Lipid prodrugs of allogeneic ketones and their uses

Abstract

This article discloses a method for treating subjects in need with an orally administered lipid prodrug of allogeneic ketone. The method described herein can be used to treat major depressive disorder (MDD) with or without anxiety distress.

Description

[0001] Cross-references to related applications

[0002] This application claims 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 entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to the oral administration of a lipid prodrug of allogeneic ketone for the treatment of human subjects in need. Summary of the Invention

[0004] On the one hand, this article discloses a method for treating human subjects, the method comprising orally administering a dose of compound 1 to a human subject in need:

[0005] (Compound 1).

[0006] In some embodiments, the dose of compound 1 is between 70 and 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, or 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.

[0007] In some embodiments, the human subject in need has major depressive disorder (MDD). In some embodiments, the human subject has MDD with anxiety distress. In some embodiments, the human subject has MDD without anxiety distress. In some embodiments, the dose of compound 1 is administered once daily. In some embodiments, the dose of compound 1 is administered once daily at bedtime (qHS).

[0008] On the one hand, this article provides a method for treating human subjects suffering from major depressive disorder (MDD), the method comprising oral administration to human subjects in need of: i) a daily starting dose of compound 1 for an initial period of up to 7 days; and ii) a daily maintenance dose of compound 1 starting after the initial period, wherein compound 1 is:

[0009] (Compound 1).

[0010] In some embodiments, the starting daily dose of compound 1 is 125 mg. In some embodiments, the starting daily 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 greater 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 less than the daily starting dose of compound 1. Attached Figure Description

[0011] Figure 1A-1C The PK parameters determined through a single escalation dose study (Part 1 of Example 1) are depicted graphically. Figure 1A Describes AUC 0-24h The dose-exposure relationship. Figure 1B The dose-exposure relationship of Cmax was depicted. Figure 1C The concentration of allogeneic ketone over time is depicted for the tested dose.

[0012] Figure 2A-2C The PK parameters determined through multiple escalation dose studies (Part 3 of Example 1) are depicted graphically. Figure 2A Plasma concentrations of allogeneic alcoholone were depicted in subjects who were administered 250 mg QAM (group 4), 375 mg QAM (group 5), 375 mg QHS (group 8), and 500 mg QAM (group 6). Figure 2B The AUC of day 7 was depicted. 0-24h The dose-exposure relationship. Figure 2C The dose-exposure relationship of Cmax on day 7 was depicted.

[0013] Figures 3A-3B The PD assessment from multiple escalation dose studies is described (Part 3 of Example 1). Figure 3A The changes in eye saccade speed in subjects who were administered compound 1 at doses of 250 mg (group 4), 375 mg (group 5), and 500 mg (group 6) with their eyes open (electrode Cz) were depicted. Figure 3B The changes in β-power were depicted in subjects administered compound 1 at doses of 250 mg (group 4), 375 mg (group 5), and 500 mg (group 6). Sagging speed ( Figure 3A ) and β power ( Figure 3B The change is expressed as the ratio of the value at a given time point to the value before administration (time = 0 hours).

[0014] Figures 4A-4CThe changes in salivary cortisol levels in subjects treated with compound 1 or placebo were depicted graphically. Figure 4A The changes in salivary cortisol levels relative to baseline over time are shown. Figure 4B The maximum change relative to the baseline is shown. Figure 4C The research design described in Example 2 is depicted. Detailed Implementation

[0015] This article discloses a method for treating subjects in need with a lipid prodrug of allogeneic ketone.

[0016] definition

[0017] While it is believed that those skilled in the art will readily understand the terminology used herein, certain definitions are set forth herein to facilitate the interpretation of this disclosure.

[0018] As used herein, the term “adverse event” refers to any event, side effect, or other adverse medical event in a subject (i.e., a clinical study participant) who has received the drug product. An adverse event is not necessarily causally related to the drug product. As used herein, a “treatment-induced adverse event” or “TEAE” refers to an adverse event that was not present prior to treatment (i.e., receiving a dose of compound 1) or that was present in a prior period and whose intensity or frequency increased after treatment. TEAEs can be classified by system organ classification (SOC); an exemplary SOC is a neurological disorder. Examples of neurological disorder TEAEs include drowsiness, headache, dizziness, somnolence, balance disorders, and cognitive impairment.

[0019] As used herein, the term "treatment" (or "treat" and "treating") refers to reversing, reducing, preventing, alleviating, delaying the onset of a condition or one or more of its symptoms, or inhibiting its progression. For example, when these terms are used in relation to treating anxiety, "treating anxiety" includes alleviating existing anxiety or preventing anxiety, as well as managing anxiety. Anxiety disorders can include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, or any anxiety disorder disclosed herein. Treatment can also include treating depression and anxiety.

[0020] The terms “subject,” “patient,” and “participant” refer to mammalian subjects, including human subjects. In some embodiments, the subject is a human subject.

[0021] As used herein, the term "anxiety disorder" refers to one or more mental disorders characterized 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).

[0022] 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 condition that develops as a result of stress. In some cases, symptoms of a stress-related disorder may overlap with one or more anxiety disorders. In some cases, anxiety disorders (e.g., social anxiety disorder or generalized anxiety disorder, GAD) may be triggered, induced, or exacerbated by stress. Stress may be acute, incidental, or chronic. Human subjects 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 disorders (e.g., nocturnal panic disorder and / or panic attacks), agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, anxiety disorder caused by another medical condition, other specified anxiety disorders, unspecified anxiety disorders, reactive attachment disorder, disinhibitory social participation disorder, acute stress disorder, adjustment disorder, post-traumatic stress disorder, prolonged grief disorder, social anxiety disorder, other specified trauma and stressor-related disorders, or unspecified trauma and stressor-related disorders. Human subjects in need may have depression or mood disorders, including but not limited to major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymia, premenstrual anxiety disorder, persistent depressive disorder, disruptive mood disorder, postpartum depression, menopausal depression, or depression related to a medical condition. Human subjects in need may have anxiety disorders and / or stress-related disorders with one or more symptoms of depression or mood disorders. For example, subjects in need may have generalized anxiety disorder (GAD) with one or more symptoms of depression or mood disorders (such as, but not limited to, major depressive disorder). In some embodiments, subjects in need may have major depressive disorder (MDD) with anxiety (also known as MDD with anxiety distress).

[0023] As used herein, “MDD with anxiety” or “MDD with distressing anxiety” means the presence of at least two of the following symptoms during a current major depressive disorder episode, a past major depressive disorder episode, or most days of a current depressive disorder episode. Symptoms of distressing anxiety include: i) feeling excited or tense, ii) feeling unusually restless, iii) having difficulty concentrating due to worry, iv) worrying that something terrible might happen, and / or v) feeling that the individual may lose control of themselves. The severity of distressing anxiety in MDD can be further classified as mild (having 2 of the above symptoms), moderate (having 3 of the above symptoms), moderate-severe (having 4-5 of the above symptoms), or severe (having 4-5 of the above symptoms plus psychomotor agitation).

[0024] As used herein, the term "daily starting dose" refers to the daily dose of a compound of formula I (e.g., compound 1) administered over an initial period of up to and including 7 days. In some embodiments, the initial period is 3, 4, 5, 6, or 7 days. In some embodiments, the daily starting dose is 125 mg of compound 1. In some embodiments, the daily starting dose is 250 mg of compound 1.

[0025] As used herein, the term "daily maintenance dose" refers to the daily dose of a Formula I compound (e.g., compound 1) administered after an initial period of up to and including 7 days. The daily maintenance dose may be equal to, higher than, or lower than the daily starting 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 efficacy and tolerability observed in a given subject at a particular dose. The daily maintenance dose may remain the same, or it may be increased or decreased based on efficacy and tolerability observed in a given subject at said dose. For example, but not as a limitation, observed efficacy may be determined based on the change in a particular subject's total Hamilton Depression Rating Scale-17 (HAM-D-17) score relative to baseline.

[0026] As used herein, the terms “pharmaceuticalally acceptable carrier,” “pharmaceuticalally acceptable adjuvant,” or “pharmaceuticalally acceptable mediator,” or combinations thereof, refer to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the reagents formulated with it. Suitable pharmaceutically acceptable carriers, adjuvants, or mediators for use in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates, lecithin, serum proteins, buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of glycerides, lipids, water, salts, or electrolytes.

[0027] Unless otherwise stated, the structures described herein mean all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of the structure: for example, the R and S configurations of each asymmetry center. Thus, single stereochemical isomers, as well as mixtures of enantiomers, diastereomers, and geometric (or conformations), are within the scope of the disclosed methods.

[0028] Lipid prodrugs of allogeneic ketones

[0029] On the one hand, this article discloses a method for treating stress-related disorders using a lipid prodrug of allogeneic ketone (compound 1), including, for example, stress-related anxiety disorders. Allogeneic ketone is an endogenous pregnane neurosteroid that acts as a γ-aminobutyric acid (GABA) inhibitor against GABA type A (GABA). A Allosteric regulators that inhibit the inhibitory effect of receptors.

