Daridorexant (Quviviq®): A Comprehensive Pharmacological and Clinical Review

1.0 Introduction and Overview of Daridorexant (Quviviq®)

1.1 Executive Summary

Daridorexant is a novel, small-molecule therapeutic agent developed by Idorsia Pharmaceuticals and marketed under the brand name Quviviq®.[1] It is classified as a dual orexin receptor antagonist (DORA) and is indicated for the treatment of adult patients with chronic insomnia disorder characterized by difficulties with sleep onset and/or sleep maintenance.[3] The development of daridorexant represents a significant evolution in the pharmacological management of insomnia. Its mechanism of action, which involves the targeted antagonism of the orexin system, addresses the underlying pathophysiology of hyperarousal in insomnia, a departure from the broad central nervous system (CNS) sedation induced by traditional hypnotic agents.[5] This targeted approach, combined with a meticulously engineered pharmacokinetic profile, allows daridorexant to improve both nighttime sleep parameters and, uniquely, daytime functioning, while minimizing the residual effects that have long been a limitation of older therapies.

1.2 The Shifting Paradigm in Insomnia Treatment

Insomnia disorder is increasingly recognized not merely as a nighttime complaint but as a complex and debilitating 24-hour condition. It is defined by persistent difficulties with initiating or maintaining sleep, which leads to significant impairment of daytime functioning, including fatigue, cognitive deficits, and mood disturbances.[3] Chronic insomnia is associated with a substantial long-term health burden, including an increased risk for comorbidities such as hypertension, type 2 diabetes, and major depressive disorder.[3]

For decades, the mainstay of pharmacological treatment has been agents that modulate the gamma-aminobutyric acid type-A (GABA-A) receptor complex, such as benzodiazepines and the non-benzodiazepine receptor agonists (BZRAs), commonly known as 'Z-drugs' (e.g., zolpidem, eszopiclone). These drugs induce sleep by enhancing the effects of GABA, the primary inhibitory neurotransmitter in the CNS, resulting in global neuronal depression.[3] While effective in promoting sleep, this non-specific mechanism is responsible for a range of undesirable side effects. These include next-morning residual sleepiness, motor incoordination, an increased risk of falls (particularly in the elderly), memory and cognitive impairment, and a notable potential for tolerance, dependence, and withdrawal phenomena.[3]

The discovery of the orexin neuropeptide system's pivotal role in promoting and stabilizing wakefulness provided a fundamentally new therapeutic target.[9] Orexin-A and Orexin-B are neuropeptides produced in the lateral hypothalamus that function as a central "wake switch." An overactive orexin system is now understood to be a key pathophysiological driver of the state of hyperarousal that characterizes insomnia.[11] This understanding shifted the therapeutic paradigm from inducing non-specific sedation to selectively turning down the overactive wake drive, paving the way for the development of orexin receptor antagonists.

1.3 Daridorexant's Unique Value Proposition

Daridorexant is the culmination of an intensive drug discovery program specifically designed to optimize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a DORA.[3] The primary goal was to create a molecule that could not only improve nighttime sleep but also demonstrate a measurable improvement in daytime functioning, a critical and often-neglected aspect of insomnia treatment.[6] This was achieved by engineering a compound with a PK profile that provides sufficient receptor blockade to maintain sleep throughout the night, yet allows for rapid elimination to minimize residual activity the following morning.[13]

It is the third DORA to receive approval from the U.S. Food and Drug Administration (FDA), following suvorexant and lemborexant, and holds the distinction of being the first DORA to be granted marketing authorization by the European Commission (EC).[1] This dual approval underscores its significance as a new therapeutic option for millions of patients suffering from chronic insomnia, offering a targeted, evidence-based approach that addresses the full 24-hour burden of the disorder.

2.0 Chemical Profile and Formulation

2.1 Identification and Nomenclature

Daridorexant is a synthetic organic small molecule belonging to the benzimidazole class of compounds.[3] For clarity in research, clinical practice, and regulatory documentation, it is essential to recognize its various identifiers. The drug was initially developed under the research code ACT-541468 and was also formerly known as nemorexant.[2] It is marketed globally under the trade name Quviviq®.[1] In the United States, it is classified by the Drug Enforcement Administration (DEA) as a Schedule IV controlled substance due to a low potential for abuse, with the assigned DEA code number 2410.[3]

2.2 Chemical Structure and Properties

The chemical structure of daridorexant is complex, featuring a central pyrrolidine ring linked to a substituted benzimidazole moiety on one side and a methoxy-triazolyl-phenyl group on the other. The precise stereochemistry of the molecule is critical for its biological activity. It possesses a single chiral center at the C2 position of the pyrrolidine ring, which has the (S) absolute configuration.[17]

The International Union of Pure and Applied Chemistry (IUPAC) name for daridorexant is-[5-methoxy-2-(triazol-2-yl)phenyl]methanone.[1] The molecule's structure is unambiguously defined by its SMILES (Simplified Molecular Input Line Entry Specification) string,

CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl, and its InChIKey, NBGABHGMJVIVBW-QHCPKHFHSA-N, which serve as universal digital identifiers for its topology and stereochemistry.[15]

Daridorexant is typically used as its hydrochloride salt for improved stability and solubility in its pharmaceutical formulation.[8] The chemical and physical properties of both the free base and the hydrochloride salt are summarized in Table 1.

