19-nor c3,3-disubstituted c21-n-pyrazolyl steroid for use in treating major depressive disorder and postpartum depression

Abstract

To provide 19-nor C3,3-disubstituted C21-n-pyrazolyl steroid for use in treating major depressive disorder and postpartum depression.SOLUTION: The present disclosure relates to a therapeutically effective amount of a compound (1) or a pharmaceutically acceptable salt thereof for use in a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need of treating major depressive disorder (MDD) with elevated anxiety. The present disclosure also relates to a therapeutically effective amount of a compound (1) or a pharmaceutically acceptable salt thereof for use in a method of treating postpartum depression (PPD) with elevated anxiety in a subject in need of treating postpartum depression (PPD) with elevated anxiety.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 181,743, filed Apr. 29, 2021; U.S. Provisional Application No. 63 / 197,025, filed Jun. 4, 2021; U.S. Provisional Application No. 63 / 210,810, filed Jun. 15, 2021; U.S. Provisional Application No. 63 / 239,096, filed Aug. 31, 2021; U.S. Provisional Application No. 63 / 285,812, filed Dec. 3, 2021; U.S. Provisional Application No. 63 / 289,506, filed Dec. 14, 2021; U.S. Provisional Application No. 63 / 289,520, filed Dec. 14, 2021; and U.S. Provisional Application No. 63 / 298,601, filed Jan. 11, 2022. The entire contents of the above - mentioned applications are hereby incorporated by reference into this specification.

[0002] Field of the Invention The present disclosure is directed to a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. The present disclosure is also directed to a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

Background Art

[0003] Background GABA, which is γ-aminobutyric acid, deeply affects the excitability of the whole brain because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA interacts with its recognition site in the GRC (GABA receptor complex) to promote the influx of chloride ions into the cell towards the lower side of the electrochemical gradient of the GRC. The increase in the intracellular level of this anion causes hyperpolarization of the membrane potential, and the neuron becomes less sensitive to excitatory inputs (i.e., a decrease in neuronal excitability). In other words, the higher the concentration of chloride ions in the neuron, the lower the excitability of the brain (the level of arousal). The GRC has been well-established to be involved in mediating anxiety, seizure effects, and sedation. Therefore, GABA, and drugs that act like GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ) such as Valium®), produce therapeutically useful effects by interacting with specific regulatory sites in the GRC. Accumulating evidence indicates that the GRC contains distinct sites for neuroactive steroids (Lan, N. C. et al., Neuwchem. Res. 16:347-356 (1991)). Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the steroid hormones progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to modify the excitability of the brain was recognized in 1986 (Majewska, M. D. et al., Science 232: 1004-1007 (1986); Harrison, N. L. et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)).

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0005] Summary of the Invention In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering a therapeutically effective amount of compound (1):

Chemical Formula

[0006] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of compound (1):

Chemical Formula

[0007] In some embodiments, the compound (1) or the pharmaceutically acceptable salt of the compound (1) is administered once a day for about 14 days, i.e., about 2 weeks. In some embodiments, the compound (1) is administered at a dose of about 20 mg to about 55 mg. In some embodiments, the compound (1) is administered at a dose of about 50 mg. In some embodiments, the compound (1) is administered at a dose of about 30 mg or about 40 mg.

[0008] In some embodiments, the pharmaceutically acceptable salt of the compound (1) is administered at a dose equivalent to about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of the compound (1) is administered at a dose equivalent to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of the compound (1) is administered at a dose equivalent to about 30 mg or about 40 mg of the free base compound.

[0009] In some embodiments, the compound (1) or the pharmaceutically acceptable salt of the compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, the compound (1) or the pharmaceutically acceptable salt of the compound (1) is administered orally. In some embodiments, the compound (1) or the pharmaceutically acceptable salt of the compound (1) is administered with food. In some embodiments, the compound (1) or the pharmaceutically acceptable salt of the compound (1) is administered once a day at night.

[0010] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks where 2θ is between 9.7 and 10.1 degrees (including the endpoints), 2θ is between 11.6 and 12.0 degrees (including the endpoints), 2θ is between 13.2 and 13.6 degrees (including the endpoints), 2θ is between 14.2 and 14.6 degrees (including the endpoints), 2θ is between 14.6 and 15.0 degrees (including the endpoints), 2θ is between 16.8 and 17.2 degrees (including the endpoints), 2θ is between 20.5 and 20.9 degrees (including the endpoints), 2θ is between 21.3 and 21.7 degrees (including the endpoints), 2θ is between 21.4 and 21.8 degrees (including the endpoints), and 2θ is between 22.4 and 22.8 degrees (including the endpoints).

[0011] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks where 2θ is between 9.3 and 9.7 degrees (including the endpoints), 2θ is between 10.6 and 11.0 degrees (including the endpoints), 2θ is between 13.0 and 13.4 degrees (including the endpoints), 2θ is between 14.7 and 15.1 degrees (including the endpoints), 2θ is between 15.8 and 16.2 degrees (including the endpoints), 2θ is between 18.1 and 18.5 degrees (including the endpoints), 2θ is between 18.7 and 19.1 degrees (including the endpoints), 2θ is between 20.9 and 21.3 degrees (including the endpoints), 2θ is between 21.4 and 21.8 degrees (including the endpoints), and 2θ is between 23.3 and 23.7 degrees (including the endpoints).

[0012] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks where 2θ is between 9.7 and 10.1 degrees (including the endpoints), 2θ is between 14.6 and 15.0 degrees (including the endpoints), 2θ is between 16.8 and 17.2 degrees (including the endpoints), 2θ is between 20.5 and 20.9 degrees (including the endpoints), and 2θ is between 21.3 and 21.7 degrees (including the endpoints).

[0013] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks where 2θ is between 9.3 and 9.7 degrees (including the endpoints), 2θ is between 10.6 and 11.0 degrees (including the endpoints), 2θ is between 13.0 and 13.4 degrees (including the endpoints), 2θ is between 18.7 and 19.1 degrees (including the endpoints), and 2θ is between 21.4 and 21.8 degrees (including the endpoints).

[0014] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is re-administered to the subject in response to a recurrence of depressive symptoms after completion of an initial treatment. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration. In some embodiments, each of the initial treatment and the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0015] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0016] In some embodiments, the subject has not been treated before.

[0017] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days before administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0018] In some embodiments, MDD with increased anxiety is characterized by a total score of 17 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) or a score of 7 or higher on the Hamilton Rating Scale for Depression (HAM-D) anxiety / physicalization subscale before administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher before administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-D anxiety / physicalization subscale score of 7 or higher before administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0019] In some embodiments, the subject shows a decrease from baseline in the HAM-D total score, the HAM-A total score, the HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject shows a decrease of at least 14 points in the HAM-D total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject shows a decrease of at least 12 points in the HAM-A total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0020] In another aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering a therapeutically effective amount of compound (1):

Chemical formula

[0021] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of compound (1):

Chemical formula

[0022] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days, i.e., about 2 weeks. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg or about 40 mg.

[0023] In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 30 mg or about 40 mg of the free base compound.

[0024] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once a day at night.

[0025] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern that includes peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 11.6 and 12.0 degrees (inclusive), 2θ between 13.2 and 13.6 degrees (inclusive), 2θ between 14.2 and 14.6 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), 2θ between 21.3 and 21.7 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 22.4 and 22.8 degrees (inclusive).

[0026] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 14.7 and 15.1 degrees (inclusive), 2θ between 15.8 and 16.2 degrees (inclusive), 2θ between 18.1 and 18.5 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), 2θ between 20.9 and 21.3 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 23.3 and 23.7 degrees (inclusive).

[0027] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), and 2θ between 21.3 and 21.7 degrees (inclusive).

[0028] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), and 2θ between 21.4 and 21.8 degrees (inclusive).

[0029] In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is re-administered to the subject in response to a recurrence of depressive symptoms after completion of an initial treatment. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration. In some embodiments, each of the initial treatment and the re-administration is performed for about 14 days, i.e., about 2 weeks.

[0030] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0031] In some embodiments, the subject has not been treated.

[0032] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0033] In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM - A) of 17 or higher, or a Hamilton Rating Scale for Depression (HAM - D) anxiety / psychosomatic subscale score of 7 or higher, prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM - D total score of 26 or higher and a HAM - A total score of 17 or higher prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM - D total score of 26 or higher and a HAM - D anxiety / psychosomatic subscale score of 7 or higher prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0034] In some embodiments, the subject shows a decrease from baseline in the HAM - D total score, the HAM - A total score, the HAM - D anxiety / psychosomatic subscale score, or a combination thereof.

[0035] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering from about 30 mg to about 50 mg of compound (1):

Chemical formula

[0036] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering a compound (1) in an amount equivalent to from about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0037] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering about 30 mg to about 50 mg of compound (1):

Chemical formula

[0038] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering a compound (1) in an amount equivalent to from about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0039] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering about 30 mg to about 50 mg of compound (1) once daily for about 14 days, i.e., about 2 weeks:

Chemical formula

[0040] ​​In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] including the step of administering a pharmaceutically acceptable salt thereof.

[0041] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount of about 30 mg to about 50 mg: [Chemical formula] including the step of administering the same.

[0042] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] including the step of administering a pharmaceutically acceptable salt thereof.

[0043] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount of about 30 mg to about 50 mg: [Chemical formula] including the step of administering the same, Provide a method in which the subject has not been treated.

[0044] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0045] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount of about 30 mg to about 50 mg:

Chemical formula

[0046] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0047] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg:

Chemical formula

[0048] In one aspect, the present disclosure provides a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a dose of a pharmaceutically acceptable salt of compound (1) that is equivalent to a free base compound of about 30 mg to about 50 mg:

Chemical formula

[0049] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg:

Chemical formula

[0050] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need thereof, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] in the form of a pharmaceutically acceptable salt thereof, wherein the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of the pharmaceutically acceptable salt of compound (1).

[0051] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need thereof, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), about 30 mg to about 50 mg of compound (1): [Chemical formula] wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of compound (1).

[0052] In one aspect, the present disclosure provides a method for treating postpartum depression (PPD) with increased anxiety in a subject in need thereof, the method comprising administering, once daily for about 14 days (i.e., about 2 weeks), a compound (1) in an amount equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] in the form of a pharmaceutically acceptable salt thereof, wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharmaceutically acceptable salt of compound (1).

[0053] ​In some embodiments, compound (1) is administered at a dose of about 50 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 50 mg of the free base compound. In some embodiments, compound (1) is administered at a dose of about 40 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 40 mg of the free base compound. In some embodiments, compound (1) is administered at a dose of about 30 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 30 mg of the free base compound.

[0054] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once daily at night.

[0055] In some embodiments, the subject has not been treated.

[0056] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0057] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0058] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is re-administered to the subject in response to a recurrence of depressive symptoms after completion of an initial treatment period. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment period and the first dose of the re-administration. In some embodiments, the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0059] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized, prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1), by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher, or by a score on the Hamilton Rating Scale for Depression (HAM-D) anxiety / somatization subscale of 7 or higher. In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized, prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1), by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher. In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized, prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1), by a HAM-D total score of 24 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher.

[0060] In some embodiments, the subject shows a decrease from baseline in the HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject shows a decrease of at least 14 points in the HAM-D total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject shows a decrease of at least 12 points in the HAM-A total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1). BRIEF DESCRIPTION OF THE DRAWINGS

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Mode for Carrying Out the Invention

[0113] Detailed Description I. Definitions

[0114] As used herein, "compound (1)" refers to a compound having the formula (or structure):

Chemical Formula

[0115] Compound (1) is also known as zuranolone, i.e., 3α-hydroxy-3β-methyl-21-(4-cyanopyrazol-1-yl)-5β-19-norpregnan-20-one, and its IUPAC name: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (CAS Registry Number 1632051-40-1). Methods for chemically synthesizing Compound (1) are described in U.S. Patent No. 9,512,165 and PCT Application Publication No. WO2014 / 169833, and the entire contents of the above-mentioned applications are incorporated herein by reference in their entirety. Some crystalline forms of Compound (1), and methods for preparing said forms, are described in U.S. Patent No. 11,236,121; U.S. Patent Application Publication No. US2019 / 0177359; and PCT Application Publication No. WO2018 / 039378, and the entire contents of the above-mentioned applications are incorporated herein by reference in their entirety. Pharmaceutical compositions of Compound (1), and methods for preparing said compositions, are described in PCT Application Publication No. WO2022 / 020363A9 and U.S. Application No. 17 / 579,541, and the entire contents of the above-mentioned applications are incorporated herein by reference in their respective entireties.

[0116] Compound (1) is a neuroactive steroid that has been shown to be a positive allosteric modulator of GABA A receptors at synapses and extrasynaptically. A As a positive allosteric modulator of GABA A receptors, Compound (1) acts as a therapeutic agent for treating CNS-related disorders such as depression, postpartum depression, and major depressive disorder, as well as neurological conditions such as essential tremor, epilepsy, and Parkinson's disease.

[0117] As used herein, "crystalline" refers to the solid phase of a given chemical entity having a sufficiently well-defined three-dimensional structural order. Atoms, ions, and / or molecules are arranged regularly and periodically within a repeating three-dimensional lattice. In various embodiments, the crystalline material may include one or more discrete crystalline forms.

[0118] As used herein, the terms "crystalline form", "crystalline solid form", "crystal form", "solid form", and related terms refer to crystalline modifications of a given substance (e.g., compound (1)), including crystalline forms of single components and crystalline forms of multiple components, and including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0119] The term "substantially crystalline" refers to a form that can be crystalline to at least a specified weight percentage. The specified weight percentage can include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In some embodiments, the specified weight percentage of crystallinity is at least 90%. In some embodiments, the specified weight percentage of crystallinity is at least 95%. In some embodiments, compound (1) can be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline forms A and C) and / or PCT Application Publication No. WO2018 / 039378, the entire contents of the above applications being incorporated herein by reference.

[0120] The term "substantially pure" relates to the composition of a particular crystalline form (e.g., the crystalline form of compound (1)) that cannot contain impurities and / or other solid forms in at least a specified weight percentage. The specified weight percentage can include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, compound (1) can be a substantially pure sample of any of the crystalline forms described herein (e.g., crystalline forms A and C). In some embodiments, compound (1) can be in substantially pure form A. In some embodiments, compound (1) can be in substantially pure form C.

[0121] As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD pattern is an x-y graph with 2θ (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. There are diffraction peaks that can be used to characterize crystalline materials. The diffraction peaks are usually represented and referred to by their position on the x-axis rather than by the intensity of the diffraction peaks on the y-axis because the diffraction peak intensity can be particularly sensitive to the orientation of the sample (see Pharmaceutical Analysis, Lee & Web, pp. 255 - 257 (2003)). Thus, intensity is not typically used by those skilled in the art to characterize crystalline materials. As with any data measurement, XRPD data can have variations. In addition to variations in the intensity of the diffraction peaks, there can also be variations in the position of the diffraction peaks on the x-axis. However, this variation can usually be taken into account when reporting the position of the diffraction peaks for characterization purposes. Such variations in the position of the diffraction peaks along the x-axis can be due to several causes. One such cause can be sample preparation. Samples of the same crystalline material prepared under different conditions can produce slightly different diffractograms. All factors such as particle size, moisture content, solvent content, temperature, and orientation can affect how the sample diffracts X-rays. Another cause of variation is due to instrument parameters. Different X-ray powder diffractometers operate using different parameters and can produce slightly different diffraction patterns from the same crystalline material. Similarly, different software packages can process XRPD data differently, which can also result in variations. These and other causes of variation are known to those skilled in the art. Due to such causes of variation, the value of each X-ray diffraction peak may be preceded by the term "about" or followed by an appropriate range defining the experimental variation (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.).

[0122] When the term "characteristic peak" refers to peaks in the XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of compound (1)), it refers to a specific set of diffraction peaks, the values of which, taken as a whole, cover a range of 2θ values (e.g., 0° to 40°) that are specific to that particular crystalline form.

[0123] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or, in the case of use in a country other than the United States, the corresponding agency for use in animals and, more particularly, in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias.

[0124] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts may be non-toxic and may be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucic acid and other organic acids; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine. The salts include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc.See, for example, Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0125] Chemical elements are specified according to the Periodic Table of the Elements (CAS Edition) on the inside cover of the Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0126] When the use of the term “about” is present before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a variation of ±10% from the nominal value, unless otherwise indicated or implied.

[0127] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0128] As used herein, the term "dose equivalent" means a biologically equivalent dose. For example, in the case of a 50 mg dose of compound (1), the dose equivalent of a pharmaceutically acceptable salt of compound (1) is the amount of the pharmaceutically acceptable salt (by weight) necessary to provide a biologically equivalent dose relative to a 50 mg dose of the free base of compound (1).

[0129] As used herein, an "effective amount" of a compound (or a pharmaceutically acceptable salt thereof) refers to an amount sufficient to elicit a desired biological response, e.g., for treating a CNS-related disorder such as, for example, depression, such as major depressive disorder (MDD) with elevated anxiety or postpartum depression (PPD) with elevated anxiety. As will be recognized by those skilled in the art, the effective amount of a compound of the invention (or a pharmaceutically acceptable salt thereof) can vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, as well as factors such as the age, weight, health and condition of the subject. Effective amounts include both therapeutic and prophylactic treatments.

[0130] As used herein, "short-term dosing regimen" refers to a dosing regimen in which a compound or a composition containing the compound is administered to a subject for a limited period of time in response to a diagnosis of a disorder or its symptoms, such as a diagnosis of depression or symptoms or an episode of major depressive disorder. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit containing the compound (1) and one or more suitable pharmaceutical excipients. In some embodiments, the short-term dosing regimen has a period of a plurality of weeks, such as about 8 weeks. In contrast to long-term administration as defined herein, short-term dosing of the compound is carried out for a limited period of time, such as about 2 weeks to about 8 weeks, in response to a diagnosis or recurrence of a disorder, such as depression or its symptoms. In some embodiments, short-term dosing is carried out once a day for a plurality of weeks, such as about 2 weeks to about 6 weeks. In one embodiment, short-term dosing has a period of 2 weeks. In some embodiments, there are more than one short-term dosing regimens, but no more than 3 short-term dosing regimens, such as 2 or more short-term regimens, are administered to the subject over a 12-month period.

[0131] As used herein, the term "modulation" refers to inhibition or activation of GABAA receptor function. A "modulator" (e.g., a compound or a pharmaceutically acceptable salt thereof that modulates GABAA receptor function) may be, for example, an agonist, partial agonist, antagonist or partial antagonist of the GABAA receptor.

[0132] "MDD with increased anxiety" or "MDD with anxiety distress" are used interchangeably and refer to a subject having MDD presenting with increased anxiety as a depressive symptom. In some embodiments, MDD with increased anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (i.e., prior to administration of compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, MDD with increased anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e., prior to administration of compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, MDD with increased anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, MDD with increased anxiety is characterized by a HAM-A total score of at least 20 at baseline. "PPD with increased anxiety" or "PPD with anxiety distress" are used interchangeably and refer to a subject having PPD presenting with increased anxiety as a depressive symptom. In some embodiments, PPD with increased anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (i.e., prior to administration of compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, PPD with increased anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e., prior to administration of compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, PPD with increased anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, PPD with increased anxiety is characterized by a HAM-A total score of at least 20 at baseline.

[0133] In other embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety and somatic items. In some embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D items: psychic anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D item: psychic anxiety. In some embodiments, "increased anxiety" is characterized by a HAM-D score based primarily on items that evaluate the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D score based primarily on items that evaluate the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items that evaluate the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items that evaluate the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score based primarily on items that evaluate the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score based primarily on items that evaluate the anxiety symptoms of depression.

[0134] As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharmaceutically acceptable salt thereof) is an amount sufficient to achieve a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound (or a pharmaceutically acceptable salt thereof) is an amount of the therapeutic agent, alone or in combination with other therapies, that achieves a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0135] In an alternative embodiment, the present disclosure contemplates administration of compound (1), or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, as a prophylaxis before a subject begins to suffer from a particular disease, disorder or condition. As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound is an amount of the therapeutic agent, alone or in combination with other agents, that achieves a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

[0136] As used herein, "solid dosage form" means a solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalation formulations, and chewables, of a pharmaceutical dosage (s).

[0137] "Subject" or "patient" refers to a human (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, adolescent), or an adult subject (e.g., a young adult, middle-aged adult or elderly adult)).

