1. Clear MoA
a) Orexin A and orexin B are hypothalamic neuropeptides.
b) Orexin A and B combine with OX1R and OX2R to activate Gq PLC/PKC/ERK, Gs/AC/cAMP/PKA/ERK (and/or CREB, p38 MAPK) and Gi pathways.
c) The OX2R signal through Gq/PLC/PKC pathway is stronger than OX1R signal.
d) Gq/PLC/PKC pathway triggers PKC mediated calcium influx and releases intracellular calcium storage. The increase of calcium level makes neurons continuously excited, thus maintaining wakefulness.
2. Efficacy—Compared with Zopiclone
a) This asset has a short incubation period and takes effect quickly. The duration of the effect was moderate, and the effect basically disappeared after 8 hours, with little risk of side effects.
b) It has no obvious influence on the process of shallow sleep (REM), which is conducive to the maintenance of normal sleep cycle and healthy sleep.
c) It can promote deep (NREM) sleep and light (REM) sleep, and reduce the amount of sleep awakening.
Fig. 1 Total sleep duration ratio in rats from 0-24 hours
3. Safety—Compared with Suvorexant
It has higher in vitro activity and target selectivity than Suvorexant, with better hERG and CYP values than Suvorexant.
4. Indication extension potential
It can further develop more sleep and cognitive related indications, including patients with sleep disorders in the population with other specific diseases.
5. Phase II summary
a) Induced a dose-response improvement on sleep efficiency in subjects with insomnia. had favorable safety profiles in the dose range studied.
b) Had no obvious CNS adverse events compared with placebo, indicating fewer next-day residual effects.
Fig. 2 Dose-related improvement in SE on D1/2 and D13/14.
Fig.3 Sleep Efficiency (%SE) of Dual Orexin Receptor Antagonists
1. Asset type: Orexin Receptor Antagonist (OX1R and OX2R)
2. Indication: Insomnia Disorder
3. Research phase: Phase 3 (China)
4. Administration route: oral (20 mg/40 mg)
5. Cooperation demands: License-out or co-development
6. Research progress：
1) The asset has higher in vitro activity and target selectivity than Suvorexant, and both hERG and CYP values are better than Suvorexant.
2) The asset is currently in the phase III clinical trial in China, and will complete the phase III clinical trial and apply for production in Q2 2023.
3) The asset can further develop more sleep and cognitive related indications, including sleep disorders in people with other specific diseases.
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