[0030] GABA A Receptors are pentamer proteins present in multiple isoforms. Typically, GABA... A The receptor comprises two α subunits, two β subunits, and one γ, δ, ε, π, or θ subunit. To date, at least six α subunits, three β subunits, and three γ subunits have been identified, resulting in a large number of potential pentamer GABAs. A Composition. GABA A The abundance and distribution of receptor subtypes vary considerably throughout the central nervous system (CNS). GABA A The composition of the receptor influences behavioral effects. The α1 subunit is associated with sedation, while the α2 subunit is associated with anxiolytic effects. GABA has been identified. A Other associations between receptor subunits, such as those known to be α 2、 α 4、 Both the β3 and δ subunits are associated with anxiety and mood symptoms (Wang, Mingde, Frontiers in Endocrinology (2011) 2:44). Therefore, the action of GABA... A The mechanism of action (MOA) of therapeutic agents and their downstream pharmacodynamic effects depend on GABA. A Both the subunit composition of the receptor and the binding site of the therapeutic agent.

[0031] As an example, benzodiazepines act on GABA. A The receptor exerts its anxiolytic and antidepressant properties. The MOA (Mean Interaction Affinity) depends on the binding of benzodiazepines at the interface between the α and γ subunits; therefore, benzodiazepines require GABA containing the γ subunit. AReceptor (Goldschen-Ohm, *Biomolecules* (2022)). In contrast, allogeneic alcohol ketones relative to GABA... A The subunits exhibit broad specificity and can further act on GABA containing the δ subunit. A Receptor. GABA with δ subunit. A Receptors are primarily located extrasynaptic and in the perisynaptic cleft (Glkyks J et al., *Journal of Neuroscience* (2008) 28(6): 1421-1426; Brickley and Mody (2012) *Neuron* 73(1):23-34). These GABA receptors... A Receptors have a high affinity for GABA and mediate tetanic inhibition (Paul S et al., *Neurobiology of Stress* (2020)). Therefore, allogeneic ketones act as various GABA receptors. A It is a potent modulator of receptor isotypes and has the ability to exert antidepressant, sedative, anti-anxiety and stress-reducing effects.

[0032] Therefore, allogeneic alcoholones have the potential to treat stress-related disorders. However, due to extensive first-pass metabolism, the oral bioavailability of allogeneic alcoholones is low, less than 5%. This disclosure provides a lipid prodrug of allogeneic alcoholone that bypasses first-pass metabolism, enabling oral delivery of allogeneic alcoholone. Lipid-mimicking compounds, such as lipid prodrugs, can behave similarly to natural triglycerides, allowing them to be transported via the lymphatic system before reaching systemic circulation, thereby effectively bypassing first-pass metabolism. Lipid prodrugs are further discussed in WO2016 / 023082, WO2017 / 041139, and WO2021 / 159021, the entire contents of which are hereby incorporated by reference.

[0033] The development of oral allopregnantlanolone has been limited due to its poor oral bioavailability. An intravenous formulation of allopregnantlanolone (brexanolone) has been approved for the treatment of major postpartum depression (marketed as Zulresso®), which is administered in a hospital setting over a 60-hour infusion period. Zulresso® infusions are titrated over 60 hours (2.5 days), increasing from 30 µg / kg / hr to 60 µg / kg / hr in the first 24 hours and continuing at 90 µg / kg / hr from 24 to 52 hours. After 52 hours of treatment, the infusion is titrated down to 60 µg / kg / hr for 4 hours, and then down to 30 µg / kg / hr for 4 hours. Patients receiving Zulresso® require continuous monitoring during this period due to a higher risk of sedation and / or loss of consciousness (product label, Zulresso®). The antidepressant efficacy following the 2.5-day infusion has been reported to last up to 30 days.

[0034] This article discloses a lipid prodrug of allopregnanetanolone, namely compound 1, administered orally to subjects in need:

[0035] (Compound 1).

[0036] Compound 1 can be administered as a diastereomer or a mixture thereof. Therefore, in some embodiments, the methods disclosed herein and formulations of compound 1 may comprise compound 1-R:

[0037] (Compound 1-R).

[0038] In some embodiments, the methods disclosed herein and formulations of compound 1 may comprise compound 1-S:

[0039] (Compound 1-S).

[0040] In some embodiments, the methods and formulations of Compound 1 disclosed herein comprise a diastereomeric mixture of Compound 1-R and Compound 1-S. In some embodiments, the diastereomeric mixture of Compound 1-R and Compound 1-S is in a molar ratio of approximately 1:1. Compound 1 is designed to bypass first-pass metabolism and subsequently release free allogeneic ketone (the lipid mimicry compounds are further discussed in WO2016 / 023082 and WO2017 / 041139, the entire contents of which are hereby incorporated by reference) upon entering systemic circulation. Compound 1 can be synthesized as described in WO2021 / 149021. Without wishing to be bound by any particular theory, each diastereomeric form of Compound 1 (i.e., Compound 1-R and Compound 1-S) is considered to release unmodified allogeneic ketone at a nearly equivalent level.

[0041] On the one hand, this article discloses a lipid prodrug of allogeneic ketone, orally administered to subjects in need, namely Formula I:

[0042] (Formula I)

[0043] Where R 1 and R 2 Each is independently -C(O)R 3 ;and

[0044] Each R 3 Independently saturated or unsaturated, straight or branched, optionally substituted C3-C 17 Hydrocarbon chain. In some embodiments, each R 3 Independently saturated straight-chain C3-C 17 Hydrocarbon chain. In some embodiments, each R 3 Independently unsaturated straight-chain C3-C 17 Hydrocarbon chain.

[0045] Compounds of Formula I can be applied as diastereomers or mixtures thereof. Therefore, in some embodiments, the methods disclosed herein and formulations of Formula I may comprise Formula IR:

[0046] (Formula IR)

[0047] Where R 1 and R 2 As defined above.

[0048] In some embodiments, the methods disclosed herein and formulations of Formula I may comprise Formula I:

[0049] (Form IS)

[0050] Where R 1and R 2 As defined above.

[0051] In some embodiments, the methods disclosed herein and formulations of Formula I comprise a diastereomeric mixture of Formula IR and Formula IS. In some embodiments, the diastereomeric mixture of Formula IR and Formula IS is in a molar ratio of about 1:1.

[0052] Treatment

[0053] Compared to intravenously administered allogeneic ketone, compound 1 exhibits high oral bioavailability and therefore unique pharmacokinetic (PK) and pharmacodynamic (PD) properties. Without being bound by any particular theory, it should be understood that allogeneic ketones have an anxiolytic effect in mammals when exogenously provided.

[0054] Therefore, in one aspect, the method disclosed herein comprises orally administering a dose of compound 1 to a human subject in need. In some embodiments, the dose of compound 1 is between 70 and 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 within a range of 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 diastereomeric mixture of compound 1-R and compound 1-S.

[0055] On the other hand, this article discloses a method comprising orally administering a dose of a compound of formula I to a human subject in need. After taking into account the molecular weight of the prodrug, the amount of allogeneic alcoholone can be determined based on the dose or the total amount of allogeneic alcoholone present in the formulation. For example, compound 1:

[0056] (Compound 1)

[0057] The molecular weight of compound 1 is 846.55 g / mol. The molecular weight of allogeneic alcoholone is 317.25 g / mol. Therefore, 70 mg of compound 1 is approximately 26.3 mg of allogeneic alcoholone, and 500 mg of compound 1 is approximately 187.5 mg of allogeneic alcoholone.

[0058] Therefore, in some embodiments, the dosage of the compound of formula I is sufficient to deliver an allogeneic ketone between 26.3 and 187.5 mg. 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 allogeneic ketone.

[0059] On one hand, dose titration is used to administer the dosage of compound 1. For example, a small amount of compound 1 may be administered to the subject initially. If a certain dose of compound 1 is well tolerated over a period of time, a larger amount of compound 1 may then be administered to the subject (i.e., up titration). In some embodiments, the time period is 3-7 days. This up titration can be repeated with a higher dose. If a certain dose of compound 1 is not well tolerated over a period of time, a smaller amount of compound 1 may be administered to the subject (i.e., down titration).

[0060] For example, and without limitation, 125 mg of compound 1 may be administered to the subject initially. If the 125 mg of compound 1 is well tolerated over a period of time, 250 mg of compound 1 may then be administered to the subject. If the 250 mg of compound 1 is well tolerated over a period of time, 375 mg of compound 1 may then be administered to the subject. In some embodiments, the time period is 3-7 days.

[0061] Alternatively, the subject may initially be administered 250 mg of compound 1 once daily. If the 250 mg dose of compound 1 is well tolerated over a period of time, the dose may be increased to 375 mg of compound 1 once daily, reduced to 125 mg of compound 1 once daily, or maintained at 250 mg of compound 1 once daily for the duration of treatment. The duration of treatment may be 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, or longer.

[0062] The timing of administration is flexible, and compound 1 can be administered at any time of day. In some embodiments, compound 1 is administered in the morning. In some embodiments, compound 1 is administered in the evening. Compound 1 can be administered with or without food. In a preferred embodiment, the dose of compound 1 is administered at bedtime in the evening.