Property	Value / Description	Source(s)
Generic Name (INN)	Daridorexant	2
Brand Name	Quviviq®	1
Chemical Class	Dual Orexin Receptor Antagonist (DORA), Benzimidazole derivative	6
DrugBank ID	DB15031	1
CAS Number	1505484-82-1 (Free Base) 1792993-84-0 (Hydrochloride Salt)	1
IUPAC Name	-[5-methoxy-2-(triazol-2-yl)phenyl]methanone	2
Chemical Formula	C23​H23​ClN6​O2​ (Free Base) C23​H24​Cl2​N6​O2​ (Hydrochloride Salt)	8
Molecular Weight	450.93 g/mol (Free Base) 487.39 g/mol (Hydrochloride Salt)	12
SMILES String	CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl	3
InChIKey	NBGABHGMJVIVBW-QHCPKHFHSA-N	15
XLogP	4.57	2
Topological Polar Surface Area (TPSA)	88.41 A˚2	2
Hydrogen Bond Donors	1	2
Hydrogen Bond Acceptors	5	2
Rotatable Bonds	5	2

2.3 Formulation and Dosage Forms

Daridorexant is formulated for oral administration as its hydrochloride salt, daridorexant hydrochloride.[8] It is manufactured as film-coated tablets with a distinctive arc-triangle shape, available in two strengths to allow for dose titration based on patient need and tolerability [12]:

• 25 mg tablet: Light purple, debossed with "25" on one side and the Idorsia company logo ("i") on the other.
• 50 mg tablet: Light red, debossed with "50" on one side and the Idorsia company logo ("i") on the other.

3.0 Pharmacology: Mechanism of Action

3.1 The Orexin System: The "Wake Switch"

The pharmacological action of daridorexant is rooted in its interaction with the orexin neurochemical system, a key regulator of the sleep-wake cycle. This system consists of two neuropeptides, Orexin-A (also known as hypocretin-1) and Orexin-B (hypocretin-2), and their cognate G-protein-coupled receptors (GPCRs), Orexin Receptor 1 (OX1R) and Orexin Receptor 2 (OX2R).[9] These peptides are synthesized exclusively by a small population of neurons located in the lateral and perifornical areas of the hypothalamus. Despite their localized origin, these orexin neurons project widely throughout the central nervous system, innervating and activating key arousal centers.[9] These centers include the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, and dopaminergic neurons of the ventral tegmental area.[9]

The activity of orexin neurons is highest during periods of active wakefulness and is virtually silent during sleep.[9] This dynamic activity profile establishes the orexin system as a master regulator of arousal, acting to stabilize the wakeful state and prevent inappropriate transitions into sleep. The critical role of this system is starkly illustrated by the neurological disorder narcolepsy with cataplexy, a condition caused by the autoimmune destruction of orexin-producing neurons, which results in profound and uncontrollable daytime sleepiness.[16] In insomnia, the opposite is believed to occur: a state of hyperarousal driven by an overactive orexin system contributes to the inability to initiate and maintain sleep.

3.2 Daridorexant as a Dual Orexin Receptor Antagonist (DORA)

Daridorexant functions as a potent and selective dual orexin receptor antagonist (DORA).[5] It acts as a

competitive, orthosteric antagonist at both OX1R and OX2R, meaning it binds directly to the same receptor site as the endogenous orexin peptides, thereby physically preventing them from binding and activating the receptors.[9] This blockade effectively "turns down" the wake-promoting signals originating from the hypothalamus.

A key feature of daridorexant is its equipotent antagonism at both receptor subtypes.[5] It demonstrates high affinity for human receptors, with inhibitor constant (

Ki​) values of 0.5 nM for OX1R and 0.8 nM for OX2R.[9] This balanced, dual antagonism is considered advantageous as it ensures a comprehensive blockade of the wake drive mediated by both Orexin-A (which binds both receptors) and Orexin-B (which preferentially binds OX2R).[10]

3.3 Targeted Action vs. Global Sedation

The mechanism of daridorexant marks a fundamental departure from that of traditional hypnotics. Older agents, such as benzodiazepines and Z-drugs, are positive allosteric modulators of the GABA-A receptor, a receptor type that is ubiquitously distributed throughout the CNS.[3] By enhancing the activity of GABA, the brain's primary inhibitory neurotransmitter, these drugs induce a state of widespread, non-specific CNS depression. This global sedation is effective for inducing sleep but is also the direct cause of their well-known side effects, including motor incoordination, cognitive deficits, and amnesia.[3]

