Seltorexant for use in treating major depressive disorder with insomnia symptoms

Abstract

The disclosure provides methods for stratifying human patients with MDD in order to identify a human patient with MDD with insomnia symptoms (MDDIS) where such patients can benefit from treatment with an orexin-2 receptor antagonist, such as seltorexant.

Description

SELTOREXANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER WITH INSOMNIA SYMPTOMSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 63 / 651,792, filed May 24, 2024, the contents of which are hereby incorporated by reference.TECHNICAL FIELD

[0002] The disclosure provides methods of identifying and treating patients with major depressive disorder with insomnia symptoms (MDDIS) using seltorexant.BACKGROUND

[0003] Orexins (also known as hypocretins) are neuropeptides expressed by neurons in the perifornical area, the dorsomedial hypothalamus and the lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). Orexinergic neurons project to many areas of the brain including other hypothalamic nuclei, the midline paraventricular thalamus, brain stem nuclei, the ventral tegmental area and nucleus accumbens shell. (Peyron et al., 1998, J. Neurosci. 18, 9996- 10016) Orexin neuropeptides, classified as either orexin-A or orexin-B, bind to the seven transmembrane G-protein coupled receptors orexin-1 (OX1R) and orexin-2 (OX2R) (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). While orexin-A is non-selective for OX1R and OX2R, orexin-B shows higher affinity for OX2R (Sakaurai et al, 1998, Cell 92, 573-585). Orexin receptor antagonists are classified as single orexin receptor antagonists (SORAs) or dual orexin receptor antagonists (DORAs).

[0004] Major depressive disorder (MDD) is a common, serious, recurrent mental disorder. MDD is the leading cause of disability, and its prevalence is rising. Current therapies, commonly used as first-line antidepressant treatment in patients with MDD, are sub-optimally effective in some patients who require adjunctive treatment, or who are otherwise poorly compliant because of their associated adverse events (AEs), such as weight gain and sexual side effects. Currently approved treatments are limited to the atypicalantipsychotic drug class, which also present considerable tolerability concerns (e.g., metabolic syndrome, akathisia, and extrapy rami dal symptoms).

[0005] Major depressive disorder with moderate to severe insomnia symptoms (MDDIS) also presents as subset of MDD which is difficult to treat. Recently, seltorexant was shown to be very effective in treating MDDIS patients in a phase 2b trial. Since seltorexant appears to work much better in MDDIS patients rather than normal MDD patients, correctly identifying and defining MDDIS patients is quite important for successful patient treatment. The phase 2b study used the clinician rated ISI to identify patients suitable for treatment. Unfortunately, the ISI instrument is insufficient to differentiate among MDD patients with varying insomnia symptom severity levels, so MDDIS patients are missed. Additionally, there are concerns that the ISI items may not be appropriate to use in MDD populations. As a result of these and other short comings of the ISI instrument, another method of identifying the MDDIS patients for treatment with seltorexant needs to be developed.SUMMARY

[0006] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as defined in the appended claims. Other aspects of the present disclosure will be apparent to those skilled in the art in view of the detailed description of the disclosure as provided herein. Any references to methods of treatment herein may also be interpreted as referring to the compounds, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutical compositions and / or medicaments as described therein for use in said methods of treatment.

[0007] The disclosure provides methods for stratifying human patients with MDD in order to identify a human patient with MDD with insomnia symptoms (MDDIS) where such patients can benefit from treatment with an orexin-2 receptor antagonist, such as seltorexant. As disclosed herein, such patients can be identified through clinician-reported insomnia symptoms and patient reported sleep disturbances. Because not all MDD patients receive the same benefit from treatment, identifying patients that get a particular benefit is needed.

[0008] As disclosed herein, criteria are provided to identify patients having moderate to severe insomnia symptoms (MDDIS) as opposed to those with no or mild insomnia symptoms, herein also referred to as a non-MDDIS patient population. Based onthese criteria, methods are disclosed that identify and treat patients that will experience a clinically meaningful change in overall depressive symptoms.

[0009] In certain embodiments, a method of stratifying patients as MDDIS patients comprises identifying patients having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0010] Likewise, methods of treating a patient with major depressive disorder with insomnia symptoms (MDDIS) is disclosed. Such methods comprise administering to the patient about 10 mg to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof. In particular embodiments, the MDDIS patient is one having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items. Such patients achieve a clinically meaningful change in overall depressive symptoms as compared to patients classified as MDD with no or mild IS.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The present disclosure may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. The summary, as well as the following detailed description, is further understood when read in conjunction with the appended figures:

[0012] FIG. l is a line graph of MADRS Total Score: Analysis Under Estimand 1 : LS Mean (+ / - SE) of Change From Baseline (DB) Over Time (Line Plot) - MMRM Observed Case - Double-blind Phase; FAS1 Analysis Set (Study 42847922MDD3001). In this figure, intercurrent events are handled by the following strategies: discontinuation of add-on study agent only: hypothetical; discontinuation of both add-on study agent and underlying antidepressant: hypothetical; switch of add-on study agent and / or underlying antidepressant: hypothetical. LS Mean and SE were based on a mixed model for repeated measures (MMRM) with treatment (Placebo, Seltorexant 20 mg), country, age group (adults [< 65 years] and elderly [>= 65 years]), baseline (DB) rumination level (RRS total score < 54, >= 54), time, and time-by-intervention interaction as factors and baseline(DB) MADRS total score as a covariate. Negative change in score indicates improvement. FAS1 analysis set includes all randomized participants with MDDIS per IWRS who received at least 1 dose of study intervention in the DB phase and had baseline MADRS total score >= 24 (per IWRS).

[0013] FIG. 2 is a plot of MADRS Total Score: Analysis Under Estimand 2: LS Mean (+ / - SE) of Change From Baseline (DB) Over Time (Line Plot) - CR MI Analysis - Double-blind Phase; FAS2 Analysis Set (Study 42847922MDD3001). In this figure, intercurrent events are handled by the following strategies: discontinuation of add-on study agent only: treatment policy; discontinuation of both add-on study agent and underlying antidepressant: hypothetical; switch of add-on study agent and / or underlying antidepressant: hypothetical. LS Mean and SE were based on a mixed model for repeated measures (MMRM) with treatment (Placebo, Seltorexant 20 mg), country, age group (adults [< 65 years] and elderly [>= 65 years]), baseline(DB) rumination level (RRS total score < 54, >= 54), time, and time-by-intervention interaction as factors and baseline(DB) MADRS total score as a covariate. Missing data is imputed using Copy Reference (CR) Multiple Imputation (MI) method. Results are based on 500 imputations. Ns reflect number of subjects with observed values. Negative change in score indicates improvement. FAS2 analysis set includes all randomized participants with MDDIS per IWRS who received at least 1 dose of study intervention in the DB phase.

[0014] FIG. 3 is a Forest plot of MADRS Total Score: Change From Baseline (DB) to Day 43: MMRM by Different MDDIS Criteria based on HAM-D (or SIGH-D), PROMIS- SD-8a, and both instruments - FAS2 ALL (MDD3001). In this figure, HAM-D Early: No difficulty falling asleep (0) - complains of occasional difficulty falling asleep, i.e., more than U hour (1) - complains of nightly difficulty falling asleep (2); HAM-D Middle: No difficulty (0) - patient complains of being restless and disturbed during the night (1) - waking during the night, any getting out of bed rates 2 (except for purposes of voiding) (2); HAM-D Late: No difficulty (0) - Waking in early hours of the morning but goes back to sleep (1) - Unable to fall asleep again if he / she gets out of bed (2); HAM-D Sum: Sum of responses to early, middle, and late insomnia items. MDDIS classification: Moderate to severe IS = HAM-D criterion (Any HAM-D item = 2 or sum > 3) and PROMIS-SD-8a criterion (T-score > 54). No or mild IS = all other patients. FAS2 ALL: includes all randomized participants who received at least 1 dose of study intervention in the DB phase. N: Number of subjects in the given category with observed change from baseline to Day 43 data.

[0015] FIG. 4 is a Received Operator Characteristic (ROC) Curve showing that PROMIS-SD Total Score >54 identifies patients with IS. In this figure, instrument / item is PGIS: Moderate or Greater Sleep Difficulty; CoA Type is PRO; AUC is 0.94; Selected Cutoff is 55; Sensitivity is 0.88; and Specificity is 0.88

[0016] FIG. 5 is a schematic of the clinical outcome assessment (COA) conceptual- measurement framework for insomnia symptoms in MDD.

[0017] FIG. 6 is are MDD3001 Forest Plots showing Change in MADRS Total Score by threshold score on patient and clinician 1ST

[0018] FIG. 7 are the PROMIS-SD-8a items.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTSDefinitions

[0019] “Depression” includes major depressive disorder, persistent depressive disorder, depression associated with bipolar disorder (aka bipolar depression), seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, mid-life depression, late-life depression, depression due to identifiable stressors, treatment resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, the depression is bipolar depression.

[0020] The methods described herein are useful in the treatment of the core (or psychic) symptoms of depression. These “psychic symptoms” include depressed mood and / or loss of interest or pleasure in nearly all activities. Other examples include, irritable mood, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and indecisiveness. In particular, core depressive symptoms include depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and general somatics (tiredness and pains). In general, the effect on the psychic symptoms are overall unrelated to the seltorexant’ s effect on sleep related items.

