Lipid prodrug of allopregnanolone and its uses

Abstract

A method for treating subjects requiring this with an orally administered lipid prodrug of allopregnanolone is disclosed herein. The method described herein may be used for the treatment of major depressive disorder (MDD) accompanied by anxiety distress or major depressive disorder (MDD) not accompanied by anxiety distress.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 598,495 filed November 13, 2023, U.S. Provisional Application No. 63 / 561,060 filed March 4, 2024, and U.S. Provisional Application No. 63 / 635,832 filed April 18, 2024, the whole of which is incorporated herein by reference.

[0003] Technology field

[0004] The present disclosure relates to the oral administration of a lipid prodrug of allopregnanolone for the treatment of human subjects who generally require this.

[0005] In one embodiment, a method for treating a human subject is disclosed herein, said method comprising the step of orally administering a dose of compound 1 to a human subject in need thereof:

[0006] (Compound 1).

[0007] In some embodiments, the dosage of compound 1 is 70 to 500 mg. In some embodiments, the dosage of compound 1 is 70 mg, 125 mg, 140 mg, 250 mg, 280 mg, 375 mg, 420 mg, or 500 mg. In some embodiments, the dosage of compound 1 is 125 mg. In some embodiments, the dosage of compound 1 is 250 mg. In some embodiments, the dosage of compound 1 is 375 mg.

[0008] In some embodiments, the human subject requiring this has major depressive disorder (MDD). In some embodiments, the human subject has MDD accompanied by anxiety distress. In some embodiments, the human subject has MDD not accompanied by anxiety distress. In some embodiments, a dose of compound 1 is administered once daily. In some embodiments, a dose of compound 1 is administered once daily at bedtime (qHS).

[0009] In one embodiment, a method for treating a human subject suffering from major depressive disorder (MDD) is provided herein, the method comprising the step of orally administering the following to a human subject in need thereof, wherein: i) a daily starting dose of compound 1 for an initiation period of up to 7 days; and ii) a daily maintenance dose of compound 1 starting after said initiation period; said compound 1 is as follows:

[0010] (Compound 1).

[0011] In some embodiments, the daily starting dose of Compound 1 is 125 mg. In some embodiments, the daily starting dose of Compound 1 is 250 mg. In some embodiments, the daily maintenance dose of Compound 1 is 125 mg, 250 mg, or 375 mg. In some embodiments, the initiation period is 3 to 7 days. In some embodiments, the daily maintenance dose of Compound 1 is higher than the daily starting dose of Compound 1. In some embodiments, the daily maintenance dose of Compound 1 is the same as the daily starting dose of Compound 1. In some embodiments, the daily maintenance dose of Compound 1 is lower than the daily starting dose of Compound 1. Brief explanation of the drawing

[0012] Figures 1a~1c The graph plots the PK parameters determined from a single elevated dose study (Part 1 of Example 1). Fig. 1a is AUC 0-24시간 It illustrates the dose-exposure relationship of. Fig. 1b It illustrates the dose-exposure relationship of Cmax. Fig. 1c It plots the concentration of allopregnanolone over time for the tested dose. Figures 2a~2c The graph shows the PK parameters determined from the multiple ascending dose study (Part 3 of Example 1). Fig. 2a This shows the plasma concentrations of allopregnanolone in subjects administered 250 mg of QAM (Cohort 4), 375 mg of QAM (Cohort 5), 375 mg of QHS (Cohort 8), and 500 mg of QAM (Cohort 6). Fig. 2b AUC on Day 7 0-24시간 It illustrates the dose-exposure relationship of. Fig. 2c It illustrates the dose-exposure relationship of Cmax on day 7. Figures 3a~3b This shows the PD evaluation from the multiple elevated dose study (Part 3 of Example 1). Fig. 3a Figure Cz illustrates the change in saccadic eye velocity in subjects administered 250 mg (Cohort 4), 375 mg (Cohort 5), and 500 mg (Cohort 6) of Compound 1 with their eyes open. Fig. 3b Figure 1 illustrates the change in beta power in subjects administered Compound 1 at 250 mg (Cohort 4), 375 mg (Cohort 5), and 500 mg (Cohort 6). Saccadic eye movements ( Fig. 3a ) and beta power( Fig. 3b The change in ) is expressed as the ratio of the value at a given time point to the value before administration (time = 0 hours). Figures 4a–4c Graphs the change in salivary cortisol levels in subjects treated with compound 1 or placebo. Fig. 4a represents the change in salivary cortisol levels over time relative to baseline. Fig. 4b It plots the maximum change relative to the baseline. Fig. 4c This illustrates the study design described in Example 2. Specific details for implementing the invention

[0013] A method for treating a subject in need of this with a lipid prodrug of allopregnanolone is disclosed herein.

[0014] definition

[0015] Although the terms used herein are considered to be sufficiently understood by those skilled in the art, specific definitions are provided herein to facilitate the description of this disclosure.

[0016] As used herein, the term "adverse reaction" refers to a subject administered with a drug (i.e., It refers to any event, side effect, or other undesirable medical event in a clinical trial participant. An adverse reaction is not necessarily causally related to the drug. As used herein, “post-treatment adverse reaction” or “TEAE” refers to an adverse reaction that was not present prior to treatment (i.e., receiving a dose of Compound 1) or a pre-existing case that worsens in intensity or frequency after treatment. TEAEs may be classified according to System of Organ (SOC); an exemplary SOC is neurological disorders. Examples of neurological disorder TEAEs include somnolence, headache, dizziness, lethargy, balance disorders, and cognitive impairment.

[0017] As used herein, the terms “treatment,” “treat,” and “treating” refer to the reversal, alleviation, prevention, mitigation, delay of onset, or inhibition of progression of a disorder or one or more of its symptoms. For example, when these terms are used in relation to the treatment of anxiety, “treatment of anxiety” includes both managing anxiety and alleviating existing anxiety or preventing anxiety. Anxiety disorders may include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, or any one of the anxiety disorders disclosed herein. Treatment may also include treating both depression and anxiety.

[0018] The terms "subject," "patient," and "participant" refer to mammalian subjects, including human subjects. In some embodiments, the subject is a human subject.

[0019] As used herein, the term “anxiety disorder” refers to one or more mental disorders characterized particularly by feelings of worry, anxiety, fear, and stress. Anxiety disorders may include, but are not limited to, social anxiety disorder and generalized anxiety disorder (GAD).

[0020] As used herein, the term “stress” is the result of conscious or unconscious feelings or thoughts caused by a traumatic event or external pressure (e.g., a stressor). As used herein, the term “stress-related disorder” refers to a disorder that occurs as a result of stress. In some cases, a stress-related disorder may have symptoms that overlap with one or more anxiety disorders. In some cases, an anxiety disorder (e.g., social anxiety disorder or generalized anxiety disorder, GAD) may be triggered, induced, or exacerbated by stress. Stress may be acute, intermittent, or chronic. A human subject may experience one or more stressors or one or more stress-related disorders and may exhibit one or more symptoms associated with the stressor and / or its stress-related disorder. Stress-related disorders (including stress-related or stress-induced anxiety disorders) include, but are not limited to, separation anxiety disorder, selective mutism, specific phobias, social phobia, panic disorder (e.g., nocturnal panic disorder and / or panic attacks), agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, anxiety disorder due to another medical condition, other specified anxiety disorders, unspecified anxiety disorders, reactive attachment disorder, uninhibited social engagement disorder, acute stress disorder, regulation disorder, post-traumatic stress disorder, long-term grief disorder, social anxiety disorder, other specified trauma and stress-related disorders, or unspecified trauma and stress-related disorders. Human subjects requiring this may have depression or mood disorders, which include, but are not limited to, major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic mood disorder, premenstrual dysphoric disorder, persistent depression, disruptive mood dysregulation disorder, postpartum depression, perimenopausal depression, or depression associated with medical conditions.A human subject requiring this may have one or more depressive or mood disorders or symptoms of a depressive or mood disorder simultaneously with an anxiety disorder and / or a stress-related disorder. For example, a subject requiring this may have one or more symptoms of a mood or depressive disorder, such as but not limited to Generalized Anxiety Disorder (GAD) or Major Depressive Disorder, having one or more depressive or mood disorders. In some embodiments, a subject requiring this may have Major Depressive Disorder (MDD) accompanied by anxiety (also referred to as MDD accompanied by anxiety distress).

[0021] As used herein, “MDD with anxiety” or “MDD with anxiety distress” refers to the presence of at least two of the symptoms described below during the majority of a current episode of major depressive disorder, a past episode of major depressive disorder, or a current episode of depressive disorder. Symptoms of anxiety distress include i) tension or restlessness, ii) abnormal agitation, iii) difficulty concentrating due to worry, iv) fear that something terrible is going to happen, and / or v) a feeling of losing control over oneself. The severity of MDD with anxiety distress may be further classified as mild (two of the above symptoms), moderate (three of the above symptoms), moderate-severe (four to five of the above symptoms), or severe (four to five of the above symptoms + psychomotor agitation).

[0022] As used herein, the term “daily initiation dose” refers to a compound of Formula I administered for an initiation period of up to 7 days, e.g. Refers to the daily dose of Compound 1. In some embodiments, the initiation period is 3, 4, 5, 6, or 7 days. In some embodiments, the daily initiation dose is 125 mg of Compound 1. In some embodiments, the daily initiation dose is 250 mg of Compound 1.