In stark contrast, daridorexant's action is highly targeted. It does not interact with GABA receptors or other neurotransmitter systems associated with broad sedation.[1] Its high selectivity for OX1R and OX2R was confirmed in a large screening panel where it showed no significant activity against more than 130 other central and peripheral pharmacological targets.[9] Instead of "forcing" sleep through global inhibition, daridorexant is thought to facilitate it by reducing the overactive wake drive, allowing the brain's natural, endogenous sleep-promoting processes to take over.[5] This targeted mechanism is hypothesized to be the reason for its more favorable effect on sleep architecture, preserving the natural proportions of REM and non-REM sleep stages, which is crucial for restorative sleep.[5] Furthermore, the drug's activity is context-dependent; its antagonist effects are most pronounced when the orexin system is pathologically overactive, as in insomnia, and are expected to be limited when the system is naturally quiescent following a restful night.[9] This highly specific mechanism of action is the pharmacological foundation for daridorexant's distinct clinical profile, characterized by effective sleep promotion with a reduced burden of the off-target side effects that have limited the utility of older hypnotic agents.

4.0 Pharmacokinetic Profile (ADME)

The clinical utility of daridorexant is defined as much by its pharmacokinetic (PK) profile as by its mechanism of action. The absorption, distribution, metabolism, and excretion (ADME) properties of the drug were deliberately optimized during its development to achieve a specific therapeutic window: providing efficacy throughout a typical night's sleep while minimizing the potential for residual effects the following day.[3]

4.1 Absorption

Following oral administration, daridorexant is absorbed rapidly, with peak plasma concentrations (Tmax) reached within 1 to 2 hours in a fasted state.[1] This rapid absorption profile is well-suited for its indication in treating sleep-onset insomnia. The absolute bioavailability of daridorexant is 62%.[1]

A significant food effect has been observed. When administered with a high-fat, high-calorie meal, the Tmax is delayed by approximately 1.3 hours, and the peak concentration (Cmax) is reduced by 16%.[1] Importantly, the total drug exposure, as measured by the area under the curve (AUC), is not affected.[10] The clinical implication of this finding is that taking the medication with or shortly after a meal can delay its sleep-promoting effects, a key counseling point for patients.[16]

4.2 Distribution

Daridorexant has an apparent volume of distribution (Vd) of 31 L, indicating that it distributes into tissues beyond the circulatory system.[10] It is highly bound to plasma proteins, with a bound fraction of 99.7%.[1] A critical aspect of its distribution is its ability to effectively cross the blood-brain barrier, which is necessary to reach its target orexin receptors in the hypothalamus and exert its pharmacological effect.[9]

4.3 Metabolism

Daridorexant undergoes extensive metabolism, with only trace amounts of the parent drug being excreted unchanged in the urine or feces.[10] The metabolic clearance is predominantly mediated by the cytochrome P450 enzyme system, with

CYP3A4 being the primary enzyme responsible, accounting for approximately 89% of its metabolism.[1] Other CYP enzymes, such as CYP2C8, make only minor contributions (less than 3% each).[10] The main metabolic pathways involve oxidative transformations, such as hydroxylation of the benzimidazole ring's methyl group.[13] The resulting metabolites have significantly lower affinity for the orexin receptors and are not considered to contribute meaningfully to the drug's pharmacological activity.[13]

4.4 Excretion

The elimination of daridorexant and its metabolites occurs primarily through the feces (approximately 57% of the administered dose) and to a lesser extent through the urine (approximately 28%).[1] The terminal elimination half-life (

t1/2​) is consistently reported to be approximately 8 hours.[1]

This 8-hour half-life is a deliberately engineered feature and a cornerstone of the drug's clinical profile. It is long enough to provide sustained receptor antagonism throughout a standard 7- to 8-hour sleep period, addressing both sleep onset and sleep maintenance. At the same time, it is short enough to ensure that a substantial portion of the drug is eliminated from the body by the morning. After one half-life (8 hours), plasma concentrations are reduced by 50%; after three half-lives (24 hours), over 87% of the drug has been eliminated. This PK profile directly underpins the clinical trial findings of improved sleep throughout the night coupled with improved daytime functioning and a low incidence of next-morning somnolence, as drug levels are significantly diminished upon waking.[22] This contrasts with some other hypnotics that have longer half-lives, which can lead to more pronounced residual effects.