[0021] “Night” includes the period of time from sunset to sunrise, occurring once each twenty -four hours. In some embodiments, night refers to a timeframe in a twenty -four period in a day that precedes sleep by a subject.

[0022] “Insomnia symptoms” refer to symptoms arising from a diagnosis using criteria found in the American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and the Third Edition of the World Health Organization’s International Classification of Sleep Disorders (ICSD-3). In some embodiments, an “insomnia symptoms” include difficulty initiating or maintaining sleep and waking too early and / or obtaining non-restorative sleep, where the sleep difficulty results in some form of daytime impairment.

[0023] Some of the quantitative expressions given herein are not qualified with “about.” It is understood that whether “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value.

[0024] As used herein, unless otherwise noted, “treating,” “treatment,” and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and include the administration of a compound described herein to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder. Similarly, “treatment” is used to encompass (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition, or any combination thereof.

[0025] As used herein, unless otherwise noted, “subject” and “patient” may be used interchangeably and refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject or patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. One skilled in the art will further recognize that the methods of treatment are directed to subjects or patients in need of such treatment, prevention or dosing regimen, more particularly to subjects or patients diagnosed with or exhibiting at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) regardless of type or underlying cause. In further embodiments, the subject has MDD with insomnia symptoms (MDDSI). In other embodiments, the patient has bipolar depression with insomnia symptoms. In particular, the MDDIS patient or the patient with bipolar depression with insomnia symptoms is one having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0026] One skilled in the art will recognize that wherein methods of prevention are described, a subject in need thereof (i.e. a subject in need of prevention) shall include any subject who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of thedisorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of having new episodes of depression (and therefore in need of secondary prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.

[0027] Further, some of the quantitative expressions herein are recited as a range from about value X to about value Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about value X through about value Y, or any value or range of values therein.

[0028] As used herein, “including,” “containing,” and “comprising” are used herein in their open, non-limiting sense.

[0029] The term “antagonist” as used herein refers to a compound that binds to a receptor that blocks or attenuates the receptor’s response to an agonist.Compounds

[0030] Seltorexant is an orexin-2 antagonist and may be used in the treatment of depression. Seltorexant, z.e., [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4- c]pyrrol-2-yl]-(2-fluoro-6-[l,2,3]triazol-2-yl-phenyl)-methanone, is also known as MIN-202 and JNJ-42847922 and has the chemical structure below:

[0031] Seltorexant may be administered such that it has a time to maximal plasma concentration of less than about 3 hours, less than about 2 hours, and preferably less than about 1 hour, i.e., less than about 45 minutes, less than about 30 minutes, less than about 15 minutes, among others. In other embodiments, seltorexant has an elimination half-life of about 4 hours and typically less than about 4 hours. For example, seltorexant has a half-life of about 2 to about 3 hours, e.g., about 2 hours, about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, or about 2.9 hours to about 3 hours. Given the short half-life, the amount of seltorexant remaining in the subject upon waking is typically below the threshold required forpharmacodynamic effect. In particular embodiments, the antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0032] Seltorexant also includes pharmaceutically acceptable salts thereof and methods of treatment using such salts. A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of seltorexant that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G.S. Paulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.

[0033] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, mal onates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. In some embodiments, the pharmaceutically acceptable salt of seltorexant is the HC1 salt, i.e., [5-(4,6-dimethyl-pyrimidin-2-yl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[l,2,3]triazol-2-yl-phenyl)-methanone hydrochloride.

[0034] The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such asmandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acid, or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0035] Additionally, seltorexant also includes hydrates, solvates, and polymorphs thereof, and mixtures thereof, even if such forms are not listed explicitly. Certain embodiments include hydrates of the pharmaceutical salt, including a hydrate of the HCL salt of seltorexant.

[0036] Pharmaceutically acceptable prodrugs of seltorexant and treatment methods employing such pharmaceutically acceptable prodrugs are also contemplated. “Prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the seltorexant). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0037] Suitable selective orexin-2 antagonists for the methods described herein are described in PCT Patent Application Publication No. WO2011 / 050198, U.S. Patent No. RE48,841, U.S. Patent No. 9,079,911, U.S. Patent No. 11,059,828. and U.S. Patent No. 11,667,644, which are all incorporated by reference herein. An improved synthetic method for making fused heterocyclic compounds, such as seltorexant, as orexin receptor modulators is described in PCT Patent Application Publication No. W02020 / 100011, which is also incorporated by reference herein.Methods

[0038] The disclosure provides methods for stratifying human patients with MDD in order to identify a human patient with MDD with insomnia symptoms (MDDIS) where such patients can benefit from treatment with an orexin-2 receptor antagonist, such as seltorexant. As disclosed herein, such patients can be identified through clinician-reported insomnia symptoms and patient reported sleep disturbances.

[0039] Likewise, once identified, methods of treating a patient with major depressive disorder with insomnia symptoms (MDDIS) is disclosed. Such methods comprise administering to the patient about 10 mg to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0040] In certain embodiments, sleep disturbance is measured by a patient reported outcome (PRO) instrument due to its subjective nature. For example, the Patient Reported Outcomes Measurement Information System (PROMIS) captures self-reported, qualitative health aspects in the domains of physical, mental, and social health. PROMIS item banks and short forms are developed using state of the art psychometric techniques, such as Item Response Theory Models. The PROMIS Sleep Disturbance instruments are content valid measures of subjective sleep disturbance experiences.

[0041] In particular embodiments, the PROMIS Sleep Disturbance-Short Form 8a (PROMIS-SD-8a) is used to assess sleep disturbance. The recall period for all PROMIS-SD- 8a items is the “past 7 days The first item, “Sleep quality’ uses a 5-point response scale where l=Very good; 2 = Good; 3= Fair; 4=Poor; and 5=Very Poor. Items 2 through 8 also employ a 5-point response scale (l=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; 5 =Very Much) (see Fig.7). Items 2 “Sleep was refreshing" and 8 “Satisfied with sleep" are reverse coded so that higher ratings indicate poorer sleep quality. Responses to the 8 items are summed and then converted, using a provided conversion table (see Table 12 in Example 2), to a t-score metric ranging from 0 to 100 with a mean of 50 and a standard deviation (SD) of 10. Higher total PROMIS-SD-8a scores indicate poorer sleep disturbance.

[0042] As set forth in Example 2, an optimal PROMIS-SD-8a score cut off point for differentiating patients with MDD and moderate to severe IS (MDDIS) from MDD patients with no or mild IS (non-MDDIS) ranges from 52.75 to 57.8 (mean =55.8). And, at least in view of the strength of the PGIS anchor, a PROMIS-SD > 54 cut off point is recommended to maximize inclusion of patients with MDDIS who might benefit from treatment with seltorexant. See, FIG. 4.

[0043] At the same time, a PROMIS-SD-8a cut off alone may not be sufficient to adequately identify those patients that will benefit most from seltorexant treatment (see Example 2 and Table 15).

[0044] Additionally, the stratification includes criteria involving clinician-reported outcome (ClinRO) measures of depression symptom severity to supplement the patient reported outcome (PRO) criteria due to its subjective nature. This ensures that high levels of sleep disturbance as reported by the patient are insufficient on their own to include theparticipant as part of the intended patient population. As is shown in Figure 5, the PRO (e.g. provided in the PROMIS-SD-8a instrument) is indicative of the sleep disturbance experienced by the patient and provides a valuable insight into the patient’s distress associated with their sleep. Information obtained from the patient through a structured clinical interview is utilized by the clinician to confirm core diagnostic symptoms of insomnia. Incorporating both PRO and ClinRO in the approach provides a more nuanced assessment of the patient’s condition, making the overall assessment more robust and helping mitigate the effects of random fluctuations in PRO.

[0045] The HAM-D is a 17-item clinician-reported outcome (ClinRO) measure of depression symptom severity. The HAM-D includes insomnia items that are utilized in the present methods. As reflected in Table 16 of Example 2 (reproduced below), there are three insomnia items, referred to as early insomnia, middle insomnia, and late insomnia, each having responses with scores from 0 to 2.

[0046] The HAM-D is completed by clinicians through administration of a standardized interview. There may be slight variations to the item description within each concept depending on, for example, the interview guide. For example, there is a HAM-D through administration of a semi-structured Clinical Interview Guide for the HAM-D17 (Bech P. The Bech, Hamilton and Zung scales for mood disorders: screening and listening. Springer, Berlin 1996, second revised edition). In addition, there is a Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D; Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988). Both interview guides include primary questions and follow-up probes for assessing early, middle, and late insomnia over the past week, and both can be used in the stratification andtreatment methods disclosed herein. In preferred embodiments, the SIGH-D is used as it is deemed more rigorous and structured.

