The orexin receptor agonists are coming. After years of managing narcolepsy with stimulants, sodium oxybate, and wake-promoting agents, we soon will have medications that target the root cause of the disorder: the loss of orexin signaling. These new drugs—developed by Takeda, Alkermes, and Centessa—aren’t just incremental improvements. They represent a genuine shift in how we understand and treat hypersomnolence disorders. In this episode, we will:Define what orexin is and why losing it destabilizes wakefulness, REM boundaries, muscle tone, and cognitionLearn how orexin agonists work—not as stimulants, but as replacement therapy for a missing neurotransmitterFind out why OX2R is the key receptor, and how selective agonists restore stable wakefulness, reduce cataplexy, and normalize attentionReview the available clinical data from the new wave of programs: oveporexton (Takeda), alixorexton (Alkermes), and ORX750 (Centessa)See what makes these drugs different from modafinil, amphetamines, solriamfetol, and oxybate therapiesLearn why Phase 1, Phase 2, and Phase 3 trials matter—with quick insights on how these drugs reached such strong resultsConsider safety and side effects, including what Hy’s Law means and why regulators watch liver signals so closelyLook ahead to what these medications may mean for NT1, NT2, IH, and other hypersomnolence disorders in the coming yearsSpeculate why this class represents one of the most exciting moments in modern sleep medicineProduced by: Maeve WinterMore Twitter: @drchriswinter IG: @drchriwinter Threads: @drchriswinter Bluesky: @drchriswinter The Sleep Solution and The Rested Child Thanks for listening and sleep well!

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