Orexin has one of the fastest arcs in modern neuroscience: discovered in 1998, tied to a disease by 2000, drugged in one direction by 2014 — and, as of 2026, one regulatory decision away from being drugged in the other. These are the names and the years.
Luis de Lecea, Thomas Kilduff and colleagues at the Scripps Research Institute, hunting for messengers made only in the hypothalamus, isolate a precursor expressed in the dorsolateral hypothalamus that yields two peptides — which they name hypocretin-1 and hypocretin-2, for hypothalamus + secretin-family resemblance. They note the peptides excite neurons. The paper speculates about feeding and neuroendocrine roles; the sleep connection is still invisible.
de Lecea L. et al., Proc. Natl. Acad. Sci. USA 95, 322 (1998) · PubMed
Weeks later, Takeshi Sakurai in Masashi Yanagisawa's laboratory (University of Texas Southwestern, later Tsukuba) publishes the same two peptides from the opposite direction: as the endogenous ligands of two orphan G-protein-coupled receptors. They name them orexin-A and orexin-B (from the Greek orexis, appetite) after showing they stimulate feeding — and they map the receptors OX1R and OX2R. Two groups, two names, one system: the field now writes "orexin (hypocretin)" and credits both.
Sakurai T. et al., Cell 92, 573 (1998) · PubMed
Emmanuel Mignot's Stanford team had spent a decade cloning the gene behind inherited narcolepsy in Dobermans. It turns out to be the hypocretin receptor 2 (OX2R) gene — the sleep disorder of these dogs is an orexin-signalling disease (Lin et al., Cell 1999). Within weeks, Yanagisawa's group shows that mice lacking the orexin peptides themselves develop narcolepsy with cataplexy (Chemelli et al., Cell 1999).
Lin L. et al., Cell 98, 365 (1999) · Chemelli R.M. et al., Cell 98, 437 (1999)
Two post-mortem studies land the same finding: in the brains of people with narcolepsy, the orexin neurons of the hypothalamus are selectively gone — 85–95% of them — while neighbouring cell groups survive (Peyron et al., Nature Medicine 2000; Thannickal et al., Neuron 2000). Nishino's group adds the living-patient signature: orexin-A is undetectable in the spinal fluid of most narcolepsy patients (Lancet 2000). Narcolepsy type 1 becomes, mechanistically, an orexin-deficiency disease — widely attributed to autoimmune destruction of those neurons.
Peyron C. et al., Nat. Med. 6, 991 (2000) · Thannickal T.C. et al., Neuron 27, 469 (2000) · Nishino S. et al., Lancet 355, 39 (2000)
Merck brings suvorexant (Belsomra) to approval (FDA, August 2014) — the first orexin receptor antagonist, blocking OX1R and OX2R to treat insomnia. The first medicine built on the orexin system works by turning the wake signal down.
FDA approval record, Aug 2014 (openFDA)
Eisai's lemborexant (Dayvigo) is approved in December 2019; Idorsia's daridorexant (Quviviq) follows in January 2022, with a phase 3 programme showing better night-time sleep and daytime functioning in insomnia (Mignot et al., Lancet Neurology 2022). The orexin antagonists are now a drug class: the DORAs.
FDA approval records 2019, 2022 · Mignot E. et al., Lancet Neurol. 21, 125 (2022)
Takeda's first oral OX2R agonist, TAK-994, shows striking wakefulness effects in narcolepsy type 1 — and a liver-safety signal. Dosing is suspended and the phase 2 studies stopped in October 2021 (Takeda); the full account, published in NEJM in 2023, records termination for hepatic adverse events (Dauvilliers et al.). The mechanism was vindicated; the molecule was not. Meanwhile the intravenous agonist TAK-925 (danavorexton) had already shown human proof of concept (Evans et al., PNAS 2022).
Takeda press release, Oct 2021 · Dauvilliers Y. et al., NEJM 389, 309 (2023) · Evans R. et al., PNAS 119 (2022)
Takeda's oral, OX2R-selective agonist oveporexton (TAK-861) reports phase 2 results in NEJM — dose-dependent gains in wakefulness and cataplexy control in narcolepsy type 1 (May 2025). The phase 3 FirstLight and RadiantLight trials report positive topline results in July 2025, presented in full at World Sleep 2025 (Takeda, Sept 2025). In February 2026 the FDA accepts the oveporexton application with priority review, decision expected in Q3 2026 (Takeda, Feb 2026). Twenty-eight years after discovery, the system may get its first agonist medicine.
Dauvilliers Y. et al., NEJM 392, 1905 (2025) · Takeda newsroom, 2025–2026
The orexin system is where Panacea's amino acid chain design practice meets neuropharmacology: the endogenous agonists are peptides, the receptors are mapped, and the clinical need is documented by the record above. Panacea's programme explores peptide agonist design for the orexin receptors as a research direction — disclosed at concept level, with no compound or result claimed here. The clinical milestones belong to the scientists and companies named on this page.
Research-direction disclosure · disclosure follows data