Seltorexant (DB14961): A Comprehensive Review of its Pharmacology, Clinical Development, and Regulatory Landscape

Abstract

Seltorexant (DrugBank ID: DB14961), an investigational small molecule also known by developmental codes MIN-202 and JNJ-42847922, is a selective orexin-2 receptor (OX2R) antagonist. Its primary mechanism involves the modulation of the orexin system, which is crucial for regulating sleep-wake cycles, arousal, and mood. Seltorexant exhibits high affinity and selectivity for the OX2R over the OX1R. Preclinical studies in animal models demonstrated its efficacy in promoting sleep, particularly by reducing sleep latency and prolonging non-rapid eye movement (NREM) sleep, without significantly impacting REM sleep or showing abuse potential. Human pharmacokinetic studies reveal rapid absorption (Tmax 0.3-1.5 hours) and a short elimination half-life (2-3 hours), primarily metabolized by CYP3A4. Clinical development has focused on Major Depressive Disorder (MDD), especially with comorbid insomnia symptoms, and insomnia disorder. Phase 3 trials, such as MDD3001 (NCT04533529), have shown that adjunctive seltorexant significantly improves depressive symptoms (measured by MADRS) and sleep disturbances in patients with MDD and insomnia. It has been generally well-tolerated, with common adverse events including somnolence, headache, and nausea. A dedicated study (NCT03494907) evaluated its effects on electrocardiogram intervals in healthy adults, though specific QT results are not detailed in the available data. Seltorexant is under active development by Janssen, following an earlier co-development with Minerva Neurosciences. Regulatory activities include an agreed Paediatric Investigation Plan with the European Medicines Agency for MDD in adolescents. This report synthesizes the available pharmacological, preclinical, clinical efficacy, safety, and regulatory information on seltorexant.

1. Introduction to Seltorexant

1.1. Overview and Chemical Identity

Seltorexant is an investigational small molecule drug, identified by the DrugBank Accession Number DB14961.[1] It is also recognized by its developmental code names MIN-202 and JNJ-42847922.[2] The primary therapeutic areas for seltorexant development are Major Depressive Disorder (MDD), particularly as an adjunctive therapy for MDD with insomnia symptoms, and insomnia disorder.[2]

The orexin system, which seltorexant targets, is integral to the regulation of sleep-wake cycles, arousal, and mood.[5] Dysregulation of this system, leading to a state of hyperarousal, is implicated in the pathophysiology of both MDD and insomnia.[5] This dual developmental focus on MDD with insomnia and insomnia disorder itself suggests a therapeutic strategy targeting this common pathophysiological link. By addressing hyperarousal, seltorexant aims to provide a more nuanced treatment than broad sedative-hypnotics or traditional antidepressants, which may not adequately resolve comorbid sleep disturbances.

1.2. Chemical Properties

Seltorexant is chemically defined by the CAS Number 1452539-75-1.[1] An alternative CAS number, 1293281-49-8, is also noted in some sources, potentially referring to a different salt form or an earlier registration [2]; PubChem lists 1452539-75-1 as primary.[13]

The molecular formula for seltorexant is C21​H22​FN7​O.[1] Its molecular weight is approximately 407.45 g/mol.[1] The chemical structure,pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone [13] or 2--octahydropyrrolo[3,4-c]pyrrol-2-yl]-4,6-dimethylpyrimidine [1], indicates a specific stereochemistry, noted as (3aS,6aR) or (3aR,6aS) depending on the nomenclature source.[13]

Seltorexant is soluble in DMSO.[18] Its predicted water solubility is low (0.303 mg/mL according to ALOGPS).[1] Key physicochemical properties include:

• Hydrogen Bond Acceptors: 6-7 [1]
• Hydrogen Bond Donors: 0 [1]
• Rotatable Bonds: 3-4 [1]
• Topological Polar Surface Area (TPSA): Approximately 80 Ų [1]
• XLogP: Predicted values range from 2.32 to 3.49 [1]
• Lipinski's Rule of Five: Generally compliant [1]

These physicochemical properties, such as moderate lipophilicity (indicated by XLogP values), a TPSA around 80 Ų, and compliance with Lipinski's rules, are consistent with those of an orally bioavailable drug candidate intended for central nervous system (CNS) activity. The TPSA value suggests good membrane permeability, potentially including the blood-brain barrier, while the XLogP values indicate a balance between aqueous solubility and lipid permeability necessary for oral absorption and CNS penetration. However, the low aqueous solubility might necessitate specific pharmaceutical formulation strategies to ensure adequate bioavailability.

1.3. Rationale for Development: The Orexin System and Therapeutic Targeting

The development of seltorexant is centered on its interaction with the orexin system. Orexins (also known as hypocretins) are neuropeptides that play a pivotal role in regulating fundamental physiological processes, including wakefulness, arousal, sleep-wake cycles, reward processing, and cognitive functions.[4] Dysregulation of this system, often manifesting as hyperarousal, has been implicated in the pathophysiology of both Major Depressive Disorder (MDD) and insomnia.[5] Specifically, overstimulation of orexin-2 receptors (OX2R) can lead to manifestations such as insomnia and excessive cortisol release, both of which can contribute to or exacerbate depressive states.[5]

The therapeutic rationale for seltorexant is based on the hypothesis that by selectively antagonizing OX2R, it can normalize this excessive arousal. This modulation is expected to improve sleep quality and alleviate mood symptoms associated with depression.[5] Targeting the orexin system represents a novel mechanistic approach for MDD, offering an alternative to traditional monoamine-based therapies. This approach holds particular promise for patients suffering from MDD with comorbid insomnia, a prevalent and challenging-to-treat subgroup where existing treatments often fall short in addressing both aspects of the condition effectively.[5]

2. Mechanism of Action

2.1. Selective Orexin-2 Receptor (OX2R) Antagonism

The primary pharmacological action of seltorexant is its function as a selective antagonist of the human orexin-2 receptor (OX2R).[2]

2.2. Receptor Binding Affinity and Selectivity

Seltorexant exhibits high in vitro affinity for the human OX2R, with a reported pKi value of 8.0, and a similar affinity for the rat OX2R (pKi = 8.1).[9] A key characteristic of seltorexant is its pronounced selectivity for the OX2R over the orexin-1 receptor (OX1R). It demonstrates over 100-fold greater binding affinity for OX2R compared to OX1R, for which the pKi is reported as 6.1.[2] This 2-log selectivity ratio distinguishes seltorexant from dual orexin receptor antagonists (DORAs) such as suvorexant, lemborexant, and daridorexant, which target both OX1R and OX2R.[2]

The high selectivity for OX2R over OX1R is a significant aspect of seltorexant's pharmacological profile. OX1R and OX2R have distinct distributions and functional roles within the brain. OX2R is considered to be more directly involved in the regulation of sleep and mood.[6] Therefore, selective antagonism of OX2R may confer a more favorable therapeutic profile, potentially by preserving normal sleep architecture or reducing side effects that might be associated with OX1R modulation. Emerging research indeed suggests that selective OX2R antagonists might offer a more adequate sleep profile, possibly by better preserving the natural structure of sleep compared to less selective agents.[20] For instance, OX1R blockade in the presence of OX2R antagonism has been linked to dysregulation of REM sleep, an effect that selective OX2R antagonism might avoid.[9]

2.3. Downstream Physiological Effects Relevant to Insomnia and Depression

By selectively antagonizing OX2R, seltorexant is understood to reduce the activity of orexin neurons. This dampening of orexinergic signaling leads to a decrease in wakefulness and arousal.[6] Such an effect is therapeutically relevant for insomnia and for the hyperarousal symptoms commonly observed in individuals with MDD.[5]

Beyond its effects on sleep and arousal, the modulation of the orexin system by seltorexant is hypothesized to contribute to mood stabilization and a reduction in anxiety.[6] Furthermore, by mitigating excessive orexin-2 receptor stimulation, seltorexant may help normalize physiological processes such as cortisol release, which can be dysregulated in depression and contribute to both mood and sleep disturbances.[5]

The therapeutic mechanism of seltorexant is thus aimed at restoring physiological sleep patterns and controlling brain arousal levels, rather than inducing general sedation.[21] This targeted approach distinguishes it from traditional hypnotics, like benzodiazepines or Z-drugs, which often cause broad CNS depression. By specifically targeting the orexin system, seltorexant may lead to more natural sleep and potentially fewer "hangover" effects or impairments in cognitive and motor functions upon waking.

3. Preclinical Development

3.1. In Vitro Pharmacological Profile

In vitro studies have consistently confirmed seltorexant's high affinity and selectivity for the orexin-2 receptor (OX2R). The reported pKi values are 8.0 for the human OX2R and 8.1 for the rat OX2R, while the affinity for the orexin-1 receptor (OX1R) is significantly lower, with a pKi of 6.1.[9] This translates to an approximate 100-fold selectivity for OX2R over OX1R.

