Daridorexant: A New Dual Orexin Receptor Antagonist for Insomnia

Abstract

Objective: To review the safety, efficacy, and tolerability of daridorexant in treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adult patients. Data Sources: A literature search was performed through PubMed using the following key terms: daridorexant, ACT-541468, orexin, insomnia, and sleep. Study Selection and Data Extraction: Selected articles included those which described clinical studies of the pharmacokinetics, efficacy, safety, or tolerability of daridorexant. Data Synthesis: Daridorexant works through antagonism of the dual orexin receptor. It is the third agent in this class of medications approved by the U.S. Food and Drug Administration (FDA). Daridorexant, at a dose of 25 mg to 50 mg, was shown to be effective in improving sleep parameters in phase 3 clinical studies and was well tolerated. Adverse event rates from phase 2 and 3 clinical trials were low with fatigue, nasopharyngitis, gait disturbance, somnolence, diarrhea, and headache most commonly reported. Conclusions: All currently available agents for treating insomnia have received a “weak” recommendation in the clinical practice guidelines, including the dual orexin receptor antagonist class of medications. Initial data suggest that with routine use daridorexant does not impair next day functioning, a common issue with other agents used to treat insomnia. In addition, daridorexant appears to be as safe and effective in treating insomnia in patients of all ages including those ≥65 years of age.

Introduction

Insomnia is characterized by difficulty in initiating sleep, difficulty maintaining sleep, and/or early morning awakening with inability to resume sleep. ¹ According to Centers for Disease Control and Prevention (CDC) data from 2014, 35% of U.S. adults get less than 7 hours of sleep per 24-hour period. ² Health risk factors reported by 20% or more of U.S. adults who have insomnia include obesity, physical inactivity, tobacco use, and excessive alcohol consumption. In addition, chronic health conditions, such as arthritis, cancer, depression, asthma, and diabetes are more common in these patients. ²

Data from a 2005 National Sleep Foundation survey of U.S. adults found 25% of respondents use some type of sleep agent several times per month. Commonly used options include prescription agents, alcohol, over-the-counter sleep aids, and melatonin. Furthermore, data from the National Center for Health Statistics show 4% of U.S. adults have used a prescription sleep agent in the past month and that use increases with age as well as educational level. ³ Despite the prevalence of insomnia in the United States, choices of pharmacologic agents are limited and the use of many agents is restricted by their associated precautions and warnings. ⁴

Dual orexin receptor antagonists (DORAs) inhibit orexin receptors which promote wakefulness. Selectivity for the OX1R and OX2R receptors affords this class of medications efficacy in treating insomnia with a more favorable adverse effect profile than other sleep agents. Daridorexant, the newest DORA, was approved by the U.S. Food and Drug Administration (FDA) in January 2022 for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. ⁵

Data Selection

A literature search was performed using PubMed (2010 to April 2022) with the search terms daridorexant, ACT-541468, insomnia, sleep, and orexin. All relevant English-language studies assessing the pharmacokinetics, efficacy, or safety of daridorexant were selected. Information was also obtained from FDA-approved product labeling. References from previously published review articles were also examined to identify additional sources.

Pharmacology

Orexin neuropeptides, which are specifically expressed from the hypothalamus, stabilize wakefulness through activation of OX1R and OX2R receptors. Their highest levels of activity are during periods of wakefulness and lowest during sleep. DORAs inhibit both of these receptors and allow sleep to occur. They target a multitude of wake-promoting neuronal pathways such as the histaminergic neurons of the tuberomammillary nucleus, serotonergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area, cholinergic neurons of the basal forebrain, and the pedunculopontine and laterodorsal tegmental nuclei.^6-10 This medication class selectively targets and reduces the wake-promoting activity through widespread inhibition of these neuronal pathways, thereby avoiding unwanted adverse effects as seen with other agents used for insomnia such as GABA-A receptor modulators. Daridorexant is a selective and equipotent antagonist at both receptors. The driving force behind the development of this class of medications was to identify a potent brain penetrating antagonist with a fast onset and a duration of action just long enough to cover nighttime sleep while avoiding residual morning effects. ¹¹