[0047] For purposes of this disclosure, reference is made to items 3, 4, and 5 for the concepts early insomnia (3), middle insomnia (4), and late insomnia (5) respectively. Items 3, 4, 5 typically are associated with the SIGH-D, whereas the same items under HAM-D are items 4, 5, and 6. However, regardless of the numbering, the three concepts: early insomnia, middle insomnia, and late insomnia are used for the disclosed stratification and treatment methods. And unless otherwise noted, reference to HAM-D and SIGH-D may be used interchangeably for purposes of the stratification and treatment methods disclosed herein. The SIGH-D scoring being most often used in clinical study because it has been validated.

[0048] SIGH-D offers advantages over cISI for a number of reasons. For example, whereas the cISI uses a 2-week recall period, the SIGH-D utilizes a 7-day recall period. Thus, using SIGH-D items in lieu of cISI items for patient stratification decreases susceptibility to recall bias and matches the timeframe from the PROMIS-SD-8a. And unlike the cISI, the SIGH-D is completed by clinicians through administration of a standardized interview which improves measurement reliability and who are trained and calibrated in its’ administration.

[0049] The stratification criteria includes SIGH-D items 3, 4, and 5 to measure clinical manifestations of insomnia resulting in lost sleep time as well as the PROMIS-SD-8a. In particular embodiments, a MDDIS patient is one having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items. All other patients are stratified as MDD with no or mild IS (or non-MDDIS).

[0050] Methods of treating a patient with major depressive disorder with insomnia symptoms (MDDIS) is disclosed. Such methods comprise administering to the patient about 10 mg to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof. In particular embodiments, the MDDIS patient is one having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items. Such patients achieve a clinically meaningful change in overall depressive symptoms as compared to patients classified as MDD with no or mild IS (See Example 2, Table 19 and 20).

[0051] In another embodiment of the invention clinical practice health care providers may administer the PROMIS-SD-8a and SIGH-D (or HAM-D) orally and / or using electronic questionnaires, preferably the SIGH-D instrument will be administered orally todepressed patients. In circumstances where the physician does not have the resources or time to formally administer the PR0MIS-SD-8a and / or SIGH-D instruments, the health care provider should interview the patients to assess their sleep disturbance and insomnia. Health care providers should ask the patient about their sleep disturbances with clinical questions consistent with items on the PR0MIS-SD-8a and independently assess whether the patient has insomnia and the patient’s level of insomnia (e.g. with questions 3, 4 and 5 provided above) to assess whether the patient has MDDIS.

[0052] Seltorexant is preferably administered once daily. In certain embodiments, seltorexant is administered to the subject prior to sleep. For example, Seltorexant is administered within about 2 hours of sleep, within about 1 hour, or within about 30 minutes before sleep. In other embodiments, Seltorexant is administered at least about 4 hours before the subject wakes or intends to wake from sleep, including about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, or about 12 hours before the subject wakes or intends to wake from sleep. In certain embodiments, seltorexant is administered at least 6 hours to about 12 hours before the subject wakes or intends to wake from sleep. In preferred embodiments, seltorexant is administered at night.

[0053] After administration of seltorexant, it undergoes at least one half-life before the subject wakes from sleep. In other embodiments, seltorexant undergoes at least two halflives, and preferably at least three half-lives before the subject wakes from sleep.

[0054] Therapeutically effective amounts for seltorexant include amounts that elicit the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Optimal dosages to be administered may be readily determined by those skilled in the art, and may vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. Such factors including the particular patient being treated, including patient’s sex, age, weight, diet, time of administration and concomitant diseases, hepatic impairment among others. Methods for dosing patients with hepatic impairment have been described in US provisional patent application 63 / 524,198.

[0055] The effective amount of seltorexant may be described without reference to the weight of the subject. In some embodiments, about 10 mg of seltorexant is administered. In further embodiments, about 15 mg of seltorexant is administered. In still otherembodiments, about 20 mg of seltorexant is administered. All dosage amounts mentioned herein, unless otherwise indicated, refers to the free form (z.e., free base or free base equivalent, non-salt or non-hydrate form) of seltorexant. The amounts are recited as freeform equivalents, z.e., quantities as if the free form would be administered. If salts or solvates are administered the amounts need to be calculated in function of the molecular weight ratio between the salt or solvate and the free form.

[0056] In certain embodiments, seltorexant is administered to a human patient for the treatment of MDDIS or bipolar depression with insomnia symptoms, where the patient had an inadequate response to other antidepressant therapy (z.e., antidepressant medication or treatment used to treat depression other than seltorexant), such as, for example, selective serotonin reuptake inhibitor (SSRI) and / or serotonin-norepinephrine reuptake inhibitor (SNRI). More specifically, seltorexant, or the other compounds described herein, may be administered with a second pharmaceutically active agent to a human subject for the treatment of MDDIS or bipolar depression with insomnia symptoms, where the subject has an inadequate response to a SSRI and / or a SNRI. In some examples, the second pharmaceutically active agent is a SSRI or a SNRI.

[0057] Subjects have an inadequate response to a treatment when the treatment partially reduces severity of symptoms, but the subject continues to have symptoms. More specifically, an inadequate response may be defined as less than 50% reduction but with some improvement (that is, improvement greater than 0%) in symptom severity. For example, subjects have an inadequate response to a treatment for depression when the treatment partially reduces severity of depression symptoms, but the subject continues to have depression symptoms. Specifically, an inadequate response may be defined as less than 50% reduction but with some improvement (that is, improvement greater than 0%) in depressive symptom severity with residual symptoms other than insomnia present, and overall good tolerability. The level of response to a treatment may be assessed by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH- ATRQ), which is a self-rated scale used to determine treatment resistance in MDD. A patient’s response may also be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by MADRS. In other embodiments, inadequate response is defined as < 50% improvement) taken for at least 6 weeks during the current episode as obtained in the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire).

[0058] The prevention and / or reduction of severity of depression may be observed qualitatively (e.g., by general patient evaluation by a clinician during visits to a clinic) or as a quantitative reduction in scores over a period of time (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, etc.) determined using any suitable clinical scale (e.g., diagnostic questionnaires) for measuring severity of depression symptoms as would be understood by those of ordinary skill in the art, such as, for example, Clinical Global Impression-Severity (CGI-S) scale, EuroQol; 5 dimension; 5 level (EQ-5D-5L), Patient Health Questionnaire-9 Item (PHQ-9), Sheehan Disability Scale (SDS), Inventory of Depressive Symptomatology- Clinician rated, 30-item scale (IDS-C30), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton rating scale for depression (HAM-D or HDRS) Beck Scale for Depression, Quick Inventory of Depressive Symptomology (QIDS), 17-item Hamilton Depression Rating Scale (HDRS 17), Patient Health Questionnaire (PHQ-9),

[0059] As described herein, seltorexant may be administered as a monotherapy or may be administered in combination with additional active ingredients in the treatment of the above conditions, i.e., adjunctive treatment. The additional active ingredients may be administered simultaneously, separately or sequentially. In some embodiments, the additional active ingredients are effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound herein), decrease one or more side effects, or decrease the required dose of the compound described herein or additional active agent. In certain embodiments, the additional active ingredient is an antidepressant. In other embodiments, the additional active ingredient is a monoaminergic antidepressant.

[0060] Accordingly, seltorexant may be used in combination with a second antidepressant. The second antidepressant may be a conventional drug used to combat depression such as N-methyl-D-aspartate receptor antagonists, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), corticotropin releasing factor (CRF) antagonists, alpha-adrenoreceptor antagonists and atypical antidepressants. In some embodiments, the N-methyl-D-aspartate (NMD A) receptor antagonist is ketamine including racemates esketamine, arketamine, or combinations thereof. In further embodiments, the norepinephrine reuptake inhibitor includesamitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine, or pharmaceutically acceptable salts thereof. In other embodiments, the selective serotonin reuptake inhibitor includes fluoxetine, fluvoxamine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof. In further embodiments, the monoamine oxidase inhibitor includes isocarboxazid, phenelzine, tranylcypromine, selegiline and pharmaceutically acceptable salts thereof. In yet other embodiments, the reversible inhibitor of monoamine oxidase includes moclobemide or pharmaceutically acceptable salts thereof. In still further embodiments, the serotonin and noradrenaline reuptake inhibitor includes venlafaxine or pharmaceutically acceptable salts thereof. In other embodiments, the atypical antidepressant includes bupropion, lithium, nefazodone, trazodone, viloxazine, sibutramine, or pharmaceutically acceptable salts thereof. In yet further embodiments, the second antidepressant includes adinazolam, alaproclate, amineptine, amitriptyline / chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, monirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine zometapine, or pharmaceutically acceptable salts thereof; or St. John's wort herb, Hypericum perforatum, or extracts thereof.

[0061] In some embodiments, seltorexant is co-administered with esketamine. In further embodiments, seltorexant is administered separately from esketamine such as, e.g., sequentially. Seltorexant may be administered prior or subsequent to esketamine.

[0062] In certain embodiments, the patient to be treated meets DSM-5 diagnostic criteria for MDD and is treated in an outpatient setting. Typically, the depression is as least of moderate depression severity based on an industry accepted scale. For example, generally, a score of 17 on the HDRS-17 scale is recognized as a cutoff for moderate to severe depression. In another embodiment, MDDIS patients with mild to severe depression symptoms may be treated for MDDIS wherein mild depression is from 8 to 16 on theHDRS17; moderate is from 17-23 on the HDRS17 and severe is 24 and above on theHDRS 17 scale.

