19-nor C3,3-disubstituted C21-N-pyrazolyl steroids for use in the treatment of major depressive disorder and postpartum depression

Abstract

The present disclosure relates to a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof for use in a method for treating major depressive disorder with elevated anxiety (MDD) in a subject in need of such treatment. The present disclosure also relates to a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof for use in a method for treating postpartum depression with elevated anxiety (PPD) in a subject in need of such treatment. TIFF2024515829000106.tif3249

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 181,743, filed April 29, 2021; U.S. Provisional Application No. 63 / 197,025, filed June 4, 2021; U.S. Provisional Application No. 63 / 210,810, filed June 15, 2021; U.S. Provisional Application No. 63 / 239,096, filed August 31, 2021; U.S. Provisional Application No. 63 / 285,812, filed December 3, 2021; U.S. Provisional Application No. 63 / 289,506, filed December 14, 2021; U.S. Provisional Application No. 63 / 289,520, filed December 14, 2021; and U.S. Provisional Application No. 63 / 298,601, filed January 11, 2022. The entire contents of the above-referenced applications are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure is directed to a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof by administering a therapeutically effective amount of Compound (1) or a pharma- ceutically acceptable salt thereof. The present disclosure is also directed to a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof by administering a therapeutically effective amount of Compound (1) or a pharma- ceutically acceptable salt thereof. [Background technology]

[0003] background GABA, gamma-aminobutyric acid, profoundly influences the excitability of the entire brain, as up to 40% of 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 down the electrochemical gradient of the GRC. The increase in the level of this anion in the cell causes hyperpolarization of the membrane potential, making the neuron less sensitive to excitatory inputs (i.e., reduced neuronal excitability). In other words, the higher the concentration of chloride ions in the neuron, the lower the brain's excitability (level of arousal). It is well documented that the GRC is responsible for mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA (e.g., therapeutically useful barbiturates such as Valium® and benzodiazepines (BZs)) 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, NC 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, metabolites of the steroid hormones progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to modify brain excitability was recognized in 1986 (Majewska, MD et al., Science 232: 1004-1007 (1986); Harrison, NL et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Lan, NC et al., Neuwchem. Res. 16:347-356 (1991) [Non-Patent Document 2] Majewska, MD et al., Science 232: 1004-1007 (1986) [Non-Patent Document 3] Harrison, NL et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987) Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of Compound (1): [ka] The method includes administering

[0006] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0007] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days, i.e., about two 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.

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

[0009] In some embodiments, Compound (1) or the pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day in the evening.

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

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

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

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

[0014] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of initial treatment in response to recurrence of depressive symptoms. In some embodiments, the last dose of the initial treatment and the first dose of the re-administration are spaced apart by at least 6 weeks. In some embodiments, each of the initial treatment and 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 is treatment naive.

[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 prior to administration of Compound (1) or the pharma- ceutical acceptable salt of Compound (1).

[0018] In some embodiments, the MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher, prior to administration of compound (1) or the pharma- ceutically acceptable salt of compound (1). In some embodiments, the MDD with elevated 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 the pharma- ceutically acceptable salt of compound (1). In some embodiments, the MDD with elevated 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, prior to administration of compound (1) or the pharma- ceutically acceptable salt of compound (1).

[0019] In some embodiments, the subject exhibits a reduction from baseline in HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject exhibits at least a 14-point reduction in HAM-D total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1). In some embodiments, the subject exhibits at least a 12-point reduction in HAM-A total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1).

[0020] In another aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] The method includes administering

[0021] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0022] In some embodiments, compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days, i.e., about two 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 pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 30 mg or about 40 mg of the free base compound.

[0024] In some embodiments, Compound (1) or the pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day in the evening.

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

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

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

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

[0029] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of initial treatment in response to recurrence of depressive symptoms. In some embodiments, the last dose of the initial treatment and the first dose of the re-administration are spaced apart by at least 6 weeks. In some embodiments, each of the initial treatment and re-administration is carried out 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 is treatment naive.

[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 pharma- ceutical acceptable salt of Compound (1).

[0033] In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher prior to administration of Compound (1) or the pharmacologic salt of Compound (1). In some embodiments, PPD with elevated 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 pharmacologic salt of Compound (1). In some embodiments, PPD with elevated 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 the pharmacologic salt of Compound (1).

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

[0035] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0036] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0037] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject from about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0038] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0039] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0040] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0041] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0042] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0043] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The method includes the steps of:

[0044] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The method includes the steps of:

[0045] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The method includes the steps of:

[0046] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The method includes the steps of:

[0047] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of Compound (1).

[0048] In one aspect, the disclosure provides a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharma- ceutical acceptable salt of Compound (1).

[0049] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The subject is taking a stable dose of an additional antidepressant for at least 30 days prior to administration of Compound (1).

[0050] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of wherein the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of the pharma- ceutical acceptable salt of Compound (1).

[0051] In one aspect, the disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering 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 disclosure provides a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of wherein the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharma- ceutical acceptable salt of Compound (1).

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

[0054] In some embodiments, Compound (1) or the pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day in the evening.

[0055] In some embodiments, the subject is treatment naive.

[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 pharma- ceutical 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 pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of the initial treatment period in response to recurrence of depressive symptoms. In some embodiments, the last dose of the initial treatment period and the first dose of the re-administration are spaced apart by at least 6 weeks. In some embodiments, the re-administration is carried out for about 14 days, i.e., about 2 weeks.

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

[0060] In some embodiments, the subject exhibits a reduction from baseline in HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject exhibits at least a 14-point reduction in HAM-D total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1). In some embodiments, the subject exhibits at least a 12-point reduction in HAM-A total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1). [Brief description of the drawings]

[0061] [Figure 1] FIG. 1 illustrates an exemplary study design for treating MDD with compound (1).

[0062] [Diagram 2] FIG. 2 shows the least squares (LS) mean change from baseline in HAMD-17 total score at day 15 and other time points.

[0063] [Diagram 3] Figure 3 shows the mean percent of CFB retained at subsequent visits on day 15. Retention of reduction in HAMD-17 total score from baseline on day 15 is the change from baseline in HAMD-17 total score at the visit 15 days later as a percentage of change from baseline on day 15, and was assessed only in HAMD-17 responders on day 15 in the compound (1) treatment group (≧50% change in HAMD-17 total score on day 15 relative to baseline).

[0064] [Figure 4] FIG. 4 shows the LS mean differences of the HAMD-17 subgroups on day 15.

[0065] [Diagram 5] FIG. 5 shows the LS mean change in CGI-S from baseline on day 15 and at other time points.

[0066] [Figure 6] FIG. 6 shows the CGI-improvement responses at day 15 and other time points.

[0067] [Figure 7]Figure 7 shows the CGI-Improvement scores on day 15 for the clinical trial study of Example 1 and three other clinical trials conducted by the applicant. Phase 3 study* is a phase 3 clinical trial study conducted by the applicant (ClinicalTrials.gov Identifier / NCT Number: NCT03864614). Phase 3 study** is a phase 3 clinical trial study conducted by the applicant (ClinicalTrials.gov Identifier / NCT Number: NCT0672175). Phase 2 study*** is a phase 2 clinical trial study conducted by the applicant (ClinicalTrials.gov Identifier / NCT Number: NCT03000530).

[0068] [Figure 8] FIG. 8 shows the change from baseline in MADRS total score at day 15 and other time points.

[0069] [Figure 9] FIG. 9 shows that treatment differences in HAMD-17 and MADRS total scores at day 15 were significantly in favor of compound (1).

[0070] [Figure 10A] FIG. 10A shows HAMD-17 responses at day 15 and other time points.

[0071] [Figure 10B] FIG. 10B shows HAMD-17 remission at day 15 and other time points.

[0072] [Figure 11] FIG. 11 shows the MADRS response rate and remission rate on days 8 and 15.

[0073] [Figure 12] FIG. 12 shows the HAM-A total score change from baseline on day 15 and at other time points.

[0074] [Figure 13] FIG. 13 shows HAMD-17 anxiety / somatization score change from baseline on day 15 and other time points.

[0075] [Figure 14A] FIG. 14A shows that improvement in both anxiety and depression symptoms favors compound (1) compared to placebo at day 8.

[0076] [Figure 14B] FIG. 14B shows that improvement in both anxiety and depression symptoms favors compound (1) compared to placebo at day 15.

[0077] [Figure 15A] FIG. 15A shows the LS mean change from baseline in HAMD-17 for compound (1)-treated patients with MDD with elevated anxiety and compound (1)-treated patients with MDD without elevated anxiety.

[0078] [Figure 15B] FIG. 15B shows the LS mean change from baseline in HAM-A for compound (1)-treated patients with MDD with elevated anxiety and compound (1)-treated patients with MDD without elevated anxiety.

[0079] [Figure 16] FIG. 16 shows the pooled LS mean change from baseline in HAMD-17 for Compound (1)-treated patients with MDD without elevated anxiety and Compound (1)-treated patients with MDD with elevated anxiety.

[0080] [Figure 17] FIG. 17 shows the pooled mean HAMD-17 total scores for Compound (1)-treated patients with MDD without elevated anxiety and Compound (1)-treated patients with MDD with elevated anxiety.

[0081] [Figure 18A]FIG. 18A shows the pooled mean SF-36v2 scores of Compound (1)-treated patients with MDD without elevated anxiety.

[0082] [Figure 18B] FIG. 18B shows the pooled mean SF-36v2 scores of Compound (1)-treated patients with MDD with elevated anxiety.

[0083] [Figure 19] FIG. 19 is a line graph showing the improvement in depressive symptoms achieved with Compound (1) compared to placebo based on change from baseline in HAMD-17 score.

[0084] [Figure 20A] FIG. 20A is a bar graph showing concurrent improvement of depression and anxiety symptoms with Compound (1) compared to placebo based on HAMD-17 and HAM-A scores.

[0085] [Figure 20B] FIG. 20B is a bar graph showing concurrent improvement of depression and anxiety symptoms with Compound (1) compared to placebo based on MADRS and HAM-A scores.

[0086] [Figure 21] FIG. 21 is a bar graph showing the percentage of patients with sustained simultaneous improvement in depression and anxiety.

[0087] [Figure 22A] FIG. 22A is a bar graph comparing NNT vs. placebo for response and remission.

[0088] [Figure 22B] FIG. 22B is a bar graph comparing NNT vs. placebo for sustained remission.

[0089] [Figure 23A]FIG. 23A is a line graph showing change from baseline in HAMD-17A / S.

[0090] [Figure 23B] FIG. 23B is a line graph showing the change from baseline in EPDS-3A.

[0091] [Figure 24A] FIG. 24A is a bar graph showing HAM-A response rates.

[0092] [Figure 24B] FIG. 24B is a bar graph showing HAM-A remission rates.

[0093] [Figure 24C] FIG. 24C is a bar graph showing HAMD-17A / S response rates.

[0094] [Figure 25A] FIG. 25A is a line graph showing improvement in insomnia symptoms based on change from baseline in HAMD-17-Ins score.

[0095] [Figure 25B] FIG. 25B is a line graph showing improvement in insomnia symptoms based on change from baseline in MADRS-Ins scores.

[0096] [Figure 26A] FIG. 26A is a line graph showing PHQ-9 change from baseline.

[0097] [Figure 26B] FIG. 26B shows correlation with HAM-D in the pooled population.

[0098] [Figure 27] FIG. 27 is a bar graph showing EPDS remission percentage.

[0099] [Figure 28] FIG. 28 shows the correlation between HAMD-17 and EPDS scores by visit.

[0100] [Figure 29A] FIG. 29A is a bar graph comparing improvement in SF-36 domain and summary scores.

[0101] [Figure 29B] FIG. 29B is a bar graph comparing the proportion meeting SF-36 population norms at baseline, day 15, and day 45.

[0102] [Figure 30A] Figure 30A shows the study design for the dose selection phase of the study in Example 7. For the dose selection phase, the dose of Compound (1) did not exceed 90 mg. *Sentinel dosing was used for each cohort, and on day 1, one participant was randomized to receive Compound (1) and one participant was randomized to receive placebo. The remaining six participants were dosed approximately 24 hours later after tolerability was confirmed.