4.5 Pharmacokinetics in Special Populations and Drug Interactions

Daridorexant's PK profile is consistent across various demographic groups, with no clinically relevant effects of age, sex, race, or body size observed.[13] Furthermore, single- and multiple-dose administration studies show a similar PK profile, with no significant drug accumulation over time.[13]

• Renal Impairment: The pharmacokinetics of daridorexant are not significantly altered in patients with any degree of renal impairment, from mild to severe (not requiring dialysis). Therefore, no dose adjustment is necessary in this population.[13]
• Hepatic Impairment: While mild hepatic impairment (Child-Pugh Class A) does not require a dose adjustment, moderate impairment (Child-Pugh Class B) prolongs the drug's half-life. In these patients, the maximum recommended dose is reduced to 25 mg per night.[13] Daridorexant has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and its use is therefore not recommended.[1]
• Drug-Drug Interactions (DDI): Due to its primary metabolism by CYP3A4, daridorexant is susceptible to significant drug interactions.
• CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) is contraindicated or to be avoided, as it can dramatically increase daridorexant exposure (AUC increased by >400%).[13] With moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil), the maximum recommended dose of daridorexant is 25 mg.[13]
• CYP3A4 Inducers: Co-administration with moderate or strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's Wort) is not recommended, as it can significantly reduce daridorexant plasma concentrations and compromise its efficacy.[13]
• CNS Depressants: Concomitant use with alcohol or other CNS depressants (e.g., benzodiazepines, opioids, antihistamines) can lead to additive impairment of psychomotor skills and should be avoided or undertaken with extreme caution and potential dose adjustments.[13]

Pharmacokinetic Parameter	Value / Description	Source(s)
Time to Peak (Tmax)	1–2 hours (fasted); delayed by 1.3 hours with a high-fat meal.	1
Absolute Bioavailability	62%	1
Volume of Distribution (Vd)	31 L	10
Plasma Protein Binding	99.7%	1
Terminal Half-Life (t1/2​)	~8 hours; supports once-nightly dosing with minimal next-day accumulation.	1
Primary Metabolic Enzyme	Cytochrome P450 3A4 (CYP3A4), accounting for ~89% of clearance.	1
Primary Excretion Routes	Feces (~57%) and Urine (~28%), primarily as inactive metabolites.	1

5.0 Clinical Efficacy in the Treatment of Insomnia Disorder: The Pivotal Phase 3 Program

5.1 Overview of the Pivotal Trials

The global regulatory approvals of daridorexant were supported by a robust clinical development program, headlined by two pivotal, large-scale, multicenter, randomized, double-blind, placebo-controlled Phase 3 trials.[23] These studies were designed to rigorously evaluate the efficacy and safety of daridorexant in adults with moderate to severe insomnia disorder.

• Study 1 (NCT03545191): This trial enrolled 930 patients and evaluated two doses of daridorexant (50 mg and 25 mg) against a placebo over a three-month treatment period.[23]
• Study 2 (NCT03575104): This trial enrolled 924 patients and evaluated two different doses (25 mg and 10 mg) against a placebo, also for three months.[23]

The trials employed a comprehensive set of endpoints to capture the full impact of the treatment. The primary endpoints were objective measures of sleep, assessed via in-laboratory polysomnography (PSG) at Month 1 and Month 3 [23]:

• Wake After Sleep Onset (WASO): A measure of sleep maintenance, defined as the total time spent awake after initially falling asleep.
• Latency to Persistent Sleep (LPS): A measure of sleep onset, defined as the time from lights-out to the first 10 consecutive minutes of sleep.

The key secondary endpoints included validated patient-reported outcomes (PROs) to assess the subjective experience of sleep and, crucially, its impact on the subsequent day [23]:

• Subjective Total Sleep Time (sTST): The patient's self-reported estimate of total sleep duration from a daily sleep diary.
• Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ): This validated PRO was a cornerstone of the trials, designed to quantify the impact of insomnia on daytime functioning. A specific "sleepiness domain" score was a key secondary endpoint, measuring patient-reported feelings of mental and physical tiredness, sleepiness, and energy levels.[23]

The successful measurement of this daytime functioning endpoint was a critical and strategic component of the clinical program. Historically, insomnia treatments have focused almost exclusively on nighttime sleep metrics. By incorporating a validated PRO like the IDSIQ, the developers were able to formally quantify a benefit that directly addresses a core patient complaint—the debilitating daytime consequences of poor sleep. This provided the robust evidence required by regulatory agencies like the FDA and EMA to grant a label claim for improved daytime functioning, a powerful differentiator that older hypnotics could not scientifically substantiate.[6] This transformed a desired therapeutic feature into a scientifically validated and marketable clinical advantage, particularly for the 50 mg dose.

5.2 Efficacy Results: A Dose-Dependent Response

The results from the two pivotal trials demonstrated a clear, dose-dependent effect of daridorexant on both objective and subjective measures of sleep and daytime functioning.