[0063] In certain embodiments, the patient does not have a history of treatment resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal (<25% improvement in symptoms) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks). Additionally, in other embodiments, the patent does not have a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia which has been the primary focus of psychiatric treatment within the past 2 years. In other embodiments, the patient does not have any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias.

[0064] Patients from 17 to 74 have been studied with seltorexant. Seltorexant, generally appears suitable for adults and adolescents. For example, adolescent patients from about 12 to about 17 years old with MDD or from about 10 to about 17 years old with bipolar disorder could be administer seltorexant. Typically the patient is from 18 to 74 years of age.

[0065] In other embodiments, the patient has a score of 0-7 and is classified as “not depressed.”Compositions

[0066] Seltorexant may be formulated as a pharmaceutical composition to administration to a subject. Accordingly, a pharmaceutical composition may comprise (a) an effective amount of seltorexant and (b) a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0067] Delivery forms of the pharmaceutical compositions containing one or more dosage units of seltorexant may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, ocular routes, or by inhalation.

[0068] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, or liquid preparations. In some embodiments, the compositions are formulated for intravenous infusion, topical administration, or oral administration. In certain embodiments, the compositions are formulated for immediate release.

[0069] For oral administration, seltorexant can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. In certain embodiments, seltorexant may be taken with food.

[0070] Oral tablets may include seltorexant mixed with pharmaceutically acceptable excipients such as inert fillers, diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, glidants and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, lactose monohydrate, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, hypromellose, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinyl N-pyrrolidone or PVP), and alginic acid are suitable disintegrating agents. Binding agents may include hypromellose (hydroxypropyl methylcellulose or HPMC), starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. The glidant, if present, may be silica (SiCh) such as colloidal silica. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0071] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, seltorexant may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing seltorexant with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0072] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, orwater; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0073] Seltorexant may also be administered by non-oral routes. For example, seltorexant may be formulated for rectal administration. For parenteral use, including intravenous, intramuscular, or intraperitoneal routes, seltorexant may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 pg / kg / minute of seltorexant, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0074] For topical administration, seltorexant may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering seltorexant may utilize a patch formulation to affect transdermal delivery.

[0075] Seltorexant may alternatively be administered by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.Kits

[0076] Also described herein are kits for administering seltorexant to a patient for the treatment of depression in subjects. The representative kits include one or more dosage units comprising an effective amount of seltorexant for administration to a patient and at a given frequency.

[0077] The dosage unit may be formulated for delivery by any means. In certain embodiments, the dosage unit is formulated for oral, intravenous, intranasal, intramuscular, sublingual, transdermal, optic, or rectal delivery. In certain embodiments, the dosage unit is formulated for oral delivery.

[0078] The dosage unit may be formulated to contain any amount of seltorexant, depending on the route of administration. Accordingly, each dosage unit may comprise the required dosage for the patient or may comprise a portion of seltorexant Which is required for a single dosage.

[0079] Also optionally included in the kits is a depression symptom rating scale questionnaire. The questionnaire may be for use by the patient alone or in combination with a physician. The questionnaire may be useful for determining the level of depression of thepatient at any stage of seltorexant administration. In one embodiment, the questionnaire is one or more of the questionnaires noted herein.

[0080] Instructions for performing the claimed methods and administering seltorexant may also be included in the kits described herein.

[0081] The kits may be organized to indicate a single formulation containing seltorexant described herein or combination of formulations, each containing seltorexant. The composition may be sub-divided to contain appropriate quantities of seltorexant. The unit dosage can be packaged compositions such as packeted powders, vials, ampoules, prefilled syringes, tablets, caplets, capsules, or sachets containing liquids.

[0082] Seltorexant may be a single dose or for continuous or periodic discontinuous administration. For continuous administration, a kit may include seltorexant in each dosage unit. When varying concentrations of seltorexant, the components of the composition containing seltorexant described herein, or relative ratios of seltorexant or other agents within a composition over time is desired, a kit may contain a sequence of dosage units.

[0083] The kit may contain packaging or a container with seltorexant formulated for the desired delivery route. The kit may also contain dosing instructions, an insert regarding seltorexant, instructions for monitoring circulating levels of seltorexant, or combinations thereof. Materials for using seltorexant may further be included and include, without limitation, reagents, well plates, containers, markers, or labels, and the like. Such kits may be packaged in a manner suitable for treatment of a desired indication

[0084] Other suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route. The kits also may include, or be packaged with, instruments for assisting with the injection / administration of seltorexant to the patient. Such instruments include, without limitation, an inhalant, syringe, pipette, forceps, measuring spoon, eye dropper, or any such medically approved delivery means. Other instrumentation may include a device that permits reading or monitoring reactions in vitro.

[0085] Seltorexant may be provided in dried, lyophilized, or liquid forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a solvent. The solvent may be provided in another packaging means and may be selected by one skilled in the art.

[0086] A number of packages or kits are known to those skilled in the art for dispensing pharmaceutical agents. In certain embodiments, the package is a labeled blister package, dial dispenser package, or bottle.Aspects

[0087] Aspect 1. A method of treating a patient with major depressive disorder with insomnia symptoms (MDDIS) comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0088] Aspect 2. The method of Aspect 1, wherein the MDDIS is determined by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

[0089] Aspect 3. The method of Aspect 1 or 2, wherein the patient has a PROMIS-SD-8a T-score of > 54, and either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0090] Aspect 4. A method of stratifying human patients with major depressive disorder to identify a human patient with MDDIS to be treated with an orexin-2 receptor antagonist.

[0091] Aspect 5. The method of Aspect 4, wherein the orexin-2 receptor antagonist is seltorexant.

[0092] Aspect 6. The method of Aspect 4 or 5, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

[0093] Aspect 7. The method of Aspect 6, wherein the patient with MDDIS is identified by the following criteria: a PROMIS-SD-8a T-score of > 54, and either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0094] Aspect 8. The method of Aspect 3, wherein seltorexant is administered as a free base.

[0095] Aspect 9. The method of Aspect 8, wherein a hydrochloride salt of seltorexant is administered.

[0096] Aspect 10. The method of Aspect 9, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

[0097] Aspect 11. The method of any one of Aspects 8-10, wherein seltorexant is administered orally.

[0098] Aspect 12. The method of any one of Aspects 8-11, wherein seltorexant is administered once daily.

[0099] Aspect 13. The method of any of Aspects 8-12, wherein seltorexant is administered prior to sleep.

[0100] Aspect 14. The method of any of Aspects 8-13, wherein seltorexant is administered at night.

[0101] Aspect 15. The method of Aspect 14, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0102] Aspect 16. The method of any one of Aspects 8-15, wherein seltorexant treats a psychic symptom of the depression.

[0103] Aspect 17. The method of any of Aspects 8-16, wherein the patient has an inadequate response to an antidepressants other than seltorexant or a pharmaceutically acceptable salt thereof.

[0104] Aspect 18. The method of Aspect 17, wherein the patient has an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

[0105] Aspect 19. The method of any one of Aspects 8-18, wherein seltorexant or a pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

[0106] Aspect 20. The method of Aspect 19, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

[0107] Aspect 21. The method of Aspect 20, wherein the MDD is at least of moderate depression severity based on an industry accepted scale, such as the 17-item Hamilton Depression Rating Scale (HDRS17).Examples

[0108] Example 1 (Study 42847922MDD3001)

[0109] A. Trial Design

[0110] Randomization: 588 participants with MDD (444 with IS and 144 without IS) were randomly assigned to receive 1 of 2 treatments in a 1 : 1 ratio to placebo (N=304; 228with IS and 76 without IS): seltorexant 20 mg (N=284; 216 with IS and 68 without IS). MDDIS is defined as MDD with moderate to severe IS by a patient version ISI total score of >15 at the end of screening, a clinician version ISI total score >15 at the end of screening, and a positive response for IS (MDD symptoms Item 4a) on the Structured Clinical Interview for DSM-5 Axis I Disorders Clinical Trials Version (SCID-CT) during the first screening visit. All three criteria must be met to be stratified into the MDDIs group, otherwise the participant will be stratified to the MDD without IS group. Two separate randomization lists were generated: a list for MDDIS participants and a list for MDD participants without IS. The randomization was further stratified by country, age group (adults [18 to 64 years, inclusive] versus elderly [65 to 74 years, inclusive]), baseline rumination level (RRS total score <54 and >54), and baseline MADRS group (MADRS total score <24 and >24).