[0138] As used herein and unless otherwise specified, the terms "treating," "treatment," and "treat" contemplate an act that is performed while a subject is suffering from a particular disease, disorder, or condition, and that act reduces the severity of the disease, disorder, or condition (or any symptoms thereof), or delays or decelerates the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplates a prophylactic act that is performed before a subject begins to suffer from a particular disease, disorder, or condition.

[0139] As used herein, "treatment-naive" refers to a subject who has not been previously treated with additional antidepressants within the scope of the current depressive episode. "Treatment-naive" also refers to a subject who has not taken any antidepressants within at least 30 days prior to the start of treatment (e.g., day 1), or within at least 60 days prior to the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressants within at least 30 days prior to the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressants within at least 60 days prior to the start of treatment.

[0140] As used herein, the term "unit dosage form" is defined to refer to the form in which compound (1) is administered to a subject. In some embodiments, the unit dosage form can be, for example, a pill, capsule, or tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, a typical amount of compound (1) in a unit dosage form useful in the present disclosure is from about 10 mg to about 100 mg, from about 20 mg to about 55 mg, or from about 30 mg to about 50 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, or about 55 mg).

[0141] In some embodiments, the unit dosage form contains about 40 mg of compound (1) and is in the form of a capsule. In other embodiments, the unit dosage form contains about 50 mg of compound (1) and is in the form of a capsule. In another embodiment, the unit dosage form contains about 45 mg of compound (1) and is in the form of a capsule. In some embodiments, the capsule containing about 40 mg, about 45 mg or about 50 mg of compound (1) is administered to the subject once a day. In some embodiments, two or more capsules are combined to contain 40 mg of compound (1). In some embodiments, two or more capsules are combined to contain 45 mg of compound (1). In some embodiments, two or more capsules are combined to contain 50 mg of compound (1).

[0142] In other embodiments, the unit dosage form contains about 20 mg of compound (1) and is in the form of a capsule. In other embodiments, the unit dosage form contains about 10 mg of compound (1) and is in the form of a capsule. In other embodiments, the unit dosage form contains about 15 mg of compound (1) and is in the form of a capsule. In other embodiments, the unit dosage form contains about 25 mg of compound (1) and is in the form of a capsule. In some embodiments, one or more capsules containing about 30 mg or 45 mg of compound (1) are administered to the subject once a day. In some embodiments, three capsules are combined to contain 30 mg of compound (1). In some embodiments, three capsules are combined to contain 45 mg of compound (1).

[0143] In some embodiments, administering compound (1) improves cognitive function. In some embodiments, cognitive function refers to a collection of mental tasks and functions, including, but not limited to, memory (e.g., semantic, temporal, procedural, priming, or working); orientation; language; problem-solving; visual perception, construction, and integration; planning; organization; selective attention; inhibitory control, and the ability to mentally manipulate information. In one embodiment, cognitive function is one or more selected from the group consisting of memory (e.g., semantic, temporal, procedural, priming, or working); orientation; language; problem-solving; visual perception, construction, and integration; planning; organization; selective attention; inhibitory control, and the ability to mentally manipulate information. Measures of cognitive function include, for example, assessment instruments designed to measure (a) general intelligence, (b) non-verbal intelligence, (c) achievement, (d) attention / executive function, (e) memory and learning, (f) visual-motor and motor function, and (g) language.

[0144] For example, any change in cognitive function over time or due to treatment can be monitored by using one or more of these well-established tests at two or more time points and comparing results.The phrase " improve cognitive function " as referred to herein refers to the positive change in the ability of subject to carry out symbolic operations, for example, perceive, remember, create mental images, have clarity of thought, be aware, reason, think or judge.Positive change can be measured using any of the above-mentioned tests on two or more occasions, for example, the first occasion to measure baseline cognitive function, and the second occasion to measure cognitive function after a certain period (may be treated).

[0145] II. Treatment Methods

[0146] MDD with elevated anxiety

[0147] In one aspect, the present disclosure is directed to a method of treating major depressive disorder (MDD) accompanied by an increase in anxiety. In some embodiments, the diagnosis and severity of the major depressive disorder treated by the methods described herein are characterized as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-5).

[0148] Depressive disorders

[0149] Depressive disorders include severe mood dysregulation disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. A common feature of all of these disorders is a sad, empty, or irritable mood, accompanied by physical and cognitive changes that significantly affect the individual's ability to function. What differs among them are matters of duration, timing, or presumed etiology.

[0150] Major depressive disorder presents a classical condition among this group of disorders. It is characterized by distinct episodes of at least two weeks' duration (however, most episodes last considerably longer), accompanied by clear changes in mood, cognition, and autonomic nervous system function, as well as remission between episodes. Individual episodes of major depressive disorder may be referred to as "major depressive episodes" or "depressive episodes".

[0151] Major depressive disorder (MDD)

[0152] Major depressive disorder is generally known in the art.

[0153] In some embodiments, MDD, also known as depression or clinical depression, is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD can affect how a subject feels, thinks, and behaves, and can lead to a variety of emotional and physical problems.

[0154] In some embodiments, MDD is defined and diagnosed according to the DSM-5. For example, MDD is diagnosed according to Diagnostic Criterion A as follows.

[0155] Diagnostic Criterion A. Five (or more) of the following symptoms have been present during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, mood swings may be present.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gains.) 4. Insomnia or hypersomnia nearly every day. [[ID=@17]] 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8. Almost every day, there is a decline in thinking ability or concentration, or the person is indecisive (either by subjective description or by observation by others). 9. Repeatedly thinking about death (not just the fear of death), recurrent suicidal thoughts without a specific plan, or a suicide attempt or a specific plan to commit suicide.

[0156] The following Diagnostic Criteria B - E are additional descriptions of MDD. They may be considered as explanations or diagnoses of MDD, but are not necessary.

[0157] Diagnostic Criterion B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0158] Diagnostic Criterion C. The episode cannot be attributable to the physiological effects of a substance or to another medical condition.

[0159] Diagnostic Criteria A - C may represent a major depressive episode.

[0160] Diagnostic Criterion D. The occurrence of a major depressive episode is not better explained by schizophrenia, schizoaffective disorder, schizotypal disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum disorders, as well as other psychotic disorders.

[0161] Diagnostic Criterion E. There has never been a manic episode or a hypomanic episode.

[0162] In some embodiments, a major depressive episode (MDE) is a period characterized by the symptoms of MDD as described above.

[0163] In some embodiments, MDD is a clinical pathway characterized by one or more major depressive episodes (MDEs) in a subject.

[0164] In some embodiments, MDD is diagnosed in accordance with Diagnostic Criteria A - C as described above. In some embodiments, MDD is diagnosed in accordance with Diagnostic Criteria A - E as described above.

[0165] Diagnostic Features

[0166] For the symptoms of major depressive disorder criteria, excluding weight change and suicidal thoughts, to be considered present, they must be present almost every day. In addition to being present almost every day, the depressed mood must be present for most of the day. Often, insomnia or fatigue is the main complaint, and if the accompanying depressive symptoms are overlooked, underdiagnosis may occur. Sadness may initially be denied but may be elicited by interview or inferred from facial expression and attitude. In the case of an individual focusing on physical complaints, the clinician should determine whether the distress caused by those complaints is related to specific depressive symptoms. Fatigue and sleep disturbances are present in a high percentage of cases. Psychomotor disturbances are less common but, like delusional or near - delusional guilt, are indicators of a higher overall severity.

[0167] The essential feature of a major depressive episode is a period of at least 2 weeks in which there is either depressed mood or loss of interest or pleasure in almost all activities (Criterion A above). In children and adolescents, the mood may be irritable rather than sad. The individual also experiences at least 4 additional symptoms drawn from the list including changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation or plans or attempts. For an episode to be counted as a major depressive episode, the symptoms must either be new or represent a clear worsening compared to the person's pre-episode state. The symptoms must be present almost every day for the majority of the day, continuously for at least 2 weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational, or other important areas of functioning. In some individuals with mild episodes, functioning may appear normal but require significant effort to maintain.

[0168] Sleep disturbances may take the form of either difficulty falling asleep or excessive sleep (Criterion A4). When insomnia is present, it usually takes the form of middle insomnia (i.e., difficulty returning to sleep after waking up during the night) or terminal insomnia (i.e., waking up too early and being unable to return to sleep). Initial insomnia (i.e., difficulty falling asleep) may also occur. Individuals who present with hypersomnia (excessive sleep) may experience long sleep episodes at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is due to the sleep disorder.

[0169] <0, Major depressive disorder with anxious distress

[0170] The specifier “with anxious distress” for MDD as defined by DSM-5 indicates that at least 2 of the following symptoms are present on most days during a major depressive episode or persistent depressive disorder (dysthymia): 1. Feel excited or tense. 2. Feel unusually restless. 3. Unable to concentrate due to worry. 4. Fear that something terrible might happen. 5. Feel as if one is losing self - control.

[0171] "The distress of anxiety" and "the escalation of anxiety" are used interchangeably herein.

[0172] Severity is defined as follows: Mild: Two symptoms. Moderate: Three symptoms. Moderate to severe: Four or five symptoms. Severe: Four or five symptoms, accompanied by motor agitation.

[0173] The distress of anxiety has been noted as a prominent feature of both bipolar disorder and major depressive disorder in both primary medical and mental health specialty settings. High levels of anxiety have been associated with a higher risk of suicide, longer illness duration, and a higher likelihood of non - response to treatment.

[0174] Accordingly, one aspect of the present disclosure is a method for treating major depressive disorder (MDD) with escalating anxiety in a subject in need of treating major depressive disorder (MDD) with escalating anxiety, the method comprising administering a therapeutically effective amount of compound (1):

Chemical formula

[0175] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with escalating anxiety in a subject in need of treating major depressive disorder (MDD) with escalating anxiety, the method comprising administering a therapeutically effective amount of compound (1):

Chemical formula

[0176] In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered once daily for about 14 days, i.e., about 2 weeks. In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered once daily for about 14 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered once daily for about 2 weeks.

[0177] In some embodiments, compound (1) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 40 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg.

[0178] In some embodiments, compound (1) is administered once daily at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once daily at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg.

[0179] In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 55 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg to about 50 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 45 mg to about 55 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for about 14 days.

[0180] In other embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 10 mg to about 100 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 15 mg to about 75 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 20 mg to about 60 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 20 mg to about 55 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 30 mg to about 50 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound from about 45 mg to about 55 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound of about 50 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound of about 40 mg. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dosage equivalent of the free base compound of about 30 mg.

[0181] In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily at a dosage equivalent of about 30 mg of the free base compound.

[0182] In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 30 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 30 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 30 mg of the free base compound.

[0183] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

[0184] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered for a long term.

[0185] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered in one or more capsules. In some embodiments, a therapeutically effective amount is administered over two capsules. In some embodiments, a therapeutically effective amount is administered over three capsules.

[0186] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal. Examples of fat-containing meals include nuts, peanut butter, avocado, eggs and cheese. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal at night (e.g., within one hour of a fat-containing dinner or with a fat-containing snack).

[0187] In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof at night. In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof within 15 minutes before the patient goes to sleep. In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof once a day at night. In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof once a day within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered compound (1) or a pharmaceutically acceptable salt thereof once a day within 15 minutes before the patient goes to sleep.

[0188] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any of the crystalline forms disclosed in PCT Application Publication No. WO2018 / 039378, the entire contents of the foregoing application being incorporated herein by reference.

[0189] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.7 and 10.1 degrees (including the endpoints), at 2θ between 11.6 and 12.0 degrees (including the endpoints), at 2θ between 13.2 and 13.6 degrees (including the endpoints), at 2θ between 14.2 and 14.6 degrees (including the endpoints), at 2θ between 14.6 and 15.0 degrees (including the endpoints), at 2θ between 16.8 and 17.2 degrees (including the endpoints), at 2θ between 20.5 and 20.9 degrees (including the endpoints), at 2θ between 21.3 and 21.7 degrees (including the endpoints), at 2θ between 21.4 and 21.8 degrees (including the endpoints), and at 2θ between 22.4 and 22.8 degrees (including the endpoints). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.7 and 10.1 degrees (including the endpoints), at 2θ between 14.6 and 15.0 degrees (including the endpoints), at 2θ between 16.8 and 17.2 degrees (including the endpoints), at 2θ between 20.5 and 20.9 degrees (including the endpoints), and at 2θ between 21.3 and 21.7 degrees (including the endpoints).

[0190] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (including the endpoints), at 2θ between 10.6 and 11.0 degrees (including the endpoints), at 2θ between 13.0 and 13.4 degrees (including the endpoints), at 2θ between 14.7 and 15.1 degrees (including the endpoints), at 2θ between 15.8 and 16.2 degrees (including the endpoints), at 2θ between 18.1 and 18.5 degrees (including the endpoints), at 2θ between 18.7 and 19.1 degrees (including the endpoints), at 2θ between 20.9 and 21.3 degrees (including the endpoints), at 2θ between 21.4 and 21.8 degrees (including the endpoints), and at 2θ between 23.3 and 23.7 degrees (including the endpoints). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (including the endpoints), at 2θ between 10.6 and 11.0 degrees (including the endpoints), at 2θ between 13.0 and 13.4 degrees (including the endpoints), at 2θ between 18.7 and 19.1 degrees (including the endpoints), and at 2θ between 21.4 and 21.8 degrees (including the endpoints).

[0191] In some embodiments, the crystalline form of compound (1) comprises a mixture of two or more crystalline forms.

[0192] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is re-administered to the subject in response to a recurrence of depressive symptoms after completion of an initial treatment. In some embodiments, an interval of at least 6 weeks is provided between the last dose of the initial treatment and the first dose of the re-administration. In some embodiments, each of the initial treatment and the re-administration is conducted for about 14 days, i.e., about 2 weeks.

[0193] In some embodiments, the method comprises administering a second therapeutic agent.

[0194] In some embodiments, the subject has not been treated. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0195] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0196] In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher, 18 or higher, 19 or higher, or 20 or higher. In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher, or a score on the Hamilton Rating Scale for Depression (HAM-D) anxiety / physicalization subscale of 7 or higher, prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher. In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 18 or higher. In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 19 or higher. In some embodiments, MDD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 20 or higher. In some embodiments, MDD with increased anxiety is characterized by a score on the Hamilton Rating Scale for Depression (HAM-D) anxiety / physicalization subscale of 7 or higher.

[0197] In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 18 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 19 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 20 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-A total score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) before administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, MDD with increased anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-D anxiety / somatization subscale score of 7 or higher before administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0199] In other embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety and somatic items. In some embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D items: psychic anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D item: psychic anxiety. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items evaluating the anxiety symptoms of depression.

[0200] In some embodiments, the subject shows a decrease from baseline in the HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject shows a decrease of at least 14 points in the HAM-D total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject shows a decrease of at least 12 points in the HAM-A total score on day 15 after administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0201] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale (HAM-D) total score) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a decrease from the baseline HAM-D total score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after initiation of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)). In some embodiments, the decrease from the baseline HAM-D total score is from severe (e.g., HAM-D total score of 24 or higher, or score of 26 or higher) to asymptomatic, i.e., remission of depression (e.g., HAM-D total score of 7 or less). In some embodiments, the decrease from the baseline HAM-D total score is from severe (e.g., HAM-D total score of 24 or higher, or total score of 26 or higher) to normal or mild depression (e.g., HAM-D total score of 7 or less, or HAM-D total score of 18 - 13).

[0202] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale subscale score (HAM-D subscale)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the HAM-D subscale score is the core depression, Bech-6, Myers score, and / or anxiety score. In some embodiments, the decrease from the baseline in the HAM-D core depression subscale score LS mean on day 15 is at least about 1 - 3. In some embodiments, the decrease from the baseline in the HAM-D Bech-6 subscale score LS mean on day 15 is at least about 3. In some embodiments, the decrease from the baseline in the HAM-D Myers subscale score LS mean on day 15 is at least about 2.5. In some embodiments, the decrease from the baseline in the HAM-D anxiety subscale score LS mean on day 15 is at least about 0.5.

[0203] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Montgomery-Asberg Depression Rating Scale (MADRS)) within about 45, about 21, about 15, about 8, or about 3 days or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (regarding sadness expressed outwardly, sadness expressed verbally, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lack of energy, inability to feel emotions, pessimistic thoughts, and suicidal thoughts), and is used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. 0 - 6 indicates normal / absence of symptoms, 7 - 19 indicates mild depression, 20 - 34 indicates moderate depression, and >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease from the baseline MADRS score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days, or less). In some embodiments, the decrease from the baseline MADRS score is from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or lower). For example, the average change from the baseline in the total MADRS score due to treatment with compound (1) or a pharmaceutically acceptable salt of compound (1) is about -15, -20, -25, -30, while the average change from the baseline in the total MADRS score due to treatment with placebo is about -15, -10, -5.

[0204] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression - Improvement Scale (CGI)) within about 45, about 21, about 15, about 8, or about 3 days, or less. In some embodiments, the therapeutic effect is a CGI score of 2 or lower.

[0205] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Anxiety Score (HAM-A)) within about 45, about 21, about 15, about 8, or about 3 days. The HAM-A is scored, where <17 indicates mild severity, 18 - 24 indicates mild to moderate severity, and 25 - 30 indicates moderate to severe. In some embodiments, the therapeutic effect is a decrease from the baseline HAM-A score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)). In some embodiments, the decrease from the baseline HAM-A score is from severe (e.g., HAM-A score of 25 or higher) to asymptomatic (e.g., HAM-A score of 17 or lower). In some embodiments, the decrease from the baseline HAM-A score is from severe (e.g., HAM-A score of 25 or higher) to mild (e.g., HAM-A score of 24 or lower).

[0206] In some embodiments, the method provides a therapeutic effect (e.g., as measured by an improvement in the SF-36 score) within about 45, about 21, about 15, about 8, or about 3 days. The SF-36 Physical Function Score. The SF-36 is a short-form health survey that consists of 36 questions and is used to assess health-related quality of life (Ware, 1996). In some embodiments, the Short Form-36 (SF-36v2) assesses health-related quality of life (HRQoL) regarding eight domains (Physical Function [PF]; Role Physical [RP]; Bodily Pain [BP]; General Health [GH]; Vitality [V]; Social Function [SF]; Role Emotional [RE]; Mental Health [MH]). In some embodiments, the therapeutic effect is a decrease from the baseline of each domain of the SG-36v2 at the end of the treatment period. In some embodiments, (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)).

[0207] PPD with increased anxiety

[0208] In another aspect, the present disclosure is directed to a method for postpartum depression (PPD) with an increase in anxiety.

[0209] Postpartum depression (PPD), also known as postnatal depression, is a type of mood disorder associated with childbirth. Postpartum depression (PPD) is generally known in the art.

[0210] PPD has been identified as the most common psychopathological disorder occurring during the puerperium (O’Hara MW, Wisner KL. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):3-12); PPD can occur during the third trimester of pregnancy or after childbirth. PPD, if untreated, can have devastating consequences for the woman and her family. In some embodiments, PPD is characterized by significant functional impairment of the mother, resulting from feelings of sadness and depression, loss of interest in daily activities, changes in eating and sleeping habits, fatigue, as well as decreased motivation, inability to concentrate, and feelings of worthlessness, shame or guilt. Postpartum depression also has an increased risk of suicide, which is the leading cause of death of mothers after childbirth in developed countries.

[0211] Specialty health organizations have different definitions of the occurrence of PPD. For example, the American Psychiatric Association characterizes PPD as having an onset during pregnancy or within four weeks after childbirth (DSM-5). The American College of Obstetricians and Gynecologists characterizes PPD as having an onset during pregnancy or within 12 months after childbirth (ACOG, updated December 2021). The World Health Organization characterizes PPD as having an onset within 12 months after childbirth (International Classification of Diseases 10 thedition (ICD - 10)). Thus, in some embodiments, the diagnosis of PPD treated by the methods described herein can be characterized as defined by the DSM - 5. In some embodiments, the diagnosis of PPD treated by the methods described herein can be characterized as defined by the ACOG. In some embodiments, the diagnosis of PPD treated by the methods described herein can be characterized as defined by the ICD - 10.

[0212] In some embodiments, the diagnosis of PPD with increased anxiety treated by the methods described herein is th characterized as a MDD with peripartum onset and indicators of anxiety distress, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5

[0213] Depressive disorder

[0214] Depressive disorders include major mood disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication - induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. The common feature of all these disorders is the presence of sadness, emptiness, or irritable mood, along with physical and cognitive changes that significantly affect the individual's ability to function. What differs among them are matters of duration, timing, or presumed etiology.