[0063] As demonstrated herein, compound 1 desensitizes (e.g., reduces / minimizes) increases in cortisol levels, including, for example, increases in response to stress or stressors. Figure 4A and Figure 4BThis indicates that administration of compound 1 to human subjects significantly desensitized the increase in cortisol levels, which are typically increased in response to stressors, such as the Trier Social Stress Test (TSST) described in Example 2. The increase in cortisol levels following the TSST is a physiological response and objective biomarker of acute stress.

[0064] This document discloses a method for treating a subject, the method comprising administering a dose of compound 1 to a subject in need. In some embodiments, the dose of compound 1 partially or completely desensitizes the stress hormone response (e.g., as measured by an increase in cortisol levels). In some embodiments, the dose of compound 1 partially desensitizes an increase in cortisol levels. In some embodiments, the increase in cortisol levels is in response to a stressor. In some embodiments, the dose of compound 1 completely desensitizes an increase in cortisol levels. In some embodiments, the increase in cortisol levels is in response to a stressor. In some embodiments, the increase in cortisol levels is measured by an increase in salivary cortisol levels. In some embodiments, the increase in salivary cortisol levels is measured using TSST. In some embodiments, the subject in need suffers from a stress-related disorder. In some embodiments, the stress-related disorder is a specific phobia, social phobia, panic disorder, adjustment disorder, or post-traumatic stress disorder. In some embodiments, the subject in need suffers from an anxiety disorder, including, for example, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, generalized anxiety disorder (GAD), agoraphobia, substance / drug-induced anxiety disorder, anxiety disorder caused by another medical condition, other specified anxiety disorder, or unspecified anxiety disorder. In some embodiments, the subject in need suffers from generalized anxiety disorder (GAD). In some embodiments, the subject in need further suffers from depression or mood disorder, or one or more symptoms of depression or mood disorder. In some embodiments, depression or mood disorder is selected from major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymia, premenstrual anxiety disorder, persistent depressive disorder, disruptive mood disorder, postpartum depression, menopausal depression, or depression related to a medical condition. In some embodiments, the subject in need suffers from generalized anxiety disorder (GAD) triggered, induced, or exacerbated by stress, stressors, or stress-related disorders. In some embodiments, the subject in need suffers from generalized anxiety disorder accompanied by mood or depressive disorder, or one or more symptoms of mood or depressive disorder. In some embodiments, depression or mood disorder is major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic mood disorder, premenstrual anxiety disorder, persistent depressive disorder, disruptive mood disorder, postpartum depression, menopausal depression, or depression related to a medical condition.

[0065] It is estimated that approximately 280 million people worldwide are affected by major depressive disorder (MDD), and approximately 301 million are affected by anxiety disorders (WHO; Status Bulletin on Depressive Disorders (2023)). Of these, an estimated 120 million have MDD with anxiety disorders, such as MDD with anxiety (MDD with anxiety distress) (Kessler et al., (2015) Science 24(3):210-216). Subjects with depression (i.e., subjects with MDD) have a 20-fold higher suicide risk than the general population (American Suicide Society (2009)). Furthermore, 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 without anxiety or anxiety distress (Hopwood M (2023) Neurology and Therapy 12(Supplement 1):5-12). Therefore, in some embodiments, the desired subjects have generalized anxiety disorder with one or more symptoms of mood or depression, such as, but not limited to, major depressive disorder. In some embodiments, the desired subjects have major depressive disorder with anxiety (MDD accompanied by anxiety distress).

[0066] In some embodiments, the subject in need suffers from generalized anxiety disorder, which is triggered, induced, or exacerbated by stress or stress-related disorder with mood or depression disorder or one or more symptoms of mood or depression disorder (such as, but not limited to, major depressive disorder).

[0067] An increase in cortisol levels following a stressor (such as TSST) is a physiological response and objective biomarker of acute stress. Oral administration of compound 1 resulted in a statistically significant attenuation of the stress hormone response, as measured by salivary cortisol levels. This attenuation of the stress hormone response indicates its potential as a therapeutic agent for a range of anxiety disorders. In one aspect, this document discloses a method for treating anxiety disorders comprising orally administering a dose of compound 1 to a human subject in need. In some embodiments, the dose of compound 1 is between 70 and 500 mg. In some embodiments, the anxiety disorder is generalized anxiety disorder (GAD). In some embodiments, the human subject may further suffer from depression or mood disorder or one or more symptoms of depression or mood disorder. In some embodiments, depression or mood disorder is selected from major depressive disorder (MDD), bipolar disorder, seasonal affective disorder, cyclothymic mood disorder, premenstrual anxiety disorder, persistent depressive disorder, disruptive mood disorder, postpartum depression, menopausal depression, or depression related to a medical condition. In some embodiments, depression or mood disorder is MDD. In some embodiments, depression or mood disorder is MDD with anxiety (MDD with anxiety distress).

[0068] On one hand, this article discloses a method for treating anxiety disorders, the method comprising orally administering a dose of compound 1 to a human subject in need, wherein the subject suffers from generalized anxiety disorder (GAD) accompanied by one or more depressive or mood disorders, or one or more symptoms of depressive or mood disorders. In some embodiments, the depressive or mood disorder is MDD. In some embodiments, the depressive or mood disorder is MDD with anxiety (MDD with anxiety distress).

[0069] On one hand, this document discloses a method for attenuating the stress hormonal response in human subjects, the method comprising orally administering a dose of compound 1 to a human subject in need. In some embodiments, attenuation of the stress hormonal response is measured by a reduction in cortisol (e.g., salivary cortisol). In some embodiments, the dose of compound 1 is between 70 and 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 suffers from stress-related disorder or anxiety disorder. In some embodiments, the human subject suffers from GAD. In some embodiments, the human subject suffers from GAD with one or more depressive or mood disorders or one or more symptoms of depressive or mood disorders. In some embodiments, the depressive or mood disorder is MDD. In some embodiments, the depressive or mood disorder is MDD with anxiety (MDD with anxiety distress).

[0070] Although cortisol desensitization after TSST has been observed in some benzodiazepines (alprazolam, see Fries et al., 2006), this is not GABA-mediated. A agonists or GABA A Commonly observed effects of PAM. For example, etifoxine is a non-benzodiazepine GABA. A PAM does not desensitize the increase in salivary cortisol levels after TSST.

[0071] Furthermore, current standard care for anxiety has shown significant drawbacks, including inconsistent efficacy, tolerability issues, poor tolerance (adverse events), and the potential for abuse. Given the unique pharmacokinetic (PK) and pharmacodynamic (PD) properties of Compound 1 (e.g., including its high oral bioavailability), its administration offers several advantages compared to benzodiazepines or other treatments for stress, anxiety, or stress-related disorders (e.g., beta-blockers such as propranolol). For example, the degree of cortisol desensitization induced by the agent (i.e., the degree of desensitization of increased salivary cortisol levels in response to a stressor) can vary and may include partial or complete desensitization (e.g., as provided by alprazolam). Compound 1 exhibits the ability to partially desensitize increased cortisol levels. In some cases, partial desensitization in response to a stressor may be advantageous. For example, and without being bound by any particular theory, compound 1 may be less addictive than benzodiazepines due to its partially desensitizing effect, which completely desensitizes stress hormonal responses (e.g., increased cortisol levels in response to stress). This could allow for chronic treatment with a lower likelihood of abuse. Furthermore, compound 1 has a Tmax of approximately 3–5 hours (see Example 1), which delays the onset of therapeutic effect and allows for more flexible dosing regimens (i.e., providing the possibility of longer intervals between doses). See Example 2 and... Figure 4C The patient receives a dose of compound 1 approximately 3–4 hours before experiencing a stressor (e.g., TSST). In contrast, benzodiazepines and beta-blockers require administration 30 minutes to 1 hour before experiencing a stressor (e.g., TSST). Compound 1 further allows for the desensitization of cortisol levels by reducing euphoria, loss of consciousness, drowsiness, dizziness, and / or balance disorders (e.g., reducing the incidence of neurological disorders-related adverse events).

[0072] Mixtures

[0073] Although compound 1 is designed for oral administration, it should be understood that compound 1 can be prepared as a composition having one or more pharmaceutically acceptable carriers, adjuvants, or mediators known in the art. To facilitate delivery, compound 1 can be formulated into lipid-based formulations.

[0074] Lipid formulations may contain lipids and / or surfactants, optionally with a cosolvent, and are generally classified into four types. Type I formulations include lipids that require digestion, such as monoglycerides, diglycerides, and triglycerides, and combinations thereof. Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) that contain lipids in addition to water-insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) that contain 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.

[0075] The oral dosage form of compound 1 can be administered in any orally acceptable dosage form, including but not limited to capsules, tablets, suspensions or solutions known in the art.

[0076] In one embodiment, compound 1 is prepared as a blend comprising Peceol™ (glyceryl monooleate, available from Gattefosse), Kolliphor® RH40 (a nonionic solubilizer obtained by reacting 1 mole of hydrogenated castor oil with 40 moles of ethylene oxide, also known as polyoxyethylene 40 hydrogenated castor oil or polyethylene glycol glyceryl hydroxystearate, available from BASF Corp.), and ultra-refined sesame oil.