[0103] [Figure 30B] Figure 30B shows the study design for the main study phase of the study of Example 7. †The randomization ratio was 1:1:1:1:1:1:1. ‡Dose was determined based on the results of the dose selection phase. R=randomization.

[0104] [Figure 31A] FIG. 31A shows patient treatment for the dose selection phase of the study of Example 7.

[0105] [Figure 31B] FIG. 31B shows patient disposition for the treatment phase of the study of Example 7.

[0106] [Diagram 32]Figure 32 shows the mean Drug Liking VAS Emax over time (modified completer population, n=60). Drug Liking VAS was assessed using the question "At this moment, what is my preference for this drug?", where answers range from 0 (really dislike it) to 100 (really like it), with a score of 50 being neutral. Emax=maximal effect; VAS=visual analog scale.

[0107] [Diagram 33] Figure 33 shows the paired difference of Drug Liking VAS Emax (corrected completers, n=60). Drug Liking (Current) was assessed by "At this moment, my preference for this drug is," where responses range from 0 (really dislike it) to 100 (really like it), with 50 being the neutral point. CI=confidence interval; Emax=maximum effect; VAS=visual analog scale.

[0108] [Figure 34A] Figure 34A shows the paired difference of total drug liking VAS Emax (corrected completer population, n=60). Total drug liking was assessed by "Overall, my liking for this drug is," where responses range from 0 (really dislike it) to 100 (really like it), with 50 being the neutral point. CI=confidence interval; Emax=maximum effect; VAS=visual analog scale.

[0109] [Figure 34B] Figure 34B shows the paired difference of VAS Emax of drug relapse (corrected completer population, n=60). Drug relapse was assessed by "I would take this drug again", where responses range from 0 (not at all true) to 100 (very true), with 50 being the neutral point. CI=confidence interval; Emax=maximum effect; VAS=visual analog scale.

[0110] [Diagram 35]Figure 35 shows the mean alertness / sleepiness VAS over time (modified completers, n=60). Alertness / sleepiness VAS was assessed using the question "At this moment, what is my state of mind?", where responses range from 0 (very sleepy) to 100 (very alert), with a score of 50 being neutral. VAS=visual analog scale.

[0111] [Diagram 36] Figure 36 shows the mean any drug effect VAS Emax over time (modified completer population, n=60). Any drug effect VAS was assessed using the question "At this moment, what is my preference for this drug?", where answers range from 0 (really dislike it) to 100 (really like it), with a score of 50 being neutral. Emax=maximum effect; VAS=visual analog scale.

[0112] [Figure 37] FIG. 37 shows the mean plasma concentration of Compound (1) versus time profile by treatment following single dose administration (PK population, n=71). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0113] Detailed Description I. Definition

[0114] As used herein, “compound (1)” refers to a compound having the formula (or structure): [ka] It refers to a compound having the 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 by 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. Pat. No. 9,512,165 and PCT Publication No. WO2014 / 169833, the entire contents of which 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, the entire contents of which 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, the entire contents of which are incorporated herein by reference in their entirety.

[0116] Compound (1) inhibits synaptic and extrasynaptic GABA receptors. A GABA Receptor Targeting A Compound (1) is a neuroactive steroid that has been shown to be a positive allosteric modulator of the GABA receptor. A As a positive allosteric modulator of the receptor, it serves as a therapeutic agent to treat CNS-related disorders such as depression, postpartum depression and major depressive disorder, as well as to treat neurological conditions such as essential tremor, epilepsy and Parkinson's disease.

[0117] As used herein, "crystalline" refers to a solid phase of a given chemical entity that has a well-defined three-dimensional structural order. The atoms, ions and / or molecules are arranged in a regular, periodic manner in a repeating three-dimensional lattice. In various embodiments, a crystalline material may include one or more discreet crystalline forms.

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

[0119] The term "substantially crystalline" refers to a form that may be crystalline to at least a certain weight percent. The certain weight percentage may 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 certain weight percentage of crystallinity is at least 90%. In some embodiments, the certain weight percentage of crystallinity is at least 95%. In some embodiments, Compound (1) may be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline forms A and C) and / or PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference in their entirety.

[0120] The term "substantially pure" refers to a composition of a particular crystalline form (e.g., a crystalline form of Compound (1)) that may be free of impurities and / or other solid forms at least a particular weight percentage. The particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound (1) may 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) may be substantially pure form A. In some embodiments, Compound (1) may be substantially pure form C.

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

[0122] The term "characteristic peaks," when describing peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of Compound (1)), refers to a particular collection of diffraction peaks whose values, taken as a whole, span a range of 2θ values ​​(e.g., from 0° to 40°) that is characteristic of that particular crystalline form.

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

[0124] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic 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, and the like; or with 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-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or is coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0125] Chemical elements are identified according to the Periodic Table of the Elements (CAS version) on the inside cover of Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are defined as described therein. Additionally, 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 particular quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless specifically stated or implied.

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

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

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

[0130] As used herein, a "transient dosing regimen" is a dosing regimen in which a compound or a composition comprising a compound is administered to a subject for a limited period of time in response to a diagnosis of a disorder or a symptom thereof, e.g., a diagnosis or symptom of depression or an episode of major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit comprising Compound (1) and one or more suitable pharmaceutical excipients. In some embodiments, the transient dosing regimen has a duration of multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, transient dosing of a compound is administered for a limited period of time, e.g., about 2 weeks to about 8 weeks, in response to a diagnosis or recurrence of a disorder, e.g., depression or a symptom thereof. In some embodiments, the transient dosing is administered once a day for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the episodic dosing has a duration of 2 weeks. In some embodiments, more than one episodic dosing regimen, but no more than three episodic dosing regimens, for example, two or more episodic regimens, are administered to a subject over a 12 month period.

[0131] As used herein, the term "modulation" refers to the inhibition or activation of GABA A receptor function. A "modulator" (e.g., a compound that modulates GABA A receptor function or its pharma- ceutically acceptable salt) can be, for example, an agonist, partial agonist, antagonist or partial antagonist of GABA A receptor.

[0132] "MDD with elevated anxiety" or "MDD with anxiety distress" are used interchangeably and refer to a subject with MDD who exhibits elevated anxiety as a symptom of their depression. In some embodiments, MDD with elevated anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (i.e., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 20 at baseline. "PPD with elevated anxiety" or "PPD with anxiety distress" are used interchangeably and refer to a subject with PPD who exhibits elevated anxiety as a symptom of their depression. In some embodiments, PPD with elevated anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (i.e., before administration of Compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e., before administration of Compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 20 at baseline.

[0133] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0134] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) is an amount sufficient to realize a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound (or a pharma- ceutically acceptable salt thereof) refers to the amount of a therapeutic agent, alone or in combination with other therapies, that realizes 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 the 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 pharma- ceutically acceptable salt or pharma- ceutically 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 a disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a 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 pharmaceutical dose(s) in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalation formulations and chewables.

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

[0138] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition, which actions reduce the severity of the disease, disorder, or condition (or any symptoms thereof) or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate prophylactic actions taken 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 antidepressant within at least 30 days before the start of treatment (e.g., day 1) or within at least 60 days before the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressant within at least 30 days before the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressant within at least 60 days before 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 about 10 mg to about 100 mg, about 20 mg to about 55 mg, or 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 comprises about 40 mg of Compound (1) and is in the form of a capsule. In other embodiments, the unit dosage form comprises about 50 mg of Compound (1) and is in the form of a capsule. In another embodiment, the unit dosage form comprises about 45 mg of Compound (1) and is in the form of a capsule. In some embodiments, a capsule comprising about 40 mg, about 45 mg or about 50 mg of Compound (1) is administered to a subject once a day. In some embodiments, two or more capsules together comprise 40 mg of Compound (1). In some embodiments, two or more capsules together comprise 45 mg of Compound (1). In some embodiments, two or more capsules together comprise 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 a subject once a day. In some embodiments, three capsules together contain 30 mg of Compound (1). In some embodiments, three capsules together 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 recognition, 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 recognition, 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 with treatment can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.The phrase "improve cognitive function" refers to the positive change in the subject's ability to carry out symbolic operations, for example, to perceive, to remember, to create mental images, to have clarity of thought, to be aware, to reason, to think or to judge.Positive change can be measured using any of the above-mentioned tests on two or more occasions, for example, the first occasion for measuring baseline cognitive function, and the second occasion for measuring cognitive function after a certain period of time (may be treated).

[0145] II. Method of Treatment

[0146] MDD with elevated anxiety

[0147] In one aspect, the present disclosure is directed to a method for treating major depressive disorder (MDD) with elevated anxiety. In some embodiments, the diagnosis and severity of major depressive disorder treated by the methods described herein is determined according to the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as defined by the DSM-5 Edition (DSM-5).

[0148] Depressive disorder

[0149] Depressive disorders include major 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. The common feature of all of these disorders is the presence of a sad, empty, or irritable mood accompanied by physical and cognitive changes that significantly affect an individual's ability to function. What differs between them is the matter of duration, timing, or presumed etiology.

[0150] Major depressive disorder represents the classic presentation in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although most episodes last much longer) with distinct changes in affect, cognition and autonomic nervous system function and remissions between episodes. Discrete episodes of major depressive disorder may be called "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 major depressive disorder or clinical depression, is a mood disorder that causes persistent feelings of sadness and loss of interest.

[0154] In some embodiments, MDD is defined and diagnosed according to DSM-5, for example, MDD is diagnosed according to diagnostic criterion A, as described below.

[0155] Diagnostic Criteria A. Five (or more) of the following symptoms appear 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 for most of the day, almost every day, as indicated by either subjective report (e.g., feeling sad, empty, hopeless) or observation made by others (e.g., appearing tearful) (Note: in children and adolescents, irritable mood is possible). 2. Markedly diminished interest or pleasure in all or almost all activities for most of the day, almost every day (as indicated by either subjective description or observation). 3. Significant weight loss or gain when not on a diet (e.g., more than a 5% change in body weight in one month) or decreased or increased appetite on most days (Note: in children, consider that this may not be expected weight gain). 4. Having insomnia or excessive sleep almost every day. 5. Psychomotor agitation or retardation (observable by others, not just a subjective feeling of restlessness or slowness) almost every day. 6. Feeling fatigued or inactive almost every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) almost every day (not just remorse or guilt about being ill). 8. Poor ability to think or concentrate, or indecisiveness almost every day (either subjectively described or observed by others). 9. Recurrent thoughts of death (not just the fear of death), recurrent suicidal thoughts without a specific plan, or a specific plan to attempt or commit suicide.

[0156] Diagnostic criteria B through E described below are further explanations of MDD and may be considered explanations or diagnoses of MDD, but are not required.

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

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

[0159] 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 schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0161] Diagnostic Criterion E. Never had a manic or hypomanic episode.

[0162] In some embodiments, a major depressive episode (MDE) is a period characterized by 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 according to diagnostic criteria A through C, as described above. In some embodiments, MDD is diagnosed according to diagnostic criteria A through E, as described above.

[0165] Diagnostic Features

[0166] The diagnostic criteria symptoms of major depressive disorder, except for weight change and suicidal ideation, must be present almost every day to be considered present. In addition to being present almost every day, depressed mood must be present for a large portion of the day. Often, insomnia or fatigue is the presenting complaint, leading to underdiagnosis if the patient fails to investigate the accompanying depressive symptoms. Sadness may be initially denied, but may be elicited by interview or inferred from facial expression and demeanor. For individuals who focus on somatic complaints, the clinician should determine whether the distress resulting from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disorders are less common but are indicators of greater overall severity, as are delusional or delusional feelings of guilt.