[0023] As used herein, the term “daily maintenance dose” refers to a compound of Formula I administered after an initiation period of up to 7 days, e.g. Refers to the daily dose of Compound 1. The daily maintenance dose may be equal to, higher than, or lower than the daily initiation dose. In some embodiments, the daily maintenance dose is 125 mg of Compound 1. In some embodiments, the daily maintenance dose is 250 mg of Compound 1. In some embodiments, the daily maintenance dose is 375 mg of Compound 1. The daily maintenance dose is determined based on both the efficacy and tolerability observed in subjects given a specific dose. The daily maintenance dose may remain the same, increase, or decrease based on the efficacy and tolerability observed in subjects given the said dose. For example, but not limited to, observed efficacy may be determined based on the change from baseline in the Hamilton Depression Rating Scale-17 (HAM-D-17) total score for a specific subject.

[0024] As used herein, the terms “pharmaceuticalally acceptable carrier,” “pharmaceutically acceptable adjuvant,” or “pharmaceutically acceptable vehicle,” or any combination thereof, refer to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the formulation being formulated. Pharmaceutically acceptable carriers, adjuvant, or vehicles suitable for use in the compositions disclosed herein include, but are not limited to, buffering materials such as ion exchangers, alumina, stearates, lecithin, serum proteins, phosphates, glycine, sorbic acid, potassium sorbate, glyceride mixtures, lipids, water, salts, or electrolytes.

[0025] Unless otherwise noted, the structures described herein mean that they include all isomers of the structure (e.g., enantiomers, diastereomers, and geometric (or stereomorphic) forms: e.g., R and S arrangements for each asymmetric center). Thus, not only single stereochemical isomers but also enantiomers, diastereomers, and geometric (or stereomorphic) mixtures are within the scope of the disclosed method.

[0026] lipid precursor drug of allopregnanolone

[0027] In one embodiment, a method for treating stress-related disorders, including, for example, stress-related anxiety disorders, is disclosed herein using a lipid prodrug of allopregnanolone (compound 1). Allopregnanolone is an endogenous pregnane neurosteroid that acts as a positive allosteric modulator of the inhibitory action of gamma-aminobutyric acid (GABA) on GABA type A (GABAA) receptors.

[0028] GABAA receptors are penmeric proteins present in multiple isoforms. Generally, GABAA receptors contain two α-subunits, two β-subunits, and one γ-, δ-, ε-, π-, or θ-subunit. At least six α, three β, and three γ subunits have been identified to date, providing for a number of potential penmeric GABAA compositions. The abundance and distribution of GABAA receptor subtypes vary widely across the central nervous system (CNS). The composition of GABAA receptors influences behavioral effects. The α1 subunit is associated with sedation, while the α2 subunit is associated with anxiolytic effects. Additional associations between GABAA receptor subunits have been identified, for example, α2, α4, β3, and δ subunits are all known to be associated with anxiety and mood symptoms (Wang, Mingde, Front. Endrocrinol. (2011) 2:44). Therefore, the mechanism of action (MOA) of therapeutic agents acting on GABAA and their downstream pharmacodynamic effects depend on both the composition of the GABAA receptor subunits and the binding site of said therapeutic agents.

[0029] For example, benzodiazepines act on GABAA receptors to exert anxiolytic and antidepressant properties. Since the MOA depends on the binding of benzodiazepines at the interface between the α and γ subunits, benzodiazepines require GABAA receptors containing the γ subunit (Goldschen-Ohm, Biomolecules (2022)). In contrast, allopregnanolones have broad specificity for GABAA subunits and can additionally act on GABAA receptors containing the δ subunit. GABAA receptors with the δ subunit are primarily located in the extrasynaptic and perynaptic spaces (Glkyks J, et al., J. Neurosci (2008) 28(6): 1421-1426; Brickley and Mody (2012) Neuron 73(1):23-34). These GABAA receptors have a high affinity for GABA and mediate tension inhibition (reference [Paul S et al., Neurobiology of Stress (2020)]). Therefore, allopregnanolone acts as a potent modulator across GABAA receptor isoforms, particularly those capable of exerting antidepressant, sedative, anxiolytic, and stress-reducing effects.

[0030] Therefore, allopregnanolone has the potential to treat stress-related disorders. However, allopregnanolone suffers from low oral bioavailability of less than 5% due to extensive first-pass metabolism. The present disclosure provides a lipid prodrug of allopregnanolone that enables oral delivery of allopregnanolone by bypassing first-pass metabolism. Lipid-mimicking compounds such as lipid prodrugs can act similarly to natural triglycerides, and thus, can be transported via the lymphatic system before reaching the systemic circulation and effectively bypass first-pass metabolism. Lipid prodrugs are further discussed in WO2016 / 023082, WO2017 / 041139, and WO2021 / 159021, the entirety of which is incorporated herein by reference.

[0031] The development of oral allopregnanolone has been limited due to its low oral bioavailability. An intravenous formulation of allopregnanolone (brexanolone) is approved for the treatment of severe postpartum depression (marketed as Zulresso®) and is administered in a hospital setting over a 60-hour infusion period. The Zulresso® infusion is titrated over 60 hours (2.5 days), increasing from 30 μg / kg / hour to 60 μg / kg / hour during the first 24 hours and then to 90 μg / kg / hr continuously for 24 to 52 hours. After 52 hours of treatment, the infusion is titrated to 60 μg / kg / hour for 4 hours and then to 30 μg / kg / hour for 4 hours. Patients receiving Zulresso® require continuous monitoring during this period because they are at high risk of sedation and / or loss of consciousness (Package Insert, Zulresso®). It has been reported that the antidepressant effect lasts for up to 30 days after a 2.5-day infusion.

[0032] Compound 1, a lipid precursor drug of allopregnanolone, is disclosed herein and is administered orally to a subject who requires it:

[0033] (Compound 1).

[0034] Compound 1 may be administered as a diastereomer or a mixture thereof. Accordingly, in some embodiments, the method and formulation of Compound 1 disclosed herein may comprise Compound 1-R:

[0035] (Compound 1-R).

[0036] In some embodiments, the method and formulation of compound 1 disclosed herein may comprise compound 1-S:

[0037] (Compound 1-S).

[0038] In some embodiments, the method and formulation of Compound 1 disclosed herein comprise a mixture of diastereomers of Compound 1-R and Compound 1-S. In some embodiments, the mixture of diastereomers of Compound 1-R and Compound 1-S is in an approximate 1:1 molar ratio. Compound 1 is designed to bypass first-pass metabolism and subsequently release free allopregnanolone immediately upon reaching the systemic circulation (lipid-mimicking compounds are further discussed in WO2016 / 023082 and WO2017 / 041139, the whole of which is incorporated herein by reference). Compound 1 may be synthesized as described in WO2021 / 149021. Without intending to be bound by any particular theory, each diastereomer of Compound 1 (i.e., Compounds 1-R and 1-S) are believed to release unmodified allopregnanolone to nearly equivalent levels.

[0039] In one embodiment, Formula I, a lipid precursor drug of allopregnanolone, is disclosed herein, which is orally administered to a subject in need of it:

[0040] (Chemical Formula I)

[0041] During the meal, R 1 and R 2 -C(O)R each independently 3 And;

[0042] Each R 3 It is independently saturated or unsaturated, linear or branched, and arbitrarily substituted C3-C 17 It is a hydrocarbon chain. In some embodiments, each R 3 It is independently saturated, linear C3-C 17 It is a hydrocarbon chain. In some embodiments, each R 3 It is independently unsaturated, linear C3-C 17 It is a hydrocarbon chain.

[0043] The compound of Formula I may be administered as a diastereomer or a mixture thereof. Accordingly, in some embodiments, the method and formulation of Formula I disclosed herein may comprise Formula IR and:

[0044] (Chemical formula IR),

[0045] During the meal, R 1 and R 2 is as defined above.

[0046] In some embodiments, the method and formulation of Formula I disclosed herein may comprise Formula IS:

[0047] (Chemical formula IS),

[0048] During the meal, R 1 and R 2 is as defined above.

[0049] In some embodiments, the method and formulation of Formula I disclosed herein comprise a mixture of diastereomers of Formula IR and Formula IS. In some embodiments, the mixture of diastereomers of Formula IR and Formula IS is in an approximate 1:1 molar ratio.

[0050] Treatment methods

[0051] Compound 1 exhibits high oral bioavailability and, consequently, unique pharmacokinetic (PK) and pharmacodynamic (PD) properties compared to IV-administered allopregnanolone. Without being bound by any specific theory, allopregnanolone is understood to have anxiolytic effects in mammals when provided exogenously.

[0052] Accordingly, in one embodiment, the method disclosed herein comprises the step of orally administering a dose of compound 1 to a human subject who requires it. In some embodiments, the dose of compound 1 is 70 to 500 mg. In some embodiments, the dose of compound 1 is 70 mg, 125 mg, 140 mg, 250 mg, 280 mg, 375 mg, 420 mg, 500 mg, or a range between any two of these values. In some embodiments, the dose of compound 1 comprises compound 1-R. In some embodiments, the dose of compound 1 comprises compound 1-S. In some embodiments, the dose of compound 1 comprises a mixture of diastereomers of compound 1-R and compound 1-S.

[0053] In another aspect, a method is disclosed herein comprising the step of orally administering a dose of a compound of Formula I to a human subject in need thereof. The amount of allopregnanolone may be determined based on the total amount of allopregnanolone present in the dose or formulation after taking into account the molecular weight of the prodrug. For example, compound 1 is:

[0054] (Compound 1)

[0055] It has a molecular weight of 846.55 g / mol. Allopregnanolone has a molecular weight of 317.25 g / mol. Therefore, 70 mg of Compound 1 is approximately 26.3 mg of allopregnanolone, and 500 mg of Compound 1 is approximately 187.5 mg of allopregnanolone.

[0056] Accordingly, in some embodiments, the dosage of the compound of Formula I is sufficient to deliver 26.3 to 187.5 mg of allopregnanolone. In some embodiments, the dosage of the compound of Formula I is sufficient to deliver 26.3 mg, 46.9 mg, 52.5 mg, 93.8 mg, 105.0 mg, 140.6 mg, 157.5 mg, or 187.5 mg of allopregnanolone.

