Small Molecule · TS-142
Vornorexant (TS-142)
Oral, once-nightly dual orexin receptor antagonist (DORA) that selectively blocks both the OX1 (HCRTR1) and OX2 (HCRTR2) orexin/hypocretin receptors, suppressing wake-promoting orexinergic signaling to initiate and maintain sleep. Discovered in-house by Taisho Pharmaceutical and deliberately engineered for fast absorption (Tmax ~0.75 h) and a short elimination half-life (~1.3-3.3 h) to minimize next-day residual 'carryover' sedation. Approved in Japan (MHLW, 25 Aug 2025) for insomnia as vornorexant hydrate under the brand name Vorzzz (tablets 2.5/5/10 mg).
Also known as: TS-142, ORN-0829, vornorexant, vornorexant hydrate, Vorzzz, 2265899-49-6, [(2S)-2-{[3-(5-Fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
- Modality
- Small molecule
- Chemical class
- 1,3-oxazinane, benzamide, pyrazole, triazole
- Chemistry
- Single enantiomer
- Mechanism
- OX2 receptor antagonist
- Highest phase
- Approved
- Lead indication
- Insomnia
- Developer
- Taisho Pharmaceutical Co., Ltd.
- Trials
- 3 tracked · 3 sites
Mechanism of action
Potent, selective dual orexin receptor antagonist (DORA). Competitively blocks orexin-A/-B signaling at both human OX1 (HCRTR1) and OX2 (HCRTR2) receptors with sub-nanomolar binding affinity (Ki ~0.46 nM OX1R, ~0.37 nM OX2R) and functional antagonist IC50 ~1.6 nM (OX1R) / ~1.8 nM (OX2R) against orexin-A-stimulated calcium flux, with no meaningful off-target activity. Orexin blockade dampens wake-promoting arousal circuitry to promote sleep onset and maintenance. A short half-life (~1.3-3.3 h) is intended to limit next-day carryover effects relative to longer-acting DORAs.
| Target | Action | Affinity |
|---|---|---|
| OX2 receptorprimaryHCRTR2 | Antagonist | IC50 1.76 nMⓘ |
| OX1RHCRTR1 | Antagonist | IC50 1.61 nMⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Vornorexant oral tablet Immediate-release oral tablet dosed at bedtime; 2.5, 5, and 10 mg tablets (Japan approval, Vorzzz); Phase 3 (NCT05453136) evaluated 5 mg and 10 mg | Oral | Once nightly | t½ 3.25 h · Tmax 0.75 h |
Development timeline
- TS142-301 completed; primary endpoint (subjective sleep latency, Week 2) and key secondary (subjective sleep efficiency) met at both doses (p<0.001).
- Pivotal Phase 3 study TS142-301 (NCT05453136 / jRCT2031220209) initiated in Japanese insomnia patients (5 mg / 10 mg / placebo, 2-week double-blind).
- Phase 2 single-dose crossover PSG study (JapicCTI173570 / NCT04573725, n=24) completed; both primary PSG endpoints (LPS and WASO) significantly improved vs placebo at 5/10/30 mg. Conducted Jul 2017-Feb 2019.↗
Vornorexant (TS-142) for Insomnia
ApprovedApprovedInsomnia indication →
Lead and (to date) sole indication. Approved in Japan: on 25 Aug 2025 Japan's MHLW granted manufacturing and marketing approval for vornorexant hydrate (Vorzzz tablets 2.5/5/10 mg) for insomnia, supported by the pivotal Phase 3 placebo-controlled study TS142-301 (NCT05453136 / jRCT2031220209) and the open-label 52-week long-term study TS142-302 (NCT05461352). TS142-301 met its primary endpoint (subjective sleep latency at Week 2) and key secondary endpoint (subjective sleep efficiency) at both 5 mg and 10 mg (p<0.001), and TS142-302 showed efficacy sustained through 52 weeks. Approval is Japan-only as of mid-2026; no US/EU regulatory filing identified.