[0167] The essential feature of a major depressive episode is a period of at least 2 weeks during which there is either a depressed mood or a 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 four additional symptoms drawn from a list including: changes in appetite or weight, sleep and psychomotor activity; decreased motivation; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or suicide attempts. To count as a major depressive episode, the symptoms must be new or have clearly worsened compared with the person's pre-episode state. Symptoms must persist for most of the day, almost every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with mild episodes, functioning may appear normal but requires significantly increased effort.

[0168] Sleep disturbances may take the form of either difficulty sleeping or excessive sleeping (criterion A4). When insomnia is present, it usually takes the form of intermediate insomnia (i.e., difficulty getting back to sleep after waking during the night) or end-stage insomnia (i.e., waking too early and not being able to get back to sleep). Early-stage insomnia (i.e., difficulty falling asleep) may also occur. Individuals who exhibit hypersomnia (excessive sleep) may experience longer episodes of sleep at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is because of a sleep disorder.

[0169] Major depressive disorder with elevated anxiety / anxiety distress

[0170] The DSM-5-defined identifier "anxiety distress" for MDD indicates the presence of at least two of the following symptoms during most days of a major depressive episode or persistent depressive disorder (dysthymia): 1. Feeling excited or nervous. 2. Feeling unusually restless. 3. Worrying makes it hard to concentrate. 4. You are afraid that something terrible might happen. 5. I feel like I'm losing control.

[0171] "Anxiety distress" and "elevated anxiety" are used interchangeably herein.

[0172] Severity is defined as follows: Mild: 2 symptoms. Moderate: 3 symptoms. Moderate to severe: 4 or 5 symptoms. Severe: Four or five symptoms with motor agitation.

[0173] Anxiety distress has been documented as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with a higher suicide risk, longer duration of illness, and a higher likelihood of not responding to treatment.

[0174] Accordingly, one embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound (1): [ka] The present invention is directed to a method comprising administering

[0175] Another aspect of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering a therapeutically effective amount of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0176] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days or about two weeks. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two 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 a day at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once a day at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once a day 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 a day at a dose of about 20 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for less than 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 14 days.

[0180] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered 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 pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg of the free base compound.

[0181] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily 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 pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg of the free base compound.

[0182] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 30 mg of the free base compound once daily for about 14 days.

[0183] In some embodiments, Compound (1) or a pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0184] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0185] In some embodiments, Compound (1) or a pharma- ceutically 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 pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharma- ceutically 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 pharma- ceutically acceptable salt of compound (1) is administered with a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0187] In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 15 minutes before the patient goes to sleep. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day within 1 hour before the patient goes to sleep. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) 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 Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference.

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

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

[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 pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of initial treatment in response to recurrence of depressive symptoms. In some embodiments, the last dose of the initial treatment and the first dose of the re-administration are spaced apart by at least 6 weeks. In some embodiments, each of the initial treatment and re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0193] In some embodiments, the methods include administering a second therapeutic agent.

[0194] In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to administration of Compound (1) or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1).

[0196] In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, 18 or higher, 19 or higher, or 20 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher before administration of compound (1) or a pharma- ceutically acceptable salt of compound (1). In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 18 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 19 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 20 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher.

[0197] In some embodiments, the MDD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0198] In some embodiments, the MDD with elevated 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) prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated 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 prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0199] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0200] In some embodiments, the subject exhibits a reduction from baseline in HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject exhibits at least a 14-point reduction in HAM-D total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1). In some embodiments, the subject exhibits at least a 12-point reduction in HAM-A total score 15 days after administration of Compound (1) or the pharmacologic acceptable salt of Compound (1).

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

[0202] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in Hamilton Depression 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 a core depression, Bech-6, Meyer score, and / or anxiety score. In some embodiments, the reduction in the HAM-D Core Depression Subscale score LS mean from baseline at day 15 is at least about 1 to 3. In some embodiments, the reduction in the HAM-D Bech-6 subscale score LS mean from baseline at day 15 is at least about 3. In some embodiments, the reduction in the HAM-D Meyer subscale score LS mean from baseline at day 15 is at least about 2.5. In some embodiments, the reduction in the HAM-D Anxiety subscale score LS mean from baseline at 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 (relating to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lethargy, inability to feel, pessimistic thoughts, and suicidal thoughts) 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 baseline in 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). In some embodiments, the decrease from baseline in MADRS score ranges from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or lower). For example, the mean change from baseline in MADRS total score resulting from treatment with compound (1) or a pharma- ceutically acceptable salt of compound (1) is about -15, -20, -25, -30, while the mean change from baseline in MADRS total score resulting from treatment with placebo is about -15, -10, -5.

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

[0205] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction 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 reduction in the HAM-A score from baseline 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 pharma- ceutically acceptable salt of Compound (1)). In some embodiments, the reduction in the HAM-A score from baseline is from severe (e.g., a HAM-A score of 25 or higher) to asymptomatic (e.g., a HAM-A score of 17 or less). In some embodiments, the decrease from baseline in the HAM-A score is from severe (eg, a HAM-A score of 25 or higher) to mild (eg, a HAM-A score of 24 or less).

[0206] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by an improvement in SF-36 score) within about 45, about 21, about 15, about 8, or about 3 days. SF-36 Physical Function Score. SF-36 is a short-form health survey that includes 36 questions 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) in eight domains (physical functioning [PF]; role functioning (physical) [RP]; bodily pain [BP]; general health [GH]; vitality [V]; social functioning [SF]; daily living functioning (mental) [RE]; mental health [MH]). In some embodiments, the therapeutic benefit is a reduction from baseline in each domain of 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 initiation of administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0207] PPD with elevated anxiety

[0208] In another aspect, the disclosure is directed to a method for postpartum depression (PPD) accompanied by elevated anxiety.

[0209] Postpartum depression (PPD), also called depression after childbirth, is a type of mood disorder that accompanies childbirth. Postpartum depression (PPD) is commonly known in the art.

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

[0211] Professional health organizations vary in their definitions of PPD occurrence. For example, the American Psychiatric Association characterizes PPD as having an onset during pregnancy or within 4 weeks of delivery (DSM-5). The American College of Obstetricians and Gynecologists characterizes PPD as having an onset during pregnancy or within 12 months after delivery (ACOG, updated December 2021). The World Health Organization characterizes PPD as having an onset within 12 months after delivery (International Classification of Diseases 10 thedition (ICD-10). Thus, in some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by DSM-5. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ACOG. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ICD-10.

[0212] In some embodiments, a diagnosis of PPD with elevated anxiety treated by the methods described herein is based on the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as MDD with perinatal onset and specifiers of anxiety distress, as defined by the DSM-5 Edition (DSM-5), i.e., as described below.

[0213] Depressive disorder

[0214] Depressive disorders include major 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. The common feature of all of these disorders is the presence of a sad, empty, or irritable mood accompanied by physical and cognitive changes that significantly affect an individual's ability to function. What differs between them is the matter of duration, timing, or presumed etiology.

[0215] Major depressive disorder represents the classic presentation in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although most episodes last much longer) with distinct changes in affect, cognition and autonomic nervous system function and remissions between episodes. Discrete episodes of major depressive disorder may be called "major depressive episodes" or "depressive episodes".

[0216] Major Depressive Disorder (MDD)

[0217] In some embodiments, MDD, also known as major depressive disorder or clinical depression, 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 DSM-5, for example, MDD is diagnosed according to diagnostic criterion A, as described below.

[0219] Diagnostic Criteria A. Five (or more) of the following symptoms appear 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 for most of the day, almost every day, as indicated by either subjective report (e.g., feeling sad, empty, hopeless) or observation made by others (e.g., appearing tearful) (Note: in children and adolescents, irritable mood is possible). 2. Markedly diminished interest or pleasure in all or almost all activities for most of the day, almost every day (as indicated by either subjective description or observation). 3. Significant weight loss or gain when not on a diet (e.g., more than a 5% change in body weight in one month) or decreased or increased appetite on most days (Note: in children, consider that this may not be expected weight gain). 4. Having insomnia or excessive sleep almost every day. 5. Psychomotor agitation or retardation (observable by others, not just a subjective feeling of restlessness or slowness) almost every day. 6. Feeling fatigued or inactive almost every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) almost every day (not just remorse or guilt about being ill). 8. Poor ability to think or concentrate, or indecisiveness almost every day (either subjectively described or observed by others). 9. Recurrent thoughts of death (not just fear of death), recurrent suicidal thoughts without a specific plan, or a specific plan to attempt or commit suicide.

[0220] Diagnostic criteria B through E described below are further explanations of MDD and may be considered explanations or diagnoses of MDD, but are not required.

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

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

[0223] 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 schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0225] Diagnostic Criterion E. Never had a manic or hypomanic episode.

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

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

[0228] In some embodiments, MDD is diagnosed according to diagnostic criteria A through C, as described above. In some embodiments, MDD is diagnosed according to diagnostic criteria A through E, as described above.

[0229] Diagnostic Features

[0230] The diagnostic criteria symptoms of major depressive disorder, except for weight change and suicidal ideation, must be present almost every day to be considered present. In addition to being present almost every day, depressed mood must be present for a large portion of the day. Often, insomnia or fatigue is the presenting complaint, leading to underdiagnosis if the patient fails to investigate the accompanying depressive symptoms. Sadness may be initially denied, but may be elicited by interview or inferred from facial expression and demeanor. For individuals who focus on somatic complaints, the clinician should determine whether the distress resulting from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disorders are less common but are indicators of greater overall severity, as are delusional or delusional feelings of guilt.

[0231] The essential feature of a major depressive episode is a period of at least 2 weeks during which there is either a depressed mood or a 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 four additional symptoms drawn from a list including: changes in appetite or weight, sleep and psychomotor activity; decreased motivation; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or suicide attempts. To count as a major depressive episode, the symptoms must be new or have clearly worsened compared with the person's pre-episode state. Symptoms must persist for most of the day, almost every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with mild episodes, functioning may appear normal but requires significantly increased effort.

[0232] Sleep disturbances may take the form of either difficulty sleeping or excessive sleeping (criterion A4). When insomnia is present, it usually takes the form of intermediate insomnia (i.e., difficulty getting back to sleep after waking during the night) or end-stage insomnia (i.e., waking too early and not being able to get back to sleep). Early-stage insomnia (i.e., difficulty falling asleep) may also occur. Individuals who exhibit hypersomnia (excessive sleep) may experience longer episodes of sleep at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is because of a sleep disorder.

[0233] In the case of perinatal onset (DSM-5 designator of depressive disorder)

[0234] This designation can be applied to a recent major depressive episode if the full diagnostic criteria are currently not met for a major depressive episode, or if the onset of mood symptoms occurred during pregnancy or within 4 weeks after delivery.

[0235] Mood episodes may have an occurrence either during pregnancy or after birth. Depending on the duration of postpartum follow-up, estimates vary, but 3% to 6% of women experience an occurrence of a major depressive episode during pregnancy or in the weeks or months after birth. Fifty percent of "postpartum" major depressive episodes actually begin before birth. These episodes are therefore collectively referred to as perinatal episodes. Women with perinatal major depressive episodes often have severe anxiety and even panic attacks. Prospective studies have demonstrated that mood and anxiety symptoms during pregnancy, as well as the "baby blues," increase the risk of a postpartum major depressive episode. Mood episodes occurring perinatally may manifest with or without psychiatric features. Infanticide is most often associated with a postpartum psychiatric episode characterized by command hallucinations to kill the infant or delusions that the infant is possessed, although psychiatric symptoms may also occur in severe postpartum mood episodes without such specific delusions or hallucinations.

[0236] Elevated anxiety / anxiety distress (DSM-5 indicator of depressive disorder)

[0237] The DSM-5 defines the "anxiety distress" specifier as the presence of at least two of the following symptoms during most days of a major depressive episode (MDD) or persistent depressive disorder (dysthymia): 1. Feeling excited or nervous. 2. Feeling unusually restless. 3. Worrying makes it hard to concentrate. 4. You are afraid that something terrible might happen. 5. I feel like I'm losing control.

[0238] Severity is defined as follows: Mild: 2 symptoms. Moderate: 3 symptoms. Moderate to severe: 4 or 5 symptoms. Severe: Four or five symptoms with motor agitation.