[0057] In one embodiment, a dose of Compound 1 is administered using a dose titration. For example, a small amount of Compound 1 may first be administered to a subject. If the dose of Compound 1 is well tolerated for a certain period, a larger amount of Compound 1 (i.e., up-titration) may then be administered to the subject. In some embodiments, the period is 3 to 7 days. This up-titration may be repeated at a higher dose. If the dose of Compound 1 is not well tolerated for a certain period, a smaller amount of Compound 1 may be administered to the subject (i.e., down-titration).

[0058] For example, without limitation, 125 mg of compound 1 may be administered to a subject first. If 125 mg of compound 1 is well tolerated for a certain period, 250 mg of compound 1 may then be administered to the subject. If 250 mg of compound 1 is well tolerated for a certain period, 375 mg of compound 1 may then be administered to the subject. In some embodiments, the period is 3 to 7 days.

[0059] Additionally or alternatively, 250 mg of Compound 1 may be administered to the subject preferentially once daily. If the 250 mg dose of Compound 1 is well tolerated for a certain period, the dose may be increased to 375 mg of Compound 1 administered once daily, decreased to 125 mg of Compound 1 administered once daily, or maintained at 250 mg of Compound 1 administered once daily during the treatment period. The treatment period may be 2, 4, 6, 8, 10, or 12 weeks or longer.

[0060] The timing of administration is variable, and Compound 1 may be administered at any time of day. In some embodiments, Compound 1 is administered in the morning. In some embodiments, Compound 1 is administered at night. Compound 1 may be administered with or without food. In a preferred embodiment, a dose of Compound 1 is administered at night before bedtime.

[0061] As demonstrated herein, compound 1 slows (e.g., reduces / minimizes) the increase in cortisol levels, including cortisol levels increased in response to stress or stressors, for example. Fig. 4a and Fig. 4b The administration of Compound 1 to human subjects causes a significant slowing of the increase in cortisol levels that rise in response to stressors (e.g., in response to stress tests such as the Trier Social Stress Test (TSST) described in Example 2). The increase in cortisol levels after the TSST is an objective biomarker of physiological response and acute stress.

[0062] A method for treating a subject is disclosed herein, the method comprising the step of administering a dose of Compound 1 to a subject requiring it. In some embodiments, the dose of Compound 1 results in a partial or complete taming of the stress hormone response (as measured, e.g., by an increase in cortisol levels). In some embodiments, the dose of Compound 1 partially tames the increase in cortisol levels. In some embodiments, the increase in cortisol levels responds to a stress factor. In some embodiments, the dose of Compound 1 completely tames the increase in cortisol levels. In some embodiments, the increase in cortisol levels responds to a stress factor. In some embodiments, the increase in cortisol levels is measured as an increase in salivary cortisol levels. In some embodiments, the increase in salivary cortisol levels is measured using TSST. In some embodiments, the subject requiring it has a stress-related disorder. In some embodiments, the stress-related disorder is a specific phobia, social phobia, panic disorder, dysregulation disorder, or post-traumatic stress disorder. In some embodiments, the subject requiring this has an anxiety disorder including, for example, separation anxiety disorder, selective mutagenicity, specific phobia, social anxiety disorder, panic disorder, generalized anxiety disorder (GAD), agoraphobia, substance / drug-induced anxiety disorder, anxiety disorder due to another medical condition, other specified anxiety disorders, or unspecified anxiety disorders. In some embodiments, the subject requiring this has generalized anxiety disorder (GAD). In some embodiments, the subject requiring this additionally has one or more symptoms of depression or mood disorder or depression or mood disorder. In some embodiments, the depression or mood disorder is selected from major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic mood disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, postpartum depression, perimenopausal depression, or depression associated with a medical condition.In some embodiments, the subject requiring this has a generalized anxiety disorder (GAD) that originates, is induced, or is exacerbated by stress, a stressor, or a stress-related disorder. In some embodiments, the subject requiring this has a mood or depressive disorder or a generalized anxiety disorder having one or more symptoms of a mood or depressive disorder. In some embodiments, the depression or mood disorder is major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, postpartum depression, perimenopausal depression, or depression associated with a medical condition.

[0063] It is estimated that approximately 280 million people worldwide are affected by major depressive disorder, and approximately 310 million people worldwide are affected by anxiety disorders (WHO; literature [depressive disorder fact sheet (2023)]). Of these, about 120 million are estimated to have MDD accompanied by anxiety disorders, such as MDD accompanied by anxiety (MDD accompanied by anxiety distress) (literature [Kessler et al.,(2015) Science 24(3):210-216]). Subjects with depression (i.e., subjects with MDD) have a higher risk of suicide compared to the general population (20 times higher; American Association of Suicidology (2009)). Additionally, subjects with MDD accompanied by anxiety are less likely to achieve remission, respond more slowly to treatment, and have a poorer quality of life compared to subjects with MDD not accompanied by anxiety or anxiety distress (Hopwood M (2023) Neurol Ther 12(suppl 1):5-12]). Therefore, in some embodiments, the subject requiring this has a mood or depressive disorder, or generalized anxiety disorder having one or more symptoms of a mood or depressive disorder that is similar to but not limited to major depressive disorder. In some embodiments, the subject requiring this has major depressive disorder accompanied by anxiety (MDD accompanied by anxiety distress).

[0064] In some embodiments, the subject requiring this has a generalized anxiety disorder that originates, is induced by, or is exacerbated by a stress or stress-related disorder having one or more symptoms of a mood or depressive disorder, such as but not limited to major depressive disorder.

[0065] An increase in cortisol levels following a stress factor such as TSST is an objective biomarker of physiological response and acute stress. Oral administration of Compound 1 achieves a statistically significant reduction in the stress hormone response as measured by salivary cortisol levels. This reduction in the stress hormone response indicates its potential as a therapeutic agent for various anxiety disorders. In one embodiment, a method for treating an anxiety disorder is disclosed herein, said method comprising the step of orally administering a dose of Compound 1 to a human subject in need thereof. In some embodiments, the dose of Compound 1 is 70 to 500 mg. In some embodiments, the anxiety disorder is Generalized Anxiety Disorder (GAD). In some embodiments, the human subject may additionally have one or more symptoms of depression or mood disorder. In some embodiments, the depression or mood disorder is selected from major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, postpartum depression, perimenopausal depression, or depression associated with a medical condition. In some embodiments, the depression or mood disorder is MDD. In some embodiments, the depression or mood disorder is MDD accompanied by anxiety (MDD accompanied by anxiety distress).

[0066] In one embodiment, a method for treating an anxiety disorder is disclosed herein, the method comprising the step of orally administering a dose of compound 1 to a human subject in need thereof, wherein the subject has one or more depressive or mood disorders or generalized anxiety disorder (GAD) having one or more symptoms of depressive or mood disorders. In some embodiments, the depressive or mood disorder is an MDD. In some embodiments, the depressive or mood disorder is an MDD accompanied by anxiety (MDD accompanied by anxiety distress).

[0067] In one embodiment, a method for reducing a stress hormone response in a human subject is disclosed herein, said method comprising the step of orally administering a dose of compound 1 to a human subject in need thereof. In some embodiments, the reduction in the stress hormone response is measured as a reduction in cortisol, e.g., salivary cortisol. In some embodiments, the dose of compound 1 is 70 to 500 mg. In some embodiments, the dose of compound 1 is 125 mg. In some embodiments, the dose of compound 1 is 250 mg. In some embodiments, the dose of compound 1 is 375 mg. In some embodiments, the human subject has a stress-related disorder or an anxiety disorder. In some embodiments, the human subject has a GAD. In some embodiments, the human subject has one or more depressions or mood disorders or a GAD having one or more symptoms of depression or mood disorders. In some embodiments, the depression or mood disorder is an MDD. In some embodiments, the depression or mood disorder is an MDD accompanied by anxiety (MDD accompanied by anxiety distress).

[0068] Cortisol attenuation after TSST with certain benzodiazepines (alprazolam, literature [Fries et al., Although observed in [see 2006], this is GABA A Agent or GABA A This is not a universally observed effect of PAM. For example, ethopoxin is a non-benzodiazepine GABA that does not slow the increase in salivary cortisol levels after TSST. A It is PAM.

[0069] Furthermore, current standard treatments for anxiety have exhibited serious drawbacks, including inconsistent efficacy, tolerance issues, poor tolerability (side effects), and potential for abuse. Considering its unique pharmacokinetic (PK) and pharmacodynamic (PD) properties (e.g., including high oral bioavailability in particular), the administration of Compound 1 offers several advantages compared to benzodiazepines or other therapeutic agents (e.g., β-blockers such as propranolol) used to treat stress, anxiety, or stress-related disorders. For example, the degree of cortisol attenuation by any agent (i.e., the extent to which the increase in salivary cortisol levels is attenuated in response to a stressor) can vary and may include partial attenuation or complete attenuation (e.g., as provided by alprazolam). Compound 1 has demonstrated the ability to partially attenuate the increase in cortisol levels. In certain cases, partial attenuation in response to a stressor may be advantageous. For example, without being bound by any specific theory, Compound 1 may be less addictive than benzodiazepines, which, due to its partial throbbing effect, result in a complete throbbing of the stress hormone response, for example, an increase in cortisol levels in response to stress. This allows for chronic treatment with a low potential for abuse. Additionally, Compound 1 has a Tmax of approximately 3 to 5 hours (see Example 1), which provides a delayed onset of therapeutic effect and enables a more flexible dosing regimen (i.e., provides the possibility for longer time intervals between administrations). Example 2 and Fig. 4cAs described in [document], the patient received a dose of Compound 1 approximately 3 to 4 hours before experiencing a stressor (e.g., TSST). In contrast, benzodiazepines and β-blockers require administration 30 minutes to 1 hour before receiving a stressor (e.g., TSST). Compound 1 also allows for the attenuation of cortisol levels with reduced euphoria, reduced loss of consciousness, reduced drowsiness, reduced dizziness, and / or reduced balance disorders (e.g., reduced incidence of neurological disorder-related AEs).