Pharmacokinetics

Daridorexant demonstrates dose proportional pharmacokinetics following either single or multiple dose administration with no resulting accumulation. Time to peak plasma concentrations (T_max) is reached within 1 to 2 hours with a half-life of approximately 8 hours. In healthy subjects consuming high calorie/high fat foods around the time of drug administration, no effect was noted on total drug exposure (AUC). However, peak plasma concentrations (C_max) were decreased by 16% and T_max by 1.3 hours. Daridorexant has an absolute bioavailability of 62% after oral administration. The volume of distribution is 31 L, with it being 99.7% bound to plasma proteins and a blood: plasma ratio of 0.64. It is primarily metabolized through cytochrome P450 (CYP) 3A4 (89%) with other CYP enzymes collectively contributing less than 3%. Daridorexant is primarily excreted as metabolites through the feces (~57%), followed by urinary excretion (~28%). Only trace amounts of parent drug were found through these excretion routes. Regarding specific populations (age, sex, race, body composition) and subjects with mild to severe renal impairment (Cockcroft-Gault < 30 mL/min, excluding dialysis), daridorexant’s pharmacokinetic profile was not meaningfully impacted by these variables.^5,12

Clinical Trials

Primary outcomes examined during clinical trials with daridorexant include wake after sleep onset (WASO) and latency to persistent sleep (LPS). WASO refers to periods of wakefulness during sleep, while LPS is defined as the amount of time it takes from lying down to sleep onset. In order to accurately interpret the results of clinical trials involving daridorexant, one must understand the thresholds for clinical significance and how the outcome was reported. For WASO, the clinical significance threshold is 20 minutes if obtained via polysomnography or actigraphy and 30 minutes if subjectively reported. A 10-minute change in LPS is considered to be clinically significant if obtained via polysomnography or actigraphy while the threshold for subjective report of LPS is 20 minutes. ⁴

Phase 2 Clinical Trials

A study in 359 subjects with insomnia was conducted to evaluate the dose-response relationship of daridorexant at various doses over 30 days. ¹³ In this study, subjects were randomized to receive daridorexant 5 mg, 10 mg, 25 mg, or 50 mg, or placebo, or zolpidem 10 mg daily for 30 days. The primary study outcome was the change in WASO measured via polysomnography from baseline to days 1 and 2. Safety and tolerability were also assessed. WASO was reduced from baseline to days 1 and 2 in a dose-dependent manner by 28.4, 32.3, 37.7, and 47.1 minutes in the daridorexant 5 mg, 10 mg, 25 mg, and 50 mg groups, respectively (p<0.001). In addition, this effect was sustained at days 15 and 16 as well as days 28 and 29. At least one adverse event was reported in 35%, 38%, 38%, 34%, 30%, and 40% of patients taking daridorexant 5 mg, daridorexant 10 mg, daridorexant 25 mg, daridorexant 50 mg, placebo, and zolpidem, respectively. Common adverse events associated with daridorexant use included headache, somnolence, diarrhea, and fatigue. At week 2, morning sleepiness, daytime alertness, and daytime ability to function were nonsignificantly increased in a dose-dependent manner (as evidenced by visual analogue scale ratings) in subjects taking daridorexant compared to placebo. These results were not sustained at week 4. Serious adverse events were reported in 2 patients taking daridorexant 10 mg and 1 patient taking daridorexant 50 mg, but these events were determined to be unrelated to treatment. No medication-related effects on blood pressure, body weight, electrocardiogram (ECG), and laboratory parameters were reported. The authors concluded that the results of this Phase 2 study showed daridorexant induces a dose-related effect on sleep and is well tolerated; however, these results should be confirmed in larger populations.