[0077] 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 illustration, in some embodiments, the capsule contains a formulation containing 125 mg, 250 mg, or 375 mg of Compound 1.

[0078] Example

[0079] The following examples demonstrate the high oral bioavailability of compound 1 and its efficacy in treating the conditions disclosed herein.

[0080] Example 1: A study evaluating the safety, tolerability, and PK / PD characteristics of compound 1 in humans.

[0081] 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-dose escalation (SAD) phase. Part 2 was a randomized, open-label phase evaluating the effects of food on compound 1. Part 3 was a randomized, double-blind, placebo-controlled, multiple-dose escalation phase.

[0082] Compound 1 was generally well tolerated at the tested dose levels, with no deaths, no severe or serious drug-related adverse events, no discontinuation due to treatment-induced adverse events (TEAEs), and no treatment-induced adverse events related to the liver, heart, or kidneys.

[0083] Part 1: Single Incremental Dose (SAD)

[0084] The SAD phase utilizes a crossover, dose-escalation design with three time slots. Dosing is scheduled in one of three sequences, such that each subject receives one placebo administration and two administrations of compound 1 (each group is randomized to low, medium, or high dose). A washout period of at least 7 days is included between each administration. Compound 1 or placebo is administered orally after a fasting period of at least 10 hours. Groups 2 and 2b are administered after a standard diet (i.e., in a fed state). The group design and dosing regimen are described in Table 1.

[0085] Table 1: SAD Groups and Dosing Regimens

[0086]

[0087] The primary objective of Part 1 is to assess the safety and tolerability of a single oral dose of Compound 1 and to determine the maximum tolerated dose (MTD) of Compound 1 after escalation of the single oral dose. The primary endpoints of Part 1 are: in healthy subjects, the incidence, severity, and duration of treatment-induced adverse events (TEAEs), serious adverse events (SAEs), as well as the incidence of clinically significant vital signs, pulse oximetry, ECG, safety laboratory or physical examination findings, and the MTD of Compound 1.

[0088] Secondary objective of Part 1: To characterize the pharmacokinetic (PK) profile of compound 1 following a single oral dose. Secondary endpoints of Part 1: Determination of PK parameters for compound 1, the combined allogeneic ketone-containing molecules, and allogeneic ketones, including but not limited to: maximum plasma concentration (Cmax); time to reach maximum concentration (Tmax); terminal elimination half-life (t0). 1 / 2 ); Area under the plasma concentration-time curve (AUC) from time zero (from the time of administration) to the last measurable concentration (AUC0-last); AUC from time zero to infinity (AUC0-last); 0-inf); estimation of elimination rate constant (λz); and apparent total clearance rate (CL / F); apparent distribution volume (Vz / F).

[0089] The exploratory objective of Part 1 is to characterize the pharmacodynamic (PD) effects and pharmacokinetic / pharmacodynamic (PK / PD) relationships of Compound 1 on its central nervous system effects using selected clinical outcome assessments (COAs) (e.g., the Stanford Somnolence Scale (SSS), the Modified Observer Assessment of Alertness / Sedation Scale (MOAA / S), and the Sleep Quality Scale (SQS)) following a single escalation of the oral dose of Compound 1. The exploratory endpoints of Part 1 are changes in SSS, MOAA / S, and / or SQS relative to baseline.

[0090] Part 1: PK Summary

[0091] Mean plasma concentrations of allogeneic ketone (free allogeneic ketone) and combined allogeneic ketone (allogeneic ketone released from all allogeneic ketone-containing molecules during analysis) increased at a dose-proportional rate of up to 560 mg; increases greater than dose-proportional were observed in several PK parameters in the range of 750 mg to 1000 mg. Figure 1A-1B AUC was demonstrated Figure 1A ) and Cmax ( Figure 1B The observed dose ratio of the two. Allopregnant alcoholone and the combination of allopregnant alcoholone appear rapidly in the blood and reach peak mean concentrations between 3 and 5 hours after administration, followed by an exponential decline. Figure 1C The figure shows the concentration of allogeneic ketone at the doses tested in Part 1 over time. For all doses, the concentration-time curves of compound 1 showed generally similar shapes. The plasma concentrations of the combined allogeneic ketone were significantly higher than those of allogeneic ketone.

[0092] Compared to eupregnanolone, the combined eupregnanolone exhibits significantly higher maximum concentrations and exposure values ​​(at least 10-fold higher). The median Tmax and mean t of the two analytes are also shown. 1 / 2 Unaffected by dose level and showing no dose-specific trend. AUC of allogeneic ketone and combined allogeneic ketones. 0-t AUC 0-inf Both Cmax and Culminate increase with increasing dose level. When calculated based on dose level (AUC... 0-inf When calculating the dose and Cmax, the dose correction parameters are determined to increase within the dose range. In general, for each analyte and test, the PK parameters (Cmax, AUC) are... 0-t and AUC 0-inf (Increase slightly more than the dose ratio, especially in the dose range of 750-1000 mg for compound 1. Table 2 provides a summary of the allopregnane PK parameters for Part 1.)

[0093] Table 2: PK parameters in single-dose escalation studies

[0094]

[0095] Part 2: The Food Effect

[0096] A 3-time crossover design was used to evaluate the effects of diets (low-fat and high-fat diets) on the safety, tolerability, and pharmacokinetic (PK) of compound 1. Dosing was scheduled in one of three sequences, such that each subject received three doses of compound 1 with a minimum 7-day washout period between doses. The cohort design and dosing regimen for Part 2 are shown in Table 3.

[0097] Table 3: Food effector groups and dosing regimens

[0098]

[0099] The primary objective of Part 2 is to estimate the effects of high-fat (HF) and low-fat (LF) diets on the bioavailability of a single oral dose of compound 1.

[0100] Secondary objective of Part 2: To evaluate the safety, tolerability, and pharmacokinetics of single doses of compound 1 under fed (HF), fed (LF), and fasting conditions.

[0101] The exploratory purpose of Part 2 is to characterize the pharmacodynamic effects of Compound 1 on the central nervous system following a single dose under HF, LF and fasting conditions in selected clinical outcome assessments (e.g. SSS, MOAA / S, C-SSRS, SQS).

[0102] A high-fat (HF) diet consists of approximately 800-1000 calories, comprised of approximately 150, 250, and 500-600 calories from protein, carbohydrates, and fat, respectively. A low-fat (LF) diet consists of approximately 400-500 calories, comprised of approximately 25% from fat (approximately 11-14 g of fat) and variable calories from protein and carbohydrates, ensuring a total calorie intake of no more than 400-500 calories.

[0103] Part 2 PK Analysis Summary

[0104] The mean plasma concentrations of eupregnanolone and its combination were slightly increased in the fed state compared to the fasted state. The concentrations of eupregnanolone and its combination rapidly appeared in the blood and reached peak concentrations between 3 and 5 hours after administration, unaffected by the feeding state. The plasma concentrations of the combination eupregnanolone were significantly higher than those of eupregnanolone.

[0105] Compared to eupregnanolone, the combined eupregnanolone had significantly higher maximum concentrations and exposures (approximately 15-fold higher). Food effects were minimal: in the fed (LF) group, the AUC of both eupregnanolone and the combined eupregnanolone was significantly lower than in the fasting and feeding (HF) group. 0-t and AUC 0-inf Both Cmax and Cmax increased slightly by about 1.3 to 1.5 times. Table 4 provides a summary of the allogeneic ketone PK parameters from Part 2.

[0106] Table 4: PK parameters in food effect studies

[0107]

[0108] Part 3: Multiple Escalation Dosage (MAD)

[0109] The safety, tolerability, and pharmacokinetics of compound 1 administered in multiple doses (up to 7 days) were determined. Subjects in groups 4–6 received compound 1 once daily in the morning (QAM) while in a fed state. Subjects in groups 7–8 received compound 1 once daily in the evening (QHS) while in a fed state. The group design and dosing regimens for Part 3 are shown in Table 5.

[0110] Table 5: MAD Groups and Dosing Regimens

[0111]

[0112] The primary objective of Part 3 is to assess the safety and tolerability of compound 1 with multiple oral doses and to determine the maximum tolerated dose of compound 1 after multiple oral administrations. The primary endpoints of Part 3 are: in healthy subjects, the incidence, severity, and duration of treatment-induced adverse events, major adverse events, as well as the incidence of clinically significant vital signs, pulse oximetry, ECG, laboratory or physical examination findings related to safety, and the maximum tolerated dose of compound 1.

[0113] Secondary objective of Part 3: To characterize the PK properties of Compound 1 after multiple oral administrations. Secondary endpoints of Part 3: To determine the PK parameters of Compound 1, the combined allogeneic ketone, and allogeneic ketone, including but not limited to: the maximum plasma concentration observed during the steady-state dosing interval; the minimum concentration observed during the steady-state dosing interval; the average steady-state concentration; the quantifiable concentration at the end of the steady-state dosing interval; the time to reach the maximum concentration during the steady-state dosing interval; the area under the drug concentration-time curve from time zero to the last measurable concentration at steady state; the area under the plasma concentration-time curve during the steady-state dosing interval; and AUC. 0-inf The percentage of AUC extrapolated to outside the last observation point; λz; t 1 / 2 Apparent total plasma clearance at steady state, apparent terminal distribution volume at steady state, mean residence time (MRT), swing and fluctuation.