[0070] Formulation

[0071] Although Compound 1 is designed for oral administration, it is understood that Compound 1 can be prepared as a composition having one or more pharmaceutically acceptable carriers, adjuvants, or vehicles as known in the art. To aid delivery, Compound 1 may be formulated into lipid-based formulations.

[0072] Lipid formulations may optionally contain lipids and / or surfactants with cosolvents and are generally classified into four types. Type I formulations include lipids requiring digestion, such as mono-, di-, and triglycerides and combinations thereof. Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) containing lipids in addition to water-insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) containing lipids in addition to water-soluble surfactants and / or cosolvents. Type IV formulations primarily contain hydrophilic surfactants and cosolvents such as PEG and propylene glycol. Examples of lipids suitable for use with Compound 1 are further described in WO2021 / 159021.

[0073] The oral administration form of Compound 1 may be administered in any oral administration form, including but not limited to capsules, tablets, suspensions, or solutions as known in the art.

[0074] In one embodiment, compound 1 is prepared in a formulation comprising Peceol™ (glycerol monooleate, available from Gattefosse), Kolliphor® RH40 (a nonionic solubilizer obtained by the reaction of 1 mole of hydrogenated castor oil and 40 moles of ethylene oxide, also referred to as polyoxyl 40 hydrogenated castor oil or macrogolglycerol hydroxystearate, available from BASF Corp.), and ultra-refined sesame oil.

[0075] In one embodiment, each gram of the formulation contains 300 mg of Compound 1, 189 mg of Peceol™, 336 mg of Kolliphor® RH40, and 175 mg of ultra-refined sesame oil. In some embodiments, the formulation is filled into capsules. In one embodiment, the capsule is a soft gelatin capsule. As an example, in some embodiments, the capsule comprises a formulation containing 125 mg, 250 mg, or 375 mg of Compound 1.

[0076] Examples

[0077] The following examples demonstrate the high oral bioavailability of Compound 1 and its efficacy in treating the disorders disclosed herein.

[0078] Example 1: Study to evaluate the safety, tolerability, and PK / PD profile of Compound 1 in humans

[0079] A three-part study was conducted to evaluate the safety, tolerability, and PK / PD characteristics of Compound 1 in humans. Part 1 was a randomized, double-blind, placebo-controlled, single elevated dose (SAD) phase. Part 2 was a randomized, open-label phase to evaluate the effects of food on Compound 1. Part 3 was a randomized, double-blind, placebo-controlled multiple elevated dose phase.

[0080] Compound 1 was generally well tolerated across all tested dosage levels, and there were no deaths, severe or serious drug-related adverse events, discontinuation due to treatment-related adverse events (TEAEs), or liver, heart, or kidney-related adverse events.

[0081] Part 1: Single Increased Dose (SAD)

[0082] The SAD phase utilized a crossover, dose-escalation design with three periods. Administration was arranged in one of three sequences so that each subject received one dose of placebo and two doses of Compound 1 (randomized to low, medium, or high doses per cohort). A rest period of at least 7 days was included between each administration. Compound 1 or placebo was administered orally after at least 10 hours of overnight fasting. Cohorts 2 and 2b received administration after a standard meal (i.e., in a feeding state). The cohort design and administration method Table 1 It is described in.

[0083]

[0084] Primary Objective of Part 1: Evaluation of the safety and tolerability of a single oral dose of Compound 1 and determination of the maximum tolerated dose (MTD) following an elevated single oral dose of Compound 1. Primary Endpoints of Part 1: Incidence, severity, and duration of adverse events (TEAEs) and serious adverse events (SAEs) occurring after treatment with Compound 1 in healthy subjects, and clinically significant vital signs, pulse oximetry, ECG, safety laboratory, or physical examination findings, and the incidence of the MTD.

[0085] Part 1 Secondary Objective: Characterization of the pharmacokinetic (PK) profile of Compound 1 after a single oral administration. Part 1 Secondary Endpoints: Determination of PK parameters for Compound 1, combined allopregnanolone-containing molecules, and allopregnanolone, including maximum plasma concentration (Cmax); time to maximum concentration (Tmax); and terminal elimination half-life (t 1 / 2); Area under the plasma concentration-time curve (AUC) from 0 hours (time of administration) to the last measurable concentration; AUC from 0 hours to infinity (AUC 0-inf ); estimation of removal rate constant (λz); and apparent total removal rate (CL / F); apparent volume of distribution (Vz / F) are included, but not limited to.

[0086] Part 1 Exploratory Objective: To characterize the pharmacodynamic (PD) effects of Compound 1 and the PK / PD relationships to selected clinical outcome assessments (COAs) of central nervous system effects following administration of an elevated single oral dose of Compound 1 (e.g., Stanford Sleepiness Scale (SSS), Modified Observer's Assessment of Alertness / Sedation Scale (MOAA / S), Sleep Quality Scale (SQS)). Part 1 Exploratory Endpoints: Changes from baseline in SSS, MOAA / S, and / or SQS.

[0087] Part 1 PK Summary

[0088] Average plasma allopregnanolone (free allopregnanolone) and combined allopregnanolone (released from all allopregnanolone-containing molecules during analysis) concentrations increased at a dose-proportional rate up to 560 mg; in the range of 750 to 1000 mg, a dose-proportional increase was observed in several PK parameters. Figures 1a~1b is AUC( Fig. 1a ) and Cmax( Fig. 1b ) plots the observed dose-proportional values ​​for all. Allopregnanolone and combined allopregnanolone appeared rapidly in the blood, reaching peak average concentrations between 3 and 5 hours after administration, followed by an exponential decline. The concentrations of allopregnanolone over time for the doses tested in Part 1 are Fig. 1cIt is illustrated in [figure]. The shape of the concentration profile of Compound 1 over time was approximately similar for all doses. The plasma concentration of the combined allopregnanolone was significantly higher than the plasma concentration of allopregnanolone.

[0089] Maximum concentrations and exposure values ​​were significantly higher for the combined allopregnanolone compared to allopregnanolone (at least 10-fold higher). Median Tmax and mean t for the two analytes. 1 / 2 It was not affected by the dosage level and did not show a dosage-specific trend. Allopregnanolone and combined allopregnanolone AUC 0-t , AUC 0-inf , and Cmax increased, respectively, as the dosage level increased. Dosage level (AUC 0-inf When calculated for / dose and Cmax / dose), it was determined that the dose correction parameter increased across the dose range. Overall, for each analyte and tested PK parameter (Cmax, AUC 0-t , and AUC 0-inf Regarding ), the increase, particularly in the 750–1000 mg dosage range of Compound 1, was slightly higher than the dose-proportional value. The summary of allopregnanolone PK parameters for Part 1 is Table 2 It is provided in.

[0090]

[0091] Part 2: Effects of Food

[0092] The safety, tolerability, and effects of diet (both low-fat and high-fat diets) on PK of Compound 1 were evaluated using a 3-period crossover design. Administration was arranged into one of three sequences so that each subject received three doses of Compound 1 with a minimum 7-day washout period between administrations. The cohort design and administration method for Part 2 Table 3 It appears in.

[0093]

[0094] Part 2 Day Objective: Estimation of the effect of high-fat (HF) and low-fat (LF) diets on the bioavailability of a single oral dose of Compound 1.

[0095] Part 2 Secondary Objective: Evaluated the safety, tolerability, and PK of a single dose of Compound 1 under fed (HF), fed (LF), and fasting conditions.

[0096] Part 2 Exploratory Objective: Characterization of the pharmacodynamic effects of Compound 1 for the evaluation of selected clinical outcomes of central nervous system effects following a single administration of Compound 1 (e.g., SSS, MOAA / S, C-SSRS, SQS) under feeding HF, feeding LF, and fasting conditions.

[0097] The consumed HF meal consisted of approximately 800–1000 calories, with macronutrient content of approximately 150, 250, and 500–600 calories from protein, carbohydrates, and fat, respectively. The consumed LF meal consisted of approximately 400–500 calories, with approximately 25% calories from fat (about 11–14 g fat) and variable caloric content derived from protein and carbohydrates, so that the total calories did not exceed the range of 400–500 calories.

[0098] Part 2 PK Analysis Summary

[0099] Average plasma allopregnanolone and combined allopregnanolone concentrations increased slightly in the feeding versus fasting state. The concentrations of allopregnanolone and combined allopregnanolone appeared rapidly in the blood, reached peak concentrations between 3 and 5 hours after administration, and were not significantly affected by the feeding state. The plasma concentration of combined allopregnanolone was significantly higher than the plasma concentration of allopregnanolone.

[0100] Maximum concentration and exposure values ​​were significantly higher for the combined allopregnanolone compared to allopregnanolone (approximately 15 times higher). Food effects were minimal: allopregnanolone and combined allopregnanolone AUC 0-t and AUC 0-inf and Cmax increased slightly by approximately 1.3 to 1.5 times in the fed (LF) group compared to the fasting and fed (HF) groups, respectively. The summary of allopregnanolone PK parameters for Part 2 is Table 4 It is provided in.