[0239] Anxiety distress has been documented as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with a higher suicide risk, longer duration of illness, and a higher likelihood of not responding to treatment.

[0240] Accordingly, one embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound (1): [ka] The present invention is directed to a method comprising administering

[0241] Another aspect of the present disclosure is a method for treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering a therapeutically effective amount of compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0242] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days or about two weeks. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two 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 a day at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once a day at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once a day 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 a day at a dose of about 20 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for less than 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 14 days.

[0246] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered 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 pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg of the free base compound.

[0247] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily 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 pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg of the free base compound.

[0248] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 30 mg of the free base compound once daily for about 14 days.

[0249] In some embodiments, Compound (1) or a pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0250] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0251] In some embodiments, Compound (1) or a pharma- ceutically 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.

[0252] In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharma- ceutically 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 pharma- ceutically acceptable salt of compound (1) is administered with a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

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

[0254] 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 Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference.

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

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

[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 pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of initial treatment in response to recurrence of depressive symptoms.In some embodiments, the last dose of initial treatment and the first dose of re-administration are spaced apart by at least 6 weeks.In some embodiments, each of initial treatment and re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0259] In some embodiments, the methods include administering a second therapeutic agent.

[0260] In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to administration of Compound (1) or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1).

[0262] In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, 18 or higher, 19 or higher, or 20 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher, prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 18 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 19 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 20 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher.

[0263] In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0264] In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0265] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0266] In some embodiments, the subject exhibits a reduction from baseline in HAM-D total score, HAM-A total score, HAM-D anxiety / somatization subscale score, or a combination thereof. In some embodiments, the subject exhibits at least a 14-point reduction in HAM-D total score 15 days after administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the subject exhibits at least a 12-point reduction in HAM-A total score 15 days after administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0267] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in Hamilton Depression Score (HAMD-17)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a reduction in HAMD-17 score from baseline 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 pharma- ceutically acceptable salt of compound (1)). In some embodiments, the reduction in HAMD-17 score from baseline is from severe (e.g., a HAMD-17 score of 24 or higher, or a score of 26 or higher) to asymptomatic, i.e., remission of depression (e.g., a HAMD-17 score of 7 or lower). In some embodiments, the decrease from baseline in HAMD-17 score ranges from severe (e.g., a HAMD-17 score of 24 or higher, or a score of 26 or higher) to normal or mild depression (e.g., a HAMD-17 score of 7 or less, or a HAMD-17 score of 18 to 13).

[0268] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in Hamilton Anxiety 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 reduction in HAM-A score from baseline 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, the reduction in HAM-A score from baseline 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 reduction in HAM-A score from baseline 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-Asberg Depression Rating Scale (MADRS)) within about 45, about 21, about 15, about 8, or about 3 days, or fewer. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (relating to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lethargy, inability to feel, pessimistic thoughts, and suicidal thoughts) 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 baseline in 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). In some embodiments, the decrease from baseline in MADRS score ranges from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or lower). For example, the mean change from baseline in MADRS total score resulting from treatment with compound (1) or a pharma- ceutically acceptable salt of compound (1) is about -15, -20, -25, -30, while the mean change from baseline in MADRS total score resulting from treatment with placebo is about -15, -10, -5.

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

[0271] In some embodiments, the methods provide a therapeutic benefit (e.g., as measured by a reduction in 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 benefit (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within about 45, about 21, about 15, or about 8 days. In some embodiments, the therapeutic benefit is an improvement as measured by the EPDS.

[0273] In some embodiments, the method improves the subject's general health (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 subject's general health as measured by at least five domains of the SF-36v2 test. In some embodiments, the five domains are social functioning, mental health, physical functioning, role functioning (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 results in a therapeutic effect (e.g., as measured by a reduction in the Insomnia Questionnaire Limited Halomitron Depression Score (HAMD-17-Ins)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a reduction in HAMD-17-Ins score from baseline 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, the reduction in HAMD-17-Ins score from baseline is 1 to 4 points, e.g., about a 1 point reduction from baseline, about a 2 point reduction from baseline, about a 3 point reduction from baseline, or about a 4 point reduction from baseline.

[0275] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0276] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0277] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to the subject about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0278] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0279] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0280] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0281] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] The method includes administering

[0282] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] The method includes administering a pharma- ceutically acceptable salt of

[0283] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The method includes wherein the subject is treatment naive.

[0284] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The method includes wherein the subject is treatment naive.

[0285] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The method includes wherein the subject is treatment naive.

[0286] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The method includes methods wherein the subject is treatment naive.

[0287] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The subject is taking a stable dose of an additional antidepressant for at least 60 days prior to administration of Compound (1).

[0288] Another embodiment of the present disclosure is a method of treating Major Depressive Disorder with Elevated Anxiety (MDD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The subject is taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharmacologic salt of Compound (1).

[0289] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of compound (1); The present invention includes a method.

[0290] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to administration of a pharma- ceutically acceptable salt of Compound (1); The present invention includes a method.

[0291] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering about 30 mg to about 50 mg of Compound (1): [ka] administering The subject is taking a stable dose of an additional antidepressant for at least 60 days prior to administration of Compound (1).

[0292] Another embodiment of the present disclosure is a method of treating postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a dose equivalent to about 30 mg to about 50 mg of the free base compound of Compound (1): [ka] administering a pharma- ceutically acceptable salt of The subject is taking a stable dose of an additional antidepressant for at least 60 days prior to administration of the pharmacologic salt of Compound (1).

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

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

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

[0296] In some embodiments, Compound (1) or the pharma- ceutically 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 pharma-ceutically acceptable salt of Compound (1) is administered orally.

[0297] In some embodiments, compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or the pharma- ceutically 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 pharma- ceutically acceptable salt of compound (1) is administered with a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

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

[0299] In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the initial treatment course. In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to the start of the initial treatment course.

[0300] 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt of Compound (1).

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

[0302] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after completion of the initial treatment period in response to recurrence of depressive symptoms. In some embodiments, the last dose of the initial treatment period and the first dose of the re-administration are spaced apart by at least 6 weeks. In some embodiments, the re-administration is carried out for about 14 days, i.e., about 2 weeks.

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

[0304] In some embodiments, the MDD with elevated anxiety or PPD with elevated 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 said pharmaceutically acceptable salt of compound (1). In some embodiments, the MDD with elevated anxiety or PPD with elevated 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 of compound (1). In some embodiments, the MDD with elevated anxiety or PPD with elevated 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 of compound (1). In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0305] In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0306] In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total 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 pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated 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 pharma- ceutically acceptable salt of Compound (1).

[0307] In some embodiments, MDD with elevated anxiety or PPD with elevated 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) prior to administration of compound (1) or a pharma- ceutically acceptable salt of compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated 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 prior to administration of compound (1) or a pharma- ceutically acceptable salt of compound (1).

[0308] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score, which is based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score, which is based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score, which is based primarily on items assessing the anxiety symptoms of depression.

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

[0310] In some embodiments, the subject exhibits at least a 14 point reduction in HAM-D total score 15 days after administration of Compound (1) or the pharma- ceutically acceptable salt of Compound (1). In some embodiments, the subject exhibits at least a 12 point reduction in HAM-A total score 15 days after administration of Compound (1) or the pharma- ceutically acceptable salt of Compound (1).

[0311] III. Pharmaceutical Compositions

[0312] Another aspect of the present disclosure provides a pharmaceutical composition comprising Compound (1) (also referred to as "active ingredient") and a pharma- ceutically acceptable excipient for use in the methods described herein. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the active ingredient and a pharma- ceutically 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 pharma- ceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient, or a pharma- ceutically acceptable salt of the active ingredient. In some embodiments, the pharmaceutical composition of Compound (1) is any of the pharmaceutical compositions disclosed in PCT Publication No. WO2022 / 020363A9, the entire contents of which 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), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM) and intranasal. In some embodiments, the pharmaceutical composition is administered orally.

[0314] The pharmaceutical composition of the present disclosure may further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given 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 active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV drip) allows for a much faster delivery that quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV drip, to achieve the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, 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. More commonly, however, compositions are supplied in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like, for solid compositions. 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), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0316] The above components of the orally administrable, injectable or topically administrable compositions are merely representative. Other materials, processing techniques, and the like 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 sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0318] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals.It is well understood that modifying compositions suitable for administration to pharmaceutical humans to make them suitable for administration to various animals is possible, and a skilled veterinary pharmacologist can use routine experimentation to design and / or carry out such modifications.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 disclosure includes a method of treating major depressive disorder in a subject in need thereof, comprising administering to the subject about 40 mg of Compound (1) once per day for 14 days. In one aspect, the disclosure includes a method of treating major depressive disorder in a subject in need thereof, comprising administering to the subject about 50 mg of Compound (1) once per day for 14 days.

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

[0321] Another embodiment of the present disclosure includes a method of treating depression in a subject in need thereof, comprising: (i) administering to the subject about 40 mg of Compound (1) once daily for 14 days; and (ii) upon recurrence of depressive symptoms, readministering to the subject about 30 mg of Compound (1) once daily for 15 days, wherein at least 6 weeks separate the administration of Compound (1) to the subject and the readministering of Compound (1) to the subject. In one aspect, the disclosure includes a method of treating depression in a subject in need thereof, comprising: (i) administering to the subject about 50 mg of Compound (1) once daily for 14 days; and (ii) upon recurrence of depressive symptoms, readministering to the subject about 50 mg of Compound (1) once daily for 15 days, wherein at least 6 weeks separate the administration of Compound (1) to the subject and the readministering 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 exhibits a reduction in depression-related symptoms. In some embodiments, the reduction in depression-related symptoms is characterized by a decrease in HAM-D score from baseline. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 20 before treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 22 before treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 24 before treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 25 before treatment. In some embodiments, the major depressive disorder is characterized by a HAM-D total score of at least 26 before treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 28 before treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 29 prior to treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 30 prior to treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 31 prior to treatment. In some embodiments, the major depressive disorder is characterized by a MADRS score of at least 32 prior to treatment. In some embodiments, the 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 a HAM-D total score. In some embodiments, the HAM-D score is a HAM-D subscale score selected from the group consisting of core depression, Bech-6 and Meyer HAM-D subscale scores.

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

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

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

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

[0328] Another embodiment of the present disclosure includes a method of simultaneously treating major depressive disorder and anxiety in a subject in need thereof, comprising: (i) administering to the subject about 40 mg of Compound (1) once daily for 14 days; and (ii) upon recurrence of depressive symptoms, readministering to the subject about 30 mg of Compound (1) once daily for 15 days, wherein at least 6 weeks separate the administration of Compound (1) to the subject and the readministering of Compound (1) to the subject. In one aspect, the disclosure includes a method of simultaneously treating major depressive disorder and anxiety in a subject in need thereof, comprising the steps of: (i) administering to the subject about 50 mg of Compound (1) once daily for 14 days; and (ii) upon recurrence of depressive symptoms, readministering to the subject about 50 mg of Compound (1) once daily for 15 days, wherein at least 6 weeks separate the administration of Compound (1) to the subject and the readministering of Compound (1) to the subject.

[0329] In embodiments of these aspects, the major depressive disorder is 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 HAM-D score from baseline. 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. In some embodiments, the HAM-D subscale score is the core depression, Bech-6 or Meyer score.

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

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

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

[0333] Another aspect of the present disclosure includes a method of simultaneously treating depression and anxiety in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1), or a pharma- ceutically acceptable salt thereof, using a transient dosing regimen to simultaneously treat depression and anxiety in the subject.

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

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

[0336] Another embodiment of the present disclosure includes a method of simultaneously treating depression and anxiety in a subject in need thereof, comprising: (i) administering to the subject a therapeutically effective amount of Compound (1) once daily for about two weeks; and (ii) upon recurrence of depressive symptoms, readministering to the subject a therapeutically effective amount of Compound (1) once daily for about two weeks, wherein at least six weeks separate the administration of Compound (1) to the subject and the readministering of Compound (1) to the subject.