[0111] Inclusion criteria (the following inclusion criteria was used in study MDD3001):

[0112] 1. Male or female, aged 18 to 74 years (inclusive);

[0113] 2 Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the SCID-CT diagnosed with first depressive episode prior to age 60. The length of the current depressive episode must be <24 months prior to randomization;

[0114] 3 Have had an inadequate response to at least 1 but no more than 2 antidepressants (see the inclusion criterion 4 below), administered at an adequate dose and duration in the current episode of depression. The current antidepressant cannot be the first antidepressant treatment for the first lifetime episode of depression. An inadequate response is defined as <50% reduction but with some improvement (i.e., improvement >0%) in depressive symptom severity with residual symptoms present other than insomnia, and overall good tolerability, as assessed by the MGH-ATRQ. An adequate trial is defined as an antidepressant treatment for at least 6 weeks on a stable dose (and no greater than 18 months in the current episode) at or above the minimum therapeutic dose specified in the MGH- ATRQ, must include the participant’s current antidepressant treatment. Note: Participants with no improvement on the current SSRI / SNRI should not be enrolled in the study. If the participant has received 2 SSRI / SNRI treatments of sufficient dose and duration in the current episode, and has shown <25% improvement to both, then the participant would not qualify based on exclusion criterion 9.

[0115] 4. Is receiving and tolerating well any one of the following SSRI or SNRI for depressive symptoms at screening, in any formulation and available in the participatingcountry: citalopram, duloxetine, escital opram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at therapeutic dose level) for at least 6 weeks, and for no greater than 18 months in the current episode.

[0116] 5. Have a HDRS-17 total score >20 at the first screening interview, must not demonstrate a clinically significant improvement (i.e., an improvement of >20% on their HDRS-17 total score) from the first to the second independent HDRS-17 rating, and must have a HDRS-17 total score >18 at the second screening interview

[0117] 6. Body mass index (BMI) between 18 and 40 kg / m2, inclusive (BMI=weight / height2) .

[0118] 7 Must be an outpatient at screening.

[0119] 8. Participant must be medically stable on the basis of the following performed at screening: physical examination (including a brief neurological examination), vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant's source documents and initialed by the investigator.

[0120] 9. Participant must be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator.

[0121] 10. Must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and be willing to participate in the study.

[0122] 11. A woman of childbearing potential must have a negative highly sensitive serum (P human chorionic gonadotropin [P-hCG]) pregnancy test at screening and a negative urine pregnancy test predose on Day 1 of the DB phase prior to randomization.

[0123] 12. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies.

[0124] 13. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 1 month after receiving the last dose of study drug.

[0125] 14. During the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 3 months) after receiving the last dose of study drug, a man (a) who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam / gel / film / cream / suppository) and his female partner must use a highly effective method of contraception; (b) who is sexually active with a woman who is pregnant must use a condom; (c) must agree not to donate sperm.

[0126] Exclusion criteria (the following exclusion criteria was used in study MDD3001):

[0127] 1. Has a recent (last 3 months) history of, or current signs and symptoms of (a) severe renal insufficiency (creatinine clearance [CrCl] <30 mL / min); (b) clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders; (c) uncontrolled Type 1 or Type 2 diabetes mellitus. Note: Participants with Type 1 or Type 2 diabetes mellitus who are controlled (hemoglobin A1C <8.5% and glucose <150 mg / dL at screening) may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering medications for at least 2 months prior to screening.

[0128] 2. Has a history of narcolepsy or seizures (except childhood seizures).

[0129] 3. Has clinically significant hepatic disease as defined by: >2x Upper Limit of Normal (ULN) increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at screening (one retest is permitted); significant liver disease including cirrhosis, ascites, active hepatitis etc. (fatty liver disease and Gilbert’s syndrome will be allowed as long as it does not meet above criteria).

[0130] 4. Has taken a strong inhibitor of CYP3A4 or CYP2C9 or moderate / strong inducer of CYP3 A4 or CYP2C9 or a dual inhibitor / inducer of CYP3 A4 and CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study.

[0131] 5. Has taken a moderate inhibitor of CYP3A4 or CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study and has: limited renal (CrCl <60 mL / min) or hepatic disease (AST / ALT >1.5X ULN and bilirubin >1.5X ULN).

[0132] 6. Has current signs / symptoms of hypothyroidism or hyperthyroidism.

[0133] 7. Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of significant medical disorders of the HPA axis.

[0134] 8. Has a current or recent history of homicidal ideation or serious suicidal ideation within the past 3 months, corresponding to a positive response on item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the past 6 months, as validated by the C-SSRS at screening or Day 1. Participants with prior suicidal behavior in the past year, or prior serious suicidal ideation / plan within the past 6 months, should be carefully screened. For current suicidal ideation, only participants with non-serious items (1-3 of the suicidal ideation section of the C-SSRS) may be included at the discretion of the investigator.

[0135] 9. Has a history of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal (<25% improvement in symptoms) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks).

[0136] 10. Has a history or evidence of clinically meaningful noncompliance with current antidepressant therapy.

[0137] 11. Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia which has been the primary focus of psychiatric treatment within the past 2 years. These are allowed as secondary diagnoses if MDD is the primary focus of treatment according to the investigator.

[0138] 12. Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, bulimia nervosa or fibromyalgia. These disorders need to be in remission for at least 1 year for the participant to be enrolled.

[0139] 13. Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, or somatoform disorders.

[0140] 14. Has any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias. Patients with insomnia disorder are allowed.

[0141] 15. Has a history of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test result(s) for alcohol and / or drugs of abuse (e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, cannabidiol [CBD], barbiturates, 3,4-Methylenedioxymethamphetamine [MDMA]) at screening or at baseline.

[0142] 16. Taking at screening benzodiazepines at high dosages greater than the equivalent of 30 mg diazepam or 3 mg of lorazepam at long duration which might result in benzodiazepine withdrawal syndrome. Participants must have a negative benzodiazepine test at baseline and be free of signs of the benzodiazepine abstinence syndrome.

[0143] 17. Had a clinically significant acute illness, per investigator judgment, within 7 days before the first dose of study drug.

[0144] 18. Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's study responsible physician / scientist or designee, is considered cured with minimal risk of recurrence).

[0145] 19. Has clinically significant ECG abnormalities at screening or Day 1 prior to randomization that may jeopardize the participants’ safety or the integrity of the study, in the Investigator’s judgment.

[0146] 20. Has within the last 5 years received any prior antidepressant treatment with ketamine / esketamine, electroconvulsive therapy, vagal nerve stimulation, or a deep brain stimulation device.

[0147] 21. Ongoing psychological treatments (e.g., Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 6 weeks prior to start of screening. Note: a participant who has been receiving ongoing psychological treatment for a period of greater than 6 weeks is eligible, if the investigator deems the psychological treatment to be of stable duration and frequency.

[0148] 22. Has received experimental therapies (psychological, pharmacologic or noninvasive device) within 30 days before screening or if greater than 2 experimental therapies in the past year prior to screening.

[0149] 23. Has known allergies, hypersensitivity, intolerance or any contraindication to seltorexant or its excipients.

[0150] 24. Has had a >7 days exposure or poor tolerability to seltorexant in previous studies (per patient report or other information).

[0151] 25. Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent amount of blood within 30 days before the first dose of study drug.

[0152] 26. Has cognitive impairment per investigator judgment that would render the informed consent invalid or limit the ability of the participant to comply with the study requirements. Participant has neurodegenerative disorder (e.g., Alzheimer’s disease, vasculardementia, Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI). Participants of age >65 years: has a MMSE <25 or <23 for those participants with less than high school equivalent education.

[0153] 27. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the wellbeing) or that could prevent, limit, or confound the protocol-specified assessments.

[0154] 28. Is pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month after the last dose of study drug.

[0155] 29. Plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.

[0156] 30. Has had major surgery, (e.g., requiring general anesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.

[0157] Treatment duration / Trial duration: The MDD3001 study consisted of 4 phases: a screening phase (up to 30 days), a DB treatment phase (43 days), OL treatment phase (1 year), and a posttreatment follow-up phase (7 to 14 days after the last treatment).

[0158] Primary analysis sets: The primary efficacy analysis for submissions other than the EU dossier (Estimand 1) is based on the full analysis set 1 (FAS1), which consists of all participants with MDDIS who were randomly assigned to study intervention and received at least 1 dose of study intervention and had baseline MADRS total score >24. The primary efficacy analysis for the EU dossier (Estimand 2) is based on the full analysis set 2 (FAS2), which includes all randomized participants with MDDIS who received at least 1 dose of study intervention in the double-blind (DB) phase. For the exploratory study population (i.e. the MDD without IS population), the main analysis will be based onFAS1 WOIS EDCIWR, which includes all randomized participants without IS who received at least 1 dose of study intervention in the DB phase and had baseline MADRS total score >24 and FAS2 WOIS EDCIWR, which includes all randomized participants without IS who received at least 1 dose of study intervention in the DB phase. All seven (1.2%) participants from site US10044 were excluded from all full analysis sets for GCP reasons. The safety outputs in this document will be based on the safety (DB) analysis set, which includes all participants who were randomly assigned to study intervention and received at least 1 dose of study intervention.

[0159] Primary efficacy variable / Primary Time point: Change in MADRS total score from baseline to Day 43. The MADRS consists of 10 items that cover the depressivesymptoms: each item is scored from 0 (symptom is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by summing the scores of all 10 items. A higher score represents more severe depressive symptoms.

[0160] Estimand 1 is the primary estimand for the non-EU dossiers. Under this estimand, treatment effect is defined as the mean treatment difference in change from baseline to Day 43 in MADRS total score in the subpopulation with MDDIS and baseline MADRS score >= 24, as if patients would have continued treatment as assigned (without discontinuing the add-on study drug, the underlying antidepressant, or switching to other antidepressant treatments).