[0101]

[0102] Part 3: Multiple Elevated Doses (MAD)

[0103] The safety, tolerability, and PK of Compound 1 administered at multiple doses (up to 7 days) were determined. Compound 1 was administered once daily in the morning (QAM) to subjects in cohorts 4–6 while fed. Compound 1 was administered once daily in the evening (QHS) to subjects in cohorts 7–8 while fed. The cohort design and administration method for Part 3 Table 5 It is presented in.

[0104]

[0105] Part 3 Day Objective: To evaluate the safety and tolerability of multiple oral doses of Compound 1 and to determine the maximum tolerated dose of Compound 1 after multiple oral doses. Part 3 Day Evaluations: Adverse events occurring after treatment with Compound 1 in healthy subjects, incidence, severity, and duration of significant adverse events, and incidence of clinically significant vital signs, pulse oximetry, ECG, safety laboratory, or physical examination findings, and the maximum tolerated dose.

[0106] Part 3 Secondary Objective: Characterization of the PK profile of Compound 1 after multiple oral administrations. Part 3 Secondary Endpoints: PK parameters for Compound 1, combined allopregnanolone, and allopregnanolone were determined, which included: maximum plasma concentration observed during the dosing interval in steady state; minimum concentration observed during the dosing interval in steady state; mean steady state concentration; quantifiable concentration at the end of the dosing interval in steady state; time to reach maximum concentration during the dosing interval in steady state; area under the drug concentration-time curve from 0 hours to the last measurable concentration in steady state; area under the plasma concentration-time curve across the dosing interval in steady state; AUC 0-inf ; Percentage of AUC extrapolated beyond the last observed data point; λz; t 1 / 2 ; Includes, but not limited to, apparent total plasma clearance rate in steady state, apparent terminal distribution volume in steady state, mean residence time (MRT), swing, and variation (%).

[0107] Part 3 Exploratory Objective: Characterization of the PD effect of Compound 1 and the PK / PD relationship regarding the selectivity effect after multiple oral administration of Compound 1. Part 3 Exploratory Endpoints: qEEG, SSS, MOAA / S, SQS, Cogstate, Body Sway, and changes from baseline in video-ocular swivel (VOG) evaluation.

[0108] Part 3 PK Analysis Summary

[0109] The mean concentrations of allopregnanolone and combined allopregnanolone appeared rapidly in the blood and reached peak mean concentrations between 3 and 5 hours after administration. The mean concentration values ​​of allopregnanolone and combined allopregnanolone increased with increasing doses of Compound 1. The mean plasma peak concentration value for allopregnanolone was higher on Day 1 compared to Day 7 across cohorts 4–6. In contrast, the mean plasma peak concentration value for combined allopregnanolone showed higher levels on Day 7 compared to Day 1, suggesting slight accumulation. No apparent difference was observed between QAM and QHS administrations.

[0110] The maximum concentration and exposure values ​​were significantly greater for the combined allopregnanolone compared to allopregnanolone alone. Allopregnanolone and combined allopregnanolone AUC 0-t , AUC 0-24 , and AUC 0- and Cmax,ss increased, respectively, as the dosage of compound 1 increased over 7 days. The increase in systemic exposure was consistent with the findings of Part 1.

[0111] Both allopregnanolone and combined allopregnanolone exhibited minimal accumulation upon multiple administration, and steady state was reached by days 2 and 3 following once-daily administration. Allopregnanolone plasma concentrations over time were Fig. 2a They are shown in [figure]. The mean AUC and Cmax on Day 7 across the tested doses are, respectively Fig. 2b and Fig. 2c It is illustrated in. The summary of allopregnanolone PK parameters for Part 3 is Table 6 It is provided in.

[0112]

[0113] Participants were evaluated using the metrics outlined below. The SSS is a single-item self-report questionnaire that measures and quantifies the progressive stages of sleepiness levels throughout the day. The subjects Table 7 As shown in [figure], select one of the seven statements that best reflects the level of drowsiness perceived at a given time.

[0114]

[0115] MOAA / S is a clinical outcome assessment that measures a subject's level of arousal / sedation determined by an evaluator; in a modified form, it uses only the reactivity component of the original observer's arousal / sedation assessment scale. As a measure of sedation, Table 8 As outlined in [document], reactivity was evaluated and scored on a scale of 0 to 5.

[0116]

[0117] The SQS is a single-item scale that has been proven to have favorable measurement characteristics for assessing sleep quality. It measures clinically significant changes in sleep quality without significantly increasing the burden on clinical trial participants. The scale was administered in the morning, and subjects were asked to rate their sleep quality over the past 7 days on a scale ranging from very poor (0 points), poor (1–3 points), average (4–6 points), good (7–9 points), and excellent (10 points).

[0118] The Columbia Suicide Severity Rating Scale (C-SSRS) is a validated tool designed to quantify the severity of suicidal ideation and behavior. The scale was administered by trained personnel, as described in more detail at https: / / cssrs.columbia.edu / the-columbia-scale-c-ssrs / about-the-scale / .

[0119] Quantitative electroencephalography (qEEG or EEG) is attracting attention as a useful biomarker in human drug research due to its continuous, objective, repeatable, sensitive, reproducible, non-invasive nature, and high potential for conversion from non-clinical data. In this protocol, EEG functions as a biomarker and provides PD results for PK-PD modeling, enabling a more complete understanding of the pharmacological effects of Compound 1. Furthermore, EEG can detect epileptic activity and provide useful safety information regarding any preconvulsive effects of the study drug. Data outputs included, in particular, spectral analysis and flat brain mapping.

[0120] EEG was collected at multiple time points before and after administration on Day 1 and Day 7 of the MAD portion of the study, with the exception of Cohort 8. For the given recordings, a cap containing electrodes was fitted to the subjects. For each session, recordings were collected for approximately 15 minutes while the subjects sat quietly, including periods with and without eyes.

[0121] The Cogstate™ neuropsychiatric evaluation battery designed for this protocol consists of five psychomotor tests designed to identify potential pharmacologically induced CNS depressant effects. The data constitute biomarkers for these CNS depressions, and the results can be correlated with other biomarker measures such as qEEG. The following provides details on the nature and operation of each test. These were performed on the MAD study cohort, excluding Cohort 8. For each participant, the participant was encouraged to move as quickly and as accurately as possible. The software measures the speed and accuracy of each response.

[0122] The detection test is a measure of psychomotor function and uses a well-validated simple reaction time paradigm (processing speed) with playing card stimuli. In this test, all playing cards depict the same Joker. Subjects are asked to press the Yes key immediately when the card in the center of the screen turns face up. The test is typically completed within 3 minutes.

[0123] The identification test is a measure of visual attention and uses a well-validated choice-reaction time paradigm with playing card stimuli. In this test, all playing cards are either red or black jokers. The subject is asked whether the card displayed in the center of the screen is red. The subject responds by pressing the Yes key if the joker card is red and the No key if it is black. The test is typically completed within 3 minutes.

[0124] The One Card Learning test is a measure of visual learning that uses a well-validated pattern separation paradigm with playing card stimuli. In this test, the playing cards are identical to those found in a standard 52-card deck (without joker cards). Subjects are asked whether the card displayed in the center of the screen has been seen previously in this test. Subjects respond by pressing the Yes or No key. The test is typically completed within 6 minutes.

[0125] The One Back test is a measure of working memory and uses the well-validated n-back paradigm with playing card stimuli. Subjects are asked whether the next card displayed in the center of the screen is the same as the card presented immediately before. Subjects respond by pressing the Yes or No key. The test typically takes 4 minutes to complete.

[0126] The Groton Maze Learning test measures executive skills and problem-solving using a maze learning paradigm. A 10x10 grid of tiles is presented to the participant on the screen. A 28-step path is hidden among these tiles. Participants must move one step at a time from the start to the end by touching the tile next to their current position. A green check mark appears if the correct move corresponding to the hidden path is made, and a red cross mark appears if the move is incorrect. Upon completion, the subject returns to the starting position for a repeat of the test and must attempt to remember the path just completed. The software records each move as either an error or a correct move. The test duration is typically 7 minutes.

[0127] Body sway is evaluated as a measure of a subject's slight postural movement required to maintain dynamic balance in a neutral position or during movement. Body sway is typically measured by the total displacement of the center of mass relative to the base of support over time. Posturography is an objective, sensitive, highly reliable, and non-invasive method designed to assess the effects of drugs and alcohol on body sway and vigilance. Body sway is recorded using a computerized force platform. Using a specific positioner, a barefoot subject is asked to stand still and immobile while observing cues placed in front of them. Measurements of body sway are performed in accordance with the recommendations of the International Society of Posturography, and results are recorded for one minute with eyes open and one minute with eyes closed. Subsequently, the length and area of ​​the postural sway are calculated.

[0128] Video-oculography (VOG) is a non-invasive visual method that uses a head-mounted mask equipped with a camera to measure the horizontal, vertical, and torsional components involved in eye tracking. Three evaluation metrics were measured using VOG: horizontal saccadic movements (eye movement toward a fixed fixation point), horizontal semi-saccadic movements (eye movement away from a fixed fixation point), and horizontal and vertical tracking movements (eye fixation on a moving object).

[0129] Binocular movement observation was measured during the tent test. During these 1-minute trials, a visual target (small square) will jump to the right or left from 0° to 10° in a pseudo-random sequence. In the screening, the duration of the target varies pseudo-randomly from 1,500 to 2,000 ms to minimize subject prediction. Then, the visual target will disappear for 200 ms before the next movement starting from the center. Participants are instructed to track the target on the screen from the center to the side and from the side to the center without prediction. The semi-saccadic test is identical to the saccadic test in terms of the procedure where the target moves in 10° intervals, but is distinguished in that the target is not erased. Participants are instructed to look at the opposite side of the target at approximately the same distance from the center and must not look at the target.