3.2. In Vivo Efficacy in Animal Models

Sleep Promotion

Animal models have provided substantial evidence for seltorexant's sleep-promoting effects. In rats, single oral administration of seltorexant at doses ranging from 3 to 30 mg/kg during their active (light) phase resulted in a dose-dependent reduction in the latency to non-rapid eye movement (NREM) sleep and an increase in the duration of NREM sleep within the first 2 hours post-administration. Notably, rapid eye movement (REM) sleep was reported to be minimally affected under these conditions.[15] The prolongation of NREM sleep was attributed to an increase in the duration of NREM bouts.[15]

The hypnotic effects of seltorexant were shown to be maintained upon repeated dosing. A 7-day regimen of 30 mg/kg seltorexant in rats sustained the reduced sleep onset latency and increased sleep duration. Following discontinuation of the treatment, these sleep parameters returned to baseline levels.[15]

Crucially, the specificity of seltorexant's action via OX2R was demonstrated in studies involving OX2R knockout mice. While seltorexant promoted sleep in wild-type mice, it had no such effect in mice lacking the OX2R, strongly suggesting that its sleep-inducing activity is mediated through this specific receptor.[20] The consistent sleep-promoting effects observed in rats, coupled with the lack of efficacy in OX2R knockout mice, robustly validates OX2R as the primary pharmacological target for seltorexant's somnogenic activity. The minimal impact on REM sleep seen in these preclinical models is a positive finding, as significant REM sleep suppression is a common and often undesirable side effect of many existing sedative-hypnotic agents.

Depression-like Behaviors

Preclinical studies have also indicated that seltorexant can reduce depressive-like behaviors in animal models, supporting its investigation for MDD.[6]

3.3. Initial Safety and Toxicology Profile from Preclinical Studies

Preclinical investigations into the safety profile of seltorexant have yielded encouraging results. The compound was found not to increase dopamine release in the nucleus accumbens of rats, a key brain region involved in reward and addiction.[20] Furthermore, in contrast to zolpidem, seltorexant did not produce place preference in mice after subchronic conditioning, indicating a lack of intrinsic motivational or abuse properties in these models.[18] This distinction is particularly important given that abuse potential is a significant concern for many CNS-active drugs, especially those used for sleep.

Pharmacokinetic studies in rats demonstrated that seltorexant effectively crosses the blood-brain barrier, achieving rapid occupancy of OX2R binding sites within the brain. This was followed by a relatively rapid clearance from the brain, consistent with its short half-life observed in human studies.[15] The lack of dopamine modulation in reward pathways and the absence of place preference behavior in animal models are significant preclinical findings. They suggest a potentially lower abuse liability for seltorexant compared to some established hypnotics like zolpidem, which has known abuse potential. This favorable preclinical safety profile, particularly regarding abuse potential, supports further clinical investigation of seltorexant as a potentially safer alternative for treating conditions like insomnia and MDD.

4. Pharmacokinetics in Humans

4.1. Absorption, Distribution, Metabolism, and Excretion (ADME)

4.1.1. Bioavailability, Tmax, Half-life

Human pharmacokinetic studies have characterized seltorexant as having rapid absorption. The time to reach maximum plasma concentration (Tmax) is typically observed between 0.3 to 1.5 hours after oral administration.[2] Data from a Phase 1 study involving single doses from 10 mg to 120 mg in healthy elderly non-Asian, young non-Asian, and Japanese adult participants showed a median Tmax ranging from 0.67 to 4.00 hours, with no significant differences between these groups or dose levels within the 10-40 mg range.[19]

Seltorexant exhibits a relatively short elimination half-life, reported to be around 2 to 3 hours.[2] The mean terminal elimination half-life (t1/2​) was comparable across different dose groups (10-40 mg) and participant demographics, ranging from 1.9 to 2.8 hours.[19] This pharmacokinetic profile, characterized by rapid absorption and short half-life, is considered advantageous for a sleep-inducing agent, as it facilitates rapid onset of action and minimizes the potential for next-day residual effects or "hangover" symptoms.[2]

Regarding dose proportionality, seltorexant demonstrated dose-linear pharmacokinetics for both maximum concentration (Cmax) and area under the curve (AUC∞) at doses between 10 mg and 40 mg in healthy young non-Asian, elderly non-Asian, and Japanese adult participants. However, at higher doses (60-120 mg) in healthy young non-Asian participants, the increase in pharmacokinetic parameters was linear but less than dose-proportional.[19] The bioavailability of seltorexant is not explicitly quantified in the provided materials.

4.1.2. Plasma Protein Binding and Volume of Distribution

Specific details regarding plasma protein binding and the volume of distribution for seltorexant in humans are not extensively detailed in the provided research snippets.[23] While general pharmacokinetic principles related to these parameters are discussed in some sources, direct empirical data for seltorexant is lacking in the reviewed material.

4.1.3. Metabolic Pathways and Excretion

Seltorexant is primarily metabolized by the cytochrome P450 enzyme CYP3A4.[2] Studies have also identified metabolites M12 and M16, which, similar to the parent drug, showed dose-proportional increases in Cmax and AUC∞ at seltorexant doses between 10 mg and 40 mg.[19] Detailed excretion pathways for seltorexant and its metabolites are not specified in the available information.

The rapid absorption and short elimination half-life are defining pharmacokinetic characteristics of seltorexant, supporting its intended use for insomnia by promoting rapid sleep onset and reducing the likelihood of next-day sedation or cognitive impairment. The prominent role of CYP3A4 in its metabolism is a crucial consideration for anticipating and managing potential drug-drug interactions, as co-administration with strong modulators of this enzyme could significantly alter seltorexant exposure.

4.2. Pharmacokinetics in Special Populations

The pharmacokinetic profile of seltorexant has been investigated in various populations:

• Elderly: Pharmacokinetic parameters for seltorexant were found to be comparable between elderly non-Asian participants and young non-Asian participants following 20 mg and 40 mg doses.[19] This suggests that age, within the studied range, may not significantly impact seltorexant disposition.
• Japanese Participants: Studies, including NCT03656232, have assessed seltorexant pharmacokinetics in healthy Japanese subjects. The results indicated that PK parameters in Japanese participants were comparable to those in young non-Asian participants at doses between 10 mg and 40 mg.[17]
• Renal Impairment: Clinical trial NCT04320305 was designed to evaluate the pharmacokinetics of seltorexant in participants with renal impairment.[1] Specific results for seltorexant from this trial are not detailed in the provided snippets. For context, a study on lemborexant, another orexin antagonist, in severe renal impairment showed an approximate 1.5-fold higher AUC, but no dose adjustment was deemed necessary.[29] This highlights that effects of renal impairment can be compound-specific within a drug class.
• Hepatic Impairment: Clinical trial NCT04260479 aimed to assess seltorexant pharmacokinetics in participants with hepatic impairment.[1] Results for seltorexant are not available in the snippets. Studies with other drugs show variable effects; for example, serelaxin PK was unaffected by hepatic impairment [35], while lemborexant exposure increased in mild to moderate hepatic impairment.[34]

The general comparability of seltorexant pharmacokinetics in elderly and Japanese populations with that in young non-Asian populations (for doses up to 40mg) is a positive finding, as it may simplify dosing regimens across these demographic groups.[19] However, the absence of specific pharmacokinetic data for seltorexant in individuals with renal and hepatic impairment represents an information gap critical for guiding safe and effective use in these special populations.

4.3. Food Effect

The influence of food on the pharmacokinetics of seltorexant was investigated in clinical trial NCT03796909, which was designed to assess this effect in healthy participants.[1] However, the specific quantitative results from this food effect study for seltorexant are not detailed in the provided research materials. For comparative purposes, a study on zolpidem, an unrelated hypnotic, indicated that food intake delayed Tmax and reduced both Cmax and AUC.[38] The absence of specific food effect data for seltorexant is a notable information gap, as food can significantly alter the absorption rate and extent of orally administered drugs, which is particularly relevant for a medication intended for rapid sleep induction. Any substantial impact of food on seltorexant's absorption could affect its clinical utility and dosing recommendations relative to meals.

4.4. Potential Drug-Drug Interactions (DDIs)

Seltorexant is metabolized by the cytochrome P450 enzyme CYP3A4.2 This metabolic pathway inherently suggests a potential for drug-drug interactions when seltorexant is co-administered with substances that inhibit or induce CYP3A4 activity.

Clinical trial NCT03663090 was specifically designed to evaluate the effect of itraconazole, a strong CYP3A4 inhibitor, and rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of seltorexant.1 The detailed outcomes of this Seltorexant-specific DDI study are not available in the provided snippets.

However, general information from studies with other compounds illustrates the potential magnitude of such interactions. For instance, daridorexant, another orexin receptor antagonist, showed increased AUC when co-administered with the moderate CYP3A4 inhibitor diltiazem, and an even greater increase was anticipated with strong inhibitors like itraconazole. Conversely, co-administration with efavirenz, a moderate CYP3A4 inducer, decreased daridorexant AUC.[41] Similarly, exposure to limertinib, an unrelated drug, was significantly increased by itraconazole and decreased by rifampin.[42]

Given that seltorexant relies on CYP3A4 for its metabolism, it is highly probable that its plasma exposure will be significantly altered by potent CYP3A4 modulators. Quantification of these effects from the dedicated DDI study (NCT03663090) is essential for developing appropriate dosing recommendations and contraindications when seltorexant is used concomitantly with such agents. Strong CYP3A4 inhibitors could lead to elevated seltorexant levels, potentially increasing the risk or severity of adverse effects, while strong CYP3A4 inducers could lower seltorexant levels, potentially diminishing its efficacy.

5. Pharmacodynamics in Humans

5.1. Target Engagement and Dose-Response Relationships

While direct human in vivo target engagement studies for seltorexant are not detailed in the provided snippets, preclinical ex vivo receptor binding studies in rats indicated that JNJ-42847922 (seltorexant) rapidly occupied OX2R binding sites in the brain.[20] This preclinical evidence supports the hypothesis of target engagement in humans.