[0215] Major depressive disorder presents the classical condition among this group of disorders. It is characterized by distinct episodes of at least two weeks' duration (although most episodes last considerably longer), with clear changes in affect, cognition, and autonomic nervous system function, as well as remission between episodes. Individual episodes of major depressive disorder may be referred to as "major depressive episodes" or "depressive episodes".

[0216] Major depressive disorder (MDD)

[0217] In some embodiments, MDD is also known as depression or clinical depression, and is a mood disorder that causes persistent feelings of sadness and loss of interest.

[0218] In some embodiments, MDD is defined and diagnosed according to the DSM-5. For example, MDD is diagnosed according to Diagnostic Criterion A as follows.

[0219] Diagnostic Criterion A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, mood may be irritable.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gains.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Almost every day, experience feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) (not merely self-reproach or guilt about being ill). 8. Almost every day, have diminished ability to think or concentrate, or are indecisive (either subjectively reported or as observed by others). 9. Think about death repeatedly (not just fear of death), have recurrent suicidal thoughts without a specific plan, or have a suicide attempt or a specific plan to commit suicide.

[0220] The following Diagnostic Criteria B - E are additional descriptions of MDD and may be considered descriptions or diagnoses of MDD but are not necessary.

[0221] Diagnostic Criterion B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0222] Diagnostic Criterion C. The episode cannot be attributable to the physiological effects of a substance or another medical condition.

[0223] Diagnostic Criteria A - C may represent a major depressive episode.

[0224] Diagnostic Criterion D. The occurrence of a major depressive episode is not better explained by schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum disorders, and other psychotic disorders.

[0225] Diagnostic Criterion E. There has never been a manic episode or a hypomanic episode.

[0226] In some embodiments, a major depressive episode (MDE) is a period characterized by the above symptoms.

[0227] In some embodiments, MDD is a clinical course characterized by one or more major depressive episodes (MDEs) in a subject.

[0228] In some embodiments, MDD is diagnosed in accordance with Diagnostic Criteria A - C as described above. In some embodiments, MDD is diagnosed in accordance with Diagnostic Criteria A - E as described above.

[0229] Diagnostic Features

[0230] For the criteria symptoms of major depressive disorder, excluding weight change and suicidal thoughts, to be considered present, they must be present almost every day. In addition to being present almost every day, the depressed mood must be present for most of the day. In many cases, insomnia or fatigue is the main complaint, and underdiagnosis may occur if the accompanying depressive symptoms are missed. Sadness may initially be denied but may be elicited by interview or inferred from facial expression and attitude. In the case of an individual who is focusing on physical complaints, the clinician should determine whether the distress caused by those complaints is related to specific depressive symptoms. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disturbances are less common but, like delusional or near - delusional guilt feelings, are indicators of a higher overall severity.

[0231] The essential feature of a major depressive episode is a period of at least 2 weeks in which there is either depressed mood or the loss of interest or pleasure in almost all activities (Criterion A above). In children and adolescents, the mood may be irritable rather than sad. The individual must also experience at least 4 additional symptoms drawn from the list including changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation or plans or attempts. For an episode to be counted as a major depressive episode, the symptoms must either be new or have clearly worsened compared to the person's pre-episode state. The symptoms must be present almost every day for the majority of the day for at least 2 consecutive weeks. The episode must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. In some individuals with mild episodes, functioning may appear normal but require significant effort to maintain.

[0232] Sleep disturbances may take the form of either difficulty falling asleep or excessive sleep (Criterion A4). When insomnia is present, it typically takes the form of middle insomnia (i.e., difficulty returning to sleep after waking up during the night) or terminal insomnia (i.e., waking up too early and being unable to return to sleep). Initial insomnia (i.e., difficulty falling asleep) may also occur. Individuals who present with hypersomnia (excessive sleep) may experience long sleep episodes at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is due to the sleep disorder.

[0233] In the case of peripartum onset (an indicator of depressive disorder in DSM-5)

[0234] This specifier can be applied to the current complete diagnostic criteria, or if they are not met for the current major depressive episode, and mood symptoms occur during pregnancy or within 4 weeks after childbirth, it can be applied to the most recent major depressive episode.

[0235] Mood episodes may occur either during pregnancy or postpartum. Depending on the period of postpartum follow-up, the estimated values vary, but 3% - 6% of women experience a major depressive episode during pregnancy or within weeks or months after childbirth. Fifty percent of "postpartum" major depressive episodes actually begin before delivery. Therefore, these episodes are collectively referred to as perinatal episodes. Women with perinatal major depressive episodes often also have severe anxiety and even panic attacks. Prospective studies have demonstrated that mood and anxiety symptoms during pregnancy, as well as "baby blues", increase the risk of postpartum major depressive episodes. Mood episodes occurring during the perinatal period can present with or without psychotic features. Infanticide is most often associated with postpartum psychotic episodes characterized by command hallucinations to kill the infant or delusions that the infant is possessed, but psychotic symptoms can also occur in severe postpartum mood episodes without such specific delusions or hallucinations.

[0236] In the case of increased anxiety / anxiety distress (a specifier for depressive disorders according to DSM-5)

[0237] DSM-5 defines the "anxiety distress" specifier as the presence of at least two of the following symptoms on most days during a major depressive episode (MDD) or persistent depressive disorder (dysthymia): 1. Feeling keyed up or tense. 2. Feeling unusually restless. 3. Being unable to concentrate because of worry. 4. Fearing that something awful may happen. 5. Feeling as if one might lose control of oneself.

[0238] Severity is defined as follows: Mild: two symptoms. Moderate: three symptoms. Moderate to severe: four or five symptoms. Severe: four or five symptoms, accompanied by motor agitation.

[0239] The distress of anxiety has been noted as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and mental health specialty settings. High levels of anxiety have been associated with a higher risk of suicide, longer illness duration, and a higher likelihood of non-responsiveness to treatment.

[0240] Accordingly, one aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need thereof, the method comprising administering a therapeutically effective amount of compound (1): [Chemical formula] The method includes the step of administration.

[0241] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of compound (1): [Chemical formula] The method includes the step of administration.

[0242] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days, i.e., about 2 weeks. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered once daily for about 2 weeks.

[0243] In some embodiments, compound (1) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 40 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg.

[0244] In some embodiments, compound (1) is administered once daily at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once daily at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg.

[0245] In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 55 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg to about 50 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 45 mg to about 55 mg for about two weeks, i.e., about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for less than two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for about two weeks. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg for about 14 days.

[0246] In other embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of from about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salts of compound (1) are administered in a dosage equivalent of about 30 mg of the free base compound.

[0247] In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once a day at a dose equivalent of about 30 mg of the free base compound.

[0248] In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks, i.e., about 14 days, at a dosage equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 40 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for less than two weeks at a dosage equivalent of about 30 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about two weeks at a dosage equivalent of about 30 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days at a dosage equivalent of about 30 mg of the free base compound.

[0249] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

[0250] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered for a long term.

[0251] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered in one or more capsules. In some embodiments, the therapeutically effective amount is administered over two capsules. In some embodiments, the therapeutically effective amount is administered over three capsules.

[0252] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal. Examples of fat-containing meals include nuts, peanut butter, avocado, eggs and cheese. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal at night (e.g., within one hour of a fat-containing dinner or with a fat-containing snack).

[0253] In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof at night. In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof within 15 minutes before the patient goes to sleep. In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof once a day at night. In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof once a day within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered the compound (1) or a pharmaceutically acceptable salt thereof once a day within 15 minutes before the patient goes to sleep.

[0254] In some embodiments, the compound (1) is in a crystalline form. In some embodiments, the crystalline form of the compound (1) is any of the crystalline forms disclosed in PCT Application Publication No. WO2018 / 039378, and the entire contents of the aforementioned application are hereby incorporated by reference.

[0255] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.7 and 10.1 degrees (including the endpoints), at 2θ between 11.6 and 12.0 degrees (including the endpoints), at 2θ between 13.2 and 13.6 degrees (including the endpoints), at 2θ between 14.2 and 14.6 degrees (including the endpoints), at 2θ between 14.6 and 15.0 degrees (including the endpoints), at 2θ between 16.8 and 17.2 degrees (including the endpoints), at 2θ between 20.5 and 20.9 degrees (including the endpoints), at 2θ between 21.3 and 21.7 degrees (including the endpoints), at 2θ between 21.4 and 21.8 degrees (including the endpoints), and at 2θ between 22.4 and 22.8 degrees (including the endpoints). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.7 and 10.1 degrees (including the endpoints), at 2θ between 14.6 and 15.0 degrees (including the endpoints), at 2θ between 16.8 and 17.2 degrees (including the endpoints), at 2θ between 20.5 and 20.9 degrees (including the endpoints), and at 2θ between 21.3 and 21.7 degrees (including the endpoints).

[0256] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (including the endpoints), at 2θ between 10.6 and 11.0 degrees (including the endpoints), at 2θ between 13.0 and 13.4 degrees (including the endpoints), at 2θ between 14.7 and 15.1 degrees (including the endpoints), at 2θ between 15.8 and 16.2 degrees (including the endpoints), at 2θ between 18.1 and 18.5 degrees (including the endpoints), at 2θ between 18.7 and 19.1 degrees (including the endpoints), at 2θ between 20.9 and 21.3 degrees (including the endpoints), at 2θ between 21.4 and 21.8 degrees (including the endpoints), and at 2θ between 23.3 and 23.7 degrees (including the endpoints). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern comprising peaks at 2θ between 9.3 and 9.7 degrees (including the endpoints), at 2θ between 10.6 and 11.0 degrees (including the endpoints), at 2θ between 13.0 and 13.4 degrees (including the endpoints), at 2θ between 18.7 and 19.1 degrees (including the endpoints), and at 2θ between 21.4 and 21.8 degrees (including the endpoints).

[0257] In some embodiments, the crystalline form of compound (1) comprises a mixture of two or more crystalline forms.

[0258] In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is re-administered to a subject in response to a recurrence of depressive symptoms after completion of an initial treatment. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration. In some embodiments, each of the initial treatment and the re-administration is conducted for about 14 days, i.e., about 2 weeks.

[0259] In some embodiments, the method administers a second therapeutic agent.

[0260] In some embodiments, the subject has not been treated. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0261] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0262] In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher, 18 or higher, 19 or higher, or 20 or higher before administration of compound (1) or a pharmaceutically acceptable salt of compound (1), or a score on the Hamilton Rating Scale for Depression (HAM-D) anxiety / physicalization subscale of 7 or higher. In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 17 or higher. In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 18 or higher. In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 19 or higher. In some embodiments, PPD with increased anxiety is characterized by a total score on the Hamilton Rating Scale for Anxiety (HAM-A) of 20 or higher. In some embodiments, PPD with increased anxiety is characterized by a score on the Hamilton Rating Scale for Depression (HAM-D) anxiety / physicalization subscale of 7 or higher.

[0263] In some embodiments, PPD with increased anxiety is characterized by a total HAM-D score of 24 or higher and a total HAM-A score of 17 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, PPD with increased anxiety is characterized by a total HAM-D score of 24 or higher and a total HAM-A score of 18 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, PPD with increased anxiety is characterized by a total HAM-D score of 24 or higher and a total HAM-A score of 19 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, PPD with increased anxiety is characterized by a total HAM-D score of 24 or higher and a total HAM-A score of 20 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, PPD with increased anxiety is characterized by a total HAM-D score of 24 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, PPD with increased anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 17 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 18 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 19 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 20 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, PPD with increased anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0265] In other embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and physical items. In some embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D items: psychic anxiety, somatic anxiety, GI somatic symptoms and / or general somatic symptoms. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D item: psychic anxiety. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items for evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items for evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items for evaluating the anxiety symptoms of depression.

[0266] In some embodiments, the subject shows a decrease from baseline in the HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject shows a decrease of at least 14 points in the HAM-D total score on day 15 after administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, the subject shows a decrease of at least 12 points in the HAM-A total score on day 15 after administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0267] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale score (HAMD-17)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a decrease from the baseline HAMD-17 score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)). In some embodiments, the decrease from the baseline HAMD-17 score is from severe (e.g., HAMD-17 score of 24 or higher, or score of 26 or higher) to asymptomatic, i.e., remission of depression (e.g., HAMD-17 score of 7 or less). In some embodiments, the decrease from the baseline HAMD-17 score is from severe (e.g., HAMD-17 score of 24 or higher, or score of 26 or higher) to normal or mild depression (e.g., HAMD-17 score of 7 or less, or HAMD-17 score of 18 - 13).

[0268] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Anxiety Rating Scale score (HAM-A)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a decrease from the baseline HAM-A score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)). In some embodiments, the decrease from the baseline HAM-A score is from severe (e.g., HAM-A score of 25 or higher) to asymptomatic, i.e., remission of anxiety (e.g., HAM-A score of 7 or less). In some embodiments, the decrease from the baseline HAM-A score is from severe (e.g., HAM-A score of 25 or higher) to normal or mild anxiety (e.g., HAM-A score of 18 - 24).

[0269] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS)) within about 45, about 21, about 15, about 8, or about 3 days, or fewer days. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (regarding sadness expressed outwardly, sadness expressed verbally, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lack of energy, inability to feel emotions, pessimistic thoughts, and suicidal thoughts), and is used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. 0 - 6 indicates normal / absence of symptoms, 7 - 19 indicates mild depression, 20 - 34 indicates moderate depression, and >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease from the baseline MADRS score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days, or fewer days). In some embodiments, the decrease from the baseline MADRS score is from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or lower). For example, the average change from the baseline of the total MADRS score due to treatment with compound (1) or a pharmaceutically acceptable salt of compound (1) is about -15, -20, -25, -30, while the average change from the baseline of the total MADRS score due to treatment with placebo is about -15, -10, -5.

[0270] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression - Improvement Scale (CGI)) within about 45, about 21, about 15, about 8, or about 3 days, or fewer days. In some embodiments, the therapeutic effect is a CGI score of 2 or lower.

[0271] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Anxiety / Somatization Score (HAMD - 17A) / S) within about 45, about 21, about 15, about 8, or about 3 days.

[0272] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Edinburgh Postnatal Depression Scale (EPDS)) within about 45, about 21, about 15, or about 8 days. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0273] In some embodiments, the method improves the overall health status of the subject (e.g., as measured by increasing the Medical Outcomes Study 36-Item Short Form Survey Instrument version 2 (SF-36v2)) within about 45, about 21, about 15, or about 3 days. In some embodiments, the method improves the overall health status of the subject as measured by at least 5 domains of the SF-36v2 examination. In some embodiments, the 5 domains are social functioning, mental health, physical function, role physical, and bodily pain. In some embodiments, the method improves the mental health component summary score as measured by the SF-36v2.

[0274] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale for Insomnia (HAMD-17-Ins)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a decrease from baseline of the HAMD-17-Ins score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (1)). In some embodiments, the decrease from baseline of the HAMD-!7-Ins score is 1 to 4 points, e.g., a decrease of about 1 point from baseline, a decrease of about 2 points from baseline, a decrease of about 3 points from baseline, or a decrease of about 4 points from baseline.

[0275] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering from about 30 mg to about 50 mg of compound (1):

Chemical formula

[0276] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering a dose of compound (1) equivalent to from about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0277] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering from about 30 mg to about 50 mg of compound (1):

Chemical formula

[0278] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering a dose of compound (1) equivalent to from about 30 mg to about 50 mg of the free base compound:

Chemical formula

[0279] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg: [Chemical formula] The method includes the step of administering.

[0280] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a dosage of compound (1) equivalent to that of the free base compound in an amount of about 30 mg to about 50 mg: [Chemical formula] The method includes the step of administering a pharmaceutically acceptable salt of.

[0281] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg: [Chemical formula] The method includes the step of administering.

[0282] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a dosage of compound (1) equivalent to that of the free base compound in an amount of about 30 mg to about 50 mg: [Chemical formula] The method includes the step of administering a pharmaceutically acceptable salt of.

[0283] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) of about 30 mg to about 50 mg:

Chemical formula

[0284] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, comprising administering, once daily for about 14 days, i.e., about 2 weeks, a dose of compound (1) equivalent to a free base compound of about 30 mg to about 50 mg:

Chemical formula

[0285] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) of about 30 mg to about 50 mg:

Chemical formula

[0286] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in a dosage equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] including the step of administering a pharmaceutically acceptable salt thereof, wherein the subject has not been treated before.

[0287] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg: [Chemical formula] including the step of administering, wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of compound (1).

[0288] Another aspect of the present disclosure is a method for treating major depressive disorder (MDD) with increased anxiety in a subject in need of treating major depressive disorder (MDD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in a dosage equivalent to about 30 mg to about 50 mg of the free base compound: [Chemical formula] including the step of administering a pharmaceutically acceptable salt thereof, wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharmaceutically acceptable salt of compound (1).

[0289] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg:

Chemical formula

[0290] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a dose of a compound (1) equivalent to the free base compound in an amount of about 30 mg to about 50 mg:

Chemical formula

[0291] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once daily for about 14 days, i.e., about 2 weeks, a compound (1) in an amount of about 30 mg to about 50 mg:

Chemical formula

[0292] Another aspect of the present disclosure is a method for treating postpartum depression (PPD) with increased anxiety in a subject in need of treating postpartum depression (PPD) with increased anxiety, the method comprising administering, once a day for about 14 days or about 2 weeks, a compound in an amount equivalent to about 30 mg to about 50 mg of the free base compound (1):

Chemical formula

[0293] In some embodiments, compound (1) is administered at a dose of about 50 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 50 mg of the free base compound.

[0294] In some embodiments, compound (1) is administered at a dose of about 40 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 40 mg of the free base compound.

[0295] In some embodiments, compound (1) is administered at a dose of about 30 mg, or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent to about 30 mg of the free base compound.

[0296] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally or transdermally. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered orally.

[0297] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal. Examples of fat-containing meals include nuts, peanut butter, avocado, eggs, and cheese. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered with a fat-containing meal at night (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0298] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered to the subject at night. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered to the subject within 1 hour before the patient goes to sleep. In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is administered to the subject within 15 minutes before the patient goes to sleep.

[0299] In some embodiments, the subject has not been treated. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days before the start of an initial treatment course. In some embodiments, the subject has not received any antidepressant treatment within at least 60 days before the start of an initial treatment course.

[0300] In some embodiments, the subject has taken a stable dose of an additional antidepressant for at least 30 days or at least 60 days before administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has taken a stable dose of an additional antidepressant for at least 30 days before administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject has taken a stable dose of an additional antidepressant for at least 60 days before administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0301] In some embodiments, the method further comprises administering a second therapeutic agent.

[0302] In some embodiments, compound (1) or the pharmaceutically acceptable salt of compound (1) is re-administered to the subject in response to a recurrence of depressive symptoms after completion of an initial treatment period. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment period and the first dose of the re-administration. In some embodiments, the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0303] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total score of the Hamilton Anxiety Rating Scale (HAM-A) for anxiety of 17 or higher, 18 or higher, 19 or higher, or 20 or higher, or a score of the anxiety / physicalization subscale of the Hamilton Depression Rating Scale (HAM-D) for depression of 7 or higher, prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total score of the Hamilton Anxiety Rating Scale (HAM-A) for anxiety of 17 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total score of the Hamilton Anxiety Rating Scale (HAM-A) for anxiety of 18 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total score of the Hamilton Anxiety Rating Scale (HAM-A) for anxiety of 19 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total score of the Hamilton Anxiety Rating Scale (HAM-A) for anxiety of 20 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a score of the anxiety / physicalization subscale of the Hamilton Depression Rating Scale (HAM-D) for depression of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0304] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 18 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 19 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 20 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0305] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-D anxiety / physicalization subscale score of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0306] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total HAM-D score of 26 or higher and a total HAM-A score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total HAM-D score of 26 or higher and a HAM-D anxiety / physicalization subscale score of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0307] In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total HAM-D score of 20 or higher, a total MADRS score of 28 or higher, and a total HAM-A score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1). In some embodiments, MDD with increased anxiety or PPD with increased anxiety is characterized by a total HAM-D score of 20 or higher, a total MADRS score of 28 or higher, and a HAM-D anxiety / physicalization subscale score of 7 or higher prior to administration of compound (1) or a pharmaceutically acceptable salt of compound (1).