[0130] Binocular movement observation was measured during tracking tests. During these tests, the target moves continuously on the screen along a horizontal (horizontal tracking test) or vertical axis (vertical tracking test). Each test lasts for 10 seconds.

[0131] Pharmacodynamic Results (Parts 1–3)

[0132] Cohorts 1, 2, and 2b (Part 1) showed a dose-dependent increase in the Stanford Sleepiness Scale (SSS) from baseline and a decrease in the MOAA / S score from baseline. The highest dose of Compound 1 resulted in the greatest increase or decrease, respectively. This indicates greater drowsiness and less alertness / agitation in subjects receiving higher doses of Compound 1. Maximum changes were observed at approximately 3–5 hours post-administration, which correlated with the peak exposure time based on the corresponding PK results. All treatment groups returned to baseline levels by 12 hours post-administration.

[0133] There was no apparent difference in mean change from baseline between the feeding status (HF or LF) and the fasting status (Cohort 3).

[0134] Cohorts 4, 5, 7, and 8 (Part 3), who received doses of 250 mg and 375 mg, showed low levels of change from baseline for both SSS and MOAA / S at the beginning of treatment, and there was no significant difference between the two dose levels regarding changes in SSS and MOAA / S over time. Cohort 6 (Part 3), who received a dose of 500 mg, showed a greater level of effect from baseline on the SSS and MOAA / S matrices compared to the lower dose. In particular, the effects on SSS and MOAA / S decreased in all treatment groups over time. The placebo group showed almost no change from baseline over the course of treatment.

[0135] When measured by SQS, there was no consistent trend between compound 1 and sleep quality, and no significant improvement or deterioration was observed in any cohort.

[0136] No subjects reported suicidal thoughts or suicidal behavior across all parts (1–3).

[0137] A slight effect on body shaking was observed on day 1, but not on day 7.

[0138] Fig. 3a As shown in [figure], a maximum decrease in peak speed of saccadic movement was observed 4 hours after administration on day 1 across all tested doses. Fig. 2a As shown in [figure], the maximum effect on the video-ocular examination (VOG) evaluation was observed around Cmax, about 3 to 5 hours after administration, which provides the concentration of allopregnanolone over time for subjects evaluated by VOG.

[0139] qEEG is a quantitative measurement of brain oscillations that account for different frequency levels. Resting brain activity was recorded under two conditions (eyes closed and eyes open). For each electrode, spectral analysis of the EEG signal was performed to derive absolute and relative power in the standard frequency band. The frequency range used was Table 9 It is outlined in.

[0140]

[0141] Compound 1 induced changes in electroencephalograms across all studied frequency bands, and the effects varied depending on the dosage, time, and studied frequency band. The strongest effect was observed at a dosage of 500 mg, while 250 mg and 375 mg showed effects similar to but reduced to those of the 500 mg dosage. Fig. 3b Figure 1 illustrates the dose-dependent increase in power for the β-bands (β1, β2, and β3) for cohorts 4 (250 mg), 5 (375 mg), and 6 (500 mg). The increase in maximum power is consistent with the observed Cmax ( Fig. 2a (Reference). In general, the effect was higher on day 1 after a single administration compared to day 7. The maximum effect was observed about 4 hours after administration on both day 1 and day 7.

[0142] Pharmacokinetic Parameters and Evaluation

[0143] PK parameters were calculated from the individual plasma concentrations of compound 1, the combined allopregnanolone-containing molecule, and allopregnanolone. Additionally, the geometric mean was calculated for all PK parameters. Dose proportionality was evaluated by performing an analysis using a linear model.

[0144] Table 10 and Table 11 The following PK parameters as described in were estimated.

[0145]

[0146]

[0147]

[0148] Safety and tolerability

[0149] Compound 1 was generally well tolerated. There were no severe or serious drug-related adverse events. Most adverse events were mild, central nervous system (CNS) related (neurological disorder AE), and dose-dependent. The most common adverse event was somnolence, which was observed most frequently at doses of Compound 1 of 500 mg or more. Food did not affect the safety or tolerability of Compound 1. A summary of adverse events occurring after treatment for the MAD study cohorts (Cohorts 4–8) is Table 12 It is provided in.

[0150]

[0151] The distribution of participants for the single elevated dose (SAD), food effect (FE), and multiple elevated dose (MAD) studies is Table 13 It is summarized in.

[0152]

[0153] Example 2: A study to evaluate the effect of Compound 1 on stress hormone responses in human subjects

[0154] A double-blind, placebo-controlled study was conducted on 80 healthy participants to determine the effect of a single dose of Compound 1 on the Trier Social Stress Test (TSST), a validated and standardized behavioral challenge. The TSST is a reliable behavioral model used to investigate neurobiological responses to acute stress in humans, thereby inducing acute stress (and related acute stress responses) under experimentally controlled conditions. The TSST induces stress through public presentations. This reflects social evaluation and unpredictability by requiring participants to speak before an unresponsive audience, followed by a surprising psychoarithmetic test. The TSST combines the threat of social evaluation with elements of uncontrollability to generate consistent and intense physiological and psychological stress responses in humans. On the day of the study, participants were given three minutes to prepare their presentation. Then, participants had to give a five-minute presentation in front of a panel under the pretext that they were being recorded. After the presentation, participants were given an unexpected psychoarithmetic task. The TSST [Allen A et al., Neurobiol. It is described in more detail in Stress (2017), Feb; 6: 113-126.

[0155] The study included a validation cohort and a randomization cohort. A placebo was provided to the validation cohort (n=10) for the purpose of validating the TSST and study endpoints. The randomization cohort (n=80) was randomized and stratified by gender into placebo or 375 mg of Compound 1 in a 1:1 ratio. The cohort Table 14 It is described in. An overview of the TSST study design is also Fig. 4c It is depicted in.

[0156]

[0157] Compound 1 was formulated as a clear to yellow viscous solution by combining it with the excipients Peceol™ (glyceryl monooleate), Kolliphor® RH40 (macrogolglycerol hydroxystearate), and ultra-refined sesame oil. Each gram of the formulation contains 300 mg of Compound 1, 189 mg of Peceol™, 336 mg of Kolliphor® RH40, and 175 mg of ultra-refined sesame oil. To prepare the final dose, the required amount is manually filled into a 17.5-inch rectangular capsule. The placebo contained only the vehicle, i.e., the above formulation without Compound 1.

[0158] The objective of the study was to evaluate the efficacy of Compound 1 versus placebo in tamping the response to endpoints measured during and after the TSST procedure. The primary efficacy endpoint was the change from baseline (before the TSST procedure) to the peak (maximum change) in salivary cortisol levels measured before, during, and after the TSST procedure. The primary outcome to determine this was salivary cortisol levels. The primary secondary outcome was the Numerical Rating Scale (NRS) for stress, anxiety, fear, embarrassment, and agitation. Additional secondary outcomes were the State Trait Anxiety Index (STAI) and blood pressure. Safety and tolerability (i.e., incidence, severity, and duration of treatment-related adverse events (TEAEs), serious adverse events (SAEs), and other clinically relevant signs) were also monitored. Prior to the TSST, post-administration samples were collected for pharmacokinetic analysis.

[0159] To normalize for food effects, participants were provided with a standardized meal to be consumed approximately 30 minutes before the administration of Compound 1. Compound 1 was administered with 240 mL of RT water approximately 3 to 4 hours before the start of the TSST.

[0160] Research Evaluation Variables and Results

[0161] Pharmacodynamics and patient-reported results were collected before, during, and after TSST to evaluate the effect of Compound 1 on blunting and / or stress responses.

[0162] Cortisol levels (e.g., salivary cortisol levels) are potent and sensitive markers of stress and stress hormone responses. Salivary cortisol concentrations were collected and measured throughout the entire study period, and the primary endpoint was the maximum change from baseline (prior to TSST).

[0163] The STAI-Y is a 40-item patient-administered questionnaire containing two subscales (20 items each): S-Anxiety and T-Anxiety. STAI-Y1 (State) was collected at baseline (before the TSST), immediately before the start of the TSST procedure, and after the completion of the TSST procedure. STAI-Y2 (Characteristics) was assessed at screening and baseline (before the TSST). The S-Anxiety questionnaire assesses the intensity of the current emotion at that moment, whereas the T-Anxiety questionnaire generally assesses the frequency of the emotion. Scores for each subtest range from 20 to 80, with higher scores indicating a higher level of anxiety.

[0164] A selection of the study-specific numerical rating scale (NRS) was used, which included questions about stress, anxiety, embarrassment, fear, and excitement. Questions were rated on a scale from 0 (not at all) to 10 (highest).

[0165] Blood pressure was collected before the TST, during recovery, and before discharge.

[0166] To confirm sufficient exposure to compound 1, PK samples were collected after a single administration on day 1, 45 to 60 minutes prior to TSST.

[0167] Compound 1 achieved the primary endpoint of the study. Fig. 4aAs shown in Figure 1, Compound 1 partially slowed the increase in salivary cortisol levels as measured by the least squares mean (LSMean) change relative to baseline (before TSST). The slowing of salivary cortisol levels was significantly different from placebo for up to 30 minutes after the end of the TSST. The maximum Log10 LSMean change relative to baseline for salivary cortisol levels (before TSST) was significantly different for Compound 1 versus placebo (p-value = 0.0001). Fig. 4b The maximum non-converted mean indicated an approximately 2.2-fold reduction in salivary cortisol levels compared to placebo. Across all time points, the mean reduction in salivary cortisol levels after TSST was 54.4% (ranging from 62.8% at 10 minutes after TSST to 45.5% at 60 minutes after TSST). The therapeutic effect size of compound 1 versus placebo was 0.72 when measured by Cohen's d (a frequently used method to measure effect size, further described in the literature [Cohen J. (1988). Statistical Power Analysis for the Behavioral Sciences (2nd ed.)]).