[0161] Estimand 2 is the primary estimand for the EU dossier. Under this estimand, treatment effect is defined as the mean treatment difference in change from baseline to Day 43 in MADRS total score in the subpopulation with MDDIS, regardless of the discontinuation of the add-on study drug and as if other antidepressant treatments to switch to were not available.

[0162] Key secondary efficacy variables: MADRS without sleep item (MADRS- WOSI), Patient-Reported Outcomes Measurement Information System - Sleep Disturbance T-score (PROMIS-SD)

[0163] Expected effect size and planned sample size: Approximately 550 participants (randomized in 1 : 1 ratio to placebo and seltorexant 20 mg) were planned to be enrolled in the DB treatment phase (including approximately 386 participants with MDDIS and approximately 164 participants with MDD without IS). The enrollment was targeted to achieve approximately 374 participants eligible to be included in FAS1. Assuming treatment difference of 4.4 points in change from baseline in MADRS total score between seltorexant and placebo, standard deviation of 12, 1-sided significance level of 0.025 (equivalently, two- sided 0.05), this sample size would provide approximately 90% power in a comparison between seltorexant and placebo in the primary efficacy analysis, accounting for a drop-out rate of approximately 15%.

[0164] The planned primary analysis for Estimand 1 was performed using the appropriate contrasts in a mixed model for repeated measures (MMRM) with main comparison at Day 43. The MMRM included country, age group (adults [<65 years] and elderly [>65 years]), baseline rumination level (RRS total score <54, >54), time, intervention (placebo and seltorexant), and intervention by time interaction as factors, baseline MADRS total score as a covariate. To align with estimand 1, any data after a switch of add-on or underlying treatment were excluded; otherwise, all data observed up to and including DBdisposition day were included. The performed MMRM model is based on a Missing at Random assumption, assuming that values for measurements that are either missing or not used are assumed similar to those from the other participants from same treatment group who remain on treatment and have a collected MADRS score.

[0165] The planned primary analysis for Estimand 2 was performed using Copy Reference Multiple Imputation (CR MI) on monotonic missing data, followed by the MMRM analysis as described for Estimand 1. To align with estimand 2, post-treatment discontinuation data were used in the analysis for participants who discontinued add-on study intervention only. Any data after a switch of add-on or underlying treatment were excluded; otherwise, all data observed up to and including DB disposition day were included. The performed CR MI model imputes based on a Missing Not at Random assumption, assuming that values for measurements that are either missing or not used are similar to those from the placebo group.

[0166] An overview of the differences between Estimands 1 and 2 may be found in Table 1 pre-planned interim analysis (IA) of efficacy data was conducted when the 276th participant in the pooled full analysis set 1 (FAS1) has completed the double-blind treatment phase in MDD3001 and MDD3002 studies. At the time of the cutoff for the interim analysis, there were 161 participants in the MDD3001 FAS1 (131 completed DB) and 179 participants in the MDD3002 FAS1 (147 completed DB). The primary objective of the IA was to evaluate futility of the two studies combined, as well as individually.

[0167] B. Objective

[0168] The primary objective of this study was to assess the efficacy of seltorexant 20 mg compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in participants with MDDIS who have had an inadequate response to current antidepressant therapy with an SSRI or SNRI.

[0169] C. Participant and Treatment Information

[0170] This was a randomized, double-blind, placebo-controlled, multicenter 6- week study, that included 588 randomized participants, of which 444 had MDDIS. Of the 444 MDDIS participants, 2 participants did not receive any study drug and are therefore not included in the safety analysis and full analysis sets. Of the 442 randomized MDDIS participants who received study drug, 335 (76.8%) were white and 338 (77.5%) were female. The mean (SD) age was 45.4 (13.40) years, ranging from 18 to 72 years. Further demographic and baseline characteristic data is presented in Tables 2 and 3.

[0171] Of the 436 FAS2 participants, 405 (92.9%) completed the double-blind phase. The most frequent reason for withdrawal was 'Withdrawal by subject', reported by 13 participants (3.0%), and 'Adverse event', reported by 8 participants (1.8%). Further treatment disposition data is presented in Table 4.

[0172] D. Efficacy

[0173] (i) Analyses Datasets

[0174] The primary efficacy analyses in the MDDIS population are based on the FAS1 for Estimand 1 and FAS2 for Estimand 2. The exploratory efficacy analyses in the MDD without IS population are based primarily on FAS1 WOIS EDCIWR and FAS2 WOIS EDCIWR.

[0175] (ii) Level of Significance

[0176] At the final analysis, the primary efficacy endpoint was evaluated at a 2- sided significance level of 0.05 to test for treatment difference in mean change from baseline at Day 43. To control family-wise error rate at 0.05, a fixed sequence testing procedure was applied for the primary and both key secondary efficacy endpoints: first MADRS total score, then MADRS-WOSI score, then PROMIS-SD T-score.

[0177] (iii) Final Analysis

[0178] Presented here are the primary pre-specified analyses. Further analyses intended to deepen our understanding of the results are pending.

[0179] Under estimand 1, the arithmetic mean (SD) change from baseline to Day 43 in MADRS total score was -12.9 (9.63) for seltorexant 20 mg and -10.5 (10.26) for placebo.

[0180] Under estimand 2, the arithmetic mean (SD) change from baseline to Day 43 in MADRS total score was -12.9 (9.53) for seltorexant 20 mg and -10.2 (10.20) for placebo.

[0181] The least squares (LS) mean differences at Day 43 between seltorexant 20 mg and placebo groups are shown in Table 5 (Estimand 1) and Table 6 (Estimand 2). Under estimand 1, a statistically significant difference in improvement in MADRS total score at Day 43 was observed between the seltorexant 20 mg and placebo groups (2-sided p-value 0.007; LS mean difference [95% CI]: -2.6 [-4.53, -0.74]). Under estimand 2, a statistically significant difference in improvement in MADRS total score at Day 43 was observed between the seltorexant 20 mg and placebo groups (2-sided p-value 0.007; LS mean difference [95% CI]: -2.5 [-4.35, -0.68]). FIGs. 1 and 2 show LS mean (+ / - SE) changes from baseline for the MADRS total score over time during the double-blind phase under each estimand.

[0182] The arithmetic mean (SD) change from baseline to Day 43 in MADRS total score in FAS1 WOIS EDCIWR was -13.1 (8.61) for seltorexant 20 mg and -9.0 (9.55) for placebo.

[0183] The arithmetic mean (SD) change from baseline to Day 43 in MADRS total score in FAS2 WOIS EDCIWR was -12.5 (8.65) for seltorexant 20 mg and -8.2 (10.14) for placebo.

[0184] G. Safety

[0185] Overall, 102 / 283 (36.0%) participants in the Seltorexant 20 mg group and 122 / 303 (40.3%) participants in the Placebo group experienced at least one treatment- emergent adverse event (TEAE) during the Double-blind Phase.

[0186] The most common (> 5%) TEAEs during the Double-blind Phase were headache (8.5%) for the Seltorexant group, and headache (8.9%) for the Placebo group.

[0187] Six (2.1%) participants in the Seltorexant 20 mg group discontinued due to TEAEs in the Double-blind Phase; one participant discontinued due to electrocardiogram qtc interval prolonged (considered related by the site investigator); one participant discontinued due to iron deficiency anaemia (not related); one participant discontinued due to insomnia exacerbated (not related); one participant discontinued due to insomnia (related); one participant discontinued due to elevated liver enzymes (not related); one participant discontinued due to dizziness postural (related) and daytime sleepiness (related). Seven (2.3%) participants in the placebo group discontinued due to TEAEs in the Double-blind Phase; one participant discontinued due to abnormal dreams (related); one participant discontinued due to stomach flu (related); one participant discontinued due to tinnitus(related); one participant discontinued due to vertebral contusion (not related) and lumbar spine compression fracture (not related); one participant discontinued due to autoimmune thyroiditis (related); one participant discontinued due to allergic dermatitis (related); one participant discontinued due to nausea (not related).

[0188] Five (1.8%) participant(s) in the Seltorexant 20 mg group experienced TEAEs of special interest during the Double-blind Phase; one participant experienced confusional arousal (related); two participants experienced fall (not related); two participants experienced motor vehicle accident (not related). Seven (2.3%) participant(s) in the Placebo group experienced TEAEs of special interest during the Double-blind Phase; one participant experienced bruxism aggravated (not related); four participants experienced fall (not related); one participant experienced sleep paralysis (related); one participant experienced sleep terror (related).

[0189] There were no deaths in this study. One (0.4%) participant in the Seltorexant 20 mg group experienced a serious TEAE of iron deficiency anaemia (not related) during the Double-blind Phase. One (0.3%) participant in the Placebo group experienced serious TEAEs of fall (not related) and lumbar spine compression fracture (not related) and spinal canal stenosis (not related) during the Double-blind Phase.

[0190] See, Tables 7-11.

[0191] Example 2: Patient Stratification Approach

[0192] A primary objective is to evaluate whether adjunctive use of seltorexant improves depression symptoms in the subgroup of MDD patients that have moderate to severe insomnia symptoms, a patient population with critical unmet need.