Zammit and colleagues studied the effect of daridorexant on WASO in 58 elderly subjects (≥65 years of age) with insomnia. ¹⁴ Inappropriately treated insomnia can lead to an increased risk of falls, decreased cognitive function, and increased nursing home placements in the elderly. These factors, in addition to a lack of appropriate insomnia agents for the elderly population, influenced the design of this study to provide initial evidence on the most appropriate dose of daridorexant in this population. In this study, 58 subjects were randomized to receive 5 different treatments (daridorexant 5 mg, 10 mg, 25 mg, and 50 mg and placebo) for 2 consecutive nights during 5 treatment periods. Each treatment period was followed by a 5- to 12-day washout period. The primary efficacy outcome was change from baseline in WASO, obtained via polysomnography, to days 1 and 2. Safety was assessed via adverse event reporting as well as vital signs, body weight, ECG, and laboratory parameters. The decrease in WASO from baseline to days 1 and 2 were 18.4^*, 32.4, 44.2, and 61.1 minutes in the daridorexant 5 mg, 10 mg, 25 mg, and 50 mg doses, respectively (^*not statistically significant). The most frequent adverse events reported across all treatment groups included fatigue, nasopharyngitis, gait disturbance, and headache. Fatigue appeared to be the only dose-related adverse event with a higher reported incidence in the daridorexant 50 mg group. Drug-related adverse events leading to discontinuation included increased alanine transaminase (ALT) levels and ventricular extrasystoles each occurring in 1 patient. No relevant changes in vital signs, body weight, or ECG were reported. Based on these results, the authors concluded that daridorexant at a dose of 10 mg, 25 mg, and 50 mg in patients 65 and older significantly improved WASO and was well tolerated.

Phase 3 Clinical Trials

Daridorexant has been evaluated in 2 large phase 3 clinical trials (Table 1). ¹⁵ The aim of these 2 randomized, double-blind, placebo-controlled trials was to evaluate the safety and efficacy of daridorexant in patients with insomnia disorder. Study 1 included 930 patients who were randomized to receive daridorexant 25 mg, daridorexant 50 mg, or placebo every night for 3 months. Study 2 enrolled 924 patients who were randomized to receive daridorexant 10 mg, daridorexant 25 mg, or placebo every night for 3 months. Primary outcomes for both studies were change from baseline in WASO and LPS, measured via polysomnography, at months 1 and 3. Results from study 1 revealed a significant reduction in WASO and LPS in both the daridorexant 25 mg and 50 mg groups compared to placebo at months 1 and 3. In study 2, daridorexant 25 mg resulted in a significant reduction in WASO, but not LPS, at months 1 and 3 compared to placebo. No significant differences in WASO or LPS were experienced in patients taking daridorexant 10 mg at months 1 or 3 compared to placebo. In both studies, the incidence of adverse events was similar between treatment groups (study 1: 38%, 38%, and 34% in the daridorexant 50 mg, daridorexant 25 mg, and placebo groups; study 2: 39%, 38%, and 33% in the daridorexant 25 mg, daridorexant 10 mg, and placebo groups) with nasopharyngitis and headache most commonly reported in all groups. The incidence of serious adverse events was low (≤2%) across all groups. There was one reported death in the daridorexant 25 mg group from study 1; however, the incident was found to be unrelated to study treatment. Adverse events leading to discontinuation were low (1%-3%) across groups as well. Based on these results, the study investigators determined daridorexant 25 mg and 50 mg were efficacious in improving sleep parameters and were well tolerated among study participants.

Table 1.