[0308] In other embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety and physical items. In some embodiments, "increased anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D items: psychic anxiety, somatic anxiety, GI somatic symptoms, and general somatic symptoms. In some embodiments, "increased anxiety" is characterized by a HAM-D score based on the following HAM-D item: psychic anxiety. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D score mainly based on the items for evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a HAM-D anxiety / somatization subscale score mainly based on the items for evaluating the anxiety symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items for evaluating the somatic symptoms of depression. In some embodiments, "increased anxiety" is characterized by a MADRS score mainly based on the items for evaluating the anxiety symptoms of depression.

[0309] In some embodiments, the subject shows a decrease from baseline in the HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof.

[0310] In some embodiments, the subject shows a decrease of at least 14 points in the HAM-D total score on the 15th day after administration of compound (1) or the pharmaceutically acceptable salt of compound (1). In some embodiments, the subject shows a decrease of at least 12 points in the HAM-A total score on the 15th day after administration of compound (1) or the pharmaceutically acceptable salt of compound (1).

[0311] III. Pharmaceutical Composition

[0312] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound (1) (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient for use in the methods described herein. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the active ingredient and a pharmaceutically acceptable excipient for use in the methods described herein. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient. In some embodiments, the pharmaceutical composition of compound (1) is any of the pharmaceutical compositions disclosed in PCT Application Publication No. WO2022 / 020363A9, and the entire contents of the above application are incorporated herein by reference in their entirety.

[0313] The pharmaceutical compositions provided herein can be administered by various routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the pharmaceutical composition is administered orally.

[0314] The pharmaceutical compositions of the present disclosure may be further delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the desired active ingredient throughout the body. For example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus agent delivered directly into a vein (e.g., by IV infusion) enables a much faster delivery that rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered, for example, as a continuous infusion by IV infusion to achieve maintenance of a steady-state concentration of the active ingredient in the subject's body. Further, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose and then as a continuous infusion.

[0315] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the compositions are supplied in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the remainder is various vehicles or excipients and processing aids that contribute to forming the desired dosage form.

[0316] The above components of the orally administrable, injectable or topically administrable compositions are merely representative examples. Other materials, processing techniques, etc. are described in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0317] The compositions of the present disclosure can also be administered in a sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0318] The description of the pharmaceutical compositions provided herein is mainly directed to pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals. To render the compositions suitable for administration to various animals, it is well understood that the compositions suitable for administration to humans can be modified, and a skilled veterinary pharmacologist can design and / or carry out such modifications using routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0319] Another aspect of the present disclosure is a method for treating a major depressive disorder in a subject in need thereof, the method comprising administering to the subject about 40 mg of compound (1) once a day for 14 days. In one aspect, the present disclosure is a method for treating a major depressive disorder in a subject in need thereof, the method comprising administering to the subject about 50 mg of compound (1) once a day for 14 days.

[0320] In embodiments of these aspects, the major depressive disorder is severe major depressive disorder. In some embodiments, the subject shows a reduction in depression-related symptoms. In some embodiments, the reduction in depression-related symptoms is characterized by a decrease in the HAM-D score from baseline. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 22 prior to treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 24 prior to treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 25 prior to treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 26 prior to treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 28 prior to treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 32 prior to treatment.

[0321] Another aspect of the present disclosure is a method for treating depression in a subject in need thereof, the method comprising: (i) administering to the subject, once daily for 14 days, about 40 mg of compound (1) once daily; and (ii) re-administering to the subject, once daily for 15 days, about 30 mg of compound (1) in response to a recurrence of depressive symptoms, provided that there is an interval of at least 6 weeks between the administration of compound (1) to the subject and the re-administration of compound (1) to the subject. In one aspect, the present disclosure is a method for treating depression in a subject in need thereof, the method comprising: (i) administering to the subject, once daily for 14 days, about 50 mg of compound (1) once daily; and (ii) re-administering to the subject, once daily for 15 days, about 50 mg of compound (1) in response to a recurrence of depressive symptoms, provided that there is an interval of at least 6 weeks between the administration of compound (1) to the subject and the re-administration of compound (1) to the subject.

[0322] In embodiments of these aspects, the depression is major depressive disorder or severe major depressive disorder. In some embodiments, the subject shows a reduction in depression-related symptoms. In some embodiments, the reduction in depression-related symptoms is characterized by a decrease in the HAM-D score from baseline. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 20 prior to treatment. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 22 prior to treatment. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 24 prior to treatment. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 25 prior to treatment. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 26 prior to treatment. In some embodiments, major depressive disorder is characterized by a MADRS score of at least 28 prior to treatment. In some embodiments, major depressive disorder is characterized by a MADRS score of at least 29 prior to treatment. In some embodiments, major depressive disorder is characterized by a MADRS score of at least 30 prior to treatment. In some embodiments, major depressive disorder is characterized by a MADRS score of at least 31 prior to treatment. In some embodiments, major depressive disorder is characterized by a MADRS score of at least 32 prior to treatment. In some embodiments, major depressive disorder is characterized by a HAM-D total score of at least 20 and a MADRS score of at least 28 prior to treatment.

[0323] In some embodiments, the HAM-D score is the HAM-D total score. In some embodiments, the HAM-D score is a HAM-D subscale score selected from the group consisting of the core depression, Bech-6, and Meyer HAM-D subscale scores.

[0324] In some embodiments, the method improves the state of general well-being in a subject. In some embodiments, the improvement in the state of general well-being is characterized by a decrease in at least one domain of the SF-36v2 score from a baseline. In some embodiments, the at least one domain is physical function (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (V), social function (SF), role emotional (RE), or mental health (MH).

[0325] Another aspect of the disclosure is a method for treating depression and anxiety simultaneously in a subject in need thereof, the method comprising administering to the subject a compound (1) of about 40 mg once a day for 14 days. In one aspect, the disclosure is a method for treating depression and anxiety simultaneously in a subject in need thereof, the method comprising administering to the subject a compound (1) of about 50 mg once a day for 14 days.

[0326] In embodiments of these aspects, the depression is a major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the subject shows a reduction in anxiety-related and depression-related symptoms. In some embodiments, the reduction in depression-related symptoms is characterized by a decrease in the HAM-D score from baseline. In some embodiments, the HAM-D score is the total HAM-D score. In some embodiments, the HAM-D score is a subscale score of HAM-D. In some embodiments, the HAM-D subscale score is the core depression, Bech-6 or Myers score. In some embodiments, the anxiety-related symptoms are characterized by a decrease in the HAM-A score from baseline. In some embodiments, the anxiety-related symptoms are characterized by a decrease in the HAM-D anxiety subscale score from baseline. In some embodiments, the subject has a HAM-D total score of at least 20 before treatment. In some embodiments, the subject has a HAM-D total score of at least 21 before treatment. In some embodiments, the subject has a HAM-D total score of at least 22 before treatment. In some embodiments, the subject has a HAM-D total score of at least 24 before treatment. In some embodiments, the subject has a HAM-D total score of at least 25 before treatment. In some embodiments, the subject has a HAM-D total score of at least 26 before treatment. In some embodiments, the subject has a MADRS total score of at least 28 before treatment. In some embodiments, the subject has a MADRS total score of at least 32 before treatment. In some embodiments, the subject has a HAM-D total score of at least 20 and a MADRS total score of at least 28 before treatment.

[0327] In some embodiments, the subject has a decrease of at least 13 points from the baseline HAM-D score and a decrease of at least 10 points in the HAM-A score on the 15th day after the start of treatment. In some embodiments, the subject has a decrease of at least 14 points from the baseline HAM-D score and a decrease of at least 10 points in the HAM-A score on the 15th day after the start of treatment. In some embodiments, the subject has a decrease of at least 16 points from the baseline MADRS score and a decrease of at least 10 points in the HAM-A score on the 15th day after the start of treatment.

[0328] Another aspect of the disclosure is a method of simultaneously treating major depressive disorder and anxiety disorder in a subject in need thereof, the method comprising: (i) administering to the subject, once daily for 14 days, about 40 mg of compound (1); and (ii) re-administering to the subject, once daily for 15 days, about 30 mg of compound (1) in response to recurrence of depressive symptoms, provided that there is an interval of at least 6 weeks between the administration of compound (1) to the subject and the re-administration of compound (1) to the subject. In one aspect, the disclosure is a method of simultaneously treating major depressive disorder and anxiety disorder in a subject in need thereof, the method comprising: (i) administering to the subject, once daily for 14 days, about 50 mg of compound (1); and (ii) re-administering to the subject, once daily for 15 days, about 50 mg of compound (1) in response to recurrence of depressive symptoms, provided that there is an interval of at least 6 weeks between the administration of compound (1) to the subject and the re-administration of compound (1) to the subject.

[0329] In embodiments of these aspects, the depressive disorder is a major depressive disorder. In some embodiments, the subject shows a reduction in anxiety-related and depression-related symptoms. In some embodiments, the reduction in depression-related symptoms is characterized by a decrease in the HAM-D score from baseline. In some embodiments, the HAM-D score is the total HAM-D score. In some embodiments, the HAM-D score is a subscale score of HAM-D. In some embodiments, the HAM-D subscale score is the core depression, Bech-6 or Myers score.

[0330] In some embodiments, the anxiety-related symptoms are characterized by a decrease in the HAM-A score from baseline. In some embodiments, the anxiety-related symptoms are characterized by a decrease in the HAM-D anxiety subscale score from baseline.

[0331] In some embodiments, the subject has a HAM-D score of at least 20 before treatment. In some embodiments, the subject has a HAM-D score of at least 21 before treatment. In some embodiments, the subject has a HAM-D score of at least 22 before treatment. In some embodiments, the subject has a HAM-D score of at least 24 before treatment. In some embodiments, the subject has a HAM-D score of at least 25 before treatment. In some embodiments, the subject has a HAM-D score of at least 26 before treatment. In some embodiments, the subject has a MADRS score of at least 28 before treatment. In some embodiments, the subject has a MADRS score of at least 32 before treatment. In some embodiments, the subject has a HAM-D score of at least 20 and a MADRS score of at least 28 before treatment.

[0332] In some embodiments, the subject has, on the 15th day after the start of treatment, a decrease from the baseline of at least 13 points in the HAM-D score and a decrease of at least 10 points in the HAM-A score. In some embodiments, the subject has, on the 15th day after the start of treatment, a decrease from the baseline of at least 14 points in the HAM-D score and a decrease of at least 10 points in the HAM-A score. In some embodiments, the subject has, on the 15th day after the start of treatment, a decrease from the baseline of at least 16 points in the MADRS score and a decrease of at least 10 points in the HAM-A score.

[0333] Another aspect of the present disclosure is a method of simultaneously treating depression and anxiety in a subject in need of simultaneous treatment of depression and anxiety, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof using a short-term dosing regimen for simultaneously treating depression and anxiety in the subject.

[0334] In embodiments of this aspect, the short-term dosing regimen has a duration of about 2 to about 8 weeks. In some embodiments, the short-term dosing regimen has a duration of about 2 to about 6 weeks. In some embodiments, the short-term dosing regimen has a duration of about 2 to about 4 weeks. In some embodiments, the short-term dosing regimen has a duration of about 2 weeks or 14 days. In some embodiments, the short-term dosing regimen has a duration of 14 days.

[0335] In some embodiments, the subject shows a response to the short-term dosing regimen, the response being indicated by a decrease of more than or equal to about 50% from the baseline of the subject's HAMD-17 total score and HAM-A total score. In some embodiments, the subject is evaluated for recurrence or reappearance of depressive symptoms. In some embodiments, the method comprises a plurality of short-term dosing regimens. In some embodiments, the short-term dosing regimens are spaced at least 6 weeks apart.

[0336] Another aspect of the present disclosure is a method for treating depression and anxiety simultaneously in a subject in need of such treatment, the method comprising: (i) administering to the subject a therapeutically effective amount of compound (1) once daily for about two weeks; and (ii) readministering to the subject a therapeutically effective amount of compound (1) once daily for about two weeks in response to a recurrence of depressive symptoms, provided that there is an interval of at least six weeks between the administration of compound (1) to the subject and the readministration of compound (1) to the subject.

[0337] In embodiments of this aspect, compound (1) is readministered to the subject for about four weeks. In some embodiments, compound (1) is readministered to the subject for about two weeks. In some embodiments, the interval between the administration of compound (1) to the subject and the readministration of compound (1) to the subject is about 45 days. In some embodiments, the interval between the administration of compound (1) to the subject and the readministration of compound (1) to the subject is about eight weeks.

[0338] In some embodiments, the subject is female and the depression is postpartum depression (PPD). In some embodiments, the subject is female and is postpartum, about six months or less. In some embodiments, PPD is defined as a major depressive episode occurring at a time point from the third trimester of pregnancy to four weeks postpartum in the subject.

[0339] In some embodiments, the subject had a score of 24 or higher on the HAMD-17 test before administration of compound (1). In some embodiments, the subject had a score of 26 or higher on the HAMD-17 test before administration of compound (1). In some embodiments, the subject had a score of 10 or less on the HAMD-17 test and 10 or less on the HAM-A test on the 15th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 7 or less on the HAMD-17 test and 7 or less on the HAM-A test on the 15th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 13 or less on the MADRS test and 10 or less on the HAM-A test on the 15th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 10 or less on the MADRS test and 7 or less on the HAM-A test on the 15th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 10 or less on the HAMD-17 test and 10 or less on the HAM-A test on the 45th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 7 or less on the HAMD-17 test and 7 or less on the HAM-A test on the 45th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 13 or less on the MADRS test and 10 or less on the HAM-A test on the 45th day after the start of the single-dose regimen. In some embodiments, the subject had a score of 10 or less on the MADRS test and 7 or less on the HAM-A test on the 45th day after the start of the single-dose regimen. In some embodiments, the subject is between about 18 and about 65 years of age. In some embodiments, the subject is between about 18 and about 45 years of age.

[0340] In some embodiments, the therapeutically effective amount is from about 25 mg to about 35 mg of compound (1). In some embodiments, the therapeutically effective amount is about 30 mg of compound (1). In some embodiments, the subject is administered a therapeutically effective amount of compound (1) once a day. In some embodiments, the amount of compound (1) administered to the subject is reduced if severe adverse effects occur. In some embodiments, compound (1) is administered in the evening. In some embodiments, compound (1) is administered with food. In some embodiments, compound (1) is present in a capsule. In some embodiments, a method further comprising administering a second therapeutic agent.

[0341] Another aspect of the disclosure is a method of treating depression and anxiety simultaneously in a subject in need thereof using a kit comprising a plurality of individual dosage units containing compound (1) and a set of instructions for use, wherein the set of instructions describes a method for administering the dosage units to the subject using a short-term dosing regimen.

[0342] In embodiments of this aspect, the short-term dosing regimen has a duration of from about 2 to about 8 weeks. In some embodiments, the short-term dosing regimen has a duration of from about 2 to about 6 weeks. In some embodiments, the short-term dosing regimen has a duration of from about 2 to about 4 weeks. In some embodiments, the short-term dosing regimen has a duration of about 2 weeks. In some embodiments, the short-term dosing regimen has a duration of 2 weeks. In some embodiments, the subject is a female diagnosed with postpartum depression.

[0343] Another aspect of the disclosure includes a kit comprising a plurality of therapeutically effective dosages of compound (1) and a set of instructions for use that describe a method for administering the dosages using a short-term dosing regimen for treating depression and anxiety simultaneously.

[0344] In an embodiment of this aspect, the dosage is an individual dosage unit of compound (1). In some embodiments, the individual dosage unit comprises from about 25 mg to about 35 mg of compound (1). In some embodiments, the individual dosage unit comprises about 30 mg of compound (1). In some embodiments, the short-term dosing regimen has a duration of from about 2 to about 8 weeks. In some embodiments, the short-term dosing regimen has a duration of from about 2 to about 6 weeks. In some embodiments, the short-term dosing regimen has a duration of from about 2 to about 4 weeks. In some embodiments, the short-term dosing regimen has a duration of about 2 weeks or 14 days. In some embodiments, the short-term dosing regimen has a duration of 2 weeks. In some embodiments, the depression is postpartum depression (PPD).

[0345] In some embodiments, the set of instructions is printed on a suitable material. In some embodiments, the individual dosage unit is a capsule or a tablet. In some embodiments, the individual dosage unit is a capsule. In some embodiments, the individual dosage unit is a size 1, 2, 3, or 4 capsule. In some embodiments, the capsule is size 1.

[0346] In some embodiments, the method improves cognitive function in a subject. In some embodiments, the method does not result in cognitive impairment in a subject.

[0347] In some embodiments, the subject also experiences insomnia prior to administration of compound (1). In some embodiments, the subject has a score that is at least 3 points lower for the HAMD-17-Ins test on day 3 after initiation of the single-dose regimen, compared to the subject's HAMD-17-Ins test score prior to administration of compound (1). In some embodiments, the subject has a score that is at least 2 points lower for the MADRS-Ins test on day 3 after initiation of the single-dose regimen, compared to the subject's MADRS-Ins test score prior to administration of compound (1). In some embodiments, the subject has a score that is at least 3 points lower for the HAMD-17-Ins test on day 15 after initiation of the single-dose regimen, compared to the subject's HAMD-17-Ins test score prior to administration of compound (1). In some embodiments, the subject has a score that is at least 2 points lower for the MADRS-Ins test on day 15 after initiation of the single-dose regimen, compared to the subject's MADRS-Ins test score prior to administration of compound (1). In some embodiments, the subject has a score that is at least 3 points lower for the HAMD-17-Ins test on day 45 after initiation of the single-dose regimen, compared to the subject's HAMD-17-Ins test score prior to administration of compound (1). In some embodiments, the subject has a score that is at least 2 points lower for the MADRS-Ins test on day 45 after initiation of the single-dose regimen, compared to the subject's MADRS-Ins test score prior to administration of compound (1).

[0348] In some embodiments, the subject has a score that is at least 5 points lower for the HAMD-17-A / S test on day 15 after initiation of the single-dose regimen, compared to the subject's HAMD-17-A / S test score prior to administration of compound (1).

[0349] In some embodiments, the subject has a score that is at least 2 points lower for the EPDS-3A test on day 15 after initiation of the single-dose regimen, compared to the subject's EPDS-3A test score prior to administration of compound (1).

[0350] In some embodiments, the subject has a score that is at least 5 points lower for the HAMD-17-A / S test on day 45 after the start of the single-dose regimen, compared to the subject's HAMD-17-A / S test score before administration of compound (1).

[0351] In some embodiments, the subject has a score that is at least 3 points lower for the EPDS-3A test on day 45 after the start of the single-dose regimen, compared to the subject's EPDS-3A test score before administration of compound (1).

[0352] In some embodiments, the methods described herein improve the state of the overall sense of well-being in the subject.

[0353] In some embodiments, the subject has a score that is at least 10 points higher in five domains of the SF-36v2 test on day 15 after the start of the single-dose regimen, compared to the subject's SF-36v2 test score before administration of compound (1). In some embodiments, the subject has a score that is at least 10 points higher in five domains of the SF-36v2 test on day 45 after the start of the single-dose regimen, compared to the subject's SF-36v2 test score before administration of compound (1). In some embodiments, the five domains of the SF-36v2 test are social functioning, mental health, physical function, role physical, bodily pain, and mental health component summary.

Example

[0354] (Example 1) A phase 3 double-blind randomized placebo-controlled study at multiple sites to evaluate the efficacy of compound (1) in the treatment of adult subjects with major depressive disorder.

Table 27-1

Table 27-2

[0355] Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy of Compound (1) in the Treatment of Adults with Major Depressive Disorder

[0356] ClinicalTrials.gov Identifier: NCT04442490

[0357] Anticipated Duration of Subject Participation: Up to 70 days (up to 28 days for screening period, 14 days for double-blind treatment period, and 28 days for double-blind follow-up period).

[0358] Introduction

[0359] Major depressive disorder (MDD) is a complex heterogeneous disorder and one of the leading causes of disability in the United States and worldwide. In 2019, 19.4 million adults in the United States experienced a major depressive episode within the past year, and nearly 12.8 million received treatment. Patients with MDD experience depressive episodes associated with severe functional impairment. In the United States, nearly 60% of adults who experienced a major depressive episode in the past year also experienced severe or very severe impairment in at least one functional area (social, occupational, educational, or family) as measured by the Sheehan Disability Scale. The goals of MDD treatment are remission of symptoms, prevention of relapse and recurrence by reducing functional impairment, and improvement in quality of life.