[0193] In Study 42847922MDDMDD3001, participants who met all of 3 of the following criteria at baseline were classified as MDD with moderate to severe IS:

[0194] (1) Clinician-reported Insomnia Severity Index (cISI) score ^ 15;

[0195] (2) Patient-reported Insomnia Severity Index (pISI) score ^ 15; and

[0196] (3) Positive response on Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-5th Edition Axis I Disorders - Clinical Trials Version (SCID-CT) item inquiring about presence of insomnia as a symptom in current major depressive episode (MDE).

[0197] Participants who failed to meet at least 1 of the 3 criteria were classified as MDD with mild or no IS. Of those participants, only 8.4% failed all three criteria. The remaining 91.6% of participants identified as having no or mild IS had clinically meaningful symptoms according to 1 or 2 of the stratification criteria. Thus, the IS stratification approach used in Study MDD3001 was insufficient for differentiating among MDD patients with varying IS severity levels, (see. Fig. 6). Limitations of the measurement tools used for IS stratification in MDD3001 likely contributed to the poor agreement amongst the criteria. These include multidimensionality of the ISI instruments, concerns about content validity of ISI items in MDD populations, inconsistencies in patients’ responses to the pISI lateinsomnia item, and failure of the SCID-CT item to capture variation in the type and severity of IS.

[0198] Accordingly, a stratification approach that utilizes the unique and combined contributions of clinician-reported insomnia symptoms and patient-reported sleep disturbance was explored to identify patients who may derive a meaningful benefit from adjunctive seltorexant treatment.

[0199] Conceptual-measurement framework for insomnia symptoms in MDD.

[0200] The approach considers the sleep experiences of MDD patients, which were identified through semi-structured interviews conducted with 25 MDD patients. A patient qualitative study to identify sleep experiences of importance to patients with MDD and varying insomnia symptom severity levels was conducted. A secondary objective was to gauge the degree to which a set of clinical outcome assessment (COA) instruments captured patient-identified sleep experiences. A second, independent analysis of the sleep-related concepts referenced by patients during the interviews was conducted.

[0201] Six meaningful sleep-related aspects of health were identified through the qualitative analysis of patient interviews. These are:

[0202] 1. Insomnia symptoms - clinical manifestations resulting in lost sleep time due to difficulty initiating or maintaining sleep.

[0203] 2. sleep disturbances - subjective ratings of sleep disturbances, satisfaction with sleep, and the degree to which sleep is restful or restorative.

[0204] 3. Sleep quantity - amount of time spent asleep versus awake and trying to sleep.

[0205] 4. Impacts of insomnia / sleep disturbances - symptoms and functional impairments associated with poor sleep.

[0206] 5. Hypersomnia - symptoms and behaviors associated with extreme daytime sleepiness despite adequate sleep quantity and quality.

[0207] 6. Nightmares - disturbing dreams associated with negative feelings such as anxiety or fear.

[0208] From the above sleep domains, two concepts of interest were selected to define the MDDIS patient population: insomnia symptoms and sleep disturbance. The framework shown is FIG. 5 which includes measurement models to generate scores for each concept of interest.

[0209] Insomnia symptoms are consistent with the three primary diagnostic criteria for Insomnia Disorder as defined by DSM-5 (namely, difficulty initiating sleep, difficultymaintaining sleep, and early-morning awakenings). Patient interviews revealed that difficulty falling asleep, staying asleep, or falling back asleep after waking in the night are common experiences for many people with MDD. Those who experienced insomnia were bothered by the symptoms as well as the negative effects of insomnia on their energy levels, mood, cognition, and social role performance. Whereas insomnia symptoms characterize quantitative dimensions of sleep patterns, sleep disturbance represents qualitative aspects of sleep. Sleep disturbance is the degree to which patients perceive their sleep to be restful, satisfying, and free of experiences that make their sleep non-restorative in nature. Sleep disturbance is also indicated by feeling refreshed and rejuvenated upon awakening.

[0210] Measurement model: Sleep disturbance

[0211] Sleep disturbance is best measured by a patient reported outcome (PRO) instrument due to its subjective nature. The Patient Reported Outcomes Measurement Information System (PROMIS) captures self-reported, qualitative health aspects in the domains of physical, mental, and social health. PROMIS item banks and short forms are developed using state of the art psychometric techniques, such as Item Response Theory Models. The PROMIS Sleep Disturbance instruments are content valid measures of subjective sleep quality experiences. Here, the PROMIS Sleep Disturbance-Short Form 8a (PROMIS-SD-8a) was used to assess sleep disturbance. The recall period for all PROMIS- SD-8a items is the “past 7 days The first item, “Sleep quality’ uses a 5-point response scale where l=Very good; 2 = Good; 3= Fair; 4=Poor; and 5=Very Poor. Items 2 through 8 also employ a 5-point response scale (l=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; 5 =Very Much) (see Fig. 7). Items 2 “Sleep was refreshing" and 8 “Satisfied with sleep" are reverse coded so that higher ratings indicate poorer sleep quality. Responses to the 8 items are summed and then converted, using a provided conversion table (Table 12), to a t-score metric ranging from 0 to 100 with a mean of 50 and a standard deviation (SD) of 10. Higher total PROMIS-SD-8a scores indicate greater sleep disturbance.Table 12: PROMIS Adult Short Form vl.-Depression 8a Short Form Conversion Table*SE= Standard Error on T-score metricAdult version

[0212] Receiver Operating Characteristic (ROC) Analysis to IdentifyPROMIS-SD-8A Threshold

[0213] PROMIS-SD-8A A series of ROC analyses were conducted to identify a PROMIS-SD-8a score cut point that optimally differentiates between MDD patients with moderate to severe IS from MDD patients with no or mild IS. Analyses were conducted using data from MDD3001 (Example 1).

[0214] ROC curves show sensitivity (true positive rate) (y-axis) versus 1- specificity (false negative rate) (x-axis) of all possible PROMIS-SD-8a score cut points for binary classifications based on responses to 4 anchor items. Each anchor item was dichotomized to differentiate IS severity categories (no or mild vs moderate to severe). The anchors and classification strata are shown below:• Patient Global Impression of Severity (PGI-S) - sleep difficulty: In the past 7 days, how would you describe your difficulty falling asleep or staying asleep? o Classification: MDD with no or mild IS (no difficulty / mild) vs MDD with moderate to severe IS (moderate / severe / very severe)• PGI-S-unrested: Thinking about the past 7 days, please choose the response below that best describes the problem of not feeling rested the next day. o Classification: MDD with no or mild IS (did not have this problem / mild) vs MDD with moderate to severe IS (moderate / severe / very severe)• PGI-S-sleep difficulty or PGI-S-unrested: items shown above. o Classification: MDD with no or mild IS (PGI-S-sleep difficulty: no difficulty / mild and PGI-S-unrested: did not have this problem / mild) vs MDD with moderate to severe IS (PGI-S-sleep difficulty: moderate / severe / very severe and / or PGI-Sunrested: moderate / severe / very severe)• SCID-CT insomnia symptoms: MDD with no or mild IS vs MDD with moderate to severe IS based on a single item from the MDE module of the SCID-CT. Raters indicated whether insomnia symptoms (difficulty falling asleep, staying asleep, and / or waking up too early) were present (moderate to severe IS) or absent (no or mild IS) nearly every night in the worst 2 weeks over the past month.

[0215] ROC analyses showed that the best cut points for differentiating patients with MDD and no or mild IS from those with MDD and no or mild IS were 54.8 for PGI-S- sleep difficulty (area under the curve [AUC]=0.94; FIG. 4), 57.8 for PGI-S-unrested(AUC=0.81), 52.75 for PGI-S-sleep difficulty or PGI-S-unrested (AUC= 0.97), and 57.8 for SCID-CT IS (AUC=0.74).

[0216] Across all anchors, the optimal PROMIS-SD-8a score cut point for differentiating patients with MDD and moderate to severe IS from MDD patients with no or mild IS ranges from 52.75 to 57.8 (mean =55.8).

[0217] Although slightly lower than the average of the optimal cut points identified for each anchor, a cut point of 54 reflects the greater emphasis placed on ROC results for anchors with the highest AUC values (Anchors 1 and 3). Sensitivity and specificity rates for the PROMIS-SD-8a cut point of 54 JNJ-42847922 (seltorexant) are shown in Tables 13 and 14. Accordingly, a PROMIS-SD-8a cut point of >54 for identifying patients with MDD and moderate to severe IS was determined as a way for such patients to benefit from adjunctive seltorexant 20 mg treatment.

[0218] For all anchors, a PROMIS-SD-8a cut point of 54 has good sensitivity for identifying patients with moderate to severe IS (Tables 13 and 14). The cut point also has strong specificity for anchors that include the PGI-S-sleep difficulty item. Specificity is lower for anchors that are rater-reported (SCID-CT) and reflect concepts that are related to, but not directly assessed by PROMIS-SD-8a (the PGI-Sunrested item). In this context, sensitivity is valued over specificity to ensure that the PROMIS-SD-8a cut point does not exclude patients who have meaningful IS and could potentially benefit from adjunctive seltorexant 20 mg.