Phase 3 Clinical Trial Results. ¹⁵

Study design	Duration	Population size (n)	Comparator	Primary endpoints: Change from baseline in WASO and LPS at months 1 and 3	Secondary endpoints: Change from baseline in self-reported TST and sleepiness domain score of the IDSIQ at months 1 and 3
R, DB, PC	12 weeks	930	D 50 mg, D 25 mg, or PBO	WASO: D 50 vs. PBO (month 1) LSM difference -22.8 minutes (95% CI: -28.0 to -17.6; P < 0.0001) D 25 vs. PBO (month 1) LSM difference -12.2 minutes (95% CI: -17.4 to -7.0; P < 0.0001) D 50 vs. PBO (month 3) LSM difference -18.3 minutes (95% CI: -23.9 to -12.7; P < 0.0001) D 25 vs. PBO (month 3) LSM difference -11.9 minutes (95% CI: -17.5 to -6.2; P < 0.0001) LPS: D 50 vs. PBO (month 1) LSM difference -11.4 minutes (95% CI: -16.0 to -6.7; P < 0.0001) D 25 vs. PBO (month 1) LSM difference -8.3 minutes (95% CI: -13.0 to -3.6; P = 0.0005) D 50 vs. PBO (month 3) LSM difference -11.7 minutes (95% CI: -16.3 to -7.0; P < 0.0001) D 25 vs. PBO (month 3) LSM difference -7.6 minutes (95% CI: -12.3 to -2.9; P = 0.0015)	TST: D 50 vs. PBO (month 1) LSM difference 22.1 minutes (95% CI: 14.4 to 29.7; P < 0.0001) D 25 vs. PBO (month 1) LSM difference 12.6 minutes (95% CI: 5.0 to 20.3; P = 0.0013) D 50 vs. PBO (month 3) LSM difference 19.8 min (95% CI: 10.6 to 28.9; P < 0.0001) D 25 vs. PBO (month 3) LSM difference 9.9 minutes (95% CI: 0.8 to 19.1; P = 0.033) IDSIQ Sleepiness Domain Score: D 50 vs. PBO (month 1) LSM difference -1.8 (95% CI: -2.5 to -1.0; P < 0.0001) D 25 vs. PBO (month 1) LSM difference -0.8 (95% CI: -1.5 to 0.01; P = 0.055)* D 50 vs. PBO (month 3) LSM difference -1.9 (95% CI: -2.9 to -0.9; P =0.0002) D 25 vs. PBO (month 3) LSM difference -1.0 (95% CI: -2.0 to 0.01; P = 0.053)*
R, DB, PC	12 weeks	924	D 25 mg, D 10 mg, or PBO	WASO: D 25 vs. PBO (month 1) LSM difference -11.6 minutes (95% CI: -17.6 to -5.6; P = 0.0001) D 10 vs. PBO (month 1) LSM difference -2.7 minutes (95% CI: -8.7 to 3.2; P = 0.37)* D 25 vs. PBO (month 3) LSM difference -10.3 minutes (95% CI: -17.0 to -3.5; P = 0.0028) D 10 vs. PBO (month 3) LSM difference -2.0 minutes (95% CI: -8.7 to 4.8; P =0.57)* LPS: D 25 vs. PBO (month 1) LSM difference -6.5 minutes (95% CI: -12.3 to -0.6; P = 0.030)* D 10 vs. PBO (month 1) LSM difference -2.6 minutes (95% CI: -8.4 to 3.2; P =0.38)* D 25 vs. PBO (month 3) LSM difference -9.0 minutes (95% CI: -15.3 to -2.7; P = 0.0053)* D 10 vs. PBO (month 3) LSM difference -3.2 minutes (95% CI: -9.5 to 3.1; P = 0.32)*	TST: D 25 vs. PBO (month 1) LSM difference 16.1 minutes (95% CI: 8.2 to 24.0; P < 0.0001) D 10 vs. PBO (month 1) LSM difference 13.4 minutes (95% CI: 5.5 to 21.2; P = 0.0009)* D 25 vs. PBO (month 3) LSM difference 19.1 minutes (95% CI: 10.1 to 28.0; P < 0.0001) D 10 vs. PBO (month 3) LSM difference 13.6 minutes (95% CI: 4.7 to 22.5; P = 0.0028)* IDSIQ Sleepiness Domain Score: D 25 vs. PBO (month 1) LSM difference -0.8 (95% CI: -1.6 to 0.1; P =0.073)* D 10 vs. PBO (month 1) LSM difference -0.4 (95% CI: -1.3 to 0.4; P = 0.30)* D 25 vs. PBO (month 3) LSM difference -1.3 (95% CI: -2.2 to -0.3; P =0.012)* D 10 vs. PBO (month 3) LSM difference -0.7 (95% CI: -1.7 to 0.2; P = 0.14)*

Abbreviations: CI, confidence interval; D, daridorexant; DB, double blind; IDSIQ, Insomina Daytime Symptoms and Impacts Questionnaire; LPS, latency to persistent sleep; LSM, least squares mean; PBO, placebo; PC, placebo controlled; R, randomized; TST, total sleep time; WASO, wake time after sleep onset.