[0360] Standard treatments for MDD, such as selective serotonin reuptake inhibitors, often require weeks or months to improve depressive symptoms. (Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-1917. In 2006, these treatments were also associated with several adverse side effects such as suicidal ideation, weight gain, sexual dysfunction, cognitive impairment, insomnia, anxiety, and sedation, which may lead to treatment discontinuation (Gelenberg AJ, Markowitz JC. APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder. Am J Psychiatry 2010: 1-152). The various treatment responses and adverse side effects brought about in patients with MDD often require multiple changes to antidepressant therapy (ADT) in order to achieve symptom remission. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D, NCT00021528) study, remission rates in patients with MDD decreased when multiple regimens of ADT were required (36.8% remission with the first treatment, compared to 13.0% remission with the fourth treatment). In the case of standard treatment, delayed treatment response and the frequent need for treatment changes are barriers to treatment, causing prolonged disability and delayed functional recovery. There is a need for treatment options that act rapidly, have high response and remission rates, and minimize the adverse side effects commonly seen with standard treatment ADT that has not been met.

[0361] To address this unmet need, new therapies with novel mechanisms of action are under development. For example, esketamine, a drug that modulates the activity of the excitatory neurotransmitter glutamate in the SUSTAIN-1 trial (NCT02493868), has demonstrated efficacy against treatment-resistant depression. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and plays an important role in regulating the balance of excitatory glutamatergic neurotransmission in adaptive signaling. GABA levels are decreased in the plasma and cerebrospinal fluid of patients with depression. However, the therapeutic potential of modulating GABA signaling for the treatment of MDD has been under-explored.

[0362] Inhibitory signaling by GABA is intrinsically affected by neuroactive steroids such as allopregnanolone, a progesterone metabolite. Allopregnanolone activates both phasic and tonic inhibitory neurotransmission by modulating synaptic and extrasynaptic GABA type A receptors (GABAARs), respectively. This is distinct from the mechanism of benzodiazepines, which target only phasic inhibition and synaptic GABAARs. Tonic and phasic inhibition mediate transient and long-term GABAergic signaling, respectively, and targeting both can achieve both rapid onset of treatment and sustained action, potentially treating depression.

[0363] Objectives

[0364] Primary: To evaluate the efficacy of compound (1) in the treatment of major depressive disorder (MDD) compared to placebo.

[0365] Secondary: To evaluate patient-reported outcome (PRO) measures, which are relevant to health-related quality of life and depressive symptoms.

[0366] Safety objective: To evaluate the safety and tolerability of compound (1).

[0367] Other objective: The PK of compound (1) was evaluated using the population PK approach.

[0368] Endpoint

[0369] Primary endpoint: - The primary endpoint of this study was the change from baseline in the 17-item HAM-D total score on day 15.

[0370] Important secondary endpoints: - Change from baseline in CGI-S on day 15 - Changes from baseline in the HAM-D total score on days 8, 3, and 42 The important secondary endpoints were sequentially studied at a significance level of 0.05 at each step (if the p-value was >0.05 at any step, the formal study was stopped).

[0371] Other secondary endpoints: - HAM-D response (≥50% decrease in the HAM-D total score from baseline) on days 15 and 42 - HAM-D remission (HAM-D ≤ 7) on days 15 and 42 - CGI-I response defined as "moderate improvement" or "marked improvement" on day 15 - Change from baseline in the MADRS total score on day 15 - Change from baseline in the HAM-A total score on day 15 - Time to first HAM-D response - Changes from baseline in the RPO scale of health-related quality of life evaluated by responses to SF-36v2, and the PRO scale of depressive symptoms evaluated by PHQ-9

[0372] Safety endpoints: - Incidence and severity of adverse events / serious adverse events - Changes from baseline in clinical laboratory measures, vital signs, and electrocardiogram (ECG) - Suicide thoughts and behaviors using the Columbia-Suicide Severity Rating Scale (C-SSRS) - Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist (PWC-20)

[0373] Other endpoints: - PK parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over the dosing interval, maximum plasma concentration) evaluated by population PK methods

[0374] Description of the study

[0375] This was a randomized, double-blind, parallel-group placebo-controlled study in subjects with MDD. The diagnosis of MDD was made by qualified healthcare professionals according to the Diagnostic and Structured Clinical Interview Regarding DSM-5, Clinical Trials Version (SCID-5-CT).

[0376] This study had a screening period of up to 28 days, a treatment period of 14 days, and a double-blind follow-up observation period of 28 days.

[0377] The screening period started from the signing of the ICF at the screening visit. The ICF must be signed before any screening activities are initiated. When presenting the informed consent for the study, subjects were also asked to permit the entry of their unique subject identifiers into a registry (www.subjectregistry.com) for the purpose of identifying subjects who may meet the exclusion criteria by participating in another clinical study.

[0378] Subjects underwent preliminary screening procedures at the screening visit to determine eligibility, including completion of the HAM-D and CGI-S.

[0379] The antidepressant was licensed, and the subjects who received it had taken a stable dose for at least 60 days prior to Day 1 and agreed to continue taking the stable dose until the follow-up period (Day 42). No new antidepressants or any other medications that could potentially affect the efficacy or safety endpoints were permitted to be initiated between screening and completion of the Day 42 assessment.

[0380] Eligible subjects were stratified based on the use of antidepressant treatment (on treatment / stable or untreated / withdrawal for ≥60 days) and randomized within each stratum to one of two treatment groups in a 1:1 ratio (Compound (1) - 50 mg or matching placebo). Subjects self-administered the investigational drug once daily at approximately 8 PM with a fatty meal (e.g., within 1 hour of a fatty dinner or with a fatty snack) based on outpatient criteria for 14 days. Subjects returned to the study facility during treatment and the follow-up period as outlined in Table 1.

[0381] During the treatment period, subjects were able to take the investigational drug unless there were dose-limiting safety / tolerance concerns. Subjects who could not tolerate 50 mg took 40 mg for the remainder of the treatment period. At the discretion of the study responsible physician, subjects who could not tolerate the 40 mg dose could have the investigational drug discontinued.

[0382] Number of Subjects

[0383] Up to 575 subjects were randomized and dosed to obtain a sufficient number of evaluable subjects for all analyses.

[0384] Treatment Allocation

[0385] On Day 1, subjects were randomly assigned to treatment groups and stratified based on the use of antidepressant treatment (on treatment / stable or untreated / withdrawal for ≥60 days) at baseline. Randomization was performed within each stratum in a 1:1 ratio to receive Compound (1) 50 mg or matching placebo.

[0386] Dosage adjustment criteria

[0387] Subjects were able to take the investigational drug unless there were safety / tolerability concerns limiting the dosage. Subjects who could not tolerate 50 mg took 40 mg for the remainder of the treatment period. At the discretion of the principal investigator of the clinical trial, subjects who could not tolerate a 40 mg dosage could discontinue the investigational drug.

[0388] Subject selection criteria Eligible subjects had to meet all of the following criteria: 1. The subject had signed the ICF before any of the study-specified procedures were conducted. 2. The subject was male or female between 18 and 64 years of age (inclusive). 3. The subject was in good physical health and had no clinically significant findings as determined by the principal investigator of the clinical trial with respect to physical examination, 12-lead ECG, or clinical laboratory tests. 4. The subject agreed to comply with the study requirements, including not working a night shift. 5. The subject had a diagnosis of MDD as diagnosed by SCID-5-CT, including existing symptoms, for a period of at least 4 weeks. 6. The subject had a HAM-D total score ≥ 24 at screening and on Day 1 (before dosing). 7. Subjects taking antidepressants had to have taken these drugs at the same dosage for at least 60 days prior to Day 1. Subjects who had discontinued taking antidepressants within 60 days had to have stopped for a period longer than 5 half-lives of the antidepressant prior to Day 1. Subjects receiving psychotherapy had to have been treated on a regular schedule for at least 60 days prior to Day 1. 8. The subject was willing to delay the initiation of other antidepressants or anxiolytics and any new drug therapy regimens, including benzodiazepine anxiolytics and sleep aids as needed, until after completion of the visit on Day 42. 9. Female subjects agreed to use one of the following methods of contraception during the treatment period and for 30 days after the last dose of study drug, unless they are menopausal (defined as the absence of menstruation for 12 months without another medical cause and confirmed by a follicle-stimulating hormone [FSH] > 40 mIU / mL), surgically sterile (hysterectomy or bilateral oophorectomy), or not engaged in sexual relations that pose a risk of pregnancy: - Combined oral, vaginal or transdermal hormonal contraception (containing estrogen and progestogen) with ovulation suppression. - Oral, injectable, or implantable progestogen-only hormonal contraception with ovulation suppression. - Intrauterine devices - Intrauterine hormone-releasing system - Bilateral tubal ligation / occlusion - Vasectomized partner 10. Male subjects agreed to use an acceptable method of effective contraception during the treatment period and for 5 days after taking the last dose of study drug, unless the subject was engaged in sexual relations that posed a risk of pregnancy. Acceptable methods of effective contraception for men included vasectomy, or, if the female partner was of childbearing potential, condoms with or without spermicide used in conjunction with a highly effective female contraceptive method (see inclusion criterion #9 for acceptable contraceptive methods). 11. Male subjects were willing to abstain from sperm donation during the treatment period and for 5 days after taking the last dose of study drug. 12. Subjects agreed to abstain from drugs of abuse and alcohol for the duration of the study.

[0389] Exclusion criteria for subjects

[0390] Subjects who met any of the following criteria were ineligible for study participation: 1. Subject was at significant risk for suicide or had attempted suicide related to a current episode of MDD, as determined by the investigator. 2. The subject had an episode of current major depressive disorder during pregnancy or within 4 weeks postpartum, or the subject had visited for screening during a 6-month period postpartum. 3. The subject had a history of recent or current clinically significant signs of a disorder of metabolism, liver, kidney, hematology, lung, cardiovascular, gastrointestinal tract, musculoskeletal, skin, urogenital, nervous, or eye, ear, nose, and throat, or any other acute or chronic condition, or other conditions that, in the opinion of the principal investigator, were likely to limit the subject's ability to complete or participate in this clinical study. Subjects with a BMI ≤ 18 or ≥ 45 kg / m2 were excluded. When the BMI at screening was 40 to 44.9 kg / m2 (inclusive), they were subject to a more extensive evaluation of the above medical complications. 4. The subject had treatment-resistant major depressive disorder, defined as persistent depressive symptoms, despite treatment with appropriate doses of antidepressants (excluding antipsychotics) within the range of a current major depressive episode from two different classes for at least 4 weeks. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) was used for this purpose. 5. The subject had received vagus nerve stimulation, electroconvulsive therapy, or had taken ketamine within the current major depressive episode. 6. The subject had a known allergy to compound (1), allopregnanolone, or related compounds. 7. The subject had a positive pregnancy test at screening or on the day before the start of investigational drug administration, or if the subject was breastfeeding at screening or on the day 1 (before investigational drug administration), the subject did not consent to temporarily discontinue breastfeeding the subject's child from immediately before taking the investigational drug on day 1 until 7 days after the last dose of the investigational drug. 8. The subject had detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), and positive HCV viral load or human immunodeficiency virus (HIV) antibodies at screening. 9. The subject had clinically significant 12-lead ECG abnormalities at screening or baseline visit. Note: In men, an average QT interval calculated using the Fridericia method (QTcF) > 450 msec, or in women > 470 msec, would be an exclusion criterion from the study. 10. The subject had an active mental disorder as evaluated by the study's responsible physician. 11. The subject had a history of seizures. 12. The subject had a history of bipolar disorder, schizophrenia and / or schizoaffective disorder. 13. The subject had a history of mild, moderate or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria within the 12 months prior to screening. 14. The subject was exposed to another investigational drug or device within 30 days prior to screening. 15. The subject had previously participated in a clinical trial of compound (1) or SAGE-547 (brexanolone). 16. Used any known strong inhibitor of cytochrome P450 (CYP) 3A4 within 28 days or 5 half-lives (whichever is longer) prior to the first dosing of the investigational drug, or consumed grapefruit juice, grapefruit or Seville orange, or products containing these within 14 days. 17. Used any strong CYP3A inducer such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin or St. John's wort within 28 days prior to the first dosing of the investigational drug. 18. The subject had a positive drug and / or alcohol screening at screening or on Day 1 prior to dosing. 19. The subject had a planned elective surgery prior to completion of the Day 42 visit. 20. The subject had taken benzodiazepines, barbiturates, or GABAA modulators (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) on the -28th day, or had used these drugs daily or almost daily (≥4 times per week) for more than one year. The subject had taken either a benzodiazepine with a half-life of ≥48 hours or a GABA modulator (e.g., diazepam) starting 60 days before the 1st day. 21. The subject had taken non-GABA hypnotics (e.g., melatonin, Benadryl [antihistamine], trazodone) or first-generation or second-generation (typical / atypical) antipsychotics on the -14th day. 22. The subject had been diagnosed with and / or treated for any type of cancer (excluding basal cell carcinoma and in situ melanoma) within the past year before screening. 23. The subject had a history of sleep apnea. 24. The subject had had gastric bypass surgery, a gastric sleeve, or a lap band, or had undergone any related procedure that impeded gastrointestinal passage. 25. The subject had taken neurostimulants (e.g., methylphenidate, amphetamine) or opioids regularly or as needed on the -28th day.

[0391] Investigational drug

[0392] The subject self-administered the compound (1) (50 mg or 40 mg [only for dose adjustment if permitted]) or the matching placebo orally once a day with food at approximately 8 PM for 14 days. The 50 mg and 40 mg doses were administered as two capsules per dose (for 50 mg, as one 30 mg capsule and one 20 mg capsule, and for 40 mg, as two 20 mg capsules). The placebo was also administered as two capsules to maintain blinding.

[0393] Previous drugs, concomitant drugs, and restrictions

[0394] Previous and concomitant medications and / or supplements

[0395] The start date, end date, route, dose / unit, frequency, and indication of all medications and / or supplements taken within 30 days prior to screening and throughout the study period were recorded. Additionally, psychotropic medications taken during the 6 months prior to screening were recorded.

[0396] Any determined medications and / or supplements necessary for the well-being of the subjects could be given at the discretion of the principal investigator of the clinical trial at any time during the study.

[0397] Antidepressants taken at the same dose for at least 60 days prior to Day 1 were permitted if the subject intended to continue the stable dose until Day 42.

[0398] The following medications intended for contraception were permitted for female subjects: - Combination oral, vaginal, or transdermal hormonal contraception with ovulation suppression (containing estrogen and progestogen) - Oral, injectable, or implantable progestogen-only hormonal contraception with ovulation suppression - Intrauterine device - Intrauterine hormone-releasing system

[0399] Prohibited medications

[0400] The following specific classes of medications were prohibited: · Initiation of a new psychotropic medication until the visit on Day 42 · Initiation of a new antidepressant therapy from 60 days before Day 1 until the visit on Day 42 · Use of any benzodiazepine, barbiturate, GABAA modulator, or GABA-containing agent (for benzodiazepines with a half-life of ≧48 hours or GABAA modulators, from -60 days) from Day -28 until the visit on Day 42 · From the 28th day to the visit on the 42nd day, for a long period or as needed, neurostimulants (e.g., methylphenidate, amphetamine) or opioids · From the 14th day to the visit on the 42nd day, first-generation (typical) antipsychotics (e.g., haloperidol, perphenazine) and second-generation (atypical) antipsychotics (e.g., aripiprazole, quetiapine) · From the 14th day to the visit on the 42nd day, use of any non-GABA hypnotics (e.g., melatonin, Benadryl [antihistamine], trazodone, low-dose quetiapine, mirtazapine, etc.) · From 30 days before screening to the visit on the 42nd day, exposure to another investigational drug or device. · From 5 half-lives before the 28th day or the 1st day to the treatment period (whichever is longer), any known potent inhibitor of CYP3A4. · From the 28th day to the treatment period, use of any potent CYP3A inducer such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or St. John's wort.

[0401] Other restrictions

[0402] Intake of grapefruit juice, grapefruit or Seville orange, or products containing them was prohibited throughout the treatment period.

[0403] Consumption of alcohol or use of illicit drugs was discontinued throughout the study period.

[0404] Female subjects who are breastfeeding or actively lactating must discontinue breastfeeding their infants from the 1st day of the investigational drug until 7 days after the last dose.

[0405] Elective surgery or procedures were prohibited until the visit on the 42nd day.

[0406] Subjects must not work night shifts.

[0407] Subjects who were in a state of sedation, drowsiness and / or feeling dizzy were refrained from participating in driving or any activity that required wakefulness.

[0408] Subjects who had received psychotherapy on a regular schedule for at least 60 days prior to Day 1 were permitted if the subject intended to continue the stable dose until the follow-up period (Day 42).

[0409] Description of the investigational drug

[0410] Compound (1) was available as a hard gelatin capsule containing a white to off-white powder. The active compound (1) capsule contained, in addition to the specified amount of the drug substance of compound (1), croscarmellose sodium, mannitol, microcrystalline cellulose phthalate (SMCC), colloidal silicon dioxide and sodium stearyl fumarate as excipients. The capsules were available in dose strengths of 20 mg and 30 mg.

[0411] The matching placebo capsule was a hard gelatin capsule containing only the excipients listed for the active capsule.

[0412] Packaging and labeling of the investigational drug

[0413] The capsules of compound (1) and the matched placebo capsules were provided to the pharmacist at the clinic responsible for dispensing the investigational drug and / or the staff at the manufacturing facility in kits specific to the subject, containing appropriately labeled, sealed unit doses. Each unit dose consisted of two capsules.

[0414] Additional information regarding packaging and labeling was presented in the pharmacy manual.

[0415] Statistical methods:

[0416] A detailed description of the statistical analysis conducted in the study was presented in the Statistical Analysis Plan (SAP). Individual SAPs were created for each part of the study. The SAP for each study part was finalized and approved before unblinding each individual part of the treatment.

[0417] General Considerations

[0418] As needed, for all safety and efficacy analysis purposes, the baseline was defined as the last measurement before the start of investigational drug administration.

[0419] Continuous endpoints were descriptively summarized using n, mean, standard deviation, median, minimum, and maximum. Additionally, the change from baseline was calculated and descriptively summarized at each time point. For categorical endpoints, the descriptive summary included counts and percentages.

[0420] Analysis Population - The randomized population was defined as all randomized subjects. - The safety population was defined as all subjects who received the investigational drug. - The full analysis set was defined as all randomized subjects in the safety population with a post-baseline HAM-D total score and a valid baseline HAM-D total score of at least 1. - The modified full analysis set (mFAS) was defined as all participants with a total HAM-D score ≥ 26 at baseline in the FAS. - The PK population was defined as all subjects in the safety population with at least one plasma concentration.

[0421] Determination of Sample Size

[0422] Assuming both - sided alpha level of 0.05, the sample size of 216 evaluable subjects would provide 90% power to detect a placebo - adjusted treatment difference of approximately 4 points in the primary endpoint on day 15, i.e., the change from baseline in the HAM - D total score, assuming a standard deviation (SD) of 9 points. Assuming a dropout rate of 10% and a randomization ratio of 1:1 within each stratum (use of antidepressant at baseline, yes or no), a total of approximately 240 randomized subjects were needed to obtain 216 evaluable subjects. Evaluable subjects were defined as randomized subjects who received the investigational drug and had a valid baseline and at least one post - baseline HAM - D assessment. To obtain higher power for important secondary endpoints, up to 575 subjects were randomized.

[0423] Analysis of the primary endpoint

[0424] The estimates for the primary efficacy analysis were the mean change from baseline in the HAM - D total score on day 15. This was analyzed using a mixed - effects model for repeated measures (MMRM). The model included treatment, baseline HAM - D total score, stratification factors, assessment time points, and time points for each treatment as explanatory variables. All explanatory variables were treated as fixed effects. All post - baseline time points were included in the model. The main comparison was between compound (1) and placebo at the 15 - day time point. Model - based point estimates (e.g., least - squares [LS] means, 95% confidence intervals, and p - values) were reported as needed. The within - subject error was modeled using an unstructured covariance structure. If there were convergence problems with the unstructured covariance model, a Toeplitz or autoregressive (1) [AR(1)] covariance structure was used and this order was followed until convergence was achieved. If the model still did not converge to the AR(1) structure, the results were not reported. When the covariance structure was not UN, the sandwich estimator of the variance - covariance matrix was derived using the EMPIRICAL option in the PROC MIXED statement in SAS.

[0425] Analysis of Secondary Endpoints

[0426] Similar to the above method for primary endpoints, for changes from the baseline, MMRM was used to analyze the changes from the baseline in the HAM-D total score, MADRS total score, HAM-A total score, SF-36v2 score, PHQ-9 score, and selected individual items and / or subscale scores in HAM-D at other time points.