• Daridorexant 50 mg (evaluated in Study 1): This dose emerged as the most comprehensively effective. It demonstrated statistically significant and clinically meaningful improvements versus placebo on all four key endpoints at both the Month 1 and Month 3 assessments.6
• Objective Sleep: Compared to placebo, the 50 mg dose significantly reduced WASO by a least-squares mean (LSM) of 22.8 minutes at Month 1 and 18.3 minutes at Month 3. It also significantly reduced LPS by 11.4 minutes at Month 1 and 11.7 minutes at Month 3.[27]
• Subjective Sleep & Daytime Function: Patients taking 50 mg reported a significant increase in sTST and, most notably, a significant improvement in the IDSIQ sleepiness domain score, indicating they felt less tired and more energetic during the day.[27] This robust and consistent effect on daytime functioning was unique to the 50 mg dose.
• Daridorexant 25 mg (evaluated in both Study 1 and Study 2): This dose demonstrated consistent efficacy in improving sleep parameters. It produced statistically significant improvements in WASO and sTST compared to placebo in both studies at both time points.23 The effect on LPS was also significant in Study 1, though it did not meet the prespecified threshold for statistical significance at Month 1 in Study 2.23 However, the effect of the 25 mg dose on daytime functioning (IDSIQ) was inconsistent and generally not statistically significant.[1]
• Daridorexant 10 mg (evaluated in Study 2): This low dose was found to be largely ineffective on the objective primary endpoints of WASO and LPS. While it did show a statistically significant improvement in patient-reported sTST, its overall efficacy was insufficient, and it is not an approved therapeutic dose.23

The table below summarizes the key efficacy outcomes from the pivotal trials, highlighting the dose-response relationship.

Endpoint (LSM Difference vs. Placebo)	Daridorexant 10 mg	Daridorexant 25 mg	Daridorexant 50 mg
Study 1 (NCT03545191)
WASO (min) - Month 1	N/A	-12.2 (p<0.0001)	-22.8 (p<0.0001)
WASO (min) - Month 3	N/A	-11.9 (p<0.0001)	-18.3 (p<0.0001)
LPS (min) - Month 1	N/A	-8.3 (p=0.0005)	-11.4 (p<0.0001)
LPS (min) - Month 3	N/A	-7.6 (p=0.0015)	-11.7 (p<0.0001)
sTST (min) - Month 1	N/A	+12.6 (p=0.0013)	+22.1 (p<0.0001)
IDSIQ Sleepiness Score - Month 1	N/A	-0.8 (p=0.055)	-1.8 (p<0.0001)
Study 2 (NCT03575104)
WASO (min) - Month 1	-2.7 (p=0.37)	-11.6 (p=0.0001)	N/A
WASO (min) - Month 3	-2.0 (p=0.57)	-10.3 (p=0.0028)	N/A
LPS (min) - Month 1	-2.6 (p=0.38)	-6.5 (p=0.030)*	N/A
sTST (min) - Month 1	+13.4 (p=0.0009)	+16.1 (p<0.0001)	N/A
IDSIQ Sleepiness Score - Month 3	-0.7 (p=0.14)	-1.3 (p=0.012)	N/A
Note: p-value for LPS at Month 1 in Study 2 did not meet the pre-specified threshold for statistical significance after multiplicity adjustment. Data sourced from Mignot et al., The Lancet Neurology (2022).23

6.0 Long-Term Efficacy and Safety: The 40-Week Extension Study

6.1 Study Design and Objective

To assess the long-term effects of daridorexant, a 40-week, double-blind, placebo-controlled extension study (NCT03679884) was conducted. This study enrolled 804 patients who had successfully completed one of the 12-week pivotal trials, allowing for an assessment of continuous treatment for up to one year.[22] In the extension, patients who were already receiving an active dose of daridorexant (10 mg, 25 mg, or 50 mg) continued on their assigned treatment. Patients who had been on placebo during the pivotal trial were re-randomized in a 1:1 ratio to receive either daridorexant 25 mg or placebo for the duration of the extension.[22] The primary objective was to evaluate the long-term safety and tolerability of daridorexant. Exploratory objectives included assessing the maintenance of efficacy on self-reported sleep (sTST) and daytime functioning (IDSIQ).[22]

6.2 Key Findings

The results of the extension study provided critical evidence supporting the suitability of daridorexant for the long-term management of chronic insomnia.

• Sustained Efficacy: The improvements in sleep and daytime functioning observed in the pivotal trials were maintained throughout the 40-week extension period. There was no evidence of tolerance or tachyphylaxis (i.e., the benefits did not diminish over time). The therapeutic effects remained most pronounced and consistent in the group receiving the 50 mg dose.[1] For instance, compared to placebo, the 50 mg group maintained a significant increase in sTST and a significant improvement in IDSIQ total scores through to the end of the 12-month treatment period.[22]
• Favorable Long-Term Safety: Continuous treatment with daridorexant for up to one year was demonstrated to be generally safe and well-tolerated. The overall incidence of treatment-emergent adverse events (TEAEs) was similar across all active treatment groups and the placebo group, ranging from 35% to 40%.[22] Crucially, no new or unexpected safety signals emerged with prolonged use, confirming the safety profile observed in the shorter-term trials.
• No Evidence of Dependence or Rebound Insomnia: A key finding from the extension study relates to the drug's discontinuation. The study included a 7-day, single-blind placebo run-out period after the 40-week treatment phase. During this period, there were no signs of withdrawal symptoms or rebound insomnia (a worsening of sleep beyond baseline levels upon drug cessation).[1] This finding is a critical safety advantage over traditional hypnotics like benzodiazepines, which are often associated with physical dependence and significant withdrawal syndromes, and it supports the notion that daridorexant can be discontinued without the need for a gradual taper.