^*Not statistically significant.

A sub-group analysis of study 1 participants ≥65 years of age (n = 364) showed similar results in reduction of WASO and LPS compared to placebo. ¹⁶ When examining adverse events, it was found that falls and dizziness were less common in the daridorexant 50 mg group (n = 2) than in the daridorexant 25 mg (n = 5) or placebo (n = 5) groups. In addition, somnolence was less common with daridorexant 50 mg (n = 1) than with daridorexant 25 mg (n = 6) but similar to placebo (n = 1). Based on the small number of reported adverse events, the significance of these findings are unknown. Fatigue was reported more frequently in patients taking daridorexant; nonetheless, the incidence did not appear to be dose related. Results of this sub-analysis confirm the efficacy and safety of daridorexant as a sleep agent in elderly patients.

An additional analysis of study 1 and study 2 examined the incidence of withdrawal symptoms and rebound insomnia after treatment discontinuation. ¹⁷ Participants were included in this analysis if they received at least one dose of the 7-day placebo run-out phase (852, study 1; 851, study 2) which followed the double-blind treatment period. The change in Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) score from the end of the double-blind treatment phase to the end of the 7-day placebo run out period was used to assess withdrawal symptoms. The occurrence of rebound insomnia was assessed by the change in WASO and LPS from baseline to the first night of the placebo run out period as well as by subjective total sleep time (sTST) from baseline to the end of the placebo run out period. There was no increase in BWSQ score reported and no patient had a BWSQ score greater than 20 at the end of the run-out period. Change in WASO and LPS values indicated no rebound effects and sTST increased further indicating a lack of rebound insomnia. The authors of this analysis concluded that based on these results, daridorexant use for up to 3 months was not associated with withdrawal symptoms or rebound insomnia upon discontinuation.

Safety

Daridorexant has been shown to be well tolerated in clinical trials with few serious adverse effects. The most common adverse reactions reported in ≥2% of participants were headache (also includes tension headache, migraine, migraine with aura, head discomfort), somnolence (also includes sedation, fatigue, hypersomnia, lethargy), dizziness, and nausea. Sleep paralysis and hallucinations occurred in a small number of participants who received daridorexant in phase 3 trials, but no other complex sleep behaviors were reported. ¹⁵ There were no reported incidences of sleep paralysis or hallucinations in the placebo group. In an impact study, daridorexant at a supratherapeutic dose 4 times the maximum daily recommended dose did not prolong the QT interval. ¹⁸ Daridorexant does not affect nighttime respiratory function in subjects with mild or moderate obstructive sleep apnea or moderate chronic obstructive pulmonary disease (COPD); however, daridorexant was not studied in patients with severe obstructive sleep apnea or COPD.^19,20

Daridorexant is a federally controlled substance due to its risk for misuse and abuse. ⁵ Daridorexant does not have a history of diversion from clinical trials; however, it did show dose-related drug-liking in human abuse potential (HAP) studies. ²¹ At a dose of 50 mg, daridorexant demonstrated less euphoric events and drug-liking compared to supratherapeutic doses of the control drugs zolpidem and suvorexant. The drug-liking effects of daridorexant were dose-dependent. Daridorexant is not an immediate precursor of any controlled substances, and currently available data suggest it does not cause physical dependence. Nonetheless, it may produce psychological dependence similar to other schedule IV depressants and therefore on April 7, 2022 the U.S. Drug Enforcement Administration recommended that this becomes a schedule IV substance. ²²

Drug Interactions

Daridorexant is primarily metabolized by CYP3A4; as a result, daridorexant should be avoided in patients receiving strong or moderate CYP3A4 inducers and strong CYP3A4 inhibitors (see Table 2).^5,23 Daridorexant 50 mg does not require a dose adjustment when taken concomitantly with gastric pH modifiers or moderate CYP3A4 inducers. ²⁴ Daridorexant is also a central nervous system (CNS) depressant and may cause additive effects with other CNS depressants such as tricyclic antidepressants, benzodiazepines, or alcohol. Caution should be used when prescribing daridorexant with concomitant CNS depressants and a dose adjustment should be considered.