[0114] The exploratory objective of Part 3 was to characterize the PD effect and PK / PD relationship of Compound 1 on the selected effect after multiple oral administrations. The exploratory endpoints of Part 3 were assessed by qEEG, SSS, MOAA / S, SQS, Cogstate, body sway, and video-ocular tracking (VOG) to evaluate changes relative to baseline.

[0115] Part 3 PK Analysis Summary

[0116] The mean concentrations of eupregnanolone and the combination of eupregnanolone appeared rapidly in the blood and reached peak mean concentrations between 3 and 5 hours after administration. The mean concentrations of eupregnanolone and the combination of eupregnanolone increased with increasing dose of compound 1. In groups 4–6, the mean peak plasma concentrations of eupregnanolone were higher on day 1 than on day 7. In contrast, the mean peak plasma concentrations of the combination of eupregnanolone showed a higher level on day 7 than on day 1, suggesting a smaller degree of accumulation. No significant difference was observed between QAM and QHS administration.

[0117] Compared to eupregnanolone, the combined eupregnanolone had significantly higher maximum concentrations and exposure values. The AUC values ​​of eupregnanolone and the combined eupregnanolone were [data missing] over 7 days. 0-t AUC 0-24 and AUC 0- Both Cmax and ss increased with increasing dose of compound 1. The increase in systemic exposure was consistent with the findings in Part 1.

[0118] After multiple administrations, both allogeneic ketone and the combination of allogeneic ketone showed minimal accumulation, reaching steady state on days 2 and 3 after once-daily administration. Figure 2A The figure shows the change in plasma concentration of allogeneic ketone over time. Figure 2B and Figure 2C The mean AUC and Cmax of the doses tested on day 7 are shown in Table 6. A summary of the allopregnane PK parameters from Part 3 is provided in Table 6.

[0119] Table 6: PK parameters in multiple escalation dose studies

[0120]

[0121]

[0122] Participants were assessed using the metrics outlined below. The SSS is a single-item self-report questionnaire that measures and quantifies progressive steps of sleepiness throughout the day. Participants selected from seven statements that best represented their perceived level of sleepiness at a given time point, as depicted in Table 7.

[0123] Table 7: Stanford Somnolence Scale Rating

[0124]

[0125] MOAA / S is a clinical outcome assessment that measures a subject’s level of alertness / sedation as determined by a rater; in its modified form, it uses only the responsiveness component of the original Observer Alertness / Sedation Assessment Scale. Responsiveness is assessed and scored on a scale of 0 to 5 as a measure of sedation, as outlined in Table 8.

[0126] Table 8: MOAA / S Scoring Explanation

[0127]

[0128] The Sleep Quality Scale (SQS) is a single-item scale that has been proven to be a valuable measure of sleep quality. It measures clinically meaningful variations in sleep quality without significantly increasing the burden on clinical trial participants. The scale is administered in the morning, and participants are asked to rate their sleep quality over the past 7 days on a scale of poor (0), bad (1–3), fair (4–6), good (7–9), and excellent (10).

[0129] The Columbia Suicide Severity Rating Scale (C-SSRS) is a validated tool designed to quantify the severity of suicidal ideation and behavior. The scale is administered by individuals trained in its application, as described in further detail at https: / / cssrs.columbia.edu / the-columbia-scale-c-ssrs / about-the-scale / .

[0130] Quantitative electroencephalography (qEEG or EEG) has gained attention as a useful biomarker in human drug research because it is continuous, objective, reproducible, sensitive, reproducible, non-invasive, and highly translatable from non-clinical data. In this protocol, EEG serves as a biomarker and provides PD results for PK-PD modeling, enabling a more thorough understanding of the pharmacological effects of compound 1. Additionally, EEG can provide useful safety information regarding the detection of epileptiform activity and any proconvulsant effects of the investigational drug. Data outputs include spectral analysis and planar brain mapping.

[0131] In addition to group 8, EEG was collected at multiple time points before and after administration on days 1 and 7 of the MAD portion of the study. For each recording, subjects wore caps containing electrodes. For each session, recordings were collected for approximately 15 minutes while subjects were seated, and the recordings included portions with eyes open and closed.

[0132] The Cogstate™ neuropsychiatric assessment suite designed for this protocol consists of five psychomotor tests that identify potential pharmacologically induced CNS depressive effects. The data constitute biomarkers for this type of CNS depression, and the results can be correlated with other biomarker measures, such as qEEG. Detailed information on the nature and operation of each test is provided below. These were performed on MAD study cohorts, excluding cohort 8. Participants were encouraged to work as quickly and accurately as possible. The software measured the speed and accuracy of each response.

[0133] The test measures psychomotor function and uses a well-validated simple reaction time paradigm (processing speed) and card stimuli. In this test, all cards depict the same clown. The subject is instructed to press the "Yes" button when the card in the center of the screen is face up. The test typically takes less than 3 minutes to complete.

[0134] The recognition test is a measure of visual attention and uses a well-validated choice reaction time paradigm and card stimuli. In this test, all cards are either red or black clowns. Participants are asked whether the card displayed in the center of the screen is red. When the clown card is red, the participant responds by pressing the "yes" button, and when the clown card is black, the participant responds by pressing the "no" button. The test is typically completed within 3 minutes.

[0135] The Single Card Learning Test is a measure of visual learning and uses a well-validated pattern separation paradigm and card stimuli. In this test, the cards are identical to those in a standard 52-card deck (excluding the Joker card). Subjects are asked if they have previously seen the card displayed in the center of the screen in this test. Subjects respond by pressing "yes" or "no." The test typically takes 6 minutes to complete.

[0136] The single-recall test is a measure of working memory and uses a well-validated n-recall paradigm and card stimuli. Subjects are asked if the next card shown in the center of the screen is the same as the previously presented card. Subjects respond by pressing "yes" or "no". The test typically takes 4 minutes to complete.

[0137] The Groton Maze Learning Test uses a maze learning paradigm to measure executive function and problem-solving. Participants are presented with a 10 × 10 grid of tiles on a screen. A 28-step path is hidden within these tiles. Participants must move step-by-step from the starting point to the end point by touching the tile next to their current location. A green checkmark appears if a correct move is made corresponding to the hidden path, and a red cross appears if the move is incorrect. Once completed, participants return to the starting position to repeat the test and must try to remember the path they just completed. The software records each move as either an error or a correct move. The test typically lasts 7 minutes.

[0138] Body sway is assessed as a measure of the slight postural movements a subject makes in order to maintain balance statically in a neutral position or dynamically while in motion. Body sway is typically measured as the total displacement of the body's center of mass relative to its base of support over time. Postural mapping is an objective, sensitive, reliable, and non-invasive method designed to assess the effects of drugs and alcohol on body sway and alertness. Body sway is recorded using a computerized force table. Using a specific locator, barefoot subjects are instructed to remain still and gaze at a cue placed in front of them. Measurements of body sway are recorded according to the recommendations of the International Society for Postural Analysis (one minute with eyes open and one minute with eyes closed). The length and area of ​​the postural oscillation are then calculated.

[0139] Video eye tracking (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. VOG measures three evaluation metrics: horizontal saccades (movement of the eye toward a fixed point), horizontal reverse saccades (movement of the eye away from a fixed point), and horizontal and vertical tracking (fixing the eye on a moving object).

[0140] Binocular (two-eyed) moving viewing ability was measured during the saccadic test. During this 1-minute test, a visual target (a small square) was jumped from 0° to the right or left to 10° in a pseudo-random sequence. The duration of the target on the screen varied pseudo-randomly from 1,500 ms to 2,000 ms to minimize the subject's anticipatory preparation. The visual target was then eliminated within 200 ms before the next movement starting from the center. Participants were instructed to track the target on the screen from the center to the side and from the side to the center without anticipatory preparation. The procedure for the reverse saccadic test was the same as the saccadic test (the target jumped 10°) except that the target did not disappear. Participants were instructed to look at the opposite side of the target, which was approximately equidistant from the center, and had to resist looking at the target.

[0141] Binocular movement viewing ability was measured during the tracking test. During these tests, the target moved continuously on the screen along either the horizontal axis (horizontal tracking test) or the vertical axis (vertical tracking test). Each test lasted 10 seconds.

[0142] Pharmacodynamic results (Parts 1-3)

[0143] Groups 1, 2, and 2b (Part 1) showed a dose-dependent increase relative to baseline in the Stanford Somnolence Scale (SSS) and a decrease relative to baseline in the MOAA / S score. The highest dose of compound 1 showed the largest increase or decrease, respectively. This suggests that subjects receiving higher doses of compound 1 were more drowsy and less alert / anxious. The largest changes were observed 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 12 hours post-administration.

[0144] There was no significant difference in mean change relative to baseline between feeding (HF or LF) and fasting (group 3).