[0337] In an embodiment of this aspect, Compound (1) is readministered to the subject for about 4 weeks. In some embodiments, Compound (1) is readministered to the subject for about 2 weeks. In some embodiments, the interval between administering Compound (1) to the subject and readministering Compound (1) to the subject is about 45 days. In some embodiments, the interval between administering Compound (1) to the subject and readministering Compound (1) to the subject is about 8 weeks.

[0338] In some embodiments, the subject is a woman and the depression is postpartum depression (PPD).In some embodiments, the subject is a woman and is about 6 months or less after childbirth.In some embodiments, PPD is defined as a major depressive episode that occurs in the subject's third trimester of pregnancy to 4 weeks after childbirth.

[0339] In some embodiments, the subject scores 24 or higher on the HAMD-17 test prior to administration of compound (1). In some embodiments, the subject scores 26 or higher on the HAMD-17 test prior to administration of compound (1). In some embodiments, the subject scores 10 or lower on the HAMD-17 test and 10 or lower on the HAM-A test 15 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 7 or lower on the HAMD-17 test and 7 or lower on the HAM-A test 15 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 13 or lower on the MADRS test and 10 or lower on the HAM-A test 15 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 10 or lower on the MADRS test and 7 or lower on the HAM-A test 15 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 10 or less on the HAMD-17 test and 10 or less on the HAM-A test 45 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 7 or less on the HAMD-17 test and 7 or less on the HAM-A test 45 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 13 or less on the MADRS test and 10 or less on the HAM-A test 45 days after initiation of the transient dosing regimen. In some embodiments, the subject scores 10 or less on the MADRS test and 7 or less on the HAM-A test 45 days after initiation of the transient dosing 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 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 daily. In some embodiments, the amount of Compound (1) administered to the subject is reduced upon the occurrence of severe adverse effects. 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, the method further comprises administration of a second therapeutic agent.

[0341] Another embodiment of the present disclosure includes a method of simultaneously treating depression and anxiety in a subject in need thereof using a kit comprising a plurality of individual dosage units comprising Compound (1) and a set of instructions, wherein the set of instructions describes how to administer the dosage units to the subject using a transient dosing regimen.

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

[0343] Another embodiment of the present disclosure includes a kit comprising a plurality of therapeutically effective dosages of Compound (1) and a set of instructions describing how to administer the dosages using a transient dosing regimen for simultaneously treating depression and anxiety.

[0344] In an embodiment of this aspect, the dosage is an individual dosage unit of Compound (1). In some embodiments, the individual dosage unit contains about 25 mg to about 35 mg of Compound (1). In some embodiments, the individual dosage unit contains about 30 mg of Compound (1). In some embodiments, the transient dosing regimen has a duration of about 2 to about 8 weeks. In some embodiments, the transient dosing regimen has a duration of about 2 to about 6 weeks. In some embodiments, the transient dosing regimen has a duration of about 2 to about 4 weeks. In some embodiments, the transient dosing regimen has a duration of about 2 weeks or 14 days. In some embodiments, the transient 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 units are capsules or tablets. In some embodiments, the individual dosage units are capsules. In some embodiments, the individual dosage units are capsules of size 1, 2, 3 or 4. In some embodiments, the capsules are 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 scores at least 3 points lower on the HAMD-17-Ins test 3 days after initiation of the transient dosing regimen compared to the subject's HAMD-17-Ins test score prior to administration of compound (1). In some embodiments, the subject scores at least 2 points lower on the MADRS-Ins test 3 days after initiation of the transient dosing regimen compared to the subject's MADRS-Ins test score prior to administration of compound (1). In some embodiments, the subject scores at least 3 points lower on the HAMD-17-Ins test 15 days after initiation of the transient dosing regimen compared to the subject's HAMD-17-Ins test score prior to administration of compound (1). In some embodiments, the subject scores at least 2 points lower on the MADRS-Ins test 15 days after initiation of the transient dosing regimen compared to the subject's MADRS-Ins test score before administration of compound (1). In some embodiments, the subject scores at least 3 points lower on the HAMD-17-Ins test 45 days after initiation of the transient dosing regimen compared to the subject's HAMD-17-Ins test score before administration of compound (1). In some embodiments, the subject scores at least 2 points lower on the MADRS-Ins test 45 days after initiation of the transient dosing regimen compared to the subject's MADRS-Ins test score before administration of compound (1).

[0348] In some embodiments, the subject achieves a score at least 5 points lower on the HAMD-17-A / S test 15 days after initiation of the transient dosing regimen compared to the subject's HAMD-17-A / S test score prior to administration of Compound (1).

[0349] In some embodiments, the subject scores at least 2 points lower on the EPDS-3A test 15 days after initiation of the transient dosing regimen compared to the subject's EPDS-3A test score prior to administration of Compound (1).

[0350] In some embodiments, the subject achieves a score at least 5 points lower on the HAMD-17-A / S test 45 days after initiation of the transient dosing regimen compared to the subject's HAMD-17-A / S test score prior to administration of Compound (1).

[0351] In some embodiments, the subject scores at least 3 points lower on the EPDS-3A test 45 days after initiation of the transient dosing regimen compared to the subject's EPDS-3A test score prior to administration of Compound (1).

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

[0353] In some embodiments, the subject scores at least 10 points higher in five domains of the SF-36v2 test 15 days after initiation of the transient dosing regimen compared to the subject's SF-36v2 test score before administration of Compound (1). In some embodiments, the subject scores at least 10 points higher in five domains of the SF-36v2 test 45 days after initiation of the transient dosing 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 functioning, role functioning (physical), bodily pain, and mental health component summary. EXAMPLES

[0354] Example 1 A multi-center, Phase 3, double-blind, randomized, placebo-controlled study evaluating the efficacy of compound (1) in the treatment of adult subjects with major depressive disorder. [Table 27-1] [Table 27-2]

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

[0356] ClinicalTrials.gov identification number: NCT04442490

[0357] Planned duration of subject participation: up to 70 days (up to a 28-day screening period, a 14-day double-blind treatment period, and a 28-day 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 area of ​​functioning (social, occupational, educational, or family) as measured by the Sheehan Disability Scale. The goal of treatment for MDD is symptom remission, prevention of relapse and recurrence, and improvement of quality of life by reducing functional impairment.

[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. 2006). These treatments also have 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 FM, Markowitz JC. APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder. Am J Psychiatry 2010: 1-152). Patients with MDD experience variable treatment success and adverse side effects, often requiring multiple changes in antidepressant therapy (ADT) to achieve symptomatic remission. In the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D, NCT00021528), remission rates were reduced in patients with MDD when multiple regimens of ADT were required (36.8% remission with the first treatment vs. 13.0% remission with the fourth treatment). Delayed treatment response and frequent need for treatment changes with standard treatments are barriers to treatment, leading to prolonged disability and delayed functional recovery. There is an unmet need for treatment options that have rapid onset of action, high response and remission rates, and minimize the adverse side effects commonly seen with standard treatment ADT.

[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 study (NCT02493868), demonstrated efficacy against treatment-resistant depression. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and plays a key role in adaptive signaling by balancing excitatory glutamate neurotransmission. Levels of GABA are reduced in the plasma and cerebrospinal fluid of patients with depression. However, the therapeutic potential of modulating GABA signaling for the treatment of MDD is underexplored.

[0362] Inhibitory signaling by GABA is endogenously influenced by neuroactive steroids such as allopregnanolone, a progesterone metabolite. Allopregnanolone activates both phasic and tonic inhibitory neurotransmission by modulation of synaptic and extrasynaptic GABA type A receptors (GABAARs), respectively. This is distinct from the mechanism of benzodiazepines, which only target phasic inhibition and synaptic GABAARs. Tonic and phasic inhibition mediate both transient and long-lasting GABAergic signaling, and therapeutic targeting of both can provide both rapid onset of treatment and sustained action, with potential for the treatment of depression.

[0363] the purpose

[0364] Primary: The efficacy of compound (1) in treating major depressive disorder (MDD) compared to placebo was evaluated.

[0365] Secondary: Patient-reported outcome (PRO) measures were assessed as they relate to health-related quality of life and depressive symptoms.

[0366] Safety Objectives: The safety and tolerability of Compound (1) were evaluated.

[0367] Other Objectives: A population PK approach was used to evaluate the PK of compound (1).

[0368] Endpoints

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

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

[0371] Other secondary endpoints: - HAM-D response (≥ 50% reduction from baseline in HAM-D total score) at 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" at Day 15 - Change from baseline in MADRS total score at day 15 - Change from baseline in HAM-A total score at day 15 - Time to first HAM-D response - Change from baseline in the RPO scale of health-related quality of life, as assessed by responses to the SF-36v2, and the PRO scale of depressive symptoms, as assessed by the 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) - Suicidal thoughts and behaviors using the Columbia-Suicide Severity Rating Scale (C-SSRS) - Potential withdrawal symptoms using the 20-item Physician's 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) assessed by population PK methods

[0374] Study description

[0375] This was a randomized, double-blind, parallel-group, placebo-controlled study in subjects with MDD. The diagnosis of MDD was made according to the Structured Clinical Interview for Diagnostic and Statistical Disorders of Mental Disorders-5, Clinical Trial Version (SCID-5-CT) administered by a qualified health care professional.

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

[0377] The screening period began with the signing of the ICF at the screening visit. The ICF must be signed before any screening activities could begin. When providing informed consent for the study, subjects were also asked to allow their unique subject identifier to be entered into a registry (www.subjectregistry.com) for the purpose of identifying subjects who may meet the exclusion criteria due to their participation in another clinical study.

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

[0379] Antidepressants were permitted and offered to subjects who were on a stable dose for at least 60 days prior to Day 1 and agreed to continue on a stable dose until the follow-up period (Day 42). Initiation of new antidepressants or any other medications that may have the potential to affect efficacy or safety endpoints was not permitted between screening and completion of the Day 42 assessment.

[0380] Eligible subjects were stratified based on antidepressant treatment use (on / stable or treatment-naive / withdrawn ≥ 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 study drug once daily at approximately 8 PM with a fat-containing meal (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack) on an outpatient basis for 14 days. Subjects returned to the study site between treatment and follow-up periods as outlined in Table 1.

[0381] During the treatment period, subjects were allowed to take the study drug unless there were dose-limiting safety / tolerability concerns. Subjects who could not tolerate 50 mg received 40 mg for the remainder of the treatment period. At the investigator's discretion, subjects who could not tolerate the 40 mg dose were allowed to discontinue study drug.

[0382] Number of subjects

[0383] A maximum of 575 subjects were randomized and dosed to provide sufficient evaluable subjects for all analyses.

[0384] Treatment Allocation

[0385] On Day 1, subjects were randomly assigned to treatment groups and stratified based on baseline antidepressant treatment use (on / stable or treatment-naive / withdrawn ≥ 60 days) with randomization within each stratum in a 1:1 ratio to receive Compound (1) 50 mg or matching placebo.

[0386] Dose adjustment criteria

[0387] Subjects were allowed to receive study drug unless there were dose-limiting safety / tolerability concerns. Subjects who could not tolerate 50 mg received 40 mg for the remainder of the treatment period. At the investigator's discretion, subjects who could not tolerate the 40 mg dose were allowed to discontinue study drug.