Clinical trials have demonstrated dose-response relationships for seltorexant's efficacy. For instance, the Phase 2b insomnia trial (ISM2005, NCT03375203) showed that 10 mg and 20 mg doses were superior to placebo in improving Latency to Persistent Sleep (LPS) and Wake After Sleep Onset during the first 6 hours (WASO-6).[4] Similarly, the Phase 2b MDD trial (NCT03227224) indicated dose-dependent effects on depressive symptoms.[44] Interestingly, a study of seltorexant monotherapy in MDD (NCT03374475) suggested a potential curvilinear dose-response relationship, where the 20 mg dose showed a more favorable reduction in Hamilton Depression Rating Scale-17 item (HDRS17) scores compared to the 40 mg dose.[47]

5.2. Effects on Sleep Architecture (Polysomnography - PSG)

Polysomnography (PSG) has been utilized in several clinical trials to objectively assess seltorexant's effects on sleep architecture.

In trial NCT02067299, which enrolled MDD patients with persistent insomnia, single doses of seltorexant (10 mg, 20 mg, and 40 mg) significantly decreased Latency to Persistent Sleep (LPS) and increased Total Sleep Time (TST) and Sleep Efficiency (SE) in a dose-dependent manner compared to placebo.33

Trial NCT03375203 (ISM2005), conducted in individuals with insomnia disorder, further corroborated these findings. Seltorexant at 10 mg and 20 mg doses was superior to placebo in improving LPS and WASO-6, both at Night 1 and Night 13 of treatment. This study also highlighted that seltorexant demonstrated superior and more sustained efficacy compared to zolpidem, an active comparator.21

The consistent PSG findings across these studies provide robust, objective confirmation of seltorexant's sleep-promoting effects, particularly on sleep initiation (reduced LPS) and sleep maintenance (reduced WASO-6, increased TST and SE). The observed superiority over zolpidem in some parameters and the sustained effect over two weeks are key differentiating factors that suggest potential clinical advantages.

5.3. Effects on Mood and Depressive Symptoms

Seltorexant's effects on mood and depressive symptoms have been extensively evaluated, primarily in patients with MDD, often with comorbid insomnia.

In the Phase 1b monotherapy trial (NCT02476058 / NCT03374475) in MDD patients, seltorexant (20 mg) resulted in a significant improvement of core depressive symptoms, as measured by the HDRS17 and HAMD-6 (core symptoms subscale), compared to placebo. This antidepressant efficacy was maintained with continued treatment for up to 28 days. Notably, the therapeutic benefit remained significant even when sleep-related items were removed from the HDRS, suggesting an antidepressant effect independent of its sleep-improving properties. The efficacy appeared greater in patients with higher baseline insomnia severity.9

As an adjunctive therapy in MDD patients with an inadequate response to SSRIs/SNRIs, seltorexant 20 mg (in trial NCT03227224) demonstrated a greater improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score versus placebo at week 3 and week 6. This effect was particularly pronounced in patients with a baseline Insomnia Severity Index (ISI) score ≥ 15.[44]

The pivotal Phase 3 MDD3001 trial (NCT04533529), evaluating seltorexant as an adjunctive treatment for MDD with insomnia symptoms, met all its primary and secondary endpoints. Seltorexant showed a statistically significant and clinically meaningful improvement in depressive symptoms (MADRS total score at Day 43) and also improved sleep disturbance outcomes. Furthermore, it was reported to improve a broad range of the psychic symptoms of depression, beyond its effects on sleep.4

The consistent findings across these multiple Phase 2 and Phase 3 studies, demonstrating improvement in depressive symptoms, particularly in patients with comorbid insomnia, are noteworthy. The observation that this antidepressant effect persists even when sleep-specific items are removed from rating scales (e.g., MADRS-WOSI, adjusted HDRS) strongly supports a genuine antidepressant action beyond simple sedation or secondary benefits from improved sleep.39 This distinction is crucial for positioning seltorexant as a true antidepressant agent.

5.4. Biomarker Data

Investigations into biomarkers have provided further insights into seltorexant's pharmacodynamic effects. In the MDD trial NCT02476058 / NCT03374475, seltorexant treatment was associated with an overall increase in left posterior EEG power during stage 2 sleep. More specifically, there was a relative increase in delta power and a decrease in theta, alpha, and beta power in the posterior regions during this sleep stage.9 Additionally, the waking cortisol response was observed to decrease in the 20 mg seltorexant arm.47

These changes in EEG delta power and cortisol response offer objective neurophysiological and endocrine evidence supporting seltorexant's proposed mechanism of action. An increase in delta sleep power and normalization of the cortisol awakening response are often associated with improved sleep quality and antidepressant response, respectively. These biomarker findings align with the hypothesis that seltorexant helps to normalize hyperarousal and stress responses, which are frequently dysregulated in MDD.

5.5. Cardiovascular Safety: Effects on Electrocardiogram (ECG) Intervals (Detailed analysis of NCT03494907)

The clinical trial NCT03494907, titled "A Study to Evaluate the Effects of Single-dose Seltorexant on Electrocardiogram Intervals in Healthy Adult Participants," was specifically designed to assess the cardiovascular safety of seltorexant, with a focus on ECG parameters.[1] This type of study, often a Thorough QT (TQT) study or similar ECG assessment, is crucial for evaluating a drug's potential to affect cardiac repolarization, particularly the QT interval.

While the user query specifically mentions this trial, detailed quantitative results, such as the mean change in QTc interval from baseline, are not available in the provided research snippets.[5] However, the general safety assessments reported in other clinical trials of seltorexant have not highlighted major cardiovascular concerns, and the drug has been described as safe and well-tolerated.[5]

The existence of a dedicated ECG/QT study like NCT03494907 underscores the regulatory importance placed on thoroughly assessing cardiovascular safety, especially the risk of QT prolongation, for any new CNS-active medication. QT prolongation is a significant concern as it can predispose individuals to life-threatening cardiac arrhythmias. The fact that seltorexant has progressed through to large-scale Phase 3 clinical trials suggests that the findings from NCT03494907 were likely acceptable to regulatory authorities, with no major prohibitive cardiac safety signals identified that would have halted its development.

6. Clinical Development Program

The clinical development of seltorexant has been extensive, encompassing numerous trials across different phases, indications, and populations. Key sponsors involved in its development include Janssen Research & Development, LLC (a Johnson & Johnson company) and Minerva Neurosciences, with Minerva later selling its royalty interest to Royalty Pharma.[2] The program includes studies evaluating safety, tolerability, pharmacokinetics, and efficacy for its primary target indications of Major Depressive Disorder (MDD) and insomnia.

Table 1: Summary of Key Seltorexant Clinical Trials

NCT Number	Other Identifiers (e.g., Study Codes)	Phase	Status	Indication(s)	Sponsor(s)	Key Objective(s)	Primary Endpoint(s)	Key Results Summary
NCT03494907	JNJ-42847922	1	Completed	Healthy Volunteers (ECG Assessment)	Janssen	Evaluate effects of single-dose seltorexant on ECG intervals	Change in QTcF	Results not detailed in snippets, but development proceeded 1
NCT02833342	JNJ-42847922	1	Not specified in snippets	Healthy Volunteers	Janssen	PK/Safety	Not specified	Not detailed 54
NCT03656232	JNJ-42847922	1	Completed	Healthy Elderly (non-Asian), Healthy Young (non-Asian), Healthy Japanese Adults	Janssen	PK and safety in different demographic groups	PK parameters (Cmax, AUC), Safety (TEAEs)	PK comparable across groups (10-40mg); well-tolerated up to 120mg 19
NCT03796909	JNJ-42847922	1	Completed	Healthy Volunteers (Food Effect)	Janssen	Assess effect of food on seltorexant PK	PK parameters with/without food	Results not detailed 1
NCT03663090	JNJ-42847922	1	Completed	Healthy Volunteers (Drug-Drug Interaction)	Janssen	Assess effect of itraconazole/rifampin on seltorexant PK	PK parameters with co-administration	Results not detailed 1
NCT04320305	JNJ-42847922	1	Completed	Renal Impairment	Janssen	Assess effect of renal impairment on seltorexant PK	PK parameters	Results not detailed for seltorexant 1
NCT04260479	JNJ-42847922	1	Completed	Hepatic Impairment	Janssen	Assess effect of hepatic impairment on seltorexant PK	PK parameters	Results not detailed for seltorexant 1
NCT04951609	42847922MDD1016	1	Terminated	Adolescent MDD (adjunctive)	Janssen	Safety, tolerability, PK in adolescents	Safety, PK	Terminated 67
NCT03375203	MIN-202, ISM2005, JNJ-42847922	2b	Completed	Insomnia Disorder (without psychiatric comorbidity)	Minerva/Janssen	Efficacy (LPS, WASO-6) and safety vs placebo and zolpidem	LPS at Night 1	Met primary endpoint; 10mg & 20mg superior to placebo and zolpidem on LPS & WASO-6; well-tolerated 21
NCT02968285	JNJ-42847922	2	Not specified (likely completed)	Primary Insomnia	Janssen	Efficacy and safety	Sleep parameters	Seltorexant 40mg improved SE, TST, LPS, WASO vs placebo 4343
NCT03227224	MIN-202, MDD2001, JNJ-42847922	2b	Completed	MDD (adjunctive, inadequate response to SSRI/SNRI)	Janssen/Minerva	Efficacy (MADRS) and safety	Change in MADRS total score at Week 6	20mg improved MADRS vs placebo, especially with ISI ≥ 15; somnolence, headache, nausea common AEs 44
NCT03321526	MIN-202, MDD2002, JNJ-42847922	2	Completed	MDD (adjunctive, inadequate response to SSRI/SNRI) vs Quetiapine XR	Minerva/Janssen	Discontinuation rate, MADRS, safety	Discontinuation rate over 6 months	Quantitative advantage in discontinuations for seltorexant; 20mg seltorexant showed greater MADRS improvement, especially with sleep disturbance; favorable safety vs quetiapine 70
NCT02067299	JNJ-42847922	1b/2a	Completed	MDD with persistent insomnia (adjunctive to antidepressant)	Janssen	Effects on PSG and depressive symptoms (exploratory)	LPS, TST, SE; QIDS-SR	Dose-dependent decrease in LPS, increase in TST & SE; trend for mood improvement (40mg) 33
NCT02476058 (also linked to NCT03374475)	MIN-202, JNJ-42847922	1b	Completed	MDD (monotherapy)	Janssen/Minerva	Antidepressant effect, sleep stages, EEG, cortisol	HDRS17, HAMD-6	20mg improved core depressive symptoms vs placebo; EEG changes (increased delta power), decreased waking cortisol 9
NCT05307692	42847922ALZ2001	2a	Completed	Probable Alzheimer's Disease with agitation/aggression	Janssen	Efficacy (NPI-C A+A) and safety	Change in NPI-C Agitation/Aggression score	Development for AD agitation discontinued Oct 2024 74
NCT04533529	MDD3001, JNJ-42847922	3	Completed	MDD with insomnia symptoms (adjunctive to SSRI/SNRI)	Janssen	Efficacy (MADRS) and safety	Change in MADRS total score at Day 43	Met all primary and secondary endpoints; significant improvement in depressive symptoms and sleep; well-tolerated 4
NCT04513912	MDD3002, JNJ-42847922	3	Completed	MDD with insomnia symptoms (adjunctive vs Quetiapine XR)	Janssen	Efficacy (response rate on MADRS) and safety	Response rate (≥50% MADRS improvement) at 26 weeks	Results not detailed beyond completion 30
NCT06559306	42847922MDD3003	3	Recruiting	MDD with insomnia symptoms (adjunctive, maintenance of effect)	Janssen	Efficacy and safety (maintenance)	Time to relapse	Two-part study (DB, OL, DB maintenance) 30
NCT04533568	MDD3004	3	Not specified in snippets (likely part of OARS program)	MDD with insomnia symptoms	Janssen	Not specified	Not specified	Limited details 80
NCT04788023	MDD3005	3	Completed	MDD (Open-Label Extension)	Janssen	Long-term safety and efficacy	Safety, PANSS/CGI-S (if from other OLEs)	Long-term safety extension for OARS program 55