[0145] Groups 4, 5, 7, and 8 (Part 3) receiving 250 mg and 375 mg doses showed low magnitudes of change relative to baseline for both SSS and MOAA / S during the early stages of dosing, with no significant differences in changes over time for SSS and MOAA / S between the two dose levels. Group 6 (Part 3) receiving the 500 mg dose demonstrated a larger magnitude of effect relative to baseline for both SSS and MOAA / S compared to the lower dose. Notably, the effects on SSS and MOAA / S decreased over time in all treatment groups. Throughout the treatment period, the placebo group showed minimal change relative to baseline.

[0146] There was no consistent trend between compound 1 and sleep quality as measured by SQS, and no meaningful improvement or deterioration was observed in any group.

[0147] No subjects reported any suicidal ideation or suicidal behavior in any of the sections (1-3).

[0148] A slight effect on body sway was observed on day 1, but not on day 7.

[0149] like Figure 3A As shown, among all tested doses, the largest decrease in peak saccadic velocity was observed 4 hours after the dose on day 1. Figure 2A The maximum effect of video oculomotor (VOG) assessment was observed around Cmax approximately 3–5 hours after administration, providing information on the change in allogeneic alcohol concentration over time in subjects undergoing VOG assessment.

[0150] qEEG is a quantitative measurement of brain oscillations at different frequency levels. Resting-state brain activity was recorded under two conditions (eyes closed and eyes open). For each electrode, the EEG signal was spectrally analyzed to determine the absolute and relative power in a standard frequency band. The frequency ranges used are summarized in Table 9.

[0151] Table 9: Frequency Range of Spectral Analysis

[0152]

[0153] Compound 1 induced EEG changes in all study bands, with effects varying depending on dose, time, and study band. The strongest effect was observed at a dose of 500 mg, while 250 mg and 375 mg showed similar but reduced effects to the 500 mg dose. Figure 3B A dose-dependent increase in power in the β bands (β1, β2, and β3) was depicted for groups 4 (250 mg), 5 (375 mg), and 6 (500 mg). The maximum power increase was consistent with the observed Cmax (see [link to relevant documentation]). Figure 2A Generally, the effect of a single application on day 1 is greater than that on day 7. The maximum effect was observed approximately 4 hours after application on both day 1 and day 7.

[0154] Pharmacokinetic parameters and evaluation

[0155] PK parameters were calculated based on compound 1, the molecules containing allogeneic ketones in the combination, and the individual plasma concentrations of allogeneic ketones. Additionally, the geometric mean of all PK parameters was calculated. A linear model was used for analysis to assess dose-proportioning.

[0156] Estimate the following PK parameters as described in Tables 10 and 11.

[0157] Table 10: PK parameters for Part 1 and Part 2

[0158]

[0159] Table 11: PK Parameters in Part 3

[0160]

[0161]

[0162]

[0163] Safety and tolerability

[0164] Compound 1 is generally well tolerated. No severe or serious drug-related adverse events occurred. Most adverse events were mild, central nervous system (CNS) related (neurological disorders, AEs), and dose-dependent. The most common adverse event was drowsiness, which was most frequently observed at doses of 500 mg or higher of Compound 1. Food does not affect the safety or tolerability of Compound 1. Table 12 provides a summary of treatment-induced adverse events in the MAD study groups (groups 4–8).

[0165] Table 12: Summary of treatment-induced adverse events in the MAD study

[0166]

[0167] Table 13 summarizes the participant distribution in the single escalation dose (SAD), food effect (FE), and multiple escalation dose (MAD) studies.

[0168] Table 13: Participant Distribution

[0169]

[0170] Example 2: A study evaluating the effect of compound 1 on stress hormone responses in human subjects

[0171] A double-blind, placebo-controlled study was conducted in 80 healthy participants to determine the effect of a single dose of compound 1 on the validated standardized behavioral challenge Trier Social Stress Test (TSST). The TSST is a robust behavioral model used to examine the neurobiological responses to acute stress in humans, thereby inducing acute stress (and associated acute stress responses) under experimentally controlled conditions. The TSST induces stress through public conversation. It combines social assessment and unpredictability, forcing participants to speak in front of an unresponsive audience and further subjected to a surprising mental arithmetic test. The TSST combines elements of social assessment threat and unpredictability to produce consistent and robust physiological and psychological stress responses in the human body. On the day of the study, participants were given a speaking prompt and had 3 minutes of preparation time. Participants were then asked to deliver a 5-minute speech to a group while pretending to be recorded. Following the speech, participants were given an unexpected mental arithmetic task. TSST is described more fully in Allen A et al., Neurobiology of Stress (2017), Feb; 6: 113-126.

[0172] This study included a validation cohort and a randomization cohort. For validation of the TSST and study endpoints, the validation cohort (n=10) was given a placebo. The randomization cohort (n=80) was randomized and stratified by sex at a 1:1 ratio to either placebo or 375 mg compound 1. The cohorts are described in Table 14. Figure 4C The document also outlines an overview of the TSST study design.

[0173] Table 14: Groups in the TSST Study

[0174]

[0175] Compound 1 was formulated with excipients Peceol™ (glyceryl monooleate), Kolliphor® RH40 (polyethylene glycol glyceryl hydroxystearate), and ultra-refined sesame oil to form a clear to yellow viscous solution. Each gram of formulation contained 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 dosage, the required amount was manually filled into rectangular capsules of size 17.5. The placebo contained only the mediator, i.e., the above formulation without Compound 1.

[0176] The aim of this study was to evaluate the efficacy of compound 1 relative to placebo in inactivating the response to endpoints measured during and after the TSST procedure. The primary efficacy endpoint was the change in salivary cortisol levels from baseline (before the TSST procedure) to peak (maximum change), as measured before, during, and after the TSST procedure. The primary outcome used to determine this was salivary cortisol levels. Key secondary outcomes were the Numerical Rating Scale (NRS) for stress, anxiety, fear, embarrassment, and excitement. Additional secondary outcomes were the State-Specific Anxiety Index (STAI) and blood pressure. Safety and tolerability (i.e., the incidence, severity, and duration of treatment-induced adverse events (TEAEs), serious adverse events (SAEs), and other clinically relevant signs) were also monitored. Post-dosage samples were collected prior to the TSST for pharmacokinetic analysis.

[0177] To normalize the food effect, participants were provided with a standardized diet, which was consumed approximately 30 minutes before administration of compound 1. Compound 1 was administered with 240 mL of RT-water approximately 3–4 hours before the start of TSST.

[0178] Study endpoints and results

[0179] Pharmacodynamic and patient-reported results were collected before, during, and after TSST to assess the effectiveness of compound 1 in desensitization and / or stress response.

[0180] Cortisol levels (including, for example, salivary cortisol levels) are robust and sensitive markers of stress and stress hormone responses. Salivary cortisol concentrations were collected and measured throughout the study, with the primary endpoint being the maximum change relative to baseline (before TSST).

[0181] STAI-Y is a 40-item questionnaire completed by patients, with two subscales (20 items each): S-anxiety and T-anxiety. STAI-Y1 (status) is collected at baseline (before TSST), before the start of the TSST procedure, and after the completion of the TSST procedure. STAI-Y2 (trait) is assessed at screening and at baseline (before TSST). Generally, the S-anxiety questionnaire assesses the intensity of current feelings, while the T-anxiety questionnaire assesses the frequency of feelings. Each subtest is scored between 20 and 80, with higher scores indicating higher anxiety levels.

[0182] We used a carefully selected research-specific number rating scale (NRS) that included questions about stress, anxiety, embarrassment, fear, and excitement. Questions were rated from 0 (none at all) to 10 (most likely).

[0183] Blood pressure was collected before TSST, during recovery, and before discharge.

[0184] PK samples were collected 45 to 60 minutes before TSST on day 1 after a single dose to confirm adequate exposure to compound 1.

[0185] Compound 1 met the primary endpoint of the study. Figure 4A As shown, compound 1 partially desensitized the increase in salivary cortisol levels, as measured by the change in the least squares mean (LSMean) relative to baseline (before TSST). This desensitization of salivary cortisol levels was significantly different from placebo until 30 minutes after the end of TSST. The maximum change in the Log10 LSMean of salivary cortisol levels relative to baseline (before TSST) was significantly different between compound 1 and placebo (p = 0.0001). Figure 4B Compared with placebo, the maximum unconverted mean showed a reduction of approximately 2.2-fold in salivary cortisol levels. At all time points, the mean reduction in salivary cortisol levels after TSST was 54.4% (ranging from 62.8% at 10 minutes post-TSST to 45.5% at 60 minutes post-TSST). The therapeutic effect size of compound 1 relative to placebo was 0.72, as measured by Cohen's d (a common method for measuring effect size, and further described in Cohen J. (1988). Statistical Power Analysis for the Behavioral Sciences (2nd edition)).

[0186] Compound 1 was well tolerated in the TSST study; all treatment-related adverse events (TEAEs) were transient, mild, or moderate and consistent with the known pharmacological properties of allopregnantlone. TEAEs with an incidence >5% were drowsiness (29% in subjects receiving compound 1 compared to 13% in subjects receiving placebo), dizziness (20% in subjects receiving compound 1 compared to 3% in subjects receiving placebo), and headache (7.3% in subjects receiving compound 1 compared to 7.7% in subjects receiving placebo).