[0168] Compound 1 was well tolerated in the TSST study; all treatment-related adverse events (TEAEs) were transient, mild, or moderate, consistent with the known pharmacological profile of allopregnanolone. TEAEs occurring in >5% were drowsiness (29% in subjects receiving Compound 1 vs. 13% in placebo), dizziness (20% in subjects receiving Compound 1 vs. 3% in placebo), and headache (7.3% in subjects receiving Compound 1 vs. 7.7% in placebo).

[0169] Participant assignment for the TSST study is Table 15 It is summarized in.

[0170]

[0171] Example 3: A study to evaluate the effects of Compound 1 in adults with Major Depressive Disorder (MDD) with or without anxiety distress

[0172] A randomized, parallel-group, double-blind, placebo-controlled study is conducted to evaluate the efficacy, safety, and tolerability of compound 1 in adults with major depressive disorder (MDD), with or without anxiety distress.

[0173] Eligible subjects with MDD are randomized in a 1:1 ratio to Compound 1 or placebo cohorts within the tier based on the presence or absence of an anxiety pain specifier determined at baseline. Approximately 50–60% of subjects will have MDD accompanied by anxiety pain, and approximately 40–50% of subjects will have MDD not accompanied by anxiety pain.

[0174] The clinical trial duration is approximately 80 days, including screening (up to 4 weeks), administration period (6 weeks), and safety follow-up after administration (1 week). Eligible participants who complete all visits have the option to participate in a 6-week open extension period.

[0175] Treatment and Administration

[0176] The initial starting dose of 125 mg of Compound 1 or placebo will be administered once at bedtime (qHS) on days 0–2 of the study. The dose of Compound 1 will be increased to 250 mg qHS on days 3–6 of the study. Dose adjustments are not permitted during the first week of study treatment, and subjects requiring dose adjustments during the first week will be excluded from study treatment.

[0177] Then, subjects will be administered Compound 1 at 125 mg, 250 mg, or 375 mg, or a placebo until the end of the study treatment period, with the final dose to be administered on the evening of Day 41 of the study. During days 7–28 of the clinical trial, dose adjustments are permitted based on an evaluation of the safety, tolerability, and efficacy of the investigational drug administration. Participants requiring dose adjustments after Day 28 of the study will discontinue study treatment. An overview of the treatment and administration schedule is Table 16 It is provided in.

[0178]

[0179] If the subject experiences intolerance to the current study dose regimen, a dose reduction may occur. If the subject adequately tolerates the current study dose and the therapeutic effect is insufficient or inadequate, a dose increase may occur. If the subject is adequately tolerant to the current dose and experiences a satisfactory therapeutic response or outcome, the dose may be maintained without change.

[0180] After Day 41, the subject may receive 250 mg of Compound 1 (if a lower or higher dose is being received on Day 41), or continue to receive 250 mg of Compound 1 as qHS for an additional 6 weeks (42 days). A dose reduction to 125 mg of Compound 1 as qHS is permitted throughout the entire 6-week period. An increase in dose to 375 mg of Compound 1 as qHS is permitted throughout the entire 6-week period.

[0181] Efficacy, Objectives, and Evaluation Variables

[0182] The primary objective is to characterize the effect of compound 1 as a monotherapy for depressive symptoms in subjects with MDD accompanied by anxiety distress or with anxiety distress. The primary objective is measured as the change in the Hamilton Depression Rating Scale-17 (HAM-D-17) total score from baseline to day 42 of the study.

[0183] The primary secondary objective is to characterize the effect of Compound 1 on overall disease severity in participants with MDD accompanied by anxiety-induced distress or MDD without anxiety-induced distress. The primary secondary objective is measured as the change in clinician global impression-severity (CGI-S) from baseline to day 42 of the study.

[0184] An additional secondary efficacy objective is to characterize the effects of Compound 1 on depression, anxiety, function, and quality of life in participants with MDD, with or without anxiety-related distress. Additional secondary efficacy objectives are measured as changes from baseline to day 42 of the study in the Clinical Global Impression-Supplement (CGI-S), Hamilton Anxiety Rating Scale (HAM-A), Sheehan Disability Scale (SDS), Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), and Overall Anxiety Severity and Impairment Scale (OASIS).

[0185] The HAM-D-17 is a clinician-administered assessment scale designed to evaluate the severity of symptoms in subjects diagnosed with depression. The HAM-D-17 includes individual grades associated with the following symptoms: depressed mood (sadness, hopelessness, helplessness, worthlessness), guilt, suicidal thoughts, insomnia (early, middle, late), work and activity, retardation (slowness of thought and speech; impaired concentration; reduced motor activity), agitation, anxiety (psycho-somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondrosis, weight loss, and insight.

[0186] The HAM-D-17 assessment is scored on a scale of 0 to 52, with higher scores indicating more severe depression. Scores of 24–52 indicate severe depression, 17–23 moderate depression, 8–16 mild depression, and 0–7 normal, absent, or remission of depression. The total score is calculated by adding the scores for each question. For screening and baseline, the assessment period of the past 7 days (1 week) is used. For all other visits, the period will be after the previously recorded visit. The HAM-D-17 assessment is based on the literature [Hamilton M "A rating scale for Depression" J Neurol Neurosurg Psychiatry It is further described in

[1960] 23:56-62.

[0187] The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item scale designed to assess the severity of anxiety symptoms. Each of the 14 items is defined as a series of symptoms and measures both mental anxiety (psychological agitation and psychological distress) and somatic anxiety (physical discomfort related to anxiety). Scoring for the HAM-A assigns a score from 0 (absent) to 4 (very severe), with a total score range of 0 to 56. A score below 17 indicates mild severity, 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity.

[0188] The Clinical Global Impression-Severity (CGI-S) scale is a 7-point scale that requires clinicians to assess the severity of the disease at the time of evaluation. The evaluator selects one response based on the following question: "Given your overall clinical experience with this specific population, how severe is the patient's current condition?" The scores are as follows: 1 = Normal, not sick at all; 2 = Borderline; 3 = Mild; 4 = Moderate; 5 = Significant; 6 = Severe; 7 = One of the most severe patients.

[0189] The Clinical Global Impression-Improvement (CGI-I) scale is a 7-point scale that requires clinicians to evaluate how much a subject's disease has improved or worsened compared to their baseline condition at the start of intervention. The evaluator selects a response based on the following question: "To what extent has the patient changed compared to their condition at the start of treatment?" The scores are as follows: 1 = Very improved; 2 = Significantly improved; 3 = Slightly improved; 4 = No change; 5 = Slightly worsened; 6 = Significantly worsened; and 7 = Very worsened.

[0190] The Sheehan Disability Scale (SDS) is a patient-reported outcome scale consisting of a five-item questionnaire that evaluates functional impairment and related disabilities. The first three items use a 0- to 10-point rating scale to address (1) work / school life, (2) social life, and (3) family life / domestic responsibilities. The SDS also includes one item (4) evaluating the number of days absent from school or work and one item (5) evaluating the number of days of reduced productivity. The scores for the first three items are summed to produce a total score of 0 to 30, with higher scores indicating greater impairment. The recall period is 7 days or more.

[0191] The Questionnaire on Quality of Life, Enjoyment, and Satisfaction—Short Form (Q-LES-Q-SF) evaluates general activities using a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is derived from 14 items with a maximum score of 70, and higher scores indicate higher life satisfaction and enjoyment. Participants rate their satisfaction with activity domains such as physical health, emotions, work, household duties, school / course tasks, leisure time activities, and social relationships.

[0192] The OCD (Once Upon a Severity and Impairment of All Anxiety) is a self-report scale designed to assess the frequency and severity, as well as impairment, associated with anxiety states. The scale consists of five items, each scoring from 0 to 4 points, with a maximum total score of 20. Higher scores indicate greater anxiety-related severity and functional impairment. A 7-day period is used.

[0193] The Patient Global Impressions Scale-Severity (PGI-S) is the patient-reported equivalent of the CGI-S. The PGI-S is a single-item, 6-point scale based on the CGI and is adapted for the subjects. The PGI-S assesses the overall severity of the study subjects over the past 7 days.

[0194] The Patient Global Impressions Scale-Change (PGI-C) is a patient-reported scale corresponding to the CGI-I. The PGI-C is a 7-point single-item scale representing the degree of overall improvement assessed by the study subject. The past 7 days compared to baseline are used.

[0195] Safety Objectives and Evaluation Variables

[0196] The safety objective is to evaluate the safety and tolerability of orally administered Compound 1 in participants with MDD accompanied by anxiety distress or MDD not accompanied by anxiety distress. Safety will be measured by the incidence, severity, and duration of treatment-related adverse events (TEAEs), serious adverse events (SAEs), clinically significant vital signs, pulse oximetry, electrocardiogram (ECG), laboratory or physical examination findings, and also by the Columbia Suicide Severity Rating Scale (C-SSRS) and the Physician Withdrawal Checklist-20 (PWC-20).

[0197] In addition, changes from baseline to day 42 of the study are evaluated on the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), as well as the adverse childhood experiences questionnaire (ACE-Q).

[0198] The Epworth Sleepiness Scale (ESS) consists of eight items that assess the likelihood of falling asleep in real-life situations, such as reading, watching television, or driving. Each item is scored from 0 to 3 points on a total score of 0 to 24, with higher scores indicating greater severity of excessive daytime sleepiness.

[0199] The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-report items falling into one of the following seven subcategories: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, sleep medication use, and daytime dysfunction.

[0200] The Questionnaire on Abnormal Childhood Experiences (ACE-Q) is a 10-item self-report scale that assesses abnormal or traumatic experiences prior to age 18. These exposures may include past physical or sexual abuse, domestic violence, substance use, and confinement. The ACE-Q is scored from 0 to 10, with higher scores indicating a greater level of adverse effects.

