Orexin OX2 Receptor Antagonists as Sleep Aids

Abstract

The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX and OX receptors (OXRs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OXR antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OXR antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OXR is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OXR antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OXR antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.

Hypnotics with novel modes of action

“…a proportional increase in rapid eye movement [REM] and non‐REM [NREM] sleep), whereas blocking both receptors leads to increased REM sleep only, without effects on deep sleep . This pattern has been observed in rodents and verified in the clinic . Another DORA (SB‐649868), which has a strong OX 1 R blocking component, affected only REM, reduced latency to REM and in phase II trial produced sleep‐onset REM, which is common in narcolepsy .…”

“…If anything, DORAs strongly promote REM sleep, whereas 2SORAs promote a proportional increase in both NREM and REM sleep. Based on such findings, J&J/Minerva, decided to develop OX 2 R selective antagonists: seltorexant (JNJ‐42847922, MIN‐202) is in late stage development, with positive data in phase in insomnia and adjunctive therapy in depression (NCT03375203, NCT03321526, NCT03227224, NCT02464046).…”

“…Animals or patients treated with orexin receptor antagonists appear to be able to wake up upon adequate stimulation, contrary to most other hypnotics. For the time being, it is unclear whether selective OX 2 R antagonists and DORAs have different effects on sleep architecture in humans; this will be defined in the clinic, based on polysomnography rather than subjective patient‐reported data.…”

“…[42][43][44][45] This pattern has been observed in rodents and verified in the clinic. 30,46 Another DORA (SB-649868), which has a strong OX 1 R blocking component, affected only REM, reduced latency to REM and in phase II trial produced sleep-onset REM, which is common in narcolepsy. 47 Merck had another DORA in development, filorexant, with a similar profile to suvorexant and which in the clinic produced similar effects on sleep.…”

“…For the time being, it is unclear whether selective OX 2 R antagonists and DORAs have different effects on sleep architecture in humans 45,46,72,73 ; this will be defined in the clinic, based on polysomnography rather than subjective patient-reported data. Various calcium channel modulators have been tested in insomnia with variable success, i.e.…”