[0427] The generalized estimating equation (GEE) method was used for the analysis of HAM-D response (defined as a ≥50% decrease from the baseline in the HAM-D total score) and HAM-D remission (defined as the HAM-D total score ≤7.0). The GEE model included, as explanatory variables, treatment duration, baseline score, stratification factors, evaluation time points, and time points for each treatment. The comparison of interest was the difference between compound (1) and the matching placebo at the 15-day time point. Model-based point estimates (e.g., odds ratio), 95% confidence intervals, and p-values were reported.

[0428] The GEE method was also used for the analysis of CGI-I response, including treatment duration, baseline CGI-S score, stratification factors, evaluation time points, and time points for each treatment as explanatory variables.

[0429] Safety Analysis

[0430] The safety and tolerability of the investigational drug were evaluated by the incidence of adverse events / serious adverse events, vital signs, clinical laboratory evaluations, and 12-lead ECG.

[0431] Suicidal tendency was monitored by the C-SSRS. Potential withdrawal symptoms after discontinuation of compound (1) were evaluated using the PWC-20.

[0432] Pharmacokinetic Analysis

[0433] The concentration-time data of compound (1) were evaluated using a non-linear mixed effects model. The model was used to estimate population PK parameters and to identify any covariates that could contribute to the observed variability. The data from this study could be combined with data from other studies to support the analysis and could be reported individually.

[0434]

Table 1-1

Table 1-2

Table 1-3

[0435] (Example 2) Efficacy results of the Phase 3 study of compound (1) in major depressive disorder (MDD) of Example 1.

[0436] Compound (1) is a once-daily oral investigational drug for 2 weeks for MDD, a potential new class of drugs for managing common but severe mental health disorders. Compound (1) was evaluated in a double-blind randomized placebo-controlled Phase 3 study (NCT04442490) for major depressive disorder (MDD) as described in Example 1. The study evaluated the efficacy, safety, tolerability, and pharmacokinetics of compound (1) in adult patients diagnosed with MDD (HAM-D total score ≥ 24). Figure 1 illustrates the study design.

[0437] Dosage

[0438] Compound (1) was self-administered once daily at a dose of 50 mg in the evening for 14 days with a fat-containing meal. Patients were able to reduce the dose to 40 mg if necessary.

[0439] 2.1 Treatment and Demographics

[0440] The mean baseline HAMD-17 score at study enrollment was 26.8 (2.60) in the 50 mg treatment group of compound (1) (n = 268) and 26.9 (2.67) in the placebo group (n = 269). Table 2 shows the treatment and subject progression. Table 3 shows the study demographics.

[0441]

Table 2

[0442]

Table 3

[0443] Demographic and baseline characteristics were generally well balanced between the compound (1)-50 mg group (compound (1)-50 mg) and the placebo group. Mean (SD) age: 39.4 (12.3) vs 40.1 (12.6); percentage of female patients: 69.4% vs 61.7%; white: 63.1% vs 76.6%; existing antidepressant therapy: 29.5% vs 30.1%; mean (SD) HAMD-17 total score: 26.8 (2.6) vs 26.9 (2.7). Patients had a diagnosis of MDD for approximately 11 years (mean (SD) compound (1)-50 mg, 10.6 (10.1), placebo 11.2 (10.8)).

[0444] Table 4 summarizes the primary and selected secondary statistical outcomes at various time points.

[0445]

Table 4

[0446] 2.2 HAMD-17 total score

[0447] The study met its primary endpoint at day 15, with a statistically significant and clinically relevant decrease in the total score of the 17-item Hamilton Depression Rating Scale (HAMD-17) at day 15 (see Figure 2).

[0448] On the 15th day primary endpoint, 50 mg of compound (1) showed a statistically significant reduction in depressive symptoms compared to placebo as measured by HAMD-17 (p = 0.0141). A rapid and significant effect was observed as early as day 3 (including days 8 and 12). The least squares mean (SE) change from baseline (CFB) in the HAMD-17 total score on day 15 was -14.1 (0.51) (compound (1)) vs -12.3 (0.50) (placebo); Δ -1.7 points; 95% CI (-3.1, -0.3), p = 0.0141. Treatment effects were evident at all measurement time points, with nominal significance observed on day 3 (least squares mean (SE) CFB -9.8 (0.38) (compound (1)) vs -6.8 (0.38) (placebo)); Δ -3.0 points, 95% CI (-4.0 to -2.0, p < 0.0001), day 8 (least squares mean (SE) CFB -12.0 (0.45) (compound (1)) vs -9.5 (0.45) (placebo)) [Δ -2.6, p < 0.0001] and day 12 [Δ -2.5, p = 0.0003]. The LSM treatment difference favored compound (1). On day 42, it had a least squares mean (SE) CFB of -13.5 (0.55) (compound (1)) vs -12.6 (0.55) (placebo) with Δ -0.9.

[0449] As shown in Figure 3, among the responders to HAMD-17 on day 15 treated with compound (1), the patients maintained, on average, 86.1% of the improvement on day 15 of the patients on day 42. The patients who responded to compound (1) on day 15 maintained 86.1% improvement in the patients' HAMD-17 on day 42 (4 weeks after the end of dosing). Furthermore, 75.4% of the patients maintained a pre-specified level of at least 65% of the improvement on day 15 of the patients on day 42. Numerical evidence of the treatment effect on day 15 appeared favorably for compound (1) across all subgroups and subscales of HAMD-17 (see Figure 4), such as the use of antidepressants at baseline, age, gender, race, baseline HAMD-17 and body mass index. A similar maintenance of response was also observed in the MADRS scale, and those who responded to compound (1) on day 15 maintained 87.6% of their response on day 42. Furthermore, the response rate and remission rate were consistent with the weighted mean response rate and remission rate across placebo-controlled LANDSCAPE and NEST program clinical trials, including MDD and PPD.

[0450] 2.3 Clinical Global Impression (CGI)

[0451] Following the examination of the primary endpoint, the statistical analysis plan was advanced to the examination of CFB in the Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) of the disease. The results of CGI-S demonstrated a numerical advantage for compound (1) at all measurement time points (see Figure 5), but were not statistically significant at day 15 in the pre-specified analysis model. Regarding CGI-S, the results were similar between 50 mg of compound (1) and placebo (LS mean [SE] -1.8 [0.08] vs -1.6 [0.08]; LS mean difference -0.2, 95% CI -0.4 to 0.0; P =.12), and thus, a formal study of the important secondary endpoint was examined.

[0452] Figure 6 shows the CGI-I response (either "moderate" or "marked" improvement), one of the other secondary endpoints, indicating that numerically, the proportion of patients with a CGI-I response on day 15 was greater in those receiving compound (1) compared to placebo.

[0453] As shown in Figure 7, on day 15, the CGI-I score evaluated by the clinician indicated that the overall clinical condition of the patients was significantly improved by treatment with compound (1) in this example and in other clinical studies conducted by the applicant. * is a Phase 3 clinical trial study (ClinicalTrials.gov identifier / NCT number: NCT03864614) conducted by the applicant. ** is a Phase 3 clinical trial study (ClinicalTrials.gov identifier / NCT number: NCT0672175) conducted by the applicant. *** is a Phase 2 clinical trial study (ClinicalTrials.gov identifier / NCT number: NCT03000530) conducted by the applicant. The study design and results of the clinical trial identified by the NCT number are incorporated herein by reference in their entirety, where applicable.

[0454] 2.4 MADRS

[0455] The clinical trial of Example 1 demonstrated that in patients receiving compound (1) - 50 mg, their depressive symptoms were significantly improved compared to placebo on day 15 as evaluated by the change from baseline (CFB) in the total HAMD-17 score, which met its primary endpoint. The HAMD-17 mainly focuses on the physical symptoms of depression including anxiety, while the Montgomery-Åsberg Depression Rating Scale (MADRS) addresses the core mood symptoms such as sadness, tension, lack of energy, and pessimistic and suicidal thoughts (Table 5). Despite the differences in the content and number of items between the HAMD-17 and the MADRS, the study has shown that the two scales are correlated.

[0456]

Table 5

[0457] CFB in the total MADRS score was evaluated on Day 8, Day 15 (secondary endpoint), Day 28, and Day 42.

[0458] Consistent with the primary endpoint, it was demonstrated that patients treated with compound (1) had a significantly improved depression score on Day 15 as measured by CFB of the total MADRS score compared to placebo (LS mean [SE] -17.5 [0.77] vs -15.1 [0.76]; LS mean difference -2.4, 95% CI -4.4 to -0.3; P =.02. Patients receiving compound (1) demonstrated improved depressive symptoms as evaluated by CFB of the total MADRS score compared to placebo (LSM [SE] compound (1) -50 mg vs placebo; see Figure 8), and there was nominal significance on Day 8 and Day 15. - Day 8, -14.6 (0.69) vs -11.2 (0.68); - Day 15, -17.5 (0.77) vs -15.1 (0.76); - Day 28, -16.4 (0.80) vs -14.9 (0.80); and - Day 42, -17.5 (0.83) vs -16.2 (0.82).

[0459] CFB adjusted by placebo in MADRS demonstrated numerical advantages at all measurement time points (Days 8, 15, 28, 42).

[0460] On the 15th day, the CFB of the LSM of the total MADRS score (SE) of the patients who received 50 mg of compound (1) was -17.5 (0.77) as compared to -15.1 (0.76) in the case of the patients who received placebo (treatment difference -2.4 points; p = 0.0238). The LSM treatment difference (compound (1)-50 mg - placebo) of the CFB of the total MADRS score was -3.4 (p = 0.0003) on the 8th day, -2.4 (p = 0.0238) on the 15th day, -1.5 (NS) on the 28th day, and -1.3 (NS) on the 42nd day. The LSM treatment differences of the CFB in the HAMD-17 and total MADRS scores were both in favor of the patients who received compound (1) (see Figure 9).

[0461] In summary, patients who received 50 mg of compound (1) demonstrated improved depressive symptoms compared to placebo as evaluated by the total MADRS score. Patients who received 50 mg of compound (1) showed rapid improvement in the severity and symptoms of depression as early as on the 3rd day (HAMD-17 total score) and 8th day (the first total MADRS score evaluation at treatment), and the benefits were sustained throughout the follow-up period. The improvement evaluated by both measures continued until the 42nd day.

[0462] 2.5 Efficacy and Maintenance

[0463] Clinical study patients were followed for 28 days after treatment, including clinic visits on days 21, 28, 35, and 42. Key secondary endpoints included the CFB of the LSM HAMD-17 total score and total MADRS score at all measured time points, as well as HAMD-17 and MADRS response (≥50% improvement from baseline score) on days 15 and 42.

[0464] The duration of the treatment effect was evaluated over the post-treatment period in patients treated with compound (1) - 50 mg based on the efficacy observed on day 15. The retention rates of the HAMD-17 total score and the MADRS total score responders at day 15 over time were investigated only in responders at day 15. Except for the primary endpoint, all p-values reported here are nominal and not adjusted for multiple comparisons. This analysis included patients with a valid baseline HAMD-17 total score and at least one valid post-baseline HAMD-17 total score.

[0465] Results

[0466] Overall, patients who received compound (1) achieved a faster treatment response and symptom remission compared to placebo-treated patients.

[0467] As shown in Figure 10A, on day 15, 139 / 248 compound (1) - 50 mg treated patients (56.0%) showed a response (≥50% decrease in the HAMD-17 total score from baseline) as evaluated by the HAMD-17 total score. Of these, patients maintained, on average, 81.7% of their improvement at day 15 at day 28 and 86.1% of their improvement at day 15 at day 42. Figure 10B shows remission (HAMD-17 ≤ 7) as evaluated by the HAMD-17 total score.

[0468] As shown in Figure 10A, by Day 3, treatment efficacy was achieved in a higher proportion of patients treated with compound (1) compared to placebo-treated patients (≥50% decrease in the total HAMD-17 score from baseline) (29.3% vs 16%, odds ratio 2.14, 95% CI 1.4 - 3.3; P <.001), and the treatment difference persisted throughout the treatment period. At the first post-treatment follow-up study visit on Day 15, a numerically higher proportion of patients treated with compound (1) achieved treatment efficacy compared to placebo-treated patients (56.0% vs 47.0%, odds ratio 1.40, 95% CI 1.0 - 2.0, P = 0.06). At the end of the follow-up period (Day 42), the proportion of patients with HAMD-17 efficacy was similar between compound (1) and the placebo group.

[0469] Remission of symptoms (HAMD-17 ≤ 7; Figure 10B) was observed more often in the group of compound (1) by Day 3 compared to the placebo group (7.6% vs 2%, odds ratio 3.57, 95% CI 1.4 - 9.1, P = 0.008), and compound (1) was advantageous throughout the treatment period. At Days 15 and 42, remission of symptoms was slightly more favorable for compound (1) compared to placebo. By Day 21, 83 / 226 (81.0%) of the patients treated with compound (1) maintained ≥65% improvement in HAMD-17 at Day 15, which decreased to 173 / 231 (74.9%) by Day 42.

[0470] These results suggest that although a small proportion of patients lost robust treatment efficacy immediately after treatment cessation, generally, treatment efficacy was maintained during the post-treatment period.

[0471] As shown in Tables 6 and 7, the results of treatment efficacy and remission were either similar or numerically improved in patients who received 50 mg of compound (1) in combination with an antidepressant (ADT) compared to monotherapy with 50 mg of compound (1).

[0472]

Table 6-1

Table 6-2

[0473]

Table 7-1

Table 7-2

[0474] The response rate (≥50% decrease in the total MADRS score from baseline) during the treatment period was significantly more favorable for Compound (1) compared to placebo. The remission rate (MADRS ≤ 10) was numerically more favorable for Compound (1) during the same period (Figure 11).

[0475] On day 15, 128 / 248 (51.6%) of the patients treated with Compound (1) - 50 mg showed response (≥50% decrease in the total MADRS score as evaluated by the total MADRS score from baseline). Similar maintenance of response was also observed for the total MADRS score as in the case of the total HAMD-17 score. Among the 128 responders (i.e., having ≥50% decrease in the total MADRS score from baseline), the patients maintained, on average, 85.2% of their improvement on day 15 at day 28 and 87.6% of that improvement at day 42.

[0476] Maintenance of response to Compound (1) - 50 mg, as evaluated by the maintenance of response in both the total HAMD-17 score and the total MADRS score on day 15, was observed at all time points measured up to day 42.

[0477] 2.6 Anxiety (HAM-A and HAMD-17 Anxiety / Somatization Subscale)

[0478] Nearly two-thirds of patients with MDD also experience symptoms of anxiety, and up to 20% have comorbid anxiety disorder (Mittal D, et al. Psychiatr Serv. 2006;57(12):1731-1737; Clayton AH, et al. Am J Psychiatry. 1991;148(11):1512-1517.; Stein MB, et al. J Affect Disord. 1995;34(2):79-84).

[0479] Secondary endpoints focused on anxiety-related symptoms included the total HAM-A score and the CFB of the HAMD-17 anxiety / physicalization subscale.

[0480] The effects of compound (1) on symptoms of anxiety, as evaluated by the HAM-A and the HAMD-17 anxiety / physicalization subscale, are reported here.

[0481] Methods

[0482] The total HAM-A score was evaluated on days 8, 15, 28, and 42. The total HAMD-17 score and the HAMD-17 anxiety / physicalization subscale were evaluated on days 3, 8, 12, 15, 21, 28, 35, and 42.

[0483] Statistics are from a mixed-effects model. Except for the CFB of HAMD-17 at day 15 (primary endpoint), all p-values reported here are nominal and not adjusted for multiple comparisons.

[0484] Results

[0485] The group of 50 mg of compound (1), as evaluated by the total HAMD-17 score, demonstrated a numerical improvement in depressive symptoms at all measurement time points up to day 42 compared to placebo, with nominal significance at day 3 (LS mean difference -3.0, p<0.0001), day 8 (LS mean difference -2.6, p<0.0001), and day 12 (LS mean difference -2.5, p = 0.0003). Among the responders (≥50% improvement in total HAMD-17 score from baseline) of HAMD-17 treated with 50 mg of compound (1) at day 15, the patients maintained, on average, 86.1% of their improvement at day 15 at day 42 (4 weeks after dosing ended).

[0486] A similar trend was seen in the total HAM-A score, with a numerical improvement in anxiety symptoms compared to placebo at all measurement time points up to day 42 (days 8, 15, 28, 42), with nominal significance at day 8 (LS mean difference -1.7, p = 0.0011) and day 15 (LS mean difference -1.4, p = 0.0199) (see Figure 12).

[0487] The CFB of the total HAM-A score showed a numerical improvement in symptoms of anxiety in patients treated with compound (1) compared to those receiving placebo at all measurement time points, with nominal significance at day 8 (LS mean (SE) CFB -8.7(0.40) (compound ()) vs -7.0(0.39) (placebo)) and day 15 (LS mean (SE) CFB -10.4(0.43) (compound (1)) vs placebo (-9.1(0.43) (placebo)) (see Figure 12).

[0488] The CFB of the HAMD-17 anxiety / physicalization subscale score showed a numerical improvement in symptoms of anxiety in patients treated with compound (1) compared to those receiving placebo at all measurement time points, with nominal significance at day 3 and day 8. (See Figure 13).

[0489] The CFB of the time-course HAM-A total score and HAMD-17 anxiety / physicalization subscale score showed a trend similar to that observed for the HAMD-17 total score. On days 8 and 15, the LSM treatment differences (subtracting placebo from compound (1)) for the HAMD-17 total score, HAMD-17 anxiety / physicalization subscale score, and HAM-A total score were all in favor of compound (1) (Figures 14A and 14B).

[0490] Conclusion

[0491] Patients receiving compound (1) demonstrated a rapid improvement in anxiety symptoms (evaluated by HAM-A) as early as day 8, and the numerical improvement was maintained until the end of the study (day 42). The HAMD-17 anxiety / physicalization subscale showed a similar trend with prominent significant effects on days 3 and 8.

[0492] Similar results in depressive and anxiety symptoms have been observed throughout the LANDSCAPE clinical development program (Gunduz-Bruce H, et al. N Engl J Med. 2019;381(10):903-911; Mittal A, et al. Poster presented at the American Academy of Neurology Annual Meeting. Toronto, Canada. April 25-May 1, 2020; Cutler AJ, et al. Poster presented at the American Society of Clinical Psychopharmacology Annual Meeting. Virtual Congress. June 1-4, 2021; Deligiannidis KM, et al. JAMA Psychiatry. 2021;78(9):951-959), supporting the effect of compound (1) on anxiety symptoms that may coexist with depressive symptoms in patients with MDD.

[0493] 2.6.1 Major Depressive Disorder (MDD) with Rising Anxiety

[0494] MDD with rising anxiety as a symptom is well established to be associated with more severe illness, more difficulty in tolerating antidepressants (potentially affecting adherence), higher non-responsiveness to treatment, and a greater need for additional interventions and resources.

[0495] In the United States, up to 78% of patients with MDD are classified as "MDD with anxiety disorder distress" using DSM-5 indicators, and up to 70% are classified as "MDD with rising anxiety" using a HAM-A total score ≥20. These patients have more severe depression, respond less well to typical ADT, and have worse treatment outcomes.

[0496] The 14-item Hamilton Anxiety Rating Scale (HAM-A) assesses the effectiveness of treatment for anxiety symptoms in patients with anxiety disorders (Bourin M. Therapie. 2000;55(1):147-153; Maier W, et al. J Affect Disord. 1988;14(1):61-68). The HAM-A, which measures both mental and physical anxiety, can be a reliable and valid measure of the severity of anxiety in patients with MDD. The HAM-A mental anxiety items can be used to evaluate rising anxiety in patients with MDD. The HAMD-17 total score is the gold standard for assessing the severity of depression in clinical studies on MDD (Boessen R, et al. J Affect Disord. 2013;145(3):363-369; Bagby RM, et al. Am J Psychiatry. 2004;161(12):2163-2177; Bech P, et al. Acta Psychiatr Scand. 1981;63(3):290-299). The HAMD-17 anxiety / somatization subscale (6 items) is frequently used at a high frequency to examine the specific effects of treatment on anxiety-related symptoms in patients with MDD (Huang CJ, et al. Int J Neuropsychopharmacol. 2019;22(10):609-615; McClintock SM, et al. Int J Methods Psychiatr Res. 2011;20:e69-e82). The HAMD-17 anxiety / somatization subscale anxiety (e.g., psychic anxiety) items can similarly be used to evaluate the increase in anxiety in patients with MDD.