[0388] Subject Selection Criteria Eligible subjects had to meet all of the following criteria: 1. Subject has signed the ICF before any study-specified procedures are performed. 2. Subjects were men or women aged 18-64 years (inclusive). 3. Subjects were in good physical health and had no clinically significant findings on physical examination, 12-lead ECG or clinical laboratory tests as determined by the investigator. 4. Subject agreed to comply with the study requirements, including not working the night shift. 5. Subject had a diagnosis of MDD as diagnosed by SCID-5-CT, including symptoms present for at least 4 weeks. 6. Subjects had a HAM-D total score ≧24 at screening and on Day 1 (pre-dose). 7. Subjects taking antidepressants must have been taking these medications at the same dose for at least 60 days prior to Day 1. Subjects who have stopped taking antidepressants within 60 days must have stopped for more than five half-lives of the antidepressant prior to Day 1. Subjects receiving psychotherapy must receive treatment on a regular schedule for at least 60 days prior to Day 1. 8. Subjects were willing to delay initiation of other antidepressants or anxiolytics and any new pharmacotherapy regimens, including benzodiazepine anxiolytics and sleep aids as needed, until after completion of the Day 42 visit. 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 menses for 12 months without another medical cause and confirmed by 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, intravaginal 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 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 not engaged in sexual relations that posed a risk of pregnancy. Acceptable methods of effective contraception for men included vasectomy, or condoms with or without spermicide used in conjunction with a highly effective female contraceptive method (see inclusion criterion #9 for acceptable contraceptive methods) if the female partner was of childbearing potential. 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

[0390] Subjects were ineligible for study participation if they met any of the following criteria: 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. Subject had a current occurrence of a depressive episode during pregnancy or 4 weeks postpartum, or subject attended a screening visit during the 6-month postpartum period. 3. Subjects had a recent history or active clinically significant signs of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, cutaneous, genitourinary, neurological, or ocular, ear, nose and throat disorders, or any other acute or chronic condition, that, in the opinion of the investigator, would limit the subject's ability to complete or participate in this clinical study. Subjects with a BMI ≤ 18 or ≥ 45 kg / m2 were excluded. Subjects with a BMI between 40 and 44.9 kg / m2 (inclusive) at screening were subject to a more extensive evaluation of medical comorbidities as described above. 4. The subject had treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants (excluding antipsychotics) within the scope of a current major depressive episode from two different classes for at least 4 weeks of treatment. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) is used for this purpose. 5. Subject has had vagus nerve stimulation, electroconvulsive therapy, or is taking ketamine within a current major depressive episode. 6. The subject had a known allergy to compound (1), allopregnanolone, or a related compound. 7. The subject had a positive pregnancy test at screening or on Day 1 prior to the start of study drug administration, or, if the subject was breastfeeding at screening or on Day 1 (prior to administration of study drug), did not agree to temporarily discontinue breastfeeding the subject's child from immediately prior to taking study drug on Day 1 until Day 7 after the last dose of study drug. 8. Subjects 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. Subjects had clinically significant 12-lead ECG abnormalities at screening or baseline visit. Note: A mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in men or >470 msec in women will be an exclusion criterion from the study. 10. Subject had an active psychiatric disorder as assessed by the investigator. 11. Subject had a history of seizures. 12. Subject had a history of bipolar disorder, schizophrenia and / or schizoaffective disorder. 13. Subjects had a history of mild, moderate or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to screening. 14. Subject has been exposed to another investigational drug or device within 30 days prior to screening. 15. Subject has previously participated in a Compound (1) or SAGE-547 (brexanolone) clinical trial. 16. Have used any known strong inhibitor of cytochrome P450 (CYP) 3A4 within 28 days or 5 half-lives (whichever is longer) prior to the first dose of an investigational drug, or have consumed grapefruit juice, grapefruit or Seville orange, or products containing these within 14 days. 17. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin or St. John's wort, within 28 days prior to the first dose of the study drug. 18. Subject had a positive drug and / or alcohol screen at screening or on pre-dosing Day 1. 19. Subject was scheduled to undergo elective surgery prior to completion of the Day 42 visit. 20. On Day -28, the subject was taking a benzodiazepine, barbiturate, or GABAA modulator (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) or had used these medications daily or near daily (≧4 times per week) for more than 1 year. The subject had been taking either a benzodiazepine with a half-life of ≧48 hours, or a GABA modulator (e.g., diazepam) for 60 days prior to Day 1. 21. Subject was taking a non-GABA antiinsomnia medication (e.g., melatonin, Benadryl [antihistamine], trazodone) or a first or second generation (typical / atypical) antipsychotic on Day -14. 22. Subject has been diagnosed with and / or treated for any type of cancer (excluding basal cell carcinoma and intraepidermal melanoma) within the past year prior to screening. 23. The subject had a history of sleep apnea. 24. Subject has had gastric bypass surgery, gastric sleeve or lap band, or any related procedure that interferes with gastrointestinal transit. 25. Subject was taking stimulants (e.g., methylphenidate, amphetamine) or opioids on a regular or as-needed basis on Day -28.

[0391] Investigational Drug

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

[0393] Previous medications, concomitant medications and restrictions

[0394] Previous and concomitant medications and / or supplements

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

[0396] Any medications and / or supplements determined necessary for the subject's welfare could be given at any time during the study at the discretion of the investigator.

[0397] Antidepressants taken at the same dose for at least 60 days prior to Day 1 were allowed if subjects intended to continue on a stable dose through Day 42.

[0398] The following medicines intended for contraception are approved for use in women: - Combined oral, intravaginal 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

[0399] Prohibited Drugs

[0400] The following specific classes of drugs were banned: Initiation of new psychotropic medications by the 42nd visit Initiation of new antidepressant therapy from 60 days before Day 1 through Day 42 visit Use of any benzodiazepine, barbiturate, GABAA modulator, or GABA-containing medication from day -28 through visit day 42 (from day -60 onward in the case of a benzodiazepine or GABA modulator with a half-life of ≥48 hours) - Neurostimulants (e.g., methylphenidate, amphetamines) or opioids, either long-term or as needed, from visit day 28 through visit day 42 From visit -14 to visit 42, first-generation (typical) antipsychotics (e.g., haloperidol, perphenazine) and second-generation (atypical) antipsychotics (e.g., aripiprazole, quetiapine) Use of any non-GABA antiinsomnia medication (e.g., melatonin, Benadryl [antihistamine], trazodone, low-dose quetiapine, mirtazapine, etc.) from visit -14 through visit 42 Exposure to another study drug or device from 30 days prior to screening through visit day 42. Any known strong inhibitor of CYP3A4, starting on Day -28 or five half-lives prior to Day 1 through the treatment period (whichever is longer). · Use of any strong CYP3A inducers such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin or St. John's wort from Day -28 through the treatment period.

[0401] Other Restrictions

[0402] Consumption of grapefruit juice, grapefruit or Seville oranges, or products containing these, was prohibited throughout the treatment period.

[0403] Consumption of alcohol or use of drugs of abuse was abstained for the entire study period.

[0404] Female subjects who are breastfeeding or actively nursing must discontinue breastfeeding their baby starting on day 1 of study drug treatment through day 7 after the last dose.

[0405] No elective surgeries or procedures were permitted until the 42nd day visit.

[0406] Subjects must not work night shifts.

[0407] Subjects who felt sedated, somnolent and / or dizzy were refrained from driving or engaging in any activity requiring alertness.

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

[0409] Explanation of the investigational drug

[0410] Compound (1) was available as a hard gelatin capsule containing a white to off-white powder. Active Compound (1) capsules contained the specified amount of Compound (1) drug substance plus the excipients croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate. Capsules were available in dosage 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] Investigational Product Packaging and Labeling

[0413] Compound (1) capsules and matching placebo capsules were provided to the clinic pharmacist and / or design facility personnel responsible for dispensing the study drug in subject-specific kits containing appropriately labeled, sealed unit doses. Each unit dose consisted of two capsules.

[0414] Additional information regarding packaging and labeling was provided in the Pharmacy Manual.

[0415] Statistical methods:

[0416] A detailed description of the statistical analyses to be performed in the study was presented in the Statistical Analysis Plan (SAP). A separate SAP was prepared for each part of the study. The SAP for each study part was finalized and approved prior to unblinding of each individual part of the treatment.

[0417] General considerations

[0418] For purposes of all safety and efficacy analyses, baseline was defined as the last measurement prior to the start of study drug administration, as appropriate.

[0419] Continuous endpoints were summarized descriptively using n, mean, standard deviation, median, minimum and maximum values. In addition, changes from baseline were calculated at each time point and summarized descriptively. For categorical endpoints, descriptive summaries 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 study drug. - The full analysis set was defined as all randomized subjects in the safety population with a valid baseline HAM-D total score and a post-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 during the FAS. - The PK population was defined as all subjects in the safety population with a plasma concentration of at least 1.

[0421] Sample size determination

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

[0423] Analysis of primary endpoint

[0424] The estimate for the primary efficacy analysis was the mean change from baseline in HAM-D total score at 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 by treatment as explanatory variables. All explanatory variables were treated as fixed effects. All post-baseline time points were included in the model. The primary comparison was between compound (1) and placebo at the day 15 time point. Model-based point estimates (e.g., least squares [LS] means, 95% confidence intervals, and p-values) were reported as appropriate. Unstructured covariance structures were used to model within-subject error. If there were convergence issues with the unstructured covariance model, Toeplitz or autoregressive (1) [AR(1)] covariance structures were used, and this order was followed until convergence was achieved. If the model still did not converge to an AR(1) structure, no results were reported. When the covariance structure was not UN, sandwich estimators of the variance-covariance matrix were derived using the EMPIRICAL option in the PROC MIXED statement in SAS.

[0425] Secondary endpoint analysis

[0426] Similar to the methods described above for the primary endpoint, for change from baseline, MMRM was used for analysis of change from baseline in HAM-D total score, MADRS total score, HAM-A total score, SF-36v2 score, PHQ-9 score, and selected individual item and / or subscale scores on the HAM-D at other time points.

[0427] Generalized estimating equations (GEE) methods were used to analyze HAM-D response (defined as a ≥ 50% reduction from baseline in HAM-D total score) and HAM-D remission (defined as a HAM-D total score ≤ 7.0). The GEE model included duration of treatment, baseline score, stratification factors, assessment time points, and time points by treatment as explanatory variables. The comparison of interest was the difference between compound (1) and matching placebo at the 15-day time point. Model-based point estimates (e.g., odds ratios), 95% confidence intervals, and p-values ​​were reported.

[0428] GEE methods were also used to analyze CGI-I response, including duration of treatment, baseline CGI-S score, stratification factors, assessment time points, and time points by treatment as explanatory variables.

[0429] Safety analysis

[0430] Safety and tolerability of the study drug were assessed by incidence of adverse events / serious adverse events, vital signs, clinical laboratory assessments, and 12-lead ECG.

[0431] Suicidality was monitored by the C-SSRS. Potential withdrawal symptoms following cessation of Compound (1) were assessed using the PWC-20.