Table 2.

Examples of Cytochrome P450 Drug Interactions With Daridorexant (FDA). ²³

Moderate CYP3A4 inducers	Strong CYP3A4 inducers	Strong CYP3A4 inhibitors
Diltiazem	Carbamazepine	Clarithromycin
Dronedarone	Phenobarbital	Cobicistat
Erythromycin	Phenytoin	Ketoconazole
Fluconazole	Primidone	Ritonavir
Verapamil	Rifampin	Voriconazole

Dosing and Administration

Daridorexant is available as 25 mg and 50 mg tablets. The onset of action for the 25 mg dose is between 35 and 40 minutes, whereas the 50 mg dose is approximately 30 minutes. ¹⁵ The recommended daily dose is 50 mg once daily within 30 minutes before bedtime, as long as there are 7 hours remaining for sleep. Daridorexant should not be taken with food or within 2 hours of a meal because it may delay the time to sleep onset. A single-dose, open-label, phase 1 trial showed that moderate hepatic impairment (Child Pugh-Class B) impacts the clearance and half-life of daridorexant. Therefore, the dose should be reduced to 25 mg daily in patients with moderate hepatic impairment (Child-Pugh Class B) and its use should be avoided in patients with severe hepatic impairment (Child Pugh-Class C). ²⁵ There are no specific dosage recommendations for elderly patients or those with renal impairment. ¹² Daridorexant is contraindicated in patients with narcolepsy. Patients should initially use caution before operating heavy machinery as some may experience next-morning residual effects such as somnolence, headache, and fatigue that may affect driving performance; however, this may resolve after repeated doses. ²⁶

Place in Therapy

Insomnia is a debilitating condition which is often difficult to treat. The American College of Physicians and the American Academy of Sleep Medicine guidelines recommend cognitive-behavioral therapy for insomnia (CBT-I) as the standard of treatment; however, adherence concerns, specifically related to patients with common comorbid conditions, like depression, may reduce its impact.^27,28 For patients who fail or are unwilling to complete CBT-I, pharmacotherapy is recommended.

Currently available treatment alternatives for insomnia have various warnings and precautions relating to drug interactions, fall risk, and abuse potential. Treatment is chosen based on the patient’s needs and may require adjustment throughout the course of therapy. Daridorexant has been shown to be safe and effective for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance and will likely be considered as a second-line treatment to CBT-I similar to suvorexant. ⁴ Clinical trials indicate that daridorexant 50 mg improves multiple aspects of daytime functioning, a major concern for people with insomnia. ¹⁵

DORAs have also been tested and shown to be beneficial in patients with cognitive impairment due to mild to moderate dementia. ²⁹ Benzodiazepine receptor agonists (BZRAs) are considered inappropriate medications in older adults, paving the way for DORAs like daridorexant to make an impact in this patient population. Daridorexant may also be a great option for patients with underlying pulmonary disease as it lacks the risk of respiratory depression seen with BZRAs and does not seem to affect nighttime respiratory function. ¹⁹ The cost can be assumed to be relatively similar to other medications within its class with a possibility of manufacturer assistance. DORAs are generally more expensive than other agents available for insomnia (ex: suvorexant ~400$ vs zolpidem ~20$ for 30-day supply).^30,31 With no head-to-head trials directly comparing DORAs, further studies are needed in order to justify therapeutic preference among them. A thorough review of patient-specific factors such as comorbid conditions, insomnia type, patient age, drug interactions, and cost should be used to determine if daridorexant use is appropriate.

Conclusion

Daridorexant is DORA approved for the treatment of insomnia in adult patients. Several clinical trials have confirmed the safety and efficacy of daridorexant with little to no rebound insomnia, withdrawal effects, or abuse potential. Daridorexant is the third DORA approved in the United States and would be expected to receive at least the same recommendation as suvorexant in clinical practice guidelines. Initial data suggest daridorexant may be an appropriate option in populations underrepresented in some studies such as mild to moderate obstructive sleep apnea, moderate COPD, and elderly subjects. Therefore, use of daridorexant in a larger population of patients will further clarify the role of daridorexant in treating insomnia.