[0497] Figures 15A and 15B show that in the patients of the study of Example 1 with MDD accompanied by increased anxiety (patients with MDD having baseline HAM-A ≥ 20), the symptoms of depression (verified by CFB of HAMD-17; Figure 15A) and anxiety (verified by CFB of HAM-A; Figure 15B) were significantly improved by compound (1).

[0498] Figure 16 shows the pooled HAMD-17 CFB in MDD patients without increased anxiety (patients with MDD having baseline HAM-A < 20) and MDD patients with increased anxiety (patients with MDD having baseline HAM-A ≥ 20) treated with compound (1) versus placebo. The pooled data integrates data from the clinical trial of Example 1, the Phase 3 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT0672175), and the Phase 2 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT03000530). The study designs and results of the clinical trials identified by the NCT numbers are incorporated herein by reference in their entirety where applicable.

[0499] Figure 17 shows the pooled mean HAMD-17 total scores in placebo, MDD patients without increased anxiety (patients with MDD having baseline HAM-A < 20), and MDD patients with increased anxiety (patients with MDD having baseline HAM-A ≥ 20) treated with compound (1). The pooled data integrates data from the clinical trial of Example 1, a Phase 3 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT0672175), and a Phase 2 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT03000530).

[0500] Figures 18A - 18B show the pooled mean SF-36v2 scores at baseline, day 15, and day 42 in placebo, MDD patients without increased anxiety (patients with MDD having baseline HAM-A < 20; Figure 18A), and MDD patients with increased anxiety (patients with MDD having baseline HAM-A ≥ 20; Figure 18B) treated with compound (1). The pooled data integrates data from the clinical trial of Example 1, a Phase 3 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT0672175), and a Phase 2 clinical trial study conducted by the applicant (ClinicalTrials.gov identifier / NCT number: NCT03000530).

[0501] As additional references regarding Section 2.6, Althaus AL, et al. Neuropharmacology. 2020;181:108333; Martinez Botella G, et al. J Med Chem. 2017;60(18):7810 - 7819; Hoffmann E, et al. Clin Pharmacokinet. 2020;59(1):111-120; and Clayton A, et al. New Medication Symposium. 34th European College of Neuropsychopharmacology Hybrid Congress. Lisbon, Portugal. October 2-5, 2021 can be cited.

[0502] 2.7 HAMD-17 subscale scores

[0503] As shown above, the study of Example 1 met its primary endpoint, and Compound (1) demonstrated a significant improvement in depressive symptoms compared to placebo in the CFB of the LSM on Day 15 in the HAMD-17 total score (treatment difference was -1.7 points; p = 0.0141). This section details the HAMD-17 subscale outcomes that capture the core symptoms of depression and anxiety.

[0504] The least-squares mean CFB of the HAMD-17 subscale (core depression, Bech-6, Meyer, and anxiety) scores on Day 15 was calculated, but the study did not have enough power to perform a statistical comparison of these subscales.

[0505] Results

[0506] Similar to the primary endpoint on Day 15, patients who received Compound (1) - 50 mg demonstrated a numerical improvement in symptoms compared to placebo across all of the HAMD-17 subscales: core depression (LSM difference -2.0 points; p = 0.1906), Bech-6 (LSM difference -3.2 points; p = 0.0759), Meyer (LSM difference -3.0 points; p = 0.0586), and anxiety (LSM difference -0.9 points; p = 0.4998).

[0507] Patients who received a 50 mg dose of Compound (1) demonstrated numerical improvements in core depressive symptoms and anxiety symptoms across the HAMD-17 subscale scores, supporting the results of the primary endpoint.

[0508] 2.8 SF-36 Score

[0509] The study of Example 1 evaluated the health-related quality of life (HRQoL) of Compound (1) - 50 mg vs placebo.

[0510] The Short Form-36 (SF-36v2) evaluated patient-reported HRQoL across eight domains (Physical Function [PF]; Role Physical [RP]; Bodily Pain [BP]; General Health [GH]; Vitality [V]; Social Function [SF]; Role Emotional [RE]; Mental Health [MH]). Safety and tolerability were evaluated by adverse events (AEs).

[0511] Results

[0512] Baseline cores for SF-36v2 were similar for the placebo (PF: 49.20; RP: 46.60; BP: 47.38; GH: 47.04; V: 33.33; SF: 30.22; RE: 26.06; MH: 28.28) group and the Compound (1)-50 mg (PF: 49.40; RP: 47.42; BP: 47.07; GH: 46.97; V: 32.93; SF: 29.85; RE: 25.15; MH: 27.40) group. On Day 15, improvements in SF-26v2 were observed in the CFB of the Compound (1)-50 mg group: PF (3.41), RP (3.45), BP (5.26), GH (4.51), V (13.12), SF (12.89), RE (14.19), and MH (14.45).

[0513] On Day 15, Compound (1)-50 mg demonstrated a statistically significant (p = 0.0029) and clinically meaningful improvement in the vitality score (3.1) of the SF-36v2 least squares mean compared to placebo.

[0514] Patients who received 50 mg of compound (1) reported improvement in multiple SF-36v2 domains, particularly vitality, on day 15 and showed a significant improvement in HRQoL.

[0515] 2.9 Monotherapy versus combination with SOC ADT

[0516] The study in Example 1 permitted the use of antidepressant therapy (ADT), an existing standard of care (SOC) at stable doses. This section reports the safety and efficacy of treatment with compound (1)-50 mg as monotherapy versus combination with SOC ADT.

[0517] Results

[0518] The proportion of patients using antidepressants at baseline was balanced between compound (1)-50 mg and placebo (29.3% vs 30.2%). Irrespective of treatment, ADT use at baseline did not significantly affect the HAMD-17 total score on day 15 (LSM difference, monotherapy: -1.98; p = 0.0165 vs combination: -1.21; p = 0.3552).

[0519] On day 15, the response rates of the HAMD-17 total score for compound (1) versus placebo were overall (56.0% vs 47.0%), monotherapy (55.5% vs 46.6%) and combination with SOC ADT (57.3% vs 48.1%).

[0520] TEAEs were reported in 111 / 189 (58.7%) of patients who received compound (1)-50 mg versus placebo monotherapy and 87 / 188 (46.3%), and in 50 / 79 (63.3%) of patients who received SOC ADT versus 33 / 81 (40.7%).

[0521] Patients who received 50 mg of compound (1) demonstrated improvement in depressive symptoms regardless of concomitant SOC ADT use and there was no evidence of an increase in adverse events.

[0522] 2.10 Analysis of Subgroups

[0523] This section contains baseline demographic efficacy analysis and characteristic subgroup efficacy analysis.

[0524] Patients (N = 543) were randomized to receive either compound (1) - 50 mg (n = 271) or placebo (n = 272). On day 15, the LSM treatment difference in all analysis subgroups favored compound (1) - 50 mg over placebo. - ADT use (none: -1.98; yes: -1.21) - Age (18 - 24 years: -1.67; 25 - 50 years: -1.96; 51 - 64 years: -1.18) - Gender (female: -1.58; male: -1.81), race (black: -2.20; white: -1.47; other: -4.22) - Baseline HAMD - 17 TS (<26: -1.25; ≥26: -1.91), and - Baseline BMI (kg / m 2 )(18.5 - 24.9: -1.02; 25 - 29.9: -3.94; ≥30: -1.04).

[0525] All treatment differences in the analyzed subgroups (based on baseline demographics and characteristics) favored compound (1) - 50 mg over placebo.

[0526] (Example 3) Detailed safety results of the Phase 3 study of Example 1

[0527] Safety results

[0528] TEAEs were consistent with the known profile of compound (1), and approximately 60% (e.g., approximately 60.1%) of patients who received compound (1) - 50 mg and approximately 45% (e.g., approximately 44.6%) of patients who received placebo reported ≥1 TEAE.

[0529] Most of the TEAEs reported by patients on 50 mg of Compound (1) were of mild or moderate severity. As evaluated by the Principal Investigator (PI), severe TEAEs related to IP, namely sedation, dizziness, vertigo, somnolence, psychiatric disorder, and anxiety (6 cases in 5 subjects) in the Compound (1)-50 mg treatment group; as evaluated by the PI, 1 severe event of elevated transaminase related to IP in the placebo treatment group. Two Compound (1)-50 mg patients and 2 placebo patients experienced serious adverse events (SAEs). There were none related to sedation. No deaths, loss of consciousness, weight gain, sexual dysfunction, or elation were reported. The most common TEAEs leading to discontinuation of the investigational drug (Compound (1)) were dizziness and sedation. Table 8 is a summary of TEAEs up to Day 42.

[0530]

Table 8

[0531] The most common (>5%) events were somnolence, dizziness, headache, and sedation in patients receiving 50 mg of Compound (1), and diarrhea and headache in patients receiving placebo. The most common TEAEs observed with Compound (1)-50 mg are consistent with the previously established safety profile of Compound (1). Table 6 shows all of the TEAE incidence rates up to Day 42.

[0532] Additional safety findings.

[0533] Suicidal tendency: No precursors of increased suicidal thoughts / behavior as evaluated by the C-SSRS were observed throughout the study in patients receiving 50 mg of Compound (1) or in patients receiving placebo.

[0534] Withdrawal symptoms: On day 18 or 21, there were no signs of withdrawal symptoms as evaluated by PWC-20. The scores were the same as after discontinuation of compound (1)-50 mg or placebo. Change from the first PWC-20 assessment (SD) on day 18; compound (1) vs placebo: -1.2 (4.3) vs -1.2 (4.3); on day 21; compound (1) vs placebo -0.3 (4.6) vs -0.5 (4.4).

[0535] Combined use of antidepressant therapy (ADT): There were no clinically significant differences in the safety profile of compound (1)-50 mg monotherapy compared to when administered in combination with existing ADT.

[0536]

Table 9

[0537] Exclusions for safety

[0538] Compound (1) was generally well tolerated, demonstrating a safety profile consistent with previous clinical studies. The completion rate of the trial was 90.3% in the compound (1) group.

[0539] The incidence of treatment-emergent adverse events (TEAEs) in the compound (1) group was 60.1%, while in the placebo (PBO) group it was 44.6%. Most of the TEAEs were of mild to moderate intensity. TEAEs that occurred in at least 5% of compound (1)-treated patients included somnolence 15.3% (3.0% PBO), dizziness 13.8% (2.2% PBO), headache 10.8% (7.8% PBO) and sedation 7.5% (0.4% PBO). Loss of consciousness, as well as adverse effects such as weight gain, sexual dysfunction or euphoria, were not reported.

[0540] No deaths occurred in the study. Two patients (0.7%) in the compound (1) group and the placebo group each reported serious adverse events. The incidence of TEAE leading to discontinuation of the investigational drug was 3.4% and 1.5% in the compound (1) group and the placebo group, respectively.

[0541] When evaluated by the 20-item Physician's Withdrawal Symptom Checklist and the Columbia Suicide Severity Rating Scale, no precursors related to withdrawal symptoms or increased suicidal thoughts or behaviors were identified.

[0542] 3.1 Detailed safety results

[0543] The study of Example 1 was designed to evaluate the efficacy, safety and tolerability of compound (1)-50 mg in patients with MDD compared to placebo. Considering that AEs associated with current monoamine-acting ADTs (e.g., SSRI, SNRI, TCA) used for the treatment of MDD can lead to treatment discontinuation, the unique safety profile of compound (1) is very interesting and is reported here.

[0544] Safety and tolerability were evaluated by the incidence and severity of adverse events (AE), serious adverse events (SAE), changes from baseline in clinical laboratory evaluations, vital signs and 12-lead electrocardiogram examinations. Suicidal tendency was monitored by the Columbia Suicide Severity Rating Scale (C-SSRS). The Physician's Withdrawal Symptom Checklist-20 total score (PWC-20 TS ) was used to monitor the presence of potential withdrawal symptoms after discontinuation of compound (1)-50 mg.

[0545] Results

[0546] Patients (N = 543) were randomized 1:1 to receive either compound (1) - 50 mg (n = 271) or placebo (n = 272). The safety population included all patients who received at least 1 dose of compound (1) - 50 mg (n = 268) or placebo (n = 269). Overall, 242 patients (90.3%) in the compound (1) - 50 mg group and 235 patients (87.4%) in the placebo group completed the study. Demographic and baseline clinical characteristics were balanced between treatment groups. The proportion of patients using antidepressants at baseline was 29.5% vs 30.1% in the compound (1) and placebo groups, respectively.

[0547] Compound (1) - 50 mg was generally well tolerated, and the safety profile was consistent with previous clinical studies.

[0548] The proportion of patients reporting treatment - emergent adverse events (TEAEs) was 60.1% (161 / 268) in the compound (1) - 50 mg group and 44.6% (120 / 269) in the placebo group. Most TEAEs were mild to moderate, and 8 patients (3.0%) and 3 patients (1.1%) had severe events in the compound (1) - 50 mg group and placebo group, respectively. The most common TEAEs (≥5% in either treatment group) included somnolence (15.3% vs 3.0%), dizziness (13.8% vs 2.2%), headache (10.8% vs 7.8%), sedation (7.5% vs 0.4%) and diarrhea (3.0% vs 5.2%) in the compound (1) - 50 mg group and placebo group, respectively.

[0549] AE of loss of consciousness, weight gain, sexual dysfunction or mania were not reported.

[0550] Among the patients who discontinued the investigational drug due to TEAE(s), 3.4% (9 / 268) were in the compound (1)-50 mg group and 1.5% (4 / 269) were in the placebo group. Two patients (0.7%) in each treatment group experienced serious adverse events (SAEs). One patient in each group experienced a treatment-related SAE that occurred during the treatment period. The patient in the compound (1)-50 mg group who experienced the SAEs of mental disorder and slow speech had a complex medical history, underlying neuropathological disease, and various aspects of behavior that stood out, including post-traumatic stress disorder, anxiety, multiple psychiatric hospitalizations due to suicidal tendency, auditory hallucinations and illusions, drug and alcohol abuse, and non-compliance with medication. The patient in the placebo group had an increase in liver function levels (alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyltransferase). When evaluated by the C-SSRS observed throughout the study, there was no precursor of increased suicidal ideation / behavior in patients who received compound (1)-50 mg or placebo (on day 15, the worsening of suicidal ideation or suicidal behavior was 0% in both the compound (1)-50 mg or placebo group). Regardless of the presence or absence of existing antidepressant therapies, no significant differences in the incidence and types of adverse events were observed among patients who received compound (1) (Table 10).

[0551]

Table 10

[0552] Compound (1) brought about a numerically greater improvement in the symptoms of insomnia, as reflected by a greater decrease from baseline in the individual item scores of HAMD-Insomnia at day 15 compared to placebo.

[0553] Insomnia was evaluated based on individual items of the HAMD-17 for initial insomnia (difficulty falling asleep), middle insomnia (inability to return to sleep soon after waking up at night), and late insomnia (waking up early in the morning before the sleep cycle is completed).

[0554] The mean decrease from baseline was numerically greater compared to placebo (nominal P < 0.05 * ): initial insomnia: -1.0 vs -0.7; middle insomnia: -1.2 vs -0.8; and late insomnia: -0.8 vs -0.5.

[0555] There was no precursor related to an increase in suicidal thoughts or suicidal behavior due to compound (1) (Table 11).

[0556]

Table 11

[0557] When evaluated by the PWC-20, no precursor of withdrawal symptoms was observed (the PWC-20 total score [standard deviation] on day 15 was 7.3 [6.57] and 8.0 [6.57] for compound (1) - 50 mg and placebo, respectively). The mean decrease (indicating improvement) in the PWC-20 total score was similar between treatment groups, suggesting no withdrawal effect after completion of treatment or discontinuation of compound (1) (Table 12).

[0558]

Table 12

[0559] Conclusion

[0560] There was no clinically meaningful difference in the safety profile of compound (1) - 50mg monotherapy compared to when administered in combination with existing antidepressant therapies. No deaths were reported during the study.

[0561] Consistent with the results of previous clinical studies, compound (1) was generally safe and well tolerated in patients with MDD. Approximately 3% of patients treated with compound (1) discontinued treatment due to TEAE. TEAE of weight gain, sexual dysfunction, or mania were not reported in the study, suggesting that improvement of depressive symptoms can be achieved without these AEs that are commonly reported with standard treatment, monoamine - acting antidepressants. No evidence of withdrawal symptoms or increased suicidal thoughts / behavior was identified.

[0562] (Example 4) A multi - institutional, randomized, double - blind, parallel - group, placebo - controlled study to evaluate the efficacy, safety, and pharmacokinetics of compound (1) in the treatment of adult female subjects with severe postpartum depression

[0563] ClinicalTrials.gov Identifier: NCT02978326

[0564] Objective of primary efficacy: To determine whether treatment with compound (1) reduces depressive symptoms compared to placebo in subjects with severe postpartum depression (PPD), as evaluated by the change from baseline in the total score of the 17 - item Hamilton Rating Scale for Depression (HAM - D) on day 15.

[0565] Objective of secondary efficacy - In subjects with severe PPD, determine whether treatment with 30 mg QD of the capsule formulation of compound (1) reduces depressive symptoms compared to placebo, as evaluated by the change from baseline in the total HAM-D score at all other time points. - Determine whether treatment with 30 mg QD of the capsule formulation of compound (1) reduces depressive symptoms compared to placebo, as evaluated by the change from baseline in the total scores of HAM-D response, HAM-D remission, Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression - Improvement (CGI-I) response, and the change from baseline in the HAM-D subscale and individual item scores at day 15 and all other time points. - Determine whether treatment with 30 mg QD of the capsule formulation of compound (1) reduces anxiety symptoms compared to placebo, as evaluated by the change from baseline in the total score of the Hamilton Anxiety Rating Scale (HAM-A) at day 15 and all other time points.

[0566] Safety objective: Evaluate the safety and tolerability of compound (1) compared to placebo, as evaluated by the incidence of adverse events, measurement of vital signs, clinical laboratory evaluations, electrocardiogram (ECG) parameters, and Columbia - Suicide Severity Rating Scale (C - SSRS).

[0567] Other objectives: - Evaluate healthcare resource utilization (HCRU) at baseline and day 45. - Determine whether treatment with 30 mg QD of the capsule formulation of compound (1) reduces subject - reported depressive symptoms compared to placebo, as evaluated by the change from baseline in the total scores of the Edinburgh Postnatal Depression Scale (EPDS) and the Patient Health Questionnaire (PHQ - 9) at day 15 and other time points. - To determine whether treatment with 30 mg QD of the capsule formulation of compound (1) improves maternal behavior as evaluated by the change from baseline in the total score and subscale scores of the Birkin Index of Maternal Function (BIMF) at day 15 and other time points compared to placebo. - To determine whether treatment with 30 mg QD of the capsule formulation of compound (1) improves the state of general health perception as evaluated by the change from baseline in the total score of the Short Form-36 (SF-36) at day 15 and other time points compared to placebo.

[0568] Objectives of pharmacokinetics: To evaluate the pharmacokinetic (PK) profile of compound (1) in plasma samples after administration of compound (1) and, if possible, the concentration of compound (1) in breast milk.

[0569] Study design and methodology

[0570] This was a multi-site, randomized, double-blind, parallel-group, placebo-controlled study of the efficacy, safety, and pharmacokinetics of compound (1) in adult subjects diagnosed with severe PPD.

[0571] The study was conducted in two parts. After one subject was enrolled and dosed in Part A, enrollment was closed. The current amendment describes only Part B.

[0572] Screening period:

[0573] The screening period started with the signing of the Informed Consent Form (ICF). The diagnosis of depression was determined using the Structured Clinical Interview for DSM-5 Axis I Disorders (SCID-I). Eligibility was determined by applying the inclusion / exclusion criteria. A complete medical and family history was obtained, including all records of major depressive episodes, other Axis I and II disorders, and postpartum depressive episodes in members of the subject's immediate female family.

[0574] Treatment period:

[0575] Once the subject was confirmed eligible for the study, the subject was randomized to the active investigational drug or placebo on a 1:1 basis.

[0576] The randomized subjects received 30 mg QD of the investigational drug (capsules of compound (1) or placebo). Subjects who could not tolerate 30 mg QD took 20 mg QD for the remainder of the treatment period. Subjects who experienced intolerant adverse events (AEs) at the 20 mg QD dose level could be withdrawn from the study treatment at the discretion of the study responsible physician. Subjects were instructed to take the investigational drug with food. During the entire 14-day treatment period, the investigational drug was self-administered by the subject at the outpatient site at night (8:00 pm ± 30 minutes). The investigational drug administration was monitored by a follow-up observation call from the facility (within approximately 1 hour after the scheduled night dosing) every night on days 1 to 14.