[0187] Table 15 summarizes the distribution of participants in the TSST study.

[0188] Table 15: Participant Distribution of the TSST Study

[0189]

[0190] Example 3: A study evaluating the effects of compound 1 in adults with major depressive disorder (MDD) with or without anxiety distress.

[0191] A randomized, parallel-group, double-blind, placebo-controlled study will be conducted to evaluate the efficacy, safety, and tolerability of compound 1 in adults with major depressive disorder (MDD) with or without anxiety distress.

[0192] Eligible participants with MDD will be randomly assigned in a 1:1 ratio to either the compound 1 group or the placebo group within the strata based on the presence or absence of an anxiety distress indicator as determined at baseline. Approximately 50-60% of participants will have MDD with anxiety distress, and approximately 40-50% will have MDD without anxiety distress.

[0193] The study will last approximately 80 days, including screening (up to 4 weeks), treatment (6 weeks), and post-treatment safety follow-up (1 week). Eligible participants who complete all visits may choose to enter a 6-week open-label extension.

[0194] Treatment and administration

[0195] On days 0–2 of the study, an initial dose of 125 mg of compound 1 or placebo will be administered once at bedtime (qHS). 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—any subject requiring a dose adjustment during the first week will be discontinued from study treatment.

[0196] Subjects will then receive 125 mg, 250 mg, or 375 mg of Compound 1 or a placebo until the end of the study treatment period, with the final dose taken on the evening of day 41 of the study. Dosage adjustments will be permitted during days 7–28 of the study based on assessments of the safety, tolerability, and efficacy of the study treatment. Participants requiring dose adjustments after day 28 of the study will have their study treatment discontinued. An overview of the treatment and dosing schedule is provided in Table 16.

[0197] Table 16: Overview of Treatment and Dosing Schedule

[0198]

[0199] A dose reduction may be necessary if a subject experiences intolerance associated with the current study dose regimen. A dose increase may be necessary if a subject tolerates the current study dose adequately and may experience suboptimal or inadequate therapeutic effects. If a subject tolerates the current dose adequately and experiences a satisfactory therapeutic response or outcome, the dose may be maintained without change.

[0200] After day 41, subjects may be given 250 mg of compound 1 (if they received a lower or higher dose on day 41) or continue receiving 250 mg of compound 1 for an additional 6 weeks (42 days) with qHS administration. The dose of compound 1 administered via qHS may be reduced to 125 mg throughout the 6-week period. The dose of compound 1 administered via qHS may be increased to 375 mg throughout the 6-week period.

[0201] Efficacy, purpose and endpoint

[0202] The primary objective was to characterize the effect of compound 1 as a monotherapy on depressive symptoms in subjects with MDD accompanied by anxiety distress or without MDD accompanied by anxiety distress. The primary objective was measured by the change in total Hamilton Depression Rating Scale-17 (HAM-D-17) score from baseline to day 42 of the study.

[0203] The key secondary objective is to characterize the effect of compound 1 on the overall disease severity of participants with MDD with or without anxiety distress. The key secondary objective will be measured by the change in clinician global impression-severity (CGI-S) from baseline to day 42 of the study.

[0204] Another secondary efficacy objective was to characterize the effects of compound 1 on depression, anxiety, functioning, and quality of life in participants with MDD and those with or without anxiety-induced distress. This secondary efficacy objective was measured from baseline to day 42 of the study using changes in Clinician Global Impression-Improvement (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).

[0205] The HAM-D-17 is a rating scale used by clinicians to assess the severity of symptoms in subjects diagnosed with depression. The HAM-D-17 includes individual ratings associated with the following symptoms: depressed mood (sadness, hopelessness, helplessness, worthlessness), guilt, suicidal ideation, insomnia (early, middle, late stages), work and activity, slowing (slow thinking and speech; impaired concentration; reduced motor activity), anxiety, restlessness (mental and physical), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, weight loss, and insight.

[0206] The HAM-D-17 assessment is scored on a scale of 0-52, where a higher score indicates more severe depression. A score of 24-52 indicates major depression, 17-23 indicates moderate depression, 8-16 indicates mild depression, and 0-7 indicates normal, absent, or remitted depression. The total score is calculated by summing the scores for each question. The assessment time range of the past 7 days (1 week) will be used at screening and baseline. For all other visits, the time range will begin from the previously recorded visit. The HAM-D-17 assessment is further described in Hamilton M “Depression Rating Scale” in the *Journal of Neurology, Neurosurgery and Psychiatry* (1960) 23:56-62.

[0207] The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item scale used to rate the severity of anxiety symptoms. Each of the 14 items is defined by a series of symptoms and measures psychotic anxiety (mental restlessness and psychological distress) and somatic anxiety (physical discomfort associated with anxiety). HAM-A scores are calculated by assigning a score from 0 (absent) to 4 (very severe), with a total score ranging from 0 to 56. A score less than 17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe severity.

[0208] The Clinical Global Impression-Severity (CGI-S) scale is a 7-point scale that requires clinicians to rate the severity of a disease during assessment. The rater selects an answer based on the following question: "Given your overall clinical experience with this particular group, how would you rate the patient's condition at this point?" Ratings: 1 = Normal, no disease; 2 = Borderline disease; 3 = Mild disease; 4 = Moderate disease; 5 = Significant disease; 6 = Severe disease; 7 = Most severe patient.

[0209] The Clinical Global Impression-Improvement (CGI-I) scale is a 7-point scale that asks clinicians to assess the extent to which a subject's disease has improved or worsened relative to their baseline state at the start of intervention. Raters select an answer based on the following question: "How has the patient's condition changed compared to when treatment began?" Ratings are: 1 = Very significant improvement; 2 = Some improvement; 3 = Minimal improvement; 4 = No change; 5 = Minimal worsening; 6 = Much worse; 7 = Very poor.

[0210] The Sheehan Disability Scale (SDS) is a patient-reported outcome measure that comprises five questionnaires assessing functional impairment and related disability. The first three items cover (1) work / school, (2) social life, and (3) family life / family responsibilities, using a rating scale of 0-10. The SDS also includes one item (4) assessing the number of days missed from school or work, and one item (5) assessing the number of days of mental incapacity. The scores for the first three items are summed to produce a total score of 0-30, where a higher score indicates greater impairment. The review period is longer than 7 days.

[0211] The Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) uses a 5-point scale ranging from 1 (very poor) to 5 (very good) to assess general activities. The total score is derived from 14 items with a maximum score of 70, where higher scores indicate greater life satisfaction and enjoyment. Participants will rate their satisfaction in the following areas of activity: physical health, feelings, work, family responsibilities, school / coursework, leisure activities, and social relationships.

[0212] The Overall Anxiety Severity and Impairment Scale (OASIS) is a self-reported scale designed to assess the frequency and severity of anxiety and impairment associated with an anxiety condition. The scale consists of five items, each rated from 0 to 4, with a maximum total score of 20. Higher scores indicate greater anxiety-related severity and interference with function. A 7-day timeframe will be used.

[0213] The Patient Global Impression Scale-Severity (PGI-S) is the patient-reported counterpart to the CGI-S. The PGI-S is a single-item 6-point scale based on the CGI and applicable to all subjects. The PGI-S is assessed by the study participants based on their overall severity over the past 7 days.

[0214] The Patient Global Impression Scale-Change (PGI-C) is the patient-reported counterpart to the CGI-I. The PGI-C is a single-item 7-point scale that indicates the overall level of improvement assessed by the study participants. A timeframe of 7 days after baseline will be used.

[0215] Safety objectives and endpoints

[0216] The safety objective was to evaluate the safety and tolerability of orally administered compound 1 in participants with MDD accompanied by anxiety distress or without MDD accompanied by anxiety distress. Safety was measured by the incidence, severity, and duration of treatment-induced adverse events (TEAEs), serious adverse events (SAEs), the incidence of clinically significant vital signs, pulse oximetry, electrocardiogram (ECG), and laboratory or physical examination results. The Columbia Suicide Severity Rating Scale (C-SSRS) and the Physician Withdrawal Checklist-20 (PWC-20) were also assessed.

[0217] In addition, changes in the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Childhood Adverse Experiences Questionnaire (ACE-Q) from baseline to day 42 of the study will be assessed.

[0218] The Epworth Sleepiness Scale (ESS) consists of eight items that assess the likelihood of falling asleep in real-world situations, such as reading, watching television, or driving. Each item is scored from 0 to 3, with a total score of 0 to 24. Higher scores indicate greater severity of excessive daytime sleepiness.

[0219] The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-reported items, which fall into one of seven subcategories: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, use of sleep medications, and daytime dysfunction.

[0220] The Childhood Adverse Experiences Questionnaire (ACE-Q) is a 10-item self-reported measure that assesses adverse or traumatic experiences prior to age 18. These exposures may include past physical or sexual abuse, domestic violence, substance use, and incarceration. The ACE-Q score ranges from 0 to 10, with higher scores indicating an increased level of adverse experience.

[0221] Based on the drowsiness observed at higher doses (see Example 1), driving restrictions and restrictions on hazardous activities / complex machinery have been implemented for at least 6 hours after administration.