[0432] Pharmacokinetic analysis

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

[0434] [Table 1-1] [Table 1-2] [Table 1-3] CGI-I=Clinical Global Impression-Improvement; CGI-S-Clinical Global Impression-Severity; C-SSRS=Columbia Suicide Severity Scale; D=day; EOT=end of treatment; ET=early discontinuation; ECG=electrocardiogram; FSH=follicle stimulating hormone; HAM-A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Rating Scale for Depression, 17 items; HIV=human immunodeficiency virus; MADRS=Montgomery-Asberg Depression Rating Scale; MGH ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; PHQ-9=9-item Patient Health Questionnaire; PWC-20=20-item Physician Withdrawal Checklist; O=as needed; PK=pharmacokinetics; SCID-5-CT=Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5th edition, clinical research version; SF-36v2=36-item Short Form Questionnaire version 2; V=visit. a Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit whenever possible, preferably the day after treatment is discontinued. If necessary, the EOT and ET visits can be on the same day if the subject discontinued the investigational drug and terminated the study on the same day during a clinic visit. In this case, all EOT visit evaluations should be performed in addition to a brief physical examination. bSubjects will be asked to allow their unique subject identifier to be entered into a registry (www.subjectregistry.com) for the purpose of identifying subjects who may meet exclusion criteria due to participation in another clinical study. c Serum follicle-stimulating hormone testing will be performed at screening of non-surgically infertile female participants to determine whether female subjects with ≥12 months of spontaneous amenorrhea meet protocol-defined postmenopausal criteria. d Information regarding diagnosis, isolation, and / or hospitalization due to COVID-19 will be documented as part of medical history, collection of AEs, and collection of previous / concomitant medications / procedures at screening and throughout the study. e Subjects will be trained by site personnel in the use of software applications and devices necessary for the conduct of the study. f A complete physical examination will be performed at screening, followed by an abbreviated physical examination. The complete physical examination will include evaluation of the body systems (e.g., head, eyes, ears, nose and throat, heart, lungs, abdomen, and extremities). The abbreviated physical examination will include a brief medical history followed by a targeted physical examination. g Safety laboratory tests include hematology, serum chemistry, coagulation and urinalysis. h Urine toxicology for selected drugs of abuse (following the testing manual) and breath testing for alcohol. i Serum pregnancy test at screening and subsequent urine pregnancy test for female subjects who are not surgically infertile and do not meet protocol-defined criteria of being postmenopausal. j Blood samples for hormone and biochemistry studies as required (if consent has been given). k Genetic samples as needed for biomarker research (if consent is obtained). lVital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure are collected in the supine position at all scheduled time points after the participant has rested for 5 minutes, then approximately 3 minutes in the standing position. Vital signs may be repeated at the discretion of the investigator if clinically indicated. m ECGs are collected in triplicate. If sample collection for ECG and PK is performed on the same day, a 12-lead ECG is performed prior to PK sample collection. n The "Baseline / Screening" C-SSRS form will be completed at screening. The "Since Last Visit" C-SSRS form will be completed at all times thereafter. o The HAM-D should be completed as soon as possible during the visit. p The assessment time frame for the HAM-D scale refers to the past 7 days (1 week) at screening and "since last visit" for all other visits. The assessment time frame for the HAM-scale refers to the past 7 days (1 week) at all visits. q Plasma samples for PK analysis will be collected at any time during the clinic visit. In the event of a dose adjustment, an unscheduled PK sample should be collected immediately prior to the dose adjustment, if possible. The date and time of sample collection and the date and time of last dose administration must be recorded. If sample collection for ECG and PK is performed on the same day, a 12-lead ECG will be performed prior to PK sample collection. If a dose adjustment is performed during a visit for which a PK sample is scheduled according to Table 3, an unscheduled PK sample is not necessary. r This should only be done at the time of an ET visit. s Adverse events will be collected beginning at the time of informed consent and throughout the duration of the subject's participation in the study. t Prior medications will be collected at screening, and concomitant medications and / or procedures will be collected at each subsequent visit.

[0435] Example 2 Example 1 Efficacy Results of a Phase 3 Study of Compound (1) in Major Depressive Disorder (MDD).

[0436] Compound (1) is a 2-week, once-daily oral investigational agent for MDD, representing a potential new class of drug for managing a common but serious mental health disorder. Compound (1) was evaluated in a double-blind, randomized, placebo-controlled Phase 3 study (NCT04442490) in 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 at a daily dose of 50 mg once daily in the evening with a fat-containing meal for 14 days. Patients were allowed to decrease the dose to 40 mg if necessary.

[0439] 2.1 Treatment and Demographics

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

[0441] [Table 2]

[0442] [Table 3] BMI = body mass index; HAMD-17 = 17-item Hamilton Rating Scale for Depression; MADRS = Montgomery-Asberg Depression Rating Scale; SD = standard deviation; *Defined as stable for at least 60 days; based on the list of drugs provided by the World Health Organization's Dictionary of Anatomical and Therapeutic Chemistry, Level 3, N06A

[0443] Demographic and baseline characteristics were generally well balanced between the Compound (1)-50 mg group (Compound (1)-50 mg) and placebo groups. Mean (SD) age: 39.4 (12.3) vs. 40.1 (12.6); percentage of patients female: 69.4% vs. 61.7%; white: 63.1% vs. 76.6%; existing antidepressant treatment: 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 nearly 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] LS = least squares; TRT difference = treatment difference; CGI-Improvement response is odds ratio for "moderate" or "marked" improvement; grey rectangles indicate time points not collected according to protocol. * Not measured per protocol.

[0446] 2.2 HAMD-17 Total Score

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

[0448] At the primary endpoint on Day 15, Compound (1)-50 mg demonstrated a statistically significant reduction in depressive symptoms compared to placebo as measured by HAMD-17 (p=0.0141). Rapid and significant effects were observed as early as Day 3 (including Days 8 and 12). The LS mean (SE) change from baseline (CFB) in HAMD-17 total score at Day 15 was -14.1 (0.51) (Compound (1)) vs. -12.3 (0.50) (placebo); delta -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 (LS 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 (LS 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]. LSM treatment differences favored compound (1). Day 42 had LS mean (SE) CFB -13.5 (0.55) (compound (1)) vs. -12.6 (0.55) (placebo) Δ -0.9.

[0449] As shown in Figure 3, among HAMD-17 day 15 responders treated with compound (1), patients maintained on average 86.1% of their day 15 improvement at day 42. Patients who responded to compound (1) at day 15 maintained 86.1% of their HAMD-17 improvement at day 42 (4 weeks after dosing was terminated). Furthermore, 75.4% of patients maintained a pre-specified level of at least 65% of their day 15 improvement at day 42. Numerical evidence of treatment effect at day 15 favored compound (1) across all subgroups and HAMD-17 subscales (see Figure 4), including baseline antidepressant use, age, sex, race, baseline HAMD-17 and body mass index. Similar maintenance of response was observed for the MADRS scale, with those who responded to compound (1) at day 15 maintaining 87.6% of their response at day 42. Furthermore, the response and remission rates are consistent with the weighted mean response and remission rates across placebo-controlled LANDSCAPE and NEST program clinical trials, including MDD and PPD.

[0450] 2.3 Clinical Global Impression (CGI)

[0451] Following examination of the primary endpoint, the statistical analysis plan proceeded to examine CFB on Clinical Global Impression of Illness-Severity (CGI-S) and CGI-Improvement (CGI-I). The CGI-S results demonstrated a numerical advantage for Compound (1) at all measurement time points (see FIG. 5), but were not statistically significant at day 15 in the prespecified analysis model. For CGI-S, results were similar between Compound (1) 50 mg 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 therefore a formal study of the key secondary endpoints was examined.

[0452] FIG. 6 shows one of the other secondary endpoints, CGI-I response ("moderate" or "marked" improvement), and shows that the rate of CGI-I response at day 15 was numerically greater in those receiving compound (1) versus placebo.

[0453] As shown in FIG. 7, at day 15, clinician-assessed CGI-I scores indicated that treatment with compound (1) significantly improved the overall clinical condition of patients in this example and other clinical studies conducted by the applicant. * is a Phase 3 clinical trial study (ClinicalTrials.gov Identifier / NCT Number: NCT03864614) conducted by the present applicant. ** is a Phase 3 clinical trial study (ClinicalTrials.gov Identifier / NCT Number: NCT0672175) conducted by the present applicant. *** is a Phase 2 clinical trial study conducted by the applicant (ClinicalTrials.gov Identifier / NCT Number: NCT03000530). The study design and results of the clinical trial identified by the NCT number are hereby incorporated by reference in their entirety, if applicable.

[0454] 2.4 MADRS

[0455] The clinical trial of Example 1 met its primary endpoint for patients receiving Compound (1)-50 mg, demonstrating that depressive symptoms improved significantly at day 15 compared to placebo, as assessed by change from baseline in HAMD-17 total score (CFB). HAMD-17 focuses primarily on the physical symptoms of depression, including anxiety, while the Montgomery-Asberg Depression Rating Scale (MADRS) addresses core mood symptoms such as sadness, tension, lethargy, and pessimistic and suicidal thoughts (Table 5). Despite differences in the content and number of items between HAMD-17 and MADRS, studies have shown that the two scales are correlated.

[0456] [Table 5]

[0457] CFB on MADRS total score was assessed on days 8, 15 (secondary endpoint), 28 and 42.

[0458] Consistent with the primary endpoint, patients treated with Compound (1) compared to placebo demonstrated significantly improved depression ratings at day 15 as measured by the CFB of the MADRS total score (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 compared to placebo as assessed by the CFB of the MADRS total score (LSM [SE] Compound (1)-50 mg vs. placebo; see Figure 8), which was nominally significant at days 8 and 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 compared with placebo on the MADRS demonstrated a numerical advantage at all measurement time points (days 8, 15, 28, and 42).

[0460] On day 15, patients receiving Compound (1)-50 mg had a LSM CFB of MADRS total score (SE) of -17.5 (0.77) compared to -15.1 (0.76) for patients receiving placebo (treatment difference -2.4 points; p=0.0238). The LSM treatment difference for MADRS total score CFB (Compound (1)-50 mg-Placebo) was on day 8 (-3.4, p=0.0003), day 15 (-2.4, p=0.0238), day 28 (-1.5, NS) and day 42 (-1.3, NS). Both the LSM treatment difference for CFB for HAMD-17 and MADRS total score favored patients receiving Compound (1) (see FIG. 9).

[0461] In summary, patients receiving Compound (1)-50 mg demonstrated improved depressive symptoms compared to placebo as assessed by MADRS total score. Patients receiving Compound (1)-50 mg demonstrated rapid improvement in depression severity and symptoms as early as Day 3 (HAMD-17 total score) and Day 8 (first MADRS total score assessment at the time of treatment), with benefits sustained throughout the follow-up period. Improvements as assessed by both measures continued through Day 42.

[0462] 2.5 Response and retention

[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 CFB of LSM HAMD-17 total score and MADRS total score at all measured time points, and HAMD-17 and MADRS response (≧50% improvement from baseline score) on days 15 and 42.

[0464] Duration of treatment effect was assessed over the post-treatment period in patients treated with Compound (1)-50mg based on efficacy observed at day 15. Retention of day 15 HAMD-17 total score and MADRS total score response over time was examined only in day 15 responders. All p-values ​​reported herein, except for the primary endpoint, are nominal and not adjusted for multiple comparisons. This analysis included patients with a valid baseline HAMD-17 total score and a valid post-baseline HAMD-17 total score of at least 1.

[0465] result

[0466] Overall, patients receiving Compound (1) achieved more rapid treatment response and symptom remission compared to placebo-treated patients.

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

[0468] As shown in FIG. 10A, by day 3, a higher proportion of compound (1)-treated patients achieved a treatment response (≥50% reduction in HAMD-17 total score from baseline) compared to placebo-treated patients (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 compound (1)-treated patients achieved a treatment response 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 a HAMD-17 response was similar between compound (1) and placebo groups.

[0469] Symptom remission (HAMD-17≦7; FIG. 10B) was observed more frequently by day 3 in the compound (1) group compared with the placebo group (7.6% vs. 2%, odds ratio 3.57, 95% CI 1.4-9.1, P=0.008) in favor of compound (1) throughout the treatment period. At days 15 and 42, symptom remission was slightly in favor of compound (1) versus placebo. By day 21, 83 / 226 (81.0%) compound (1)-treated patients retained ≧65% of their day 15 HAMD-17 improvement, which decreased to 173 / 231 (74.9%) by day 42.

[0470] These results suggest that a small percentage of patients lost the robust treatment response immediately after treatment cessation, but that by and large the treatment response was maintained in the post-treatment period.

[0471] As shown in Tables 6 and 7, treatment response and remission outcomes were either similar or numerically improved in patients receiving Compound (1) 50 mg in combination with an antidepressant (ADT) versus Compound (1) 50 mg monotherapy.

[0472] [Table 6-1] [Table 6-2] N refers to the total number of patients on the study visit date; ADT = antidepressant treatment; CI = confidence interval.

[0473] [Table 7-1] [Table 7-2] N refers to the total number of patients on the study visit date. ADT = antidepressant treatment; CI = confidence interval; NA = not applicable; NE = not estimable.

[0474] MADRS response rates (≧50% reduction in MADRS total score from baseline) during the treatment period were significantly in favor of compound (1) compared to placebo. MADRS remission rates (MADRS≦10) were numerically in favor of compound (1) during this same period ( FIG. 11 ).

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

[0476] Sustained response to Compound (1)-50 mg, as assessed by retention of both HAMD-17 total score and MADRS total score responses at Day 15, was observed at all measured time points through Day 42.