7.0 Safety, Tolerability, and Risk Profile

The safety profile of daridorexant has been extensively characterized through its clinical development program, which included over 1,850 patients.[6] The data consistently show that the drug is well-tolerated, with a side effect profile that is distinct from and generally more favorable than older hypnotic agents.

7.1 Common Adverse Events

In the pivotal Phase 3 trials, the incidence of TEAEs was comparable between the daridorexant and placebo groups.[27] The most frequently reported adverse events were generally mild to moderate in intensity and included [1]:

• Headache: Reported in 6% of patients on 25 mg and 7% on 50 mg, compared to 5% for placebo.
• Somnolence or Fatigue: This composite term (including somnolence, sedation, fatigue, hypersomnia, and lethargy) was reported in 6% of patients on 25 mg and 5% on 50 mg, compared to 4% for placebo.
• Dizziness: Reported in 2% of patients on 25 mg and 3% on 50 mg, compared to 2% for placebo.
• Nausea: Reported in 3% of patients on 50 mg, compared to 2% for placebo.

7.2 Warnings and Precautions (Clinically Significant Risks)

Like all CNS-active medications, daridorexant carries certain risks that require careful consideration and patient counseling.

• CNS-Depressant Effects and Daytime Impairment: Although designed to minimize next-day effects, daridorexant can impair driving skills and other activities requiring mental alertness. Patients should be cautioned against driving or operating heavy machinery until they are reasonably certain that the drug does not adversely affect them, particularly on the day following administration.[4] The risk of impairment is significantly increased by concomitant consumption of alcohol or other CNS depressants.[13]
• Worsening of Depression and Suicidal Ideation: Insomnia is often comorbid with depression, and hypnotic medications have been associated with the worsening of depressive symptoms and the emergence of suicidal thoughts. Patients with a history of depression or other psychiatric disorders should be monitored closely for any changes in mood or behavior.[5]
• Sleep-Related Phenomena: As a class effect of orexin receptor antagonists, daridorexant has been associated with rare but potentially distressing sleep-related events:
• Sleep Paralysis: A temporary inability to move or speak that can occur during the transition between sleep and wakefulness.[16]
• Hypnagogic/Hypnopompic Hallucinations: Vivid and sometimes frightening sensory experiences that occur while falling asleep or waking up.[16]
• Cataplexy-like Symptoms: Episodes of sudden, transient muscle weakness, sometimes triggered by strong emotions like laughter or surprise, have been reported.[5]
• Complex Sleep Behaviors: These are activities such as sleep-walking, sleep-driving, preparing and eating food, or making phone calls while not fully awake. Patients typically have no memory of these events. The occurrence of any complex sleep behavior necessitates immediate discontinuation of the drug.[16]

7.3 Abuse Potential and Controlled Substance Status

Daridorexant is classified by the DEA as a Schedule IV controlled substance, a designation indicating a low potential for abuse and dependence relative to drugs in Schedules I, II, and III.[3] This classification was informed by a human abuse potential study conducted in recreational sedative drug users. In this study, a 50 mg dose of daridorexant was associated with "drug liking" scores that were significantly higher than placebo but significantly lower than those for the Z-drug zolpidem (30 mg) and a supratherapeutic dose of suvorexant (150 mg).[1] This confirms a modest but present potential for misuse, necessitating its controlled status.[1]

7.4 Contraindications

The use of daridorexant is strictly contraindicated in the following situations:

• Narcolepsy: As narcolepsy is a condition of orexin deficiency, administering an orexin antagonist would be pharmacologically irrational and would be expected to severely worsen symptoms of daytime sleepiness and cataplexy.[1]
• Concomitant Use with Strong CYP3A4 Inhibitors: Due to the profound increase in daridorexant exposure, co-administration with potent inhibitors of its primary metabolic enzyme is contraindicated.[13]

7.5 Hepatotoxicity

In pre-marketing clinical trials, daridorexant was not associated with clinically significant elevations in liver enzymes or instances of drug-induced liver injury.[19] Post-marketing surveillance has thus far supported this favorable hepatic safety profile. While rare instances of serum aminotransferase elevations have been noted, daridorexant has not been implicated in cases of clinically apparent liver injury.[3] The NIH's LiverTox database assigns it a likelihood score of E, indicating that it is an "unlikely cause of clinically apparent liver injury".[19]