Note: Status and details are based on the latest information available in the provided snippets. Some trial identifiers may overlap or represent different phases/parts of the same overall study program.

6.2. Phase 1 Clinical Trials

6.2.1. Healthy Volunteer Studies (Safety, Tolerability, PK)

Early Phase 1 development of seltorexant involved studies in healthy volunteers to establish its initial safety, tolerability, and pharmacokinetic (PK) profile. An initial single ascending dose study indicated that seltorexant increased somnolence and possessed a favorable PK and safety profile suitable for a sedative/hypnotic agent.20 Trial NCT02833342 was also conducted in healthy subjects, though specific details were not provided in the available materials.54

A key Phase 1 study, NCT03656232, specifically assessed the PK and safety of seltorexant in diverse demographic groups: non-Asian healthy elderly individuals, weight- and gender-matched non-Asian healthy young adults, and healthy Japanese adults. This study found that seltorexant's PK profile was largely comparable across these groups for doses ranging from 10 mg to 40 mg. The drug was reported to be well-tolerated up to a dose of 120 mg. The most frequently observed treatment-emergent adverse events (TEAEs) in this study were somnolence, headache, and sleep paralysis.19

6.2.2. Specific Focus: NCT03494907 – Design, Objectives, and Outcomes for ECG Assessment

Clinical trial NCT03494907, officially titled "A Study to Evaluate the Effects of Single-dose Seltorexant on Electrocardiogram Intervals in Healthy Adult Participants," was a critical component of the early clinical development program.[1] This Phase 1 study, sponsored by Janssen Research & Development, LLC, focused on assessing the cardiovascular safety of seltorexant, specifically its potential impact on cardiac repolarization as measured by ECG intervals. The study was conducted in healthy adult participants and is listed as completed.[1]

The primary objective was to evaluate the effects of single doses of seltorexant on various ECG parameters, with a particular emphasis on the QT interval, corrected for heart rate (e.g., QTcF). Such studies are standard regulatory requirements to rule out significant cardiac risks. While the specific quantitative outcomes of NCT03494907 (e.g., mean change in QTcF from baseline compared to placebo and a positive control) are not detailed in the provided research snippets [5], the progression of seltorexant into extensive Phase 3 clinical trials strongly suggests that no clinically prohibitive cardiac safety signals, such as significant QT prolongation, were identified in this dedicated ECG assessment. The general safety profile reported in other seltorexant trials has not highlighted major cardiovascular concerns.

6.2.3. Studies in Special Populations

To understand seltorexant's behavior in specific patient groups, dedicated Phase 1 studies were conducted:

• Renal Impairment: NCT04320305 was designed to evaluate the effect of renal impairment on seltorexant PK.[1] The specific results for seltorexant in this population are not available in the provided documents.
• Hepatic Impairment: NCT04260479 aimed to assess the impact of hepatic impairment on seltorexant PK.[1] Similarly, detailed results for seltorexant are not provided.

6.2.4. Drug-Drug Interaction and Food Effect Studies

• Food Effect: Trial NCT03796909 was conducted to determine the effect of food on the pharmacokinetics of seltorexant in healthy participants.[1] The outcomes of this study are not detailed in the available snippets.
• Drug-Drug Interactions: Given that seltorexant is metabolized by CYP3A4, trial NCT03663090 was designed to evaluate its PK when co-administered with itraconazole (a strong CYP3A4 inhibitor) and rifampin (a strong CYP3A4 inducer).[1] Specific results from this Seltorexant DDI study are not available.

6.3. Phase 2 Clinical Trials

6.3.1. Trials in Insomnia Disorder

Seltorexant's efficacy in insomnia was primarily evaluated in Phase 2 trials:

• NCT03375203 (ISM2005): This was a significant Phase 2b dose-ranging study in adult and elderly subjects with insomnia disorder but without psychiatric comorbidity. Sponsored by Minerva Neurosciences and Janssen, this completed trial compared seltorexant (5 mg, 10 mg, 20 mg) against placebo and zolpidem (an active comparator).[4] The primary objective was to evaluate efficacy based on LPS at Night 1, with WASO-6 as a key secondary endpoint. Results showed that seltorexant met its primary endpoint, with the 10 mg and 20 mg doses demonstrating superiority over placebo for both LPS and WASO-6 at Night 1 and Night 13. Notably, seltorexant exhibited superior and more sustained efficacy compared to zolpidem and was well tolerated, with TEAEs similar to placebo.[21]
• NCT02968285 [43]: An earlier Phase 2 study in primary insomnia. Reports suggest seltorexant 40 mg improved sleep efficiency, total sleep time, LPS, and WASO compared to placebo.[43]

6.3.2. Trials in Major Depressive Disorder (MDD)

Several Phase 2 trials investigated seltorexant's potential in MDD, often as an adjunctive therapy:

• NCT03227224 (MDD2001): A Phase 2b adaptive dose-finding study evaluating seltorexant (10 mg, 20 mg, 40 mg) as adjunctive therapy in MDD patients with an inadequate response to SSRIs/SNRIs. Sponsored by Janssen and Minerva, this trial is completed.[44] The primary endpoint was the change in MADRS total score at week 6. Seltorexant 20 mg demonstrated greater improvement in MADRS scores versus placebo, particularly in patients with a baseline Insomnia Severity Index (ISI) score ≥ 15. Common AEs included somnolence, headache, and nausea.[44]
• NCT03321526 (MDD2002): A Phase 2 trial comparing seltorexant (20 mg, 40 mg) against quetiapine XR as adjunctive therapy in MDD patients with inadequate response to SSRIs/SNRIs. This trial, sponsored by Minerva/Janssen, is completed.[70] The primary endpoint was the discontinuation rate due to all causes over 6 months. Seltorexant showed a quantitative advantage in discontinuation rates (41% vs. 47% for quetiapine XR). The 20 mg seltorexant dose led to greater MADRS improvement, especially in those with sleep disturbance (ISI ≥15), and had a favorable safety profile compared to quetiapine.[71]
• NCT02067299: An exploratory, crossover study in antidepressant-treated MDD patients with persistent insomnia, evaluating single doses of seltorexant (10 mg, 20 mg, 40 mg). Sponsored by Janssen and completed.[33] Endpoints included PSG measures and QIDS-SR. Results showed a dose-dependent decrease in LPS and an increase in TST and SE, with a trend for mood improvement at the 40 mg dose.[33]
• NCT02476058 (also linked to NCT03374475): A Phase 1b study of seltorexant monotherapy (20 mg, 40 mg) versus placebo and diphenhydramine in MDD. Sponsored by Janssen/Minerva and completed.[9] Endpoints included HDRS17, HAMD-6, EEG, and cortisol levels. Seltorexant 20 mg improved core depressive symptoms versus placebo, an effect maintained for up to 28 days. This antidepressant efficacy coincided with EEG changes (increased delta power) and a decreased waking cortisol response.[9]

6.3.3. Trials in Other Indications

• Alzheimer's Disease (AD): NCT05307692 (42847922ALZ2001) was a Phase 2a study evaluating seltorexant for behavioral and psychological symptoms of dementia (BPSD), specifically agitation/aggression, in patients with probable AD. This Janssen-sponsored trial is listed as completed.[1] However, Johnson & Johnson announced the discontinuation of seltorexant development for Alzheimer's agitation and aggression in October 2024.[76]
• Sleep Apnea: Seltorexant was also under investigation for sleep apnea, but no recent development has been reported for this indication.[2]

6.4. Phase 3 Clinical Trials (OARS Program - Orexin Adjunctive Remedy for Sleep)

The Phase 3 clinical development of seltorexant, known as the OARS program, has primarily focused on its use as an adjunctive treatment for MDD with insomnia symptoms (MDDIS). These trials typically evaluate a 20 mg dose of seltorexant against placebo, added to ongoing SSRI/SNRI antidepressant therapy, with primary outcomes related to improvements in depressive symptoms (e.g., MADRS score) and sleep.