[0577] Subjects were not permitted to initiate psychotropic drugs or other drugs that could potentially affect the efficacy or safety endpoints within 30 days prior to informed consent until the completion of the day 15 assessment. Psychotropic drugs initiated at least 30 days prior to informed consent had to be maintained at a stable dose until the completion of the day 15 assessment.

[0578] Efficacy and safety evaluations were performed periodically during the study, and blood samples could be collected for the analysis of compound (1) and metabolites of compound (1) as outlined in the schedule of events in Table 13. Blood samples were collected at pre-specified times over the 14-day treatment period to obtain outcome measurements. Additionally, breast milk could be collected from the subject for the evaluation of the concentration of compound (1) if consent was obtained from the subject.

[0579] Follow-up observation period:

[0580] Follow-up observation period evaluations were performed at the outpatient site on days 21 ± 1 and 45 ± 3 after the start of investigational drug administration.

[0581] Number of subjects:

[0582] Approximately 140 subjects were randomized at a 1:1 ratio to have approximately 70 subjects per treatment group. Additional subjects could be enrolled to ensure 130 evaluable subjects. Evaluable subjects were defined as randomized subjects who received the investigational drug and had a valid baseline and at least one post-baseline HAM-D assessment.

[0583] Inclusion criteria:

[0584] Subjects had to meet the following inclusion criteria to be eligible for the study. 1. The subject had signed the ICF before any study-specific procedures were performed. 2. The subject was a ambulatory female between 18 and 45 years of age (inclusive). 3. The subject was in good physical health and had no clinically significant findings as determined by the Investigator for physical examination, 12-lead ECG, or clinical laboratory tests. 4. The subject consented to comply with the study requirements. 5. The subject had to have stopped breastfeeding at screening or, if still breastfeeding or actively lactating at screening, had to agree to temporarily discontinue breastfeeding her infant from immediately prior to taking the investigational drug until day 21 and to have a 7-day washout period after the last dose of the investigational drug. 6. The subject had to have a negative pregnancy test at screening and within 1 day prior to the start of investigational drug administration. 7. The subject had a major depressive episode that started after the third trimester of pregnancy and within the first 4 weeks postpartum and met the criteria for a major depressive episode according to DSM-5 as diagnosed by the Structured Clinical Interview for DSM-5 Axis I Disorders (SCID-I). 8. The subject has a total HAM-D score ≥ 26 at the time of screening and on Day 1 (before randomization). 9. The subject is ≤ 6 months postpartum. 10. The subject is willing to delay the initiation of other antidepressants or anxiolytics, including benzodiazepine anxiolytics if necessary, and any new drug therapy regimens until after the end of the treatment period and until all evaluations on Day 15 are completed. 11. The subject does not have detectable hepatitis B surface antigen (HBsAg), does not have detectable anti-hepatitis C virus (HCV), has detectable anti-HCV but is negative for viral load, and does not have detectable human immunodeficiency virus (HIV) antibodies at the time of screening. 12. Unless surgically infertile, the subject agrees to use one of the following contraceptive methods during the study and for 30 days after the last dose of the investigational drug: - Combined oral, vaginal, or transdermal hormonal contraception (containing estrogen and progestogen) with ovulation suppression. - Oral, injectable, or implantable progestogen-only hormonal contraception with ovulation suppression. - Intrauterine device. - Intrauterine hormone-releasing system. - Bilateral tubal occlusion. - Partner with vasectomy.

[0585] Exclusion Criteria

[0586] The subject is excluded if they meet any of the following exclusion criteria. 1. The subject has a recent medical history or clinically significant signs of an active disorder of metabolism, liver, kidney, hematology, lung, cardiovascular, gastrointestinal tract, musculoskeletal, skin, urogenital, nervous, or eye, ear, nose, and throat, or any other acute or chronic condition that, in the opinion of the principal investigator, may limit the subject's ability to participate in or complete this clinical study. 2. The subject has a known allergy to the capsules of compound (1) or its excipients. 3. The subject has an active mental disorder as evaluated by the principal investigator of the clinical trial. 4. The subject has attempted suicide related to the current episode of PPD. 5. The subject has a history of seizures. 6. The subject has a history of bipolar disorder, schizophrenia and / or schizoaffective disorder. 7. The subject has a history of active alcohol dependence or drug dependence (including benzodiazepines) within the 12 months prior to screening. 8. The subject has been exposed to another investigational drug or device within 30 days prior to screening. 9. The subject has previously participated in a clinical study of any brexanolone or compound (1). 10. Subjects who are taking antipsychotics, atypical antipsychotics, or other psychotropic drugs used to treat depressive symptoms and have not been taking the same dose of the above psychotropic drugs for at least 30 days prior to Day 1 and are currently taking the drugs while participating in the study. (Subjects who have discontinued taking these drugs within 30 days prior to the start date of the investigational drug may be eligible if they discontinue the drugs for a period longer than 5 half-lives until the start date of the investigational drug.) 11. Use of any known potent inhibitor of cytochrome P450 (CYP) 3A4 within 14 days or within 5 half-lives (whichever is longer), or ingestion of grapefruit juice, grapefruit, Seville orange, or products containing them within 14 days prior to taking the first dose of the investigational drug and throughout the study. 12. Use of any CYP inducer such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital, or St. John's wort within 14 days or within 5 half-lives (whichever is longer) prior to the first dosing of the investigational drug and throughout the study. 13. The subject has a positive urine drug test at the screening visit. 14. The subject has a planned elective surgery during the study.

[0587] Test article, dosage, and administration method:

[0588] The compound (1) capsules could be used as hard gelatin capsules containing a white to off-white powder. The capsules of the active compound (1) contained, in addition to the specified amount of the drug substance of compound (1), croscarmellose sodium, mannitol, microcrystalline cellulose phthalate, and sodium stearyl fumarate as excipients. The capsules were available in strengths of 10 mg, 20 mg, and 30 mg to provide treatment dosages of 20 mg and 30 mg. The subjects were administered 2 capsules per dose.

[0589] Reference treatment, dosage, and administration method:

[0590] Matched placebo capsules containing only the excipients of the capsules listed above were obtained. To maintain blinding, the subjects were administered 2 placebo capsules per day.

[0591] Participation period:

[0592] Up to 76 days (14 days of treatment).

[0593] Randomization:

[0594] The subjects were randomized to receive either compound (1) or matching placebo in a 1:1 ratio. The treatment assignment was blinded to the subjects, clinicians, and the research team. Randomization was performed centrally by an interactive response technology (IRT) system.

[0595] Dose adjustment due to safety / tolerance:

[0596] During the treatment period, the subjects were able to take the investigational drug unless there were safety / tolerance concerns that would limit the dose. The dose adjustment criteria are described above.

[0597] Criteria for evaluation:

[0598] Primary efficacy endpoint

[0599] The primary efficacy endpoint was defined as the change from baseline in the total HAM-D score at the end of the treatment period (day 15). The total HAM-D score was calculated as the sum of the 17 individual item scores.

[0600] Secondary efficacy endpoint

[0601] The secondary endpoints included the following: · Change from baseline in the total HAM-D score at all time points other than day 15; · HAM-D response defined as a 50% or greater decrease from baseline in the total HAM-D score; · HAM-D remission defined as HAM-D total score ≤ 7; · Change from baseline in the total MADRS score at day 15 and other time points; · CGI-I response defined as "marked improvement" or "moderate improvement"; · Change from baseline in the total HAM-A score at day 15 and other time points; · Change from baseline in the HAM-D subscales and individual item scores at day 15 and other time points

[0602] Safety endpoints: The safety and tolerability of the investigational drug were evaluated by the frequency of adverse events; the severity, relatedness, and seriousness of adverse events; clinical laboratory measurements, vital signs, ECG; and use of concomitant medications. Suicidal tendency was monitored using the C-SSRS.

[0603] Concomitant medications: The doses of all psychotropic medications were recorded throughout the study. During the treatment period, changes and / or additions of antidepressants or anxiolytics were not permitted.

[0604] Measurement of Plasma Concentration: Plasma samples were collected and assayed for the concentration of compound (1). Pharmacokinetic concentration data were characterized using population PK modeling techniques to estimate individual measurements of exposure to compound (1). Breast milk could be collected and analyzed for compound (1) as an optional assessment if consent was obtained from the subject.

[0605] Other Endpoints

[0606] Additional measures of emotional symptoms and function related to current episodes of PPD severity, including the EPDS, PHQ-9, BIMF, and SF-36, were collected before, during, and after the treatment period. Baseline diagnostic history, baseline antidepressant treatment history, and healthcare resource utilization data including medical visits, hospitalization visits, and drug use were collected at screening and at day 45.

[0607] Total scores and subscale scores, including changes from baseline, were calculated as needed. Changes from baseline up to the end of the treatment period (day 15) and other time points were evaluated as other efficacy endpoints. In addition to the scores above, the category of the total score and individual item scores were evaluated as other endpoints.

[0608] Statistical Methods:

[0609] General:

[0610] For all purposes of safety, efficacy, and other analyses as appropriate, the baseline was defined as the last measurement before the start of blinded investigational drug administration.

[0611] Continuous endpoints were summarized using the number (n), mean, standard deviation, median, minimum, and maximum values. Additionally, the change from the baseline value was calculated at each time point and summarized descriptively. For categorical endpoints, the descriptive summary included counts and percentages.

[0612] Analysis Population and Methods:

[0613] The entire randomized population defined as the randomized all subjects was used for the target treatment, demographics, and baseline characterization summary. The subjects were classified according to the randomized treatment.

[0614] Using the safety population defined as all subjects who received the investigational drug, a descriptive summary of the safety data was obtained. The subjects were summarized according to the treatment received.

[0615] Efficacy data were analyzed using the efficacy population defined as all subjects in the entire randomized population who completed the investigational drug for at least 1 day and had a valid baseline and at least 1 post-baseline efficacy assessment. The efficacy data were analyzed using appropriate descriptive statistics and pre-specified statistical methods, and, as appropriate, other data presentation methods. A listing of the subjects was obtained for all efficacy data. The subjects were analyzed according to the randomized treatment.

[0616] The PK population consisted of all subjects in the safety population by determination of the plasma concentration for compound (1) and was used for population PK modeling.

[0617] The change from baseline in the HAM-D total score was analyzed using a mixed effects model for repeated measures (MMRM). The model included, as explanatory variables, the facility, treatment, baseline HAM-D total score, assessment time point, and time point for each treatment. All post-baseline time points were included in the model. The primary comparison was between compound (1) and placebo at the 15-day time point. Model-based point estimates (e.g., least squares [LS] means), 95% confidence intervals, and p-values were reported. An unstructured covariance structure was used to model the within-subject error. Continuous secondary variables and other variables were analyzed using a similar method.

[0618] Binary efficacy endpoints, including responders and remission endpoints, were summarized and analyzed using the generalized estimating equations method.

[0619] Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA®) version 19.1 or later. The overall incidence of adverse events was presented by major organ class, preferred term, and treatment. The incidence of adverse events was also presented by maximum severity and relationship to the investigational drug. Vital signs, clinical laboratory measures, ECGs, concomitant medication use, and C-SSRS data were summarized by treatment as appropriate. Out-of-range safety endpoints could be classified as low or high as appropriate. Safety data were summarized and, where appropriate, the possible relationship between subject characteristics and plasma concentration of compound (1) was investigated. At baseline and at each visit during the active treatment period, suicidal tendency data collected using the C-SSRS were listed for all subjects. The C-SSRS listing included the action type and / or classification regarding C-SSRS suicidal thoughts and behaviors.

[0620] Sample size calculation:

[0621] Assuming a two-sided study with an alpha level of 0.05, a sample size of approximately 65 subjects per treatment group would achieve 90% power to detect a placebo-adjusted treatment difference of approximately 4 points on the primary endpoint on day 15, i.e., the change from baseline in the HAM-D total score, assuming a standard deviation (SD) of 7 points.

[0622] Assuming a 10% dropout and a 1:1 randomization ratio, approximately 72 randomized subjects per treatment group would be needed to obtain 130 evaluable subjects. Evaluable subjects were defined as randomized subjects who received the investigational drug and had a valid baseline and at least one post-baseline HAM-D assessment. If the dropout rate was higher than 10%, additional subjects could be randomized.

[0623] Table 13 shows the schedule of events for this clinical study.

[0624]

Table 13-1

[0625] (Example 5) Rapid and sustained improvement of the concurrent symptoms of depression and anxiety in the post hoc analysis of the treatment with compound (1) in postpartum depression (PPD).

[0626] Introduction

[0627] Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy. In the United States, the estimated values of women with self-reported symptoms of PPD vary by state annually, from 9.7% to 23.5%, and the overall prevalence is 13.2%. The symptoms of PPD can be related to significant impairments in mother-child bonding, including breastfeeding and child care, which affect the health and development of the child, as well as maternal function. Multiple environmental and biological risk factors have been proposed to play a role in the onset of PPD.

[0628] Compound (1) is an oral neuroactive steroid under investigation as a once-daily, two-week treatment for major depressive disorder and PPD. Compound (1) is a positive allosteric modulator of the GABAA receptor, and its activity at these receptors may play a role in the restoration of adaptive signaling in the brain. Dysregulation of adaptive signaling in the neuronal network is thought to be an important mechanism in depression.

[0629] In adult women with PPD, in a double-blind, randomized, placebo-controlled phase 3 trial (NCT02978326; the clinical trial of Example 4), compound (1) achieved a primary endpoint of a statistically significant reduction in depressive symptoms compared to placebo as evaluated by the Hamilton Rating Scale for Depression (HAMD-17) evaluated by 17 clinicians on day 15. This example investigated the simultaneous improvement of depressive and anxiety symptoms at day 15 and day 45 (follow-up of the trial), along with a post hoc analysis. The study protocol is shown in Example 4.

[0630] Method

[0631] As shown in Example 4, women aged 18 - 45 years with PPD (defined as a major depressive episode occurring during the third trimester of pregnancy or within ≤ 4 weeks postpartum) and a baseline HAMD-17 total score ≥ 26 (N = 151) were randomized 1:1 to receive either 30 mg of compound (1) or placebo orally once daily for 14 days with a 4-week follow-up in an outpatient setting. The change from baseline (CFB) of HAMD-17 relative to placebo on day 15 was defined as the primary endpoint. Treatment-emergent adverse events (TEAEs) were evaluated throughout the study.

[0632] Patients were randomized 1:1 to receive either 30 mg of compound (1) or placebo orally once daily for 14 days with a 4-week follow-up. The CFB of HAMD-17 relative to placebo at day 15 was used as the primary endpoint. Treatment-emergent adverse events (TEAEs) were evaluated throughout the study.

[0633] Secondary endpoints included the CFB of HAMD-17, the CFB of the Hamilton Rating Scale for Anxiety (HAM-A), and the CFB of the Montgomery-Åsberg Depression Rating Scale (MADRS) at all other measurement time points, separate from the primary endpoint at day 15.

[0634] Post hoc analysis was used to explore the simultaneous improvement of anxiety and depression on days 15 and 45 using the combination of scales: (1) HAMD-17 ≤ 7 + HAM-A ≤ 7 or (2) MADRS ≤ 10 + HAM-A ≤ 7. Improvement in depression was defined as either HAMD-17 total score ≤ 7 or MADRS total score ≤ 10. Improvement in anxiety symptoms was defined as HAM-A total score ≤ 7.

[0635] The CFB of the HAMD-17 total score was evaluated using the least squares mean from a mixed effects model for repeated measures. The simultaneous improvement rate was evaluated using Fisher's exact test, while the estimates for the odds ratio (OR) and 95% confidence interval (CI) for the OR were derived using a generalized estimating equation model for repeated measures and adjusted for baseline covariates (Table 14).

[0636] Sustained simultaneous improvement was defined as meeting the simultaneous improvement criteria on both days 15 and 45 and was evaluated using Fisher's exact test. Secondary endpoints and post hoc analyses were not adjusted for multiplicity.

[0637] Results

[0638] Compound (1) and the placebo groups included 76 and 74 patients, respectively, which were randomized and included in the efficacy analysis. Baseline demographics and patient characteristics were well balanced between the two treatment groups and have been described in detail previously.

[0639] Compound (1) demonstrated a statistically significant 15-day CFB compared to placebo in the HAMD-17 total score (primary endpoint: -17.8 vs -13.6, p = 0.0029) (Figure 19) LS mean difference -2.4, 95% CI -4.4 to -0.3; P =.02).

[0640] Compound (1) was generally well tolerated as previously described. The most common TEAEs that occurred in ≥5% of patients who received compound (1) were somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, and sedation. One subject experienced a serious adverse event (SAE) in the compound (1) group that resolved after dose reduction, and one subject experienced an SAE in the placebo group. There were no reports of loss of consciousness or fainting in either group.

[0641] The possibility of achieving simultaneous improvement of depressive and anxiety symptoms (on days 15 and 45), as well as sustained simultaneous improvement, was significantly higher in patients treated with compound (1) (Table 14).

[0642] [Table 14] * Odds ratio; ** Confidence interval

[0643] Using the combination of the HAMD-17 scale and the HAM-A scale (p-value adjusted by the model), a significantly higher proportion of patients treated with compound (1) achieved simultaneous improvement of depressive and anxiety symptoms on day 3 (p = 0.003), day 15 (p = 0.007), and day 45 (p < 0.001) (Figure 20A).

[0644] Similarly, using the combination of the MADRS scale and the HAM-A scale (p-value adjusted by the model), a significantly higher proportion of patients treated with compound (1) achieved simultaneous improvement of depressive and anxiety symptoms on day 3 (p = 0.010), day 15 (p = 0.014), and day 45 (p = 0.001) (Figure 20B).

[0645] A significantly high percentage of compound (1)-treated patients achieved sustained simultaneous improvement in anxiety and depression on days 15 and 45 when using HAMD-17 / HAM-A (p<0.001). Similarly, a significantly high percentage of compound (1)-treated patients achieved sustained simultaneous improvement in anxiety and depression from day 15 to day 45 when using MADRS / HAM-A (p = 0.003) (Figure 21).

[0646] Conclusion

[0647] Compound (1) achieved a primary endpoint of a statistically significant decrease in the HAMD-17 total score on day 15. Compound (1) demonstrated rapid (days 3 and 15) and sustained (day 45) improvement in core depressive symptoms.

[0648] In a post hoc analysis, sustained simultaneous improvement in depressive and anxiety symptoms was seen from day 15 to day 45.

[0649] In summary, these findings support the development of neuroactive steroids for the treatment of core depressive symptoms and anxiety in patients with PPD.

[0650] (Example 6) Rapid improvement and sustained effect of compound (1) on depressive symptoms, residual symptoms, and patient-reported outcomes in postpartum depression

[0651] Brief summary

[0652] This study evaluated the effects of compound (1) on depressive symptoms, anxiety, and sleep-related symptoms, as well as patient-reported outcomes (PROs), in women with postpartum depression (PPD). This was a phase 3, double-blind, randomized, outpatient, placebo-controlled trial, which was a post hoc analysis of the study of Example 4 (NCT02978326) conducted from January 2017 to December 2018 at 33 US facilities. Participants included women aged 18 to 45 years, ≤6 months postpartum, with PPD and a baseline Hamilton Rating Scale for Depression (HAMD-17) score ≥26 for 17-item depression. Participants were randomized 1:1 to receive placebo (n = 76) or 30 mg of compound (1) (n = 77) administered nightly for 2 weeks. In the compound (1) group, a significantly higher percentage of patients achieved HAMD-17 response (P =.0042) and remission (P =.0088) compared with placebo on day 15. Single-digit numbers needed to treat (NNTs) for HAMD-17 response and remission were found and were maintained from day 15 through day 45. Compound (1) demonstrated a statistically significant decrease in the least-squares mean change from baseline in HAMD-17 anxiety / physicalization compared with placebo, starting on day 3 (P =.0073) and lasting through day 45 (P =.0033). A significantly higher percentage of compound (1)-treated patients achieved simultaneous improvement in anxiety and depression as early as day 3 (all P <.05), which was sustained at the group level on days 15 and 45. Compound (1) also demonstrated improvement in depressive symptoms reported by patients compared with placebo. Thus, compound (1) produces a range of beneficial effects on depressive symptoms, as well as improvement in anxiety, insomnia, and other important PROs.

[0653] Introduction

[0654] Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy (Bauman BL, et al. MMWR Morb Mortal Wkly Rep. 2020;69(19):575-581; Hamilton BE, et al. National Center for Health Statistics. Births: Provisional data for 2018. Vital Statistics Rapid Release; Report No 7. Published May 2019; De...

Claims

【Claim 1】 The invention described in the specification.

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