8.0 Comparative Analysis: Daridorexant in the Context of Other DORAs

8.1 The DORA Landscape

The therapeutic class of dual orexin receptor antagonists currently includes three agents approved by the FDA for the treatment of insomnia: suvorexant (Belsomra®), approved in 2014; lemborexant (Dayvigo®), approved in 2019; and daridorexant (Quviviq®), approved in 2022.[1] All three are Schedule IV controlled substances and share the same fundamental mechanism of action, but they possess distinct pharmacokinetic and clinical profiles that influence their place in therapy.[30]

8.2 Pharmacokinetic Distinctions

The most critical differentiating feature among the approved DORAs is their elimination half-life, which directly influences their duration of action and potential for next-day residual effects.

• Half-Life (t1/2​):
• Daridorexant: ~8 hours.[1]
• Suvorexant: ~12 hours.[30]
• Lemborexant: 17 to 19 hours.[30]
• Volume of Distribution (Vd): The extent of tissue distribution also varies. Daridorexant (31 L) and suvorexant (49 L) have relatively small volumes of distribution, whereas lemborexant has a very large Vd of 1970 L, suggesting more extensive partitioning into tissues outside the plasma.[30]

8.3 Comparative Efficacy and Safety

Direct head-to-head clinical trials are lacking, so comparisons must be drawn from individual trial data and indirect network meta-analyses. These analyses reveal a nuanced picture.

• Efficacy: Different agents may have relative strengths for different aspects of insomnia.
• Sleep Onset: Network meta-analyses suggest that lemborexant (5 mg and 10 mg) may be most effective for improving subjective sleep onset latency (sTSO), while suvorexant and daridorexant are highly effective for improving objective, PSG-measured latency to persistent sleep (LPS).[31]
• Sleep Maintenance: All three agents (at approved doses) are effective at reducing wake after sleep onset (WASO). Some analyses suggest lemborexant may have a greater magnitude of effect on reducing WASO compared to daridorexant, which is plausible given its longer half-life.[31]
• Safety and Tolerability: The differing pharmacokinetic profiles directly translate to different tolerability profiles.
• An indirect comparison using number needed to treat (NNT) and number needed to harm (NNH) metrics suggested a potential efficacy advantage for lemborexant but a tolerability advantage for daridorexant.[26]
• Somnolence: The risk of next-day somnolence appears to be correlated with half-life. Lemborexant, with its 17-19 hour half-life, is associated with a higher risk of somnolence compared to daridorexant, with its 8-hour half-life.[33] This is a key consideration for patient selection, especially for individuals who need to be fully alert in the morning for driving or other critical tasks.

The choice between these agents requires a careful, individualized assessment of the patient's specific insomnia phenotype (e.g., primary difficulty with onset vs. maintenance), their sensitivity to side effects, and their daytime responsibilities.

Feature	Daridorexant (Quviviq®)	Suvorexant (Belsomra®)	Lemborexant (Dayvigo®)
FDA Approval Year	2022	2014	2019
Approved Doses	25 mg, 50 mg	5 mg, 10 mg, 15 mg, 20 mg	5 mg, 10 mg
Terminal Half-Life	~8 hours	~12 hours	17–19 hours
Bioavailability	62%	82%	Not specified
Key Efficacy Strengths	Sleep onset & maintenance; uniquely proven to improve daytime functioning (50 mg dose)	Sleep onset & maintenance	Sleep onset & maintenance; may have larger effect size for maintenance
Reported Somnolence	Low incidence (5-6%), similar to placebo	Higher than placebo; dose-dependent	Higher than placebo and daridorexant; dose-dependent
Key Clinical Differentiator	Shorter half-life minimizes next-day effects; proven daytime function benefit.	First-in-class DORA.	Longer half-life may be advantageous for severe sleep maintenance issues.
Data compiled from sources.1

9.0 Regulatory Approvals and Controlled Substance Scheduling

Daridorexant has successfully navigated the rigorous review processes of major global health authorities, securing approvals in key markets.