• NCT04533529 (MDD3001): This pivotal Phase 3, multicenter, international, double-blind, placebo-controlled, 6-week trial, sponsored by Janssen, is completed.[4] It met all primary (change in MADRS total score at Day 43) and secondary endpoints (including MADRS-WOSI and PROMIS-SD-8a T-score), demonstrating statistically significant and clinically meaningful improvements in both depressive symptoms and sleep disturbance outcomes. Seltorexant was reported to be safe and well-tolerated.[4]
• NCT04513912 (MDD3002): A Phase 3 trial comparing seltorexant as adjunctive therapy to quetiapine XR in MDD patients with insomnia symptoms. Sponsored by Janssen, this trial is completed.[30] The primary hypothesis was seltorexant's superiority to quetiapine XR in treatment response (≥50% MADRS improvement) at 26 weeks. Specific results beyond completion are not detailed in the snippets.
• NCT06559306 (42847922MDD3003): An ongoing Phase 3 study evaluating the efficacy and maintenance of effect of adjunctive seltorexant versus placebo in MDD with insomnia. This Janssen-sponsored trial is currently recruiting and features a two-part design including double-blind treatment, open-label treatment, and a double-blind maintenance phase.[30]
• NCT04533568 (MDD3004): Details are sparse, but it is likely part of the OARS program.[80] The comprehensive nature of the Phase 3 OARS program, specifically targeting MDD with insomnia symptoms, signals a clear regulatory strategy and a focus on a patient subgroup with significant unmet medical needs.[30] The positive topline results from the MDD3001 trial represent a major milestone in seltorexant's development, underscoring its potential as an effective adjunctive treatment.

6.5. Long-Term Extension Studies

To assess the long-term safety and efficacy of seltorexant, open-label extension (OLE) studies have been conducted:

• NCT04788023 (MDD3005): This is an OLE study for participants from the OARS program, sponsored by Janssen and listed as completed.[55]
• The MDD3001 trial (NCT04533529) also incorporated a long-term safety extension component.[39] These OLE studies are vital for understanding the durability of seltorexant's effects and its safety profile with chronic administration.

7. Efficacy of Seltorexant

7.1. In Major Depressive Disorder (with and without Insomnia Symptoms)

Adjunctive Therapy (MDD with Insomnia)

Seltorexant has demonstrated notable efficacy as an adjunctive treatment for MDD, particularly in patients who also experience insomnia symptoms and have had an inadequate response to standard antidepressant therapies (SSRIs/SNRIs).

The pivotal Phase 3 trial MDD3001 (NCT04533529) showed that seltorexant (20 mg) achieved statistically significant and clinically meaningful improvements in the MADRS total score at Day 43 compared to placebo. Furthermore, the trial met all secondary endpoints, indicating improvements in sleep disturbance outcomes and a broad range of psychic symptoms of depression, independent of its effects on sleep.4

Earlier, the Phase 2b trial NCT03227224 also found that adjunctive seltorexant 20 mg led to greater improvement in MADRS total score versus placebo at weeks 3 and 6, with this effect being more pronounced in patients with a baseline Insomnia Severity Index (ISI) score ≥ 15.44

Monotherapy (MDD)

As a monotherapy for MDD, seltorexant was investigated in the Phase 1b trial NCT02476058 (also linked to NCT03374475). In this study, seltorexant 20 mg improved core depressive symptoms (measured by HDRS17 and HAMD-6) compared to placebo, and this effect was maintained for up to 28 days. The antidepressant benefit was more significant in patients with higher baseline insomnia severity and persisted even when sleep-specific items were removed from the HDRS, suggesting a direct antidepressant action.9

The consistent demonstration of antidepressant effects across multiple studies, especially in the challenging population of MDD patients with comorbid insomnia, is a key finding. The efficacy on core depressive symptoms, even when accounting for sleep improvement (e.g., through MADRS-WOSI analysis), supports its potential as a genuine antidepressant agent rather than merely a hypnotic with secondary mood benefits. This is particularly relevant as many patients with MDD continue to experience residual symptoms, including insomnia, despite treatment with standard antidepressants.

7.2. In Insomnia Disorder

Seltorexant has also shown strong efficacy in treating insomnia disorder in patients without psychiatric comorbidities.

The Phase 2b trial NCT03375203 (ISM2005) found that seltorexant 10 mg and 20 mg significantly improved Latency to Persistent Sleep (LPS) and Wake After Sleep Onset over the first 6 hours (WASO-6) compared to placebo. Importantly, seltorexant demonstrated superior and more sustained efficacy on these parameters compared to zolpidem, a commonly prescribed hypnotic.21

An earlier Phase 2 study (potentially NCT02968285 or NCT02464046) also reported that seltorexant 40 mg improved sleep efficiency (SE), total sleep time (TST), LPS, and WASO compared to placebo.43

These robust efficacy data for insomnia, based on objective PSG measures, establish seltorexant as an effective hypnotic. Its potential advantages over existing treatments like zolpidem, particularly in terms of sustained effect, could make it a valuable alternative for managing insomnia.

7.3. In Alzheimer's Disease-Related Symptoms

Seltorexant was investigated for its potential to treat behavioral and psychological symptoms of dementia (BPSD), specifically agitation and aggression, in patients with probable Alzheimer's Disease in the Phase 2a trial NCT05307692 (42847922ALZ2001).74 However, Johnson & Johnson announced the discontinuation of seltorexant development for Alzheimer's agitation and aggression in October 2024.76

The decision to discontinue development in this indication suggests that the efficacy observed in MDD and insomnia did not translate to this distinct neuropsychiatric condition, or there may have been other strategic or safety considerations. This highlights the indication-specific nature of drug efficacy, even for compounds targeting broadly implicated systems like the orexin pathway.

8. Safety and Tolerability Profile

8.1. Overview of Adverse Events from Clinical Trials

Seltorexant has been generally reported as safe and well-tolerated across numerous clinical trials.[2] In the pivotal Phase 3 MDD3001 trial (NCT04533529), the rates of common adverse events (AEs) were similar between the seltorexant and placebo arms when used as adjunctive therapy.[4] Specifically, treatment-emergent adverse events (TEAEs) were reported for 36.0% of seltorexant recipients compared to 40.3% of placebo recipients.[39]

8.2. Common Treatment-Emergent Adverse Events (TEAEs)

The most frequently reported TEAEs (≥5%) associated with seltorexant in the MDD adjunctive therapy trial NCT03227224 were somnolence, headache, and nausea.[44] In a Phase 1 study with healthy subjects (NCT03656232), the most common TEAEs were somnolence (7.1%), headache (5.7%), and sleep paralysis (2.9%).[19] Other AEs noted in early clinical trials include fatigue, dizziness, abdominal discomfort, and nightmares.[2]

8.3. Serious Adverse Events (SAEs) and Discontinuations due to Adverse Events

The incidence of SAEs and discontinuations due to AEs has generally been low with seltorexant. In the Phase 3 MDD3001 trial, there were few discontinuations due to TEAEs. One SAE was reported in each group (iron deficiency anemia in the seltorexant group; fall and lumbar spine compression fracture in the placebo group), with all SAEs deemed unrelated to the study drug. No deaths occurred in this study.[39] Similarly, in the Phase 2b insomnia trial (ISM2005), overall TEAEs were comparable to placebo, and discontinuation rates were low.[21] The Phase 1 study in diverse healthy populations (NCT03656232) reported no deaths, SAEs, or TEAEs leading to discontinuation.[19]

8.4. Human Abuse Potential

A dedicated clinical trial, NCT04040600, titled "A Study to Determine the Abuse Potential of Seltorexant Compared to Suvorexant and Zolpidem in Non-dependent, Recreational Sedative Users," was conducted to specifically evaluate seltorexant's abuse liability.[1] The specific results from this human abuse potential study are not detailed in the provided snippets. However, preclinical data from studies in rats and mice are encouraging, as seltorexant did not appear to increase dopamine release in the nucleus accumbens or produce place preference, unlike zolpidem, suggesting a lower intrinsic potential for abuse.[18] The findings from NCT04040600 will be critical for regulatory assessment and potential scheduling of seltorexant, as abuse liability is a key consideration for orexin antagonists and other CNS-active drugs.

8.5. Long-Term Safety and Tolerability

Long-term safety and tolerability of seltorexant are being assessed in open-label extension (OLE) studies, such as NCT04788023 (MDD3005), which served as an extension for the OARS Phase 3 program.55 The Phase 3 trial MDD3001 (NCT04533529) also included a long-term safety extension component.39

The overall safety profile emerging from these trials appears favorable. A particularly important aspect for long-term antidepressant therapy is the absence of common burdensome side effects associated with existing treatments like SSRIs and SNRIs, such as significant weight gain or sexual dysfunction. If seltorexant consistently demonstrates a lack of these AEs in long-term data, it would offer a significant advantage in terms of patient adherence and overall quality of life.