Clinical trials
NCT05461352TS142-302Phase 3Completedn=401
A Multi-center, Open-label Long-Term Study of TS-142 in Patients with Insomnia Disorder
metprimaryLong-term efficacy (subjective sleep latency / sleep efficiency) and safety over 52 weeks
Open-label 52-week study (n=401): improvements in sSL and sSE seen from Week 1 and maintained throughout the 52-week treatment period at both 5 mg and 10 mg, with no tendency to attenuate and good tolerability (per Taisho PR / Japanese Society of Sleep Research 2025 presentation).
NCT05453136TS142-301Phase 3Completedn=596
A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 3 Study of TS-142 in Patients with Insomnia Disorder
metsafetyTreatment-emergent somnolence (safety) — Somnolence: 3.1% (5 mg), 3.6% (10 mg) vs 1.5% placebo
Favorable tolerability; somnolence was the most common adverse event, mild, with no serious adverse events.
metsecondarySubjective sleep efficiency (sSE) change from baseline at Week 2 — vs placebo: +3.41% (5 mg); +2.94% (10 mg) (<0.001 (both doses))
Key secondary endpoint met: significant improvement in subjective sleep efficiency at both doses.
metprimarySubjective sleep latency (sSL) change from baseline at Week 2 — vs placebo: -10.6 min (5 mg); -10.1 min (10 mg) (<0.001 (both doses))
Primary endpoint met: both vornorexant 5 mg (n=196) and 10 mg (n=197) significantly shortened subjective sleep latency vs placebo (n=196) at Week 2. 596 randomized; jRCT2031220209.
NCT04573725TS142 Phase 2 (JapicCTI173570)Phase 2Completedn=24
A Multicenter, Randomized, Double-blind, Placebo-controlled, Crossover Phase 2 Study of TS-142 in Patients with Insomnia (single-dose polysomnography)
metprimaryWake time after sleep onset (WASO) by polysomnography, single dose — LSMD vs placebo: -27.52 (5 mg), -35.44 (10 mg), -54.69 (30 mg) min (significant at all doses (30 mg p<0.001))
Dose-dependent reduction in WASO vs placebo; co-primary PSG endpoint met.
metprimaryLatency to persistent sleep (LPS) by polysomnography, single dose — LSMD vs placebo: -42.38 (5 mg), -42.10 (10 mg), -44.68 (30 mg) min (<0.001 (all doses))
All three single doses significantly shortened LPS vs placebo in a crossover PSG design (n=24).
Identifiers
- ChEMBL CHEMBL4638046
- PubChem CID 137419776
- FDA UNII ZY54BP1CK3
Sources
- Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study (Psychopharmacology 2022) — Psychopharmacology (PMC)
- Efficacy and safety of vornorexant in Japanese patients with insomnia: a randomized, placebo-controlled phase 3 pivotal study (SLEEP 2026) — SLEEP / Oxford Academic
- Long-Term Study of TS-142 in Patients with Insomnia (TS142-302, NCT05461352) — ClinicalTrials.gov
- Notice of acquisition of manufacturing and marketing approval in Japan for the insomnia treatment Vorzzz tablets 2.5mg, 5mg, 10mg — Taisho Pharmaceutical Co., Ltd.
- Notice regarding J-NDA filing of orexin receptor antagonist vornorexant hydrate for insomnia in Japan — Taisho Pharmaceutical Co., Ltd.
- Phase 3 clinical trial results of orexin receptor antagonist vornorexant hydrate announced (301 & 302 studies) — Taisho Pharmaceutical Co., Ltd.
- Phase 3 Study of TS-142 in Patients with Insomnia (TS142-301, NCT05453136) — ClinicalTrials.gov
- Preclinical pharmacological profiles of vornorexant, a novel potent dual orexin receptor antagonist (J Pharmacol Exp Ther 2025) — JPET / ASPET (PubMed)
- Vornorexant — Wikipedia