[0219] Recommended cut off: PROMIS-SD > 54 because of strength of PGIS anchor and to maximize inclusion to patients with MDDIS who might benefit from adjunctive Seltorexant. See, FIG. 4.

[0220] At the same time, a PROMIS-SD-8a cut off alone may not be sufficient to adequately identify those patients that will benefit most from seltorexant treatment. For example, at a higher PROMIS-SD level, a higher MADRS estimate would be expected, but that does not happen in all instances (see Table 15).

[0221] Clinician-reported insomnia symptoms

[0222] Additionally, the stratification includes criteria involving clinician-reported outcome (ClinRO) measures of depression symptom severity to supplement the patient reported outcome (PRO) criteria due to its subjective nature. This ensures that high levels of sleep disturbance as reported by the patient are insufficient on their own to include the participant as part of the intended patient population. Information obtained from the patient through a structured clinical interview is utilized by the clinician to confirm core diagnostic symptoms of insomnia. Incorporating both PRO and ClinRO in the approach helps reduce the reliance on a single measure, making the overall assessment more robust and helping mitigate the effects of random fluctuations in PRO.

[0223] The HAM-D is a 17-item clinician-reported outcome (ClinRO) measure of depression symptom severity. The HAM-D insomnia items are shown in Table 16. There is a HAM-D through administration of a semi-structured Clinical Interview Guide for the HAM- D17 (Bech P. The Bech, Hamilton and Zung scales for mood disorders: screening and listening. Springer, Berlin 1996, second revised edition). In addition, there is a Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D; Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988). For purposes of this disclosure, reference is made to items 3 (early insomnia), 4 (middle insomnia), and 5 (late insomnia) which are associated with the SIGH-D.

[0224] SIGH-D items 3, 4, and 5 evaluate the three diagnostic symptoms of insomnia specified in the DSM-5 and ICD-11 : difficulty initiating sleep, difficulty maintaining sleep, and waking up too early and being unable to fall back asleep (Table 16). SIGH-D items / response categories:

[0225] SIGH-D offers advantages over cISI for a number of reasons. For example, whereas the cISI uses a 2-week recall period, the SIGH-D utilizes a 7-day recall period. Thus using SIGH-D items in lieu of cISI items for patient stratification decreases susceptibility to recall bias and matches the timeframe from the PROMIS-SD-8a. And unlike the cISI, the SIGH-D is completed by clinicians through administration of a standardized interview which improves measurement reliability and facilitates rater training.

[0226] Patient stratification Criteria.

[0227] The stratification criteria includes SIGH-D items 3, 4, and 5 utilizing the standardized Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D) to measure clinical manifestations of insomnia resulting in lost sleep time as well as Patient Reported Outcome Measurement Information System-Sleep Disturbance Short Form 8a (PROMIS-SD-8a).

[0228] The patient stratification criteria using SIGH-D and PROMIS-SD-8a is shown in Table 17.

[0229] When applying the IS stratification criteria shown in Table 17 to MDD3001 data, 85.8% of MDD patients were classified as having moderate / severe IS. Remaining patients (14.2%) met criteria for non-MDDIS. The SIGH-D criteria were applied as a post hoc analysis of the MDD3001 data.

[0230] Validation of the MDDIS patient stratification approach

[0231] Validity of the classification approach is supported by expected differences between the no or mild IS and moderate to high IS subgroups on baseline measures of sleep disturbance (PROMIS-SD-8a) and sleep quantity (Consensus Sleep Diary; CSD3) (Table 18). Compared to MDD patients with no or mild IS, those with moderate to severe IS report poorer sleep quality (PROMIS-SD-8a T-scores), more nighttime awakenings, longer time to fall asleep, and less total sleep time.

[0232] As shown in FIG. 3, there are no differences in the magnitude of treatment difference as measured by change in MADRS Total score between patients classified by symptom severity on any individual insomnia item of the HAM-D (or SIGH-D). However, per stratification criterion #1, patients for whom at least one HAM-D item was endorsed at the most severe level (response = 2), or for whom all 3 HAM-D items were endorsed at the moderate level (responses = 1) showed greater improvement in MADRS total scores with seltorexant. Similar improvement was observed with seltorexant for patients with PROMIS- SD-8a total scores > 54 at screening and for patients who met both the HAM-D andPR0MIS-SD-8a criteria for moderate to severe IS at screening (Table 17). These findings confirm that both moderate to severe clinician-reported insomnia symptoms of any type, and patients’ subjective ratings of sleep disturbance are important contributors to identifying patients with MDD who are most likely to benefit from seltorexant treatment.

[0233] In newly conducted post-hoc analyses, MDD3001 participants were stratified by IS severity using the SIGH-D and PROMIS-SD criteria (Table 17).

[0234] Using the new stratification strategy in MDD3001, seltorexant 20 mg was significantly better than placebo in the MDD-IS stratum. The post-hoc analysis of the MDD with no or mild IS stratum, using the new stratification strategy (the 3 insomnia items from the SIGH-D combined with the PROMIS-SD) for MDD3001, demonstrates that participants classified as MDD with no or mild IS did not experience clinically meaningful change in overall depressive symptoms.

[0235] PROMIS-SD-8a in MDD3001 with new IS stratification criteria

[0236] PROMIS-SD-8a data for participants with MDDIS and MDD with no or mild IS under the new stratification are provided in Tables 19 and 20, respectively.

[0237] Post-hoc analysis of PROMIS-SD-8a under the new stratification does not incorporate type 1 error control for analysis of data for MDD no or mild IS. To demonstrate the statistical significance of PROMIS-SD data under the new stratification for MDDIS while controlling for type I error, following the predefined testing sequence, additional analyses were done to confirm that the MADRS results remain significant under the new stratification for MDDIS.

[0238] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

[0239] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.

Claims

What is claimed is:

1. Seltorexant or a pharmaceutically acceptable salt thereof for use in a method of treating major depressive disorder with insomnia symptoms (MDDIS) in a patient, the method comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

2. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the MDDIS is determined by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

3. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 1 or 2, wherein the patient has(i) a PROMIS-SD-8a T-score of > 54, and(ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

4. A method of stratifying human patients with major depressive disorder (MDD) to identify a human patient with MDDIS to be treated with an orexin-2 receptor antagonist.

5. The method of claim 4, wherein the orexin-2 receptor antagonist is seltorexant or a pharmaceutically acceptable salt thereof.

6. The method of claim 4 or 5, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

7. The method of claim 6, wherein the patient with MDDIS is identified by the following criteria:(i) a PROMIS-SD-8a T-score of > 54, and(ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

8. The method of any one of claims 5-7, wherein seltorexant or a pharmaceutically acceptable salt thereof is a free base.

9. The method of any one of claims 5-7, wherein the seltorexant or a pharmaceutically acceptable salt thereof is a hydrochloride salt of seltorexant.

10. The method of claim 9, wherein the seltorexant or a pharmaceutically acceptable salt thereof is a hydrate of the hydrochloride salt of seltorexant.

11. The method of any one of claims 5-10, wherein the seltorexant or a pharmaceutically acceptable salt thereof is formulated for oral administration.

12. The method of any one of claims 5-11, wherein the seltorexant or a pharmaceutically acceptable salt thereof is formulated for once daily administration.

13. The method of any one of claims 5-12, wherein the seltorexant or a pharmaceutically acceptable salt thereof is formulated for administration prior to sleep.

14. The method of any one of claims 5-13, wherein the seltorexant or a pharmaceutically acceptable salt thereof is formulated for administration at night.

15. The method of claim 14, wherein antidepressant effect from seltorexant or a pharmaceutically acceptable salt thereof is maintained when the patient is awake the next day.

16. The method of any one of claims 5-15, wherein the seltorexant or a pharmaceutically acceptable salt thereof is formulated to treat a psychic symptom of the depression.

17. The method of any of claims 5-16, wherein the patient had an inadequate response to an antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the patient had an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

19. The method of any one of claims 5-18, wherein seltorexant or a pharmaceutically acceptable salt thereof is formulated for adjunctive administration with a second pharmaceutically active agent.

20. The method of claim 19, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

21. The method of any one of claims 5-20, wherein the MDD is at least of moderate depression severity based on an industry accepted scale, such as the 17-item Hamilton Depression Rating Scale (HDRS17).

22. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3, wherein seltorexant is administered as a free base.

23. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3, wherein a hydrochloride salt of seltorexant is administered.

24. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 23, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

25. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-24, wherein seltorexant is administered orally.

26. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-25, wherein seltorexant is administered once daily.

27. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-26, wherein seltorexant is administered prior to sleep.

28. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-27, wherein seltorexant is administered at night.

29. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 28, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

30. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-29, wherein seltorexant treats a psychic symptom of the depression.

31. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-30, wherein the patient has an inadequate response to an antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof.

32. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 31, wherein the patient has an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

33. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-32, wherein seltorexant or a pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

34. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 33, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

35. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-3 or 22-34, wherein the major depressive disorder with insomnia symptoms is at least of moderate depression severity based on an industry accepted scale, such as the 17-item Hamilton Depression Rating Scale (HDRS17).

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