9. Regulatory Landscape and Development History

9.1. Developers and Collaborations

Seltorexant was initially co-developed by Janssen Pharmaceutica NV (a subsidiary of Johnson & Johnson) and Minerva Neurosciences.[2] In 2020, Minerva Neurosciences exercised its right to opt out of the joint development agreement with Janssen for the future development of seltorexant.[56] Subsequently, in January 2021, Royalty Pharma acquired Minerva's royalty interest in seltorexant. This agreement involved an upfront payment of $60 million to Minerva, with potential future milestone payments up to $95 million. Minerva Neurosciences remains entitled to mid-single digit royalties on worldwide net sales of seltorexant.[56] Janssen is currently leading the Phase 3 development program for seltorexant for MDD with insomnia symptoms.[61]

9.2. Regulatory Designations and Submissions

FDA (U.S. Food and Drug Administration)

The provided research snippets do not mention any specific FDA Fast Track or Breakthrough Therapy designations for seltorexant.[56] While other drugs in development for MDD, such as REL-1017, have received Fast Track designation [56], such a status for seltorexant is not highlighted. Following the positive Phase 3 results, particularly from the MDD3001 trial, New Drug Application (NDA) submission plans by Janssen for MDD with insomnia symptoms are anticipated. However, specific timelines for regulatory filings in 2024 or 2025 are not detailed beyond Johnson & Johnson's broader strategic goal of introducing more than 20 new therapies by 2030, with seltorexant identified as a key asset.[4]

EMA (European Medicines Agency)

Seltorexant has an active Paediatric Investigation Plan (PIP) with the EMA, identified as EMEA-002746-PIP01-20-M02. This PIP concerns the treatment of MDD in adolescents (aged 12 to <18 years) with insomnia symptoms, as an adjunctive therapy to SSRI medication and psychotherapy. The decision P/0479/2023, dated December 1, 2023, accepted a modification to this PIP. The plan includes waivers for children under 7 years of age (on the grounds that the condition does not occur in this age group) and for children aged 7 to less than 12 years (on the grounds that the product is likely to be unsafe in this age group). The agreed PIP is scheduled for completion by February 2031.[13] An agreed PIP is a critical regulatory step for new medicines in Europe that may have paediatric use. Marketing Authorisation Application (MAA) submission plans to the EMA are not detailed in the available information. The active PIP with the EMA signals a clear pathway towards potential European approval and reflects a commitment to paediatric development in a specific, defined sub-population.

9.3. Current Development Status and Future Outlook

As of early 2025, seltorexant is in late-stage Phase 3 development under Janssen's stewardship, primarily for the adjunctive treatment of MDD with insomnia symptoms through the OARS (Orexin Adjunctive Remedy for Sleep) program.[2] Phase 2 trials for insomnia disorder have been completed.[2]

Notably, the development of seltorexant for Alzheimer's disease-related agitation and aggression was discontinued by Johnson & Johnson in October 2024.[76] This strategic decision likely reflects a data-driven approach to prioritize indications with the highest probability of success and market impact, especially given the positive Phase 3 results in MDD with insomnia.[4] Johnson & Johnson views seltorexant as a key asset with the potential for peak annual sales between $1 billion and $5 billion.[76] The future outlook for seltorexant appears strongly focused on its unique dual benefit for mood and sleep in the MDD population.

10. Conclusion

Seltorexant (DB14961) has emerged as a promising investigational drug, distinguished by its selective orexin-2 receptor (OX2R) antagonism. This mechanism offers a novel therapeutic approach for Major Depressive Disorder (MDD), particularly in patients with comorbid insomnia symptoms, and for insomnia disorder itself, by targeting the underlying pathophysiology of hyperarousal.

Its pharmacokinetic profile, characterized by rapid absorption and a short elimination half-life, appears well-suited for promoting sleep onset without significant next-day residual effects. Clinical trials, including the pivotal Phase 3 MDD3001 study, have demonstrated seltorexant's efficacy in improving both depressive symptoms and sleep disturbances when used as an adjunctive therapy in MDD patients with insomnia. Furthermore, it has shown efficacy in treating insomnia disorder, with some evidence suggesting advantages over existing hypnotics like zolpidem in terms of sustained effect.

The safety and tolerability profile of seltorexant observed in clinical trials to date has been generally favorable, with common adverse events such as somnolence, headache, and nausea being mostly mild to moderate. The discontinuation of its development for Alzheimer's disease-related agitation underscores the indication-specific nature of its efficacy and/or risk-benefit profile.

Seltorexant has the potential to address a significant unmet medical need for patients with MDD who experience persistent insomnia despite standard antidepressant treatment. Its dual action on mood and sleep, mediated by a novel mechanism, could offer a valuable alternative or adjunctive treatment option.

However, several questions remain. The full quantitative results from the dedicated cardiovascular safety study (NCT03494907) and the human abuse potential study (NCT04040600) are critical for a complete understanding of its safety profile. Long-term safety and efficacy data from ongoing and completed extension studies will also be important. Furthermore, comparative effectiveness studies against other treatments for MDD and insomnia will help to define its precise place in therapy. Future research should continue to focus on these areas, as well as on identifying patient populations most likely to benefit from seltorexant's unique mechanism of action. Successful completion of the ongoing Phase 3 program and subsequent regulatory approvals could establish seltorexant as an important new therapeutic agent in psychiatric care.

11. References

[1]