[0201] Considering the drowsiness observed at high doses (see Example 1), driving restrictions and prohibition of dangerous activities / operation of complex machinery were enforced for at least 6 hours after administration.

[0202] Pharmacokinetic Objectives and Evaluation Variables

[0203] The population pharmacokinetic parameters of allopregnanolone in the study subjects will be determined using population PK and exposure-response analysis of allopregnanolone in the population under study.

[0204] Selection Criteria

[0205] Subjects are males or females aged 18 to 65. Subjects must have a primary diagnosis of MDD. Subjects diagnosed with comorbid generalized anxiety disorder (GAD), social anxiety disorder, or panic disorder (with or without agoraphobia) may be included if the condition was not the primary treatment subject during the past 6 months prior to screening and MDD is considered the primary diagnosis at screening and baseline.

[0206] Eligible subjects must have a current episode of depression lasting at least 4 weeks to 18 months prior to screening.

[0207] The subject has a HAM-D-17 score of 23 or higher at screening and baseline (before administration). On Day 1, the subject must have a HAM-D-17 score that is 20% or lower of the HAM-D-17 score at the time of screening. For example, if the HAM-D-17 score at screening is 28, the eligible subject must have a Day 1 HAM-D-17 score of at least 23.

[0208] Exclusion criteria

[0209] The following exclusion criteria apply.

[0210] Subjects with a history of or currently exhibiting depressive episodes accompanied by psychotic or rigid symptoms; subjects with bipolar mania, hypomania, or mixed episodes; subjects with drug-induced (e.g., antidepressant-induced) mania, hypomania, or mixed episodes; subjects with bipolar disorder (including a history of bipolar depression) or currently exhibiting symptoms consistent with bipolar depression; subjects with schizophrenia, schizophrenic disorder, or other psychotic disorders; subjects with obsessive-compulsive disorder; and / or subjects with persistent neurocognitive disorder are not suitable.

[0211] Subjects who have been diagnosed with or treated for Attention Deficit Hyperactivity Disorder (ADHD) within the past five years prior to screening.

[0212] Subjects who have been diagnosed with or treated for an eating disorder, including bulimia or anorexia nervosa, within 5 years prior to screening.

[0213] History of treatment-resistant depression defined by two or more failed treatments of appropriate dosage and duration during a current depressive episode.

[0214] Active post-traumatic stress disorder within 3 years prior to screening.

[0215] Borderline or antisocial personality disorder or other disorders of sufficient severity that may interfere with participation in the clinical trial.

[0216] Psychiatric hospitalization during a current episode of depression.

[0217] Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurological, or allergic disease (excluding seasonal allergy).

[0218] A history of intolerance or significant adverse reactions, including drug allergy to any component of formulation 1 of compound containing allopregnanolone or sesame or sesame products.

[0219] Any condition that may interfere with drug absorption during screening or baseline, such as chronic diarrhea, inflammatory bowel disease, or previous surgery of the GI tract, or any disease or condition that may affect drug metabolism or secretion.

[0220] Subjects who have received any prohibited drugs, supplements, or herbal products, including antipsychotic, anticonvulsant, anxiolytic, benzodiazepine, or antidepressant treatments, within the longer of 2 weeks prior to baseline or 5 times the drug's half-life.

[0221] History of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental CNS treatment during the current episode or within 6 months prior to screening (whichever is longer).

[0222] Hypothyroidism or hyperthyroidism unless stabilized with appropriate drug therapy without dose changes for at least one month prior to the start of the clinical trial. Serum thyroid-stimulating hormone must be greater than 0.75 times the lower limit of normal and less than 1.25 times the upper limit of normal at screening.

[0223] Current laboratory evidence, signs, or symptoms of liver or renal failure.

[0224] Subjects with abnormal results from other laboratory tests, vital signs, or ECG findings, unless considered medically insignificant by a medical professional.

[0225] Symptoms of dysphagia or known difficulty swallowing capsules at screening or baseline.

[0226] Night shift work or other conditions that may interfere with the normal sleep / wake cycle.

[0227] Subjects who test positive for human immunodeficiency virus (HIV) antibodies, hepatitis B antigen (HbsAg), or hepatitis C virus (HCV) antibodies during screening.

[0228] Subjects who tested positive for COVID-19 within 14 days prior to screening.

[0229] A history of malignant tumors or malignant tumors, excluding appropriately treated or resected non-metastatic basal cell or squamous cell carcinoma of the skin or appropriately treated cervical intraepithelial carcinoma.

[0230] A history of substance or alcohol use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria within 12 months prior to screening, or positive test result(s) for substances of potential abuse or substances of potential abuse, including barbiturates, opioids / opioids, phencyclidine, cocaine, cannabinoids, amphetamines, and benzodiazepines at the time of screening. Subjects who have a positive test result for cannabinoids within 12 months prior to screening that does not meet the DSM-5 criteria for moderate or severe substance abuse may be eligible.

[0231] Clinically significant risk of suicide or risk of causing harm to oneself or others.

[0232] Subjects who received the investigational drug within 60 days or within 5 half-lives (the longer period applies) prior to the first administration of the study treatment, and who have not participated in more than 2 previous investigation studies in the past year. Life history of more than 5 investigation studies is excluded.

[0233] Screening 12-lead ECG after at least 5 minutes of supine rest showing a Fridericia-corrected QT (QTcF) interval >450 msec (for men) or >470 msec (for women) or a QRS interval >120 msec.

[0234] Hypertension defined by supine blood pressure of 160 mmHg (systolic) or higher or 100 mmHg (diastolic) or higher at screening.

[0235] Serum creatinine level of approximately ULN or estimated glomerular filtration rate of 80 mL / min or less at screening.

[0236] Aspartate aminotransferase or alanine aminotransferase value of 1.5x ULN or higher.

[0237] Total bilirubin levels of 1.5x ULN or higher, excluding subjects with Gilbert's syndrome.

[0238] The following concomitant drugs, defined as any drug taken by the subject after administration of the initial study treatment, are prohibited: all antidepressants, anxiolytics, mood stabilizers, psychotropic drugs, sedatives (including benzodiazepines), sedative antihistamines, opioids, anticonvulsants, lipase inhibitors, S-adenosyl methionine, St. John's wort, Ephdra, kava kava, and other medical devices for treating neuromodulation or neuropsychiatric disorders.

[0239] Non-benzodiazepine sleep aids including zolpidem 5–10 mg at bedtime, zolpidem extended-release 6.25–12.5 mg at bedtime, zaleplon 5–10 mg at bedtime, eszopiclone 1–2 mg at bedtime, melatonin 1–5 mg at bedtime, and ramelteon 8 mg at bedtime are permitted as needed.

Claims

Claim 1 A method for treating a human subject having major depressive disorder (MDD), the method comprising the step of orally administering a dose of compound 1 to said human subject who requires it: (Compound 1). Claim 2 A method according to claim 1, wherein the dosage of compound 1 is 70 to 500 mg. Claim 3 In paragraph 2, the method wherein the dosage of compound 1 is 70 mg, 125 mg, 140 mg, 250 mg, 280 mg, 375 mg, 420 mg, or 500 mg. Claim 4 A method according to any one of claims 1 to 3, wherein the dosage of compound 1 is 125 mg. Claim 5 A method according to any one of claims 1 to 3, wherein the dosage of compound 1 is 250 mg. Claim 6 A method according to any one of claims 1 to 3, wherein the dosage of compound 1 is 375 mg. Claim 7 A method according to any one of claims 1 to 6, wherein the human subject having major depressive disorder (MDD) has MDD accompanied by anxiety distress. Claim 8 A method according to any one of claims 1 to 6, wherein the human subject having major depressive disorder (MDD) has MDD that is not accompanied by anxiety distress. Claim 9 A method according to any one of claims 1 to 8, wherein the dose of compound 1 is administered once a day at bedtime (qHS). Claim 10 A method for treating a human subject having major depressive disorder (MDD), the method comprises the step of orally administering the following to a human subject requiring the method, wherein: i) a daily initiation dose of compound 1 for an initiation period of up to 7 days; and ii) a daily maintenance dose of compound 1 starting after the initiation period; wherein compound 1 is as follows, method: (Compound 1). Claim 11 In paragraph 10, the method wherein the daily starting dose of compound 1 is 125 mg. Claim 12 In paragraph 10, the method wherein the daily starting dose of compound 1 is 250 mg. Claim 13 A method according to any one of claims 10 to 12, wherein the daily maintenance dose of compound 1 is 125 mg, 250 mg, or 375 mg. Claim 14 A method according to any one of paragraphs 10 to 13, wherein the commencement period is 3 to 7 days. Claim 15 A method according to any one of claims 10 to 14, wherein the daily maintenance dose of compound 1 is higher than the daily starting dose of compound 1. Claim 16 A method according to any one of claims 10 to 14, wherein the daily maintenance dose of compound 1 is the same as the daily starting dose of compound 1. Claim 17 A method according to any one of claims 10 and 12 to 14, wherein the daily maintenance dose of compound 1 is lower than the daily starting dose of compound 1. Claim 18 A method according to any one of claims 10 through 17, wherein the human subject having major depressive disorder (MDD) has MDD accompanied by anxiety distress. Claim 19 A method according to any one of claims 10 through 17, wherein the human subject having major depressive disorder (MDD) has MDD that is not accompanied by anxiety distress. Claim 20 A method according to any one of claims 10 to 19, wherein the daily starting dose of compound 1 is administered once daily at bedtime (qHS). Claim 21 A method according to any one of claims 10 to 20, wherein the daily maintenance dose of compound 1 is administered once a day at bedtime (qHS).

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