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

[0478] Nearly two-thirds of patients with MDD also experience symptoms of anxiety, and up to 20% have a 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 focusing on anxiety-related symptoms included the HAM-A total score and the CFB of the HAMD-17 anxiety / somatization subscale.

[0480] We report here the effects of compound (1) on anxiety symptoms as assessed by the HAM-A and HAMD-17 Anxiety / Somatization subscales.

[0481] method

[0482] HAM-A total scores were assessed on days 8, 15, 28, and 42. HAMD-17 total scores and HAMD-17 anxiety / somatization subscales were assessed on days 3, 8, 12, 15, 21, 28, 35, and 42.

[0483] Statistics are from mixed effects models. All p-values ​​reported here are nominal and not adjusted for multiple comparisons, except for HAMD-17 CFB at day 15 (primary endpoint).

[0484] result

[0485] The Compound (1)-50mg group demonstrated numerical improvements in depression symptoms compared to placebo at all time points measured through Day 42, as assessed by HAMD-17 total score, 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 Compound (1)-50mg treated HAMD-17 responders (≥50% improvement in HAMD-17 total score from baseline) at Day 15, patients maintained, on average, 86.1% of their Day 15 improvement at Day 42 (4 weeks after dosing ended).

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

[0487] The CFB of the HAM-A total score showed a numerical improvement in anxiety symptoms in patients treated with compound (1) compared to patients receiving placebo at all measurement time points, with nominal significance at day 8 (LS mean (SE) CFB -8.7 (0.40) (compound (1)) 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 FIG. 12).

[0488] CFB of the HAMD-17 Anxiety / Somatization subscale scores showed that there was a numerical improvement in anxiety symptoms in patients treated with compound (1) compared to patients receiving placebo at all measurement time points, with nominal significance at days 3 and 8 (see FIG. 13).

[0489] CFB of HAM-A total score and HAMD-17 anxiety / somatization subscale scores over time showed trends similar to those observed for HAMD-17 total score. On days 8 and 15, the LSM treatment differences (compound (1) minus placebo) for HAMD-17 total score, HAMD-17 anxiety / somatization subscale score, and HAM-A total score all favored compound (1) (Figures 14A and 14B).

[0490] conclusion

[0491] Patients receiving Compound (1) demonstrated rapid improvement in anxiety symptoms (assessed by the HAM-A) as early as day 8, with numerical improvements maintained through the end of the study (day 42). The HAMD-17 Anxiety / Somatization subscale showed a similar trend, with noticeable significant effects on days 3 and 8.

[0492] Similar results in depression and anxiety symptoms have been observed across 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 impact of compound (1) on anxiety symptoms that may co-exist with depression symptoms in patients with MDD.

[0493] 2.6.1 Major depressive disorder with elevated anxiety (MDD)

[0494] It is well established that MDD with elevated anxiety as a symptom is associated with more severe illness, more difficulty tolerating antidepressants (potentially affecting adherence), higher rates of non-response 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 having "MDD with anxiety distress" using DSM-5 designators, and up to 70% are classified as having "MDD with elevated anxiety" using a HAM-A total score ≥ 20. These patients have more severe depression, respond less well to typical ADT, and have poorer treatment outcomes.

[0496] The 14-item Hamilton Anxiety Scale (HAM-A) assesses the effect of treatment on 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 somatic anxiety, may be a reliable and valid measure of anxiety severity in patients with MDD. The HAM-A mental anxiety item can be used to assess elevated anxiety in patients with MDD. The HAMD-17 total score is the gold standard for assessing depression severity in clinical studies of 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 to examine the specific effects of treatments 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., Anxiety (Psychological)) items can be used similarly to assess elevated anxiety in patients with MDD.

[0497] Figures 15A and 15B show that Compound (1) significantly improved symptoms of depression (as evidenced by the CFB of HAMD-17; Figure 15A) and anxiety (as evidenced by the CFB of HAM-A; Figure 15B) in patients from the study of Example 1 who had MDD with elevated anxiety (patients with MDD who had a baseline HAM-A > 20).

[0498] Figure 16 shows pooled HAMD-17CFB in MDD patients without elevated anxiety (patients with MDD with baseline HAM-A<20) and MDD patients with elevated anxiety (patients with MDD with baseline HAM-A>=20) treated with compound (1) versus placebo. The pooled data combines 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). The study design and results of the clinical trials identified by NCT ​​numbers are incorporated herein by reference in their entirety, where applicable.

[0499] Figure 17 shows the pooled mean HAMD-17 total scores in MDD patients without elevated anxiety (patients with MDD who had a baseline HAM-A<20) and MDD patients with elevated anxiety (patients with MDD who had a baseline HAM-A>20) treated with compound (1) versus placebo. The pooled data combines 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] 18A-18B show the pooled mean SF-36v2 scores in MDD patients without elevated anxiety (patients with MDD who had a baseline HAM-A<20; FIG. 18A) and MDD patients with elevated anxiety (patients with MDD who had a baseline HAM-A≧20; FIG. 18B) treated with Compound (1) versus placebo at baseline, day 15, and day 42. The pooled data combines 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] Further references for Section 2.6 include 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.

[0502] 2.7 HAMD-17 subscale scores

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

[0504] Least squares mean CFBs for HAMD-17 subscale (core depression, Bech-6, Meyer, and anxiety) scores at day 15 were calculated, but the study was not powered to make statistical comparisons of these subscales.

[0505] result

[0506] Similar to the primary endpoint at Day 15, patients receiving Compound (1)-50 mg demonstrated numerical improvements in symptoms compared to placebo across all 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 receiving Compound (1)-50 mg demonstrated numerical improvements in core depressive and anxiety symptoms across HAMD-17 subscale scores, supporting the primary endpoint results.

[0508] 2.8 SF-36 score

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

[0510] The Short Form-36 (SF-36v2) assessed patient-reported HRQoL in eight domains (physical functioning [PF]; role functioning (physical) [RP]; bodily pain [BP]; general health [GH]; vitality [V]; social functioning [SF]; role functioning (mental) [RE]; and mental health [MH]). Safety and tolerability were assessed by adverse events (AEs).

[0511] result

[0512] Baseline scores for the 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) and 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) groups. 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] At Day 15, Compound (1)-50 mg demonstrated a statistically significant (p=0.0029) and clinically meaningful improvement in SF-36v2 least squares mean vitality score (3.1) versus placebo.

[0514] Patients receiving Compound (1)-50 mg reported improvements in multiple SF-36v2 domains, particularly vitality, at Day 15, demonstrating significant HRQoL improvements.

[0515] 2.9 Monotherapy vs. SOC ADT Combination

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

[0517] result

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

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

[0520] TEAEs were reported in 111 / 189 (58.7%) vs. 87 / 188 (46.3%) patients receiving Compound (1)-50 mg vs. placebo monotherapy and in 50 / 79 (63.3%) vs. 33 / 81 (40.7%) patients receiving SOC ADT.

[0521] Patients receiving Compound (1)-50 mg demonstrated improvement in depressive symptoms, regardless of concurrent SOC ADT use, with no evidence of an increase in adverse events.

[0522] 2.10 Analysis of Subgroups

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

[0524] Patients (N=543) were randomized to receive 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 compared to placebo. - ADT used (without: -1.98; with: -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 (based on baseline demographics and characteristics) for the subgroups analyzed favored Compound (1)-50 mg compared to placebo.

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

[0527] safety results

[0528] TEAEs were consistent with the profile of known Compound (1), with about 60% (e.g., about 60.1%) of patients receiving Compound (1)-50 mg and about 45% (e.g., about 44.6%) of patients receiving placebo reporting ≧1 TEAE.

[0529] Most TEAEs reported by Compound (1)-50mg patients were mild or moderate in severity. Severe TEAEs (six events in five subjects) in the Compound (1)-50mg treatment group were IP-related, including sedation, dizziness, vertigo, somnolence, psychotic disorders, and anxiety, as assessed by the principal investigator (PI); one severe event in the placebo treatment group was IP-related transaminase elevation, as assessed by the PI. Two Compound (1)-50mg patients and two placebo patients experienced serious adverse events (SAEs). None were sedation-related. No deaths, loss of consciousness, weight gain, sexual dysfunction, or elation were reported. The most common TEAEs leading to study drug (Compound (1)) discontinuation were dizziness and sedation. Table 8 summarizes TEAEs through Day 42.

[0530] [Table 8]

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

[0532] Additional safety findings.

[0533] Suicidality: No precursors of increased suicidal thoughts / behaviors, as assessed by the C-SSRS, were observed throughout the study in either patients receiving Compound (1)-50 mg or placebo.

[0534] Withdrawal symptoms: There were no withdrawal symptoms as assessed by the PWC-20 on days 18 or 21. Scores were similar after discontinuation of Compound (1)-50 mg or placebo. Change from first PWC-20 assessment (SD) on day 18; Compound (1) vs. placebo: -1.2 (4.3) vs. -1.2 (4.3); day 21; Compound (1) vs. placebo -0.3 (4.6) vs. -0.5 (4.4).

[0535] Concomitant Antidepressant Therapy (ADT): There was no clinically meaningful difference in the safety profile of Compound (1)-50 mg monotherapy compared to administration of Compound (1)-50 mg in combination with existing ADT.

[0536] [Table 9]

[0537] Safety Exclusions

[0538] Compound (1) was generally well tolerated and demonstrated a safety profile consistent with previous clinical studies. Compound (1) was generally well tolerated and demonstrated a safety profile consistent with previous clinical studies. Study completion rate 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% compared with 44.6% in the placebo (PBO) group. The majority of TEAEs were mild to moderate in intensity. TEAEs occurring in at least 5% of compound (1)-treated patients included somnolence in 15.3% (3.0% PBO), dizziness in 13.8% (2.2% PBO), headache in 10.8% (7.8% PBO), and sedation in 7.5% (0.4% PBO). No loss of consciousness or the adverse effects of weight gain, sexual dysfunction, or elation were reported.

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

[0541] No warning signs were identified for either withdrawal symptoms or increased suicidal thoughts or behaviors, as assessed by the 20-item Physician's Withdrawal Checklist and the Columbia Suicide Severity Scale, respectively.

[0542] 3.1 Detailed safety results

[0543] The study in Example 1 was designed to evaluate the efficacy, safety, and tolerability of Compound (1)-50 mg compared to placebo in patients with MDD. Given that AEs associated with current monoaminergic ADTs (e.g., SSRIs, SNRIs, TCAs) used to treat MDD can lead to treatment discontinuation, the inherent safety profile of Compound (1) is of great interest and is reported here.

[0544] Safety and tolerability were assessed by the incidence and severity of adverse events (AEs), serious adverse events (SAEs), changes from baseline in clinical laboratory assessments, vital signs, and 12-lead electrocardiograms. Suicidality was monitored by the Columbia Suicide Severity Rating Scale (C-SSRS) and the Physician's Withdrawal Checklist-20 total score (PWC-20). TS ) was used to monitor for the presence of potential withdrawal symptoms following cessation of Compound (1)-50 mg.

[0545] result

[0546] Patients (N=543) were randomized 1:1 to receive Compound (1)-50 mg (n=271) or placebo (n=272). The safety population included all patients who received at least one dose of Compound (1)-50 mg (n=268) or placebo (n=269). Overall, 242 (90.3%) patients in the Compound (1)-50 mg group and 235 (87.4%) patients 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. The majority of TEAEs were mild to moderate, with eight (3.0%) and three (1.1%) patients having severe events in the Compound (1)-50 mg and placebo groups, 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 and placebo groups, respectively.

[0549] No AEs of loss of consciousness, weight gain, sexual dysfunction or elation were reported.

[0550] Of the patients who received treatment and discontinued the study drug due to TEAE(s), 3.4% (9 / 268) were in the Compound (1)-50mg 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 patients in the Compound (1)-50mg group who experienced an SAE of psychotic disorders and slow speech had complex medical histories and various aspects of underlying neuropathological disease and behavior, highlighted by post-traumatic stress disorder, anxiety, multiple psychiatric hospitalizations for