Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist

Epidemiological studies suggest that sleep problems are highly prevalent in the general population. Symptoms such as prolonged time to fall asleep, sleep disruption, and early morning awakenings associated with daytime functional impairment are consistent with the diagnosis of insomnia disorder. According to current guidelines, psychological and pharmacological therapies are recommended in order to reduce the time to fall asleep and the time spent awake after sleep onset, with subsequent improvements in daytime functioning. Under- or untreated insomnia can lead to severe physical and psychological consequences, such as impairment in cognitive functioning, daytime fatigue, increased accident risk, and increased utilization of medical care. In addition, many studies have shown an association between insomnia and psychiatric disorders, specifically depression and anxiety. Current treatment of insomnia includes sleep hygiene measures and other non-pharmacological therapies, and (short-term)pharmacotherapy. With regards to pharmacotherapy, prescription sleep drugs are associated with unwanted side effects such as morning or next-day hangover, cognitive and motor impairment, and dependence. Thus, novel pharmacological treatment options without these drawbacks are an important step forward, and in particular a long-term option that addresses the most pressing symptoms without negatively impacting next-day functioning is needed.
Since accumulating evidence is pointing to the pivotal role of the orexin system in the regulation of wakefulness and arousal, drugs interacting with the orexin system could potentially be part of improved treatment options of insomnia. This thesis discusses the pharmacological characterization of daridorexant (ACT-541468) as evaluated during the early clinical development program. Epidemiological studies suggest that sleep problems are highly prevalent in the general population. Symptoms such as prolonged time to fall asleep, sleep disruption, and early morning awakenings associated with daytime functional impairment are consistent with the diagnosis of insomnia disorder. According to current guidelines, psychological and pharmacological therapies are recommended in order to reduce the time to fall asleep and the time spent awake after sleep onset, with subsequent improvements in daytime functioning. Under- or untreated insomnia can lead to severe physical and psychological consequences, such as impairment in cognitive functioning, daytime fatigue, increased accident risk, and increased utilization of medical care. In addition, many studies have shown an association between insomnia and psychiatric disorders, specifically depression and anxiety. Current treatment of insomnia includes sleep hygiene measures and other non-pharmacological therapies, and (short-term)pharmacotherapy. With regards to pharmacotherapy, prescription seep drugs are associated with unwanted side effects such as morning or next-day hangover, cognitive and motor impairment, and dependence. Thus, novel pharmacological treatment options without these drawbacks are an important step forward, and in particular a long-term option that addresses the most pressing symptoms without negatively impacting next-day functioning is needed.
Since accumulating evidence is pointing to the pivotal role of the orexin system in the regulation of wakefulness and arousal, drugs interacting with the orexin system could potentially be part of improved treatment options of insomnia. This thesis discusses the pharmacological characterization, i.e., early clinical development of daridorexant (ACT-541468) by means of 5 published articles in peer-reviewed journals. The introduction and background information provided in this thesis is based on a published literature review, in which orexin receptor antagonists are discussed that are either marketed or in clinical development.