Works cited

1. Seltorexant: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed May 16, 2025, https://go.drugbank.com/drugs/DB14961
2. Seltorexant - Wikipedia, accessed May 16, 2025, https://en.wikipedia.org/wiki/Seltorexant
3. Seltorexant - Janssen Research & Development/Minerva Neurosciences - AdisInsight, accessed May 16, 2025, https://adisinsight.springer.com/drugs/800040115
4. Seltorexant - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/drug/f39a216b073249c48a375debfbb52597
5. Johnson & Johnson pivotal study of seltorexant shows statistically significant and clinically meaningful improvement in depressive symptoms and sleep disturbance outcomes, accessed May 16, 2025, https://www.jnj.com/media-center/press-releases/johnson-johnson-pivotal-study-of-seltorexant-shows-statistically-significant-and-clinically-meaningful-improvement-in-depressive-symptoms-and-sleep-disturbance-outcomes
6. What is Seltorexant used for? - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/article/what-is-seltorexant-used-for
7. Full article: Seltorexant for major depressive disorder - Taylor & Francis Online, accessed May 16, 2025, https://www.tandfonline.com/doi/full/10.1080/14728214.2025.2452514?src=exp-la
8. Seltorexant for major depressive disorder - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/39791866/
9. The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6722075/
10. Seltorexant for major depressive disorder - Taylor & Francis Online, accessed May 16, 2025, https://www.tandfonline.com/doi/abs/10.1080/14728214.2025.2452514
11. Johnson & Johnson pivotal study of seltorexant shows statistically significant and clinically meaningful improvement in depressive symptoms and sleep disturbance outcomes | Janssen, accessed May 16, 2025, https://www.janssen.com/johnson-johnson-pivotal-study-seltorexant-shows-statistically-significant-and-clinically-meaningful
12. Johnson & Johnson pivotal study of seltorexant shows statistically significant and clinically meaningful improvement in depressive symptoms and sleep disturbance outcomes - PR Newswire, accessed May 16, 2025, https://www.prnewswire.com/news-releases/johnson--johnson-pivotal-study-of-seltorexant-shows-statistically-significant-and-clinically-meaningful-improvement-in-depressive-symptoms-and-sleep-disturbance-outcomes-302157980.html
13. Seltorexant | C21H22FN7O | CID 86278359 - PubChem, accessed May 16, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Seltorexant
14. Seltorexant - APExBIO, accessed May 16, 2025, https://www.apexbt.com/seltorexant-ba5662.html
15. Seltorexant (JNJ-42847922) | Orexin-2 Receptor Antagonist ..., accessed May 16, 2025, https://www.medchemexpress.com/seltorexant.html
16. seltorexant | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed May 16, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9308
17. SELTOREXANT - Inxight Drugs, accessed May 16, 2025, https://drugs.ncats.io/drug/AIS8N3O50B
18. Seltorexant | CAS#1293281-49-8 | OX2R antagonist | MedKoo, accessed May 16, 2025, https://www.medkoo.com/products/10679
19. www.jnjmedicalconnect.com, accessed May 16, 2025, https://www.jnjmedicalconnect.com/media/attestation/congresses/neuroscience/2024/psych/pharmacokinetics-and-safety-of-seltorexant-a-selective-orexin2-receptor-antagonist-in-healthy-elderl.pdf
20. (PDF) Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/280121288_Characterization_of_JNJ-42847922_a_Selective_Orexin-2_Receptor_Antagonist_as_a_Clinical_Candidate_for_the_Treatment_of_Insomnia
21. Seltorexant (MIN-202) - Minerva Neurosciences, Inc., accessed May 16, 2025, https://ir.minervaneurosciences.com/static-files/4d596abb-ed12-4019-b6ed-18c4ed9d5458
22. Minerva Neurosciences Announces Achievement of Primary and ..., accessed May 16, 2025, https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-announces-achievement-primary-and-key
23. Volume of Distribution - (Intro to Pharmacology) - Vocab, Definition, Explanations | Fiveable, accessed May 16, 2025, https://library.fiveable.me/key-terms/introduction-to-pharmacology/volume-of-distribution
24. Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/6519129/
25. Volume of Distribution - StatPearls - NCBI Bookshelf, accessed May 16, 2025, https://www.ncbi.nlm.nih.gov/books/NBK545280/
26. Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/12061889/
27. Investigating the Metabolism of ACT-541468, Utilizing a Microtracer and Accelerator Mass Spectrometry in The First-in-Humans Trial | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/330928001_Investigating_the_Metabolism_of_ACT-541468_Utilizing_a_Microtracer_and_Accelerator_Mass_Spectrometry_in_The_First-in-Humans_Trial
28. Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist - edoc - Universität Basel, accessed May 16, 2025, https://edoc.unibas.ch/83159/1/2021-05-28_Dissertation%20CM_final.pdf
29. Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/33689224/
30. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms - Janssen Global Trial Finder, accessed May 16, 2025, https://globaltrialfinder.janssen.com/trial/42847922mdd3003
31. J&J antidepressant eases symptoms, improves sleep in key trial - BioPharma Dive, accessed May 16, 2025, https://www.biopharmadive.com/news/johnson-johnson-seltorexant-mdd-antidepressant-orexin/717336/
32. Intra-Cellular Therapies Announces Positive Phase 3 Topline Results from Study 501 Evaluating Lumateperone as Adjunctive Therapy in Patients with Major Depressive Disorder, accessed May 16, 2025, https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-positive-phase-3-topline
33. Seltorexant for Major Depressive Disorder With Insomnia Symptoms Sees Positive Results, accessed May 16, 2025, https://www.psychiatrictimes.com/view/seltorexant-for-major-depressive-disorder-with-insomnia-symptoms-sees-positive-results
34. Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/33822479/
35. Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/25511105/
36. Seltorexant for major depressive disorder | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/387929634_Seltorexant_for_major_depressive_disorder
37. Poster Explores Safety, Efficacy of Seltorexant for MDD, Insomnia - Psychiatric Times, accessed May 16, 2025, https://www.psychiatrictimes.com/view/poster-explores-safety-efficacy-of-seltorexant-for-mdd-insomnia
38. Influence of Food on Pharmacokinetics of Zolpidem From Fast Dissolving Sublingual Zolpidem Tartrate Tablets | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/255790081_Influence_of_Food_on_Pharmacokinetics_of_Zolpidem_From_Fast_Dissolving_Sublingual_Zolpidem_Tartrate_Tablets
39. Seltorexant, adjunctive to antidepressants, in adults with MDD with insomnia symptoms: results of a double-blind, randomized, placebo-controlled study, accessed May 16, 2025, https://www.jnjmedicalconnect.com/media/attestation/congresses/neuroscience/2024/ascp/seltorexant-adjunctive-to-antidepressants-in-adults-with-mdd-with-insomnia-symptoms-results-of-a-dou.pdf
40. J&J's Antidepressant Succeeds in Key Study - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/article/jjs-antidepressant-succeeds-in-key-study
41. Pharmacokinetic and pharmacodynamic interactions between daridorexant, a dual orexin receptor antagonist, and citalopram in healthy subjects | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/352158427_Pharmacokinetic_and_pharmacodynamic_interactions_between_daridorexant_a_dual_orexin_receptor_antagonist_and_citalopram_in_healthy_subjects
42. Phase 1 study to evaluate the effects of rifampin or itraconazole on the pharmacokinetics of limertinib (ASK120067), a novel mutant-selective inhibitor of the epidermal growth factor receptor in healthy Chinese subjects - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/37811634/
43. A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/29848147/
44. Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major ..., accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/34324636/
45. Advanced Filter - DrugBank, accessed May 16, 2025, https://go.drugbank.com/unearth/q?button=&c=_score&d=down&page=470&query=beta+cyclosporine+a&searcher=drugs
46. Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8653874/
47. Treatment effect and safety of seltorexant as monotherapy for patients with major depressive disorder: a randomized, placebo-controlled clinical trial - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/39663378/
48. The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/330414668_The_selective_orexin-2_receptor_antagonist_seltorexant_improves_sleep_An_exploratory_double-blind_placebo_controlled_crossover_study_in_antidepressant-treated_major_depressive_disorder_patients_with_p
49. The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/30644312/
50. (PDF) The selective orexin-2 antagonist seltorexant (JNJ-42847922 ..., accessed May 16, 2025, https://www.researchgate.net/publication/335581460_The_selective_orexin-2_antagonist_seltorexant_JNJ-42847922MIN-202_shows_antidepressant_and_sleep-promoting_effects_in_patients_with_major_depressive_disorder
51. Seltorexant, adjunctive to antidepressants, in adults with MDD with insomnia symptoms: results of a double-blind, randomized, placebo-controlled study - J&J Medical Connect, accessed May 16, 2025, https://www.jnjmedicalconnect.com/media/attestation/congresses/neuroscience/2024/psych/seltorexant-adjunctive-to-antidepressants-in-adults-with-major-depressive-disorder-with-insomnia-sym.pdf
52. Seltorexant Meets Primary, Secondary Endpoints in Phase 3 Trial for MDD, Insomnia, accessed May 16, 2025, https://www.hcplive.com/view/seltorexant-meets-primary-secondary-endpoints-in-phase-3-trial-for-mdd-insomnia
53. Seltorexant, Major Depressive Disorder, and Insomnia: Thoughts on the New Data, accessed May 16, 2025, https://www.psychiatrictimes.com/view/seltorexant-major-depressive-disorder-and-insomnia-thoughts-on-the-new-data
54. Adjunctive treatment with seltorexant improved patient-reported depressive symptoms, insomnia symptoms, and overall health in major - J&J Medical Connect, accessed May 16, 2025, https://www.jnjmedicalconnect.com/media/attestation/congresses/neuroscience/2024/psych/adjunctive-treatment-with-seltorexant-improved-patientreported-depressive-symptoms-insomnia-symptoms.pdf
55. EU Clinical Trials Register, accessed May 16, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000337-40/CZ
56. 7 Emerging Major Depressive Disorder Drugs To Watch - DelveInsight, accessed May 16, 2025, https://www.delveinsight.com/blog/major-depressive-disorder-drugs-to-watch
57. Major Depressive Disorder Market to Register Immense Growth by 2034 Owing to a Robust Pipeline | DelveInsight, accessed May 16, 2025, https://www.prnewswire.com/news-releases/major-depressive-disorder-market-to-register-immense-growth-by-2034-owing-to-a-robust-pipeline--delveinsight-302315136.html
58. Annual Report for Fiscal Year Ending December 31, 2024 (Form 10-K), accessed May 16, 2025, https://www.publicnow.com/view/6DBF66E907D4DD6728C3AE668E68784030A058FF
59. Seltorexant API Suppliers - Find All GMP Manufacturers - Pharmaoffer.com, accessed May 16, 2025, https://pharmaoffer.com/api-excipient-supplier/seltorexant
60. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms - Janssen Global Trial Finder, accessed May 16, 2025, https://globaltrialfinder.janssen.com/zh-cn/trial/42847922mdd3003
61. Seltorexant - Minerva Neurosciences, accessed May 16, 2025, https://www.minervaneurosciences.com/programs/seltorexant/
62. Minerva Neurosciences and Royalty Pharma Announce Sale of Seltorexant Royalty for up to $155 Million, accessed May 16, 2025, https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-and-royalty-pharma-announce-sale