[0222] Pharmacokinetic objectives and endpoints

[0223] Population pharmacokinetic parameters of allopregnanolone in study subjects will be determined using population PK and exposure-response analyses of allopregnanolone in the study population.

[0224] Inclusion criteria

[0225] Participants will be males or females aged 18 to 65 years (inclusive). Participants must have a primary diagnosis of MDD. Participants may be included if they have been diagnosed with comorbid generalized anxiety disorder (GAD), social anxiety disorder, or panic disorder (with or without agoraphobia) within the past 6 months prior to screening and have not received focused treatment for these conditions, and if MDD is considered the primary diagnosis at screening and baseline.

[0226] Eligible participants must have a current depressive episode lasting at least 4 weeks but not exceeding 18 months prior to screening.

[0227] At screening and baseline (before dosing), subjects must have a HAM-D-17 score greater than or equal to 23. On day 1, the improvement in a subject's HAM-D-17 score relative to their screening score must not exceed 20%. For example, if a subject's HAM-D-17 score was 28 at screening, then an eligible subject must have a HAM-D-17 score of at least 23 on day 1.

[0228] Exclusion criteria

[0229] The following exclusion criteria will be applied.

[0230] Subjects with the following medical history or current presentation consistent with the following will be ineligible: any depressive episode with psychotic or catatonic features, any bipolar mania, hypomania or mixed episode, and substance-induced (e.g., antidepressant-induced) mania, hypomania / mixed episode, bipolar disorder, including a history of bipolar depression, or current presentation consistent with bipolar depression, schizophrenia, schizophrenia or other mental disorders, obsessive-compulsive disorder and / or any persistent neurocognitive impairment.

[0231] Subjects diagnosed or treated for attention deficit hyperactivity disorder (ADHD) within the 5 years prior to screening.

[0232] Subjects who were diagnosed with or treated for eating disorders (including bulimia or anorexia nervosa) within the five years prior to screening.

[0233] A history of treatment-resistant depression is defined as two or more treatment failures of sufficient dosage and duration during a current depressive episode.

[0234] Post-traumatic stress disorder was active within 3 years of screening.

[0235] Borderline or antisocial personality disorder, or other disorders that may be serious enough to interfere with participation in the study.

[0236] Hospitalization for psychiatric disorders during a current depressive episode.

[0237] Clinically significant evidence or history of hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurological, or allergic disorders (excluding seasonal allergies).

[0238] History of intolerance or significant adverse events, including allergy to any component of compound 1 formulation (including sesame seed or sesame seed products).

[0239] Any condition that may interfere with drug absorption during screening or baseline, such as chronic diarrhea, inflammatory bowel disease, or previous GI tract surgery, or any disease or condition that may affect drug metabolism or secretion.

[0240] Do not take any prohibited medications, supplements, or herbal products within 2 weeks or 5 drug half-lives (whichever is longer) prior to baseline, including any antipsychotics, anticonvulsants, anxiolytics, benzodiazepines, or antidepressants.

[0241] A 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).

[0242] Hypothyroidism or hyperthyroidism, unless stable with appropriate drug treatment without dose variation for at least one month prior to the start of the study. At screening, serum thyroid-stimulating hormone (TSH) must be greater than 0.75 times the lower limit of normal and less than 1.25 times the upper limit of normal.

[0243] Current laboratory evidence, signs, or symptoms of liver or kidney dysfunction.

[0244] Subjects with other abnormal laboratory test results, vital sign results, or ECG findings, unless medical professionals consider these to be medically insignificant.

[0245] Symptoms of dysphagia at screening or baseline, or known difficulty swallowing capsules.

[0246] Working night shifts or other conditions that may disrupt the normal sleep / wake cycle.

[0247] Subjects who tested positive for human immunodeficiency virus (HIV) antibody, hepatitis B antigen (HBsAg) or hepatitis C virus (HCV) antibody during screening.

[0248] Subjects who tested positive for COVID-19 within 14 days prior to screening.

[0249] Malignant tumor or history of malignant tumor, except for non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin that has been adequately treated or removed, or cervical carcinoma in situ that has been adequately treated.

[0250] Subjects with a history of substance or alcohol use disorder meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) within the 12 months prior to screening, or those testing positive for substance abuse or potential substance abuse (including barbiturates, opioids, phencyclidine, cocaine, cannabinoids, amphetamines, and benzodiazepines) at the time of screening, may be eligible. Subjects testing positive for cannabinoids within the 12 months prior to screening but not meeting the DSM-5 criteria for moderate or severe substance abuse may also be eligible.

[0251] Clinically significant risk of suicide or harm to oneself or others.

[0252] Patients must have received treatment with the investigational product within 60 days or 5 half-lives (whichever is longer) prior to the first dose of the study treatment, and have no more than 2 prior investigational studies in the past year. Patients with more than 5 investigational studies in their lifetime are excluded.

[0253] Screening a 12-lead ECG after at least 5 minutes of supine rest confirms a Fridricia-corrected QT (QTcF) interval >450 ms (for men) or >470 ms (for women) or a QRS interval >120 ms.

[0254] Hypertension is defined as a supine blood pressure greater than or equal to 160 mmHg (systolic blood pressure) or greater than or equal to 100 mmHg (diastolic blood pressure) at the time of screening.

[0255] The serum creatinine level at screening is approximately ULN, or the estimated glomerular filtration rate is less than or equal to 80 mL / min.

[0256] The aspartate aminotransferase or alanine aminotransferase value is greater than or equal to 1.5 times the ULN.

[0257] Total bilirubin levels greater than or equal to 1.5 times the ULN, except for subjects with Gilbert's syndrome.

[0258] The following concomitant medications (defined as any medication taken by the subject after the initial study treatment administration) are prohibited: all antidepressants, anxiolytics, mood stabilizers, antipsychotics, sedative-hypnotics (including benzodiazepines), sedative-antihistamines, opioids, anticonvulsants, lipase inhibitors, S-adenosylmethionine, St. John's wort, ephedra, kava, and neuromodulation devices or other medical devices intended to treat neuropsychiatric disorders.

[0259] Non-benzodiazepine sleep aids may be permitted as needed, including zolpidem 5-10 mg before bedtime, zolpidem 6.25-12.5 mg controlled-release before bedtime, zaleplon 5-10 mg before bedtime, eszopiclone 1-2 mg before bedtime, melatonin 1-5 mg before bedtime, and ramelteon 8 mg before bedtime.

Claims

1. A method for treating a human subject suffering from major depressive disorder (MDD), the method comprising orally administering a dose of compound 1 to the human subject in need: (Compound 1).

2. The method according to claim 1, wherein the dose of compound 1 is between 70 and 500 mg.

3. The method according to claim 2, wherein the dose of compound 1 is 70 mg, 125 mg, 140 mg, 250 mg, 280 mg, 375 mg, 420 mg or 500 mg.

4. The method according to any one of claims 1 to 3, wherein the dose of compound 1 is 125 mg.

5. The method according to any one of claims 1 to 3, wherein the dose of compound 1 is 250 mg.

6. The method according to any one of claims 1 to 3, wherein the dose of compound 1 is 375 mg.

7. The method according to any one of claims 1 to 6, wherein the human subject suffering from major depressive disorder (MDD) suffers from MDD accompanied by anxiety distress.

8. The method according to any one of claims 1 to 6, wherein the human subject suffering from major depressive disorder (MDD) suffers from MDD without anxiety distress.

9. The method according to any one of claims 1 to 8, wherein the dose of said compound 1 is administered once daily at bedtime (qHS).

10. A method for treating a human subject suffering from major depressive disorder (MDD), the method comprising orally administering the following to a human subject in need: i) The daily starting dose of compound 1, for a maximum of 7 days; and ii) A daily maintenance dose of compound 1, starting after the said initial period; and wherein compound 1 is: (Compound 1).

11. The method of claim 10, wherein the starting daily dose of compound 1 is 125 mg.

12. The method of claim 10, wherein the starting daily dose of compound 1 is 250 mg.

13. The method according to any one of claims 10 to 12, wherein the daily maintenance dose of said compound 1 is 125 mg, 250 mg or 375 mg.

14. The method according to any one of claims 10 to 13, wherein the starting period is 3 to 7 days.

15. The method according to any one of claims 10 to 14, wherein the daily maintenance dose of said compound 1 is greater than the daily starting dose of said compound 1.

16. The method according to any one of claims 10 to 14, wherein the daily maintenance dose of said compound 1 is the same as the daily starting dose of said compound 1.

17. The method according to any one of claims 10 and 12 to 14, wherein the daily maintenance dose of said compound 1 is less than the daily starting dose of said compound 1.

18. The method according to any one of claims 10 to 17, wherein the human subject suffering from major depressive disorder (MDD) suffers from MDD accompanied by anxiety distress.

19. The method according to any one of claims 10 to 17, wherein the human subject suffering from major depressive disorder (MDD) suffers from MDD without anxiety distress.

20. The method according to any one of claims 10 to 19, wherein the starting daily dose of said compound 1 is administered once daily at bedtime (qHS).

21. The method according to any one of claims 10 to 20, wherein the daily maintenance dose of said compound 1 is administered once daily at bedtime (qHS).

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