeda’s earlier agonist, firazorexton, showed promise but was discontinued in 2021 after causing liver damage in several patients. Designing agonists is difficult because they must reproduce the effect of much larger peptides while crossing the blood-brain barrier.
• Commercial race: Alkermes is developing a competitor. Lilly bought Centessa in June for up to $7.8bn, contingent on trial success, and gained an agonist being tested in both narcolepsy types and idiopathic hypersomnia. Morgan Stanley estimates orexin medicines could generate $16bn annually by 2035 from narcolepsy and related sleep disorders, versus $3bn in current narcolepsy-drug sales.
• Wider ambitions: A small trial of Lilly’s acquired drug improved wakefulness by more than 20 minutes in type 1 narcolepsy and more than ten minutes in type 2. Alkermes is testing an agonist in adults with ADHD, while researchers are exploring sleep apnoea. Ideas involving OX1R in addiction and depression remain speculative.

Background

Orexins were identified independently in 1998 by teams led by Luis de Lecea and Yanagisawa Masashi. Dog and mouse studies the following year linked failed orexin signalling to narcolepsy, and researchers later found that human patients had lost the neurons producing the peptides. Orexin antagonists, which suppress wakefulness, have treated insomnia since 2014.

What’s next

The next indicators are larger trial results for Lilly’s and Alkermes’s candidates, including whether wakefulness gains persist across narcolepsy subtypes and ADHD. Post-approval monitoring of oveporexton will also test the frequency of insomnia and urinary effects, while liver-safety data will show whether the newer agents avoid firazorexton’s failure.