9.1 U.S. Food and Drug Administration (FDA)

Idorsia's New Drug Application (NDA) for daridorexant was accepted for review by the FDA on March 10, 2021.[25] Following a comprehensive evaluation of the Phase 3 clinical trial data, the FDA granted

approval on January 7, 2022.[25] The drug was made commercially available under the brand name Quviviq in May 2022, following its official scheduling as a controlled substance by the DEA.[1] The approved indication is for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.[25]

9.2 European Medicines Agency (EMA) / European Commission (EC)

In Europe, the EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending approval for daridorexant on February 24, 2022.[7] Subsequently, the European Commission granted formal

marketing authorization on May 3, 2022, making Quviviq the first dual orexin receptor antagonist to be approved for use across the European Union.[3] The European indication is slightly more specific, for the treatment of adult patients with insomnia characterised by symptoms present for at least 3 months and a considerable impact on daytime functioning.[3]

9.3 Other Major Regulatory Bodies

Following its approvals in the U.S. and EU, daridorexant has also been authorized in several other countries:

• Health Canada: Approved on April 26, 2023.[3]
• MHRA (Great Britain): Approved on August 26, 2022, through the EC Decision Reliance Procedure, which allows the MHRA to rely on the EC's decision for an expedited review.[37]
• Swissmedic (Switzerland): The drug has also been approved in Switzerland, the home country of Idorsia Pharmaceuticals.[38]

10.0 Clinical Application and Place in Therapy

10.1 Synthesizing the Evidence

Daridorexant represents a significant advancement in the pharmacological treatment of chronic insomnia. It is a well-tolerated and effective agent with a novel, targeted mechanism of action that addresses the core pathophysiology of hyperarousal. Its most defining characteristic is the carefully engineered pharmacokinetic profile, particularly its ~8-hour half-life. This property enables a dual therapeutic benefit: the improvement of nighttime sleep (both onset and maintenance) and, at the 50 mg dose, a validated improvement in daytime functioning. This is achieved with a low risk of next-day impairment, tolerance, or physical dependence, which are major limitations of older hypnotic drug classes.

10.2 Patient Selection

Based on its clinical profile, daridorexant is an appropriate first-line pharmacological option for adults with chronic insomnia disorder, particularly after non-pharmacological interventions like Cognitive Behavioral Therapy for Insomnia (CBT-I) have been attempted or are unavailable. It may be particularly well-suited for specific patient populations:

• Patients whose primary complaint includes significant impairment of daytime functioning, such as fatigue, low energy, or sleepiness. The 50 mg dose is specifically supported by evidence for this indication.
• Individuals who are sensitive to, or have previously experienced, the next-day residual effects (e.g., grogginess, cognitive "fog") of other hypnotic medications.
• Patients who require long-term, continuous treatment for chronic insomnia, given its favorable long-term safety profile and demonstrated lack of tolerance or rebound insomnia upon discontinuation.
• Elderly patients, who are at a higher risk for falls and cognitive side effects from traditional sedative-hypnotics. While caution is always warranted in this population, the targeted mechanism of daridorexant may offer a safer alternative to GABAergic agents.

10.3 Dosing and Administration Strategy

Effective and safe use of daridorexant requires adherence to specific dosing and administration guidelines.

• Initiation and Titration: Treatment can be initiated at either 25 mg or 50 mg, taken orally once per night.[19] The dose should be taken within 30 minutes of going to bed and only if the patient has at least 7 hours to dedicate to sleep before needing to be awake and active.[4]
• Optimal Therapeutic Dose: The 50 mg dose should be considered the preferred therapeutic dose for most patients, especially those seeking improvement in daytime functioning, as the 25 mg dose was not consistently effective for this key endpoint in clinical trials.[1] The 25 mg dose serves as a lower-dose option for patients who may not tolerate the higher dose or for whom a lower dose is medically indicated (e.g., moderate hepatic impairment or use with moderate CYP3A4 inhibitors).
• Patient Counseling: Clinicians must counsel patients on several key points: the potential for delayed onset if the medication is taken with food, the absolute necessity of avoiding alcohol, and the potential for daytime drowsiness, especially at the beginning of treatment. A thorough medication history is essential to screen for and manage potential drug-drug interactions, particularly with inhibitors and inducers of CYP3A4.

10.4 Future Directions and Concluding Remarks

Daridorexant has established itself as a valuable tool in the management of chronic insomnia. Its development, with a clear focus on demonstrating improved daytime functioning, may set a new standard for future insomnia drug trials, encouraging the inclusion of validated patient-reported outcomes that capture the full 24-hour impact of the disorder.

Ongoing research and surveillance will continue to refine its place in therapy. Post-market analysis of real-world data, such as from the FDA Adverse Event Reporting System (FAERS), will be crucial for confirming its long-term safety in a broader, more diverse population and for identifying any rare or unexpected adverse events.[39] There remains a clear need for direct, head-to-head comparative trials between daridorexant, suvorexant, and lemborexant to provide definitive guidance on their relative efficacy and safety profiles, moving beyond the limitations of indirect comparisons. Finally, data from ongoing studies, such as the pregnancy exposure registry and trials in pediatric populations, will be essential for expanding the evidence base and informing its use in special populations in the future.[40]

In conclusion, daridorexant is a thoughtfully designed medication that successfully leverages a targeted pharmacological mechanism and an optimized pharmacokinetic profile to offer effective treatment for both the nighttime and daytime symptoms of chronic insomnia, representing a welcome and significant addition to the therapeutic armamentarium.

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