63. Minerva Neurosciences Announces Positive Top Line Results in Phase 2b Clinical Trial With Seltorexant (MIN-202) in Treatment of Depressed Patients With an Inadequate Response to SSRIs and SNRIs, accessed May 16, 2025, https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-announces-positive-top-line-results-0
64. ir.minervaneurosciences.com, accessed May 16, 2025, https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-and-royalty-pharma-announce-sale#:~:text=(Nasdaq%3A%20NERV)%20and%20Royalty,million%20in%20additional%20milestone%20payments.
65. News | Royalty Pharma, accessed May 16, 2025, https://www.royaltypharma.com/news/page/13/
66. Major Depressive Disorder Pipeline Report 2025: Comprehensive Insights of 75+ Companies and Drugs Under Clinical Assessment - GlobeNewswire, accessed May 16, 2025, https://www.globenewswire.com/news-release/2025/05/08/3076917/0/en/Major-Depressive-Disorder-Pipeline-Report-2025-Comprehensive-Insights-of-75-Companies-and-Drugs-Under-Clinical-Assessment.html
67. A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adolescents With Major Depressive Disorder Who Have an Inadequate Response to Selective Serotonin Reuptake Inhibitor (SSRI) and Psychotherapy | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT04951609/a-study-of-seltorexant-as-adjunctive-therapy-to-antidepressants-in-adolescents-with-major-depressive-disorder-who-have-an-inadequate-response-to-selective-serotonin-reuptake-inhibitor-ssri-and-psychotherapy
68. Seltorexant Completed Phase 2 Trials for Insomnia Disorder Treatment | DrugBank Online, accessed May 16, 2025, https://go.drugbank.com/drugs/DB14961/clinical_trials?conditions=DBCOND0042470&phase=2&purpose=treatment&status=completed
69. Seltorexant Achieves Primary, Secondary Endpoints in Insomnia - NeurologyLive, accessed May 16, 2025, https://www.neurologylive.com/view/seltorexant-achieves-primary-secondary-endpoints-in-phase-2b-trial-in-insomnia
70. Seltorexant Completed Phase 2 Trials for Major Depressive Disorder (MDD) Treatment, accessed May 16, 2025, https://go.drugbank.com/drugs/DB14961/clinical_trials?conditions=DBCOND0030181&phase=2&purpose=treatment&status=completed
71. Minerva Neurosciences Announces Update for Three Clinical Trials ..., accessed May 16, 2025, https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-announces-update-three-clinical-trials
72. A Study of Seltorexant Compared to Quetiapine XR as Adjunctive Therapy to Antidepressants in Adult and Elderly Participants With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT04513912/a-study-of-seltorexant-compared-to-quetiapine-xr-as-adjunctive-therapy-to-antidepressants-in-adult-and-elderly-participants-with-major-depressive-disorder-with-insomnia-symptoms-who-have-responded-inadequately-to-antidepressant-therapy
73. Seltorexant Completed Phase 1 Trials for Major Depressive Disorder (MDD) Treatment, accessed May 16, 2025, https://go.drugbank.com/drugs/DB14961/clinical_trials?conditions=DBCOND0030181&phase=1&purpose=treatment&status=completed
74. NCT05307692 | ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/92/NCT05307692/SAP_001.pdf
75. A Study of Seltorexant in Participants With Probable Alzheimer's Disease | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT05307692/a-study-of-seltorexant-in-participants-with-probable-alzheimers-disease
76. Johnson & Johnson Makes Major Neuro Play With $14.6B Intra-Cellular Buyout - BioSpace, accessed May 16, 2025, https://www.biospace.com/business/johnson-johnson-makes-major-neuro-play-with-14-6b-intra-cellular-buyout
77. Seltorexant Completed Phase 3 Trials for Major Depressive Disorder (MDD) Treatment, accessed May 16, 2025, https://go.drugbank.com/drugs/DB14961/clinical_trials?conditions=DBCOND0030181&phase=3&purpose=treatment&status=completed
78. Double-Blind, Randomized, Parallel-Group Study With Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy - AdisInsight, accessed May 16, 2025, https://adisinsight.springer.com/trials/700326713
79. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/phase-3-study-of-adjunctive-treatment-with-seltorexant-in-adult-and-elderly-participants-with-major
80. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms - Global Trial Finder, accessed May 16, 2025, https://globaltrialfinder.janssen.com/trial/42847922MDD3003
81. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06559306/phase-3-study-of-adjunctive-treatment-with-seltorexant-in-adult-and-elderly-participants-with-major-depressive-disorder-and-insomnia-symptoms
82. Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms - Clinical Trials, accessed May 16, 2025, https://adaa.trialstoday.org/trial/NCT06559306
83. A Two-Part Multicenter, Double-Blind, Randomized Placebo-Controlled Study to Evaluate Efficacy and Safety and the Maintenance of Effect of 20-(Milligram) mg Seltorexant as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients With Major Depressive Disorder With Insomnia Symptoms - AdisInsight, accessed May 16, 2025, https://adisinsight.springer.com/trials/700375943
84. Study on Seltorexant for Adults and Elderly with Major Depressive Disorder and Insomnia Symptoms - Clinical trials, accessed May 16, 2025, https://clinicaltrials.eu/trial/study-on-seltorexant-for-adults-and-elderly-with-major-depressive-disorder-and-insomnia-symptoms/
85. J&J drops Phase III MDD programme due to lack of efficacy - Clinical Trials Arena, accessed May 16, 2025, https://www.clinicaltrialsarena.com/news/johnson-johnson-mdd-trial-failure-termination/
86. A Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive Therapy to Antidepressants in Adult Participants With Major Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy - Trials Today, accessed May 16, 2025, https://www.trialstoday.org/list/print/NCT03227224
87. EMEA-002746-PIP01-20-M02 - paediatric investigation plan - European Medicines Agency, accessed May 16, 2025, https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002746-pip01-20-m02
88. Clinical specificity profile for novel rapid acting antidepressant drugs - PMC, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10373854/
89. Janssen Research & Development * Clinical Protocol A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controll - ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/24/NCT03227224/Prot_000.pdf
90. NCT05307692 | ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/92/NCT05307692/Prot_000.pdf
91. accessed January 1, 1970, https://clinicaltrials.gov/study/NCT05307692
92. accessed January 1, 1970, https://classic.clinicaltrials.gov/ct2/show/NCT03227224
93. accessed January 1, 1970, https://www.clinicaltrials.gov/study/NCT05307692
94. A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adult and Elderly Participants With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant and Long-term Safety Extension Treatment With Seltorexant - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/a-study-of-seltorexant-as-adjunctive-therapy-to-antidepressants-in-adult-and-elderly-participants-wi-1
95. A Study to Determine the Abuse Potential of Seltorexant Compared to Suvorexant and Zolpidem - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/a-study-to-determine-the-abuse-potential-of-seltorexant-compared-to-suvorexant-and-zolpidem
96. Innate Pharma announces U.S. FDA granted Breakthrough Therapy Designation to lacutamab for relapsed or refractory Sézary Syndrome, accessed May 16, 2025, https://www.innate-pharma.com/media/all-press-releases/innate-pharma-announces-us-fda-granted-breakthrough-therapy-designation-lacutamab-relapsed-or-refractory-sezary-syndrome
97. European Medicines Agency decision P/0479/2023 of 1 December 2023 on the acceptance of a modification of an agreed paediatric in - EMA, accessed May 16, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-0479-2023-ema-decision-1-december-2023-acceptance-modification-agreed-paediatric-investigation-plan-seltorexant-emea-002746-pip01-20-m02_en.pdf
98. accessed January 1, 1970, https.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002746-pip01-20-m02
99. 2024 Key events - Pipeline - investor.jnj.com, accessed May 16, 2025, https://www.investor.jnj.com/pipeline/2024-key-events/default.aspx
100. Selective Orexin Receptor Antagonists as Novel Augmentation Treatments for Major Depressive Disorder: Evidence for Safety and Efficacy From a Phase 2B Study of Seltorexant - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/356388897_Selective_Orexin_Receptor_Antagonists_as_Novel_Augmentation_Treatments_for_Major_Depressive_Disorder_Evidence_for_Safety_and_Efficacy_From_a_Phase_2B_Study_of_Seltorexant
101. MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity - AACR Journals, accessed May 16, 2025, https://aacrjournals.org/mct/article/17/12/2665/92433/MORAb-202-an-Antibody-Drug-Conjugate-Utilizing
102. Senti Bio Announces Positive Initial Clinical Data in Phase 1 Clinical Trial of SENTI-202, a Logic Gated, Selective CD33/FLT3-Targeting CAR-NK Cell Therapy for the Treatment of Relapsed/Refractory Hematologic Malignancies Including AML, accessed May 16, 2025, https://investors.sentibio.com/news-releases/news-release-details/senti-bio-announces-positive-initial-clinical-data-phase-1/
103. CLINICAL STUDY PROTOCOL No. MYR 202 - ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/21/NCT03546621/Prot_SAP_ICF_000.pdf
104. Protocol Number: P-105-202 Official Title: Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess - ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/40/NCT05305040/Prot_000.pdf
105. Pipeline - Development pipeline | Johnson & Johnson, accessed May 16, 2025, https://www.investor.jnj.com/pipeline/development-pipeline/default.aspx?a=Oncology%3BPulmonary+Hypertension%3BInfectious+Diseases+and+Vaccines+Global+Public+Health
106. Development pipeline - investor.jnj.com, accessed May 16, 2025, https://www.investor.jnj.com/pipeline/development-pipeline/default.aspx
107. Moxifloxacin (BAY 12-8039 free base) | Antibacterial Agent | MedChemExpress, accessed May 16, 2025, https://www.medchemexpress.com/moxifloxacin.html
108. Full article: Seltorexant for major depressive disorder - Taylor & Francis Online, accessed May 16, 2025, https://www.tandfonline.com/doi/full/10.1080/14728214.2025.2452514?src=
109. ClinicalTrials.gov: Home, accessed May 16, 2025, https://clinicaltrials.gov/
110. Requirements for Registering & Reporting NIH-Funded Clinical Trials | Grants & Funding, accessed May 16, 2025, https://grants.nih.gov/policy-and-compliance/policy-topics/clinical-trials/reporting
111. Clinical Trials - Error | ClinicalTrials.gov, accessed May 16, 2025, https://clinicaltrials.gov/NCT00941070
112. Registration of Clinical Trials on ClinicalTrials.gov - Johns Hopkins Medicine, accessed May 16, 2025, https://www.hopkinsmedicine.org/institutional-review-board/guidelines-policies/guidelines/clinical-trials
113. ICTRP search portal - World Health Organization (WHO), accessed May 16, 2025, https://www.who.int/clinical-trials-registry-platform/the-ictrp-search-portal
114. International Clinical Trials Registry Platform (ICTRP) - World Health Organization (WHO), accessed May 16, 2025, https://www.who.int/clinical-trials-registry-platform
115. In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/294120029_In_vitro_and_in_vivo_characterisation_of_the_metabolism_and_disposition_of_suvorexant_in_humans
116. Itraconazole Completed Phase 1 Trials for Healthy Lifestyle Behaviors Treatment, accessed May 16, 2025, https://go.drugbank.com/drugs/DB01167/clinical_trials?conditions=DBCOND0059969&phase=1&purpose=treatment&status=completed
117. Johnson & Johnson Press Releases, accessed May 16, 2025, https://www.jnj.com/media-center/press-releases
118. accessed January 1, 1970, https://ir.minervaneurosciences.com/news-releases
119. U.S. Food and Drug Administration, accessed May 16, 2025, https://www.fda.gov
120. European Medicines Agency - European Union, accessed May 16, 2025, https://www.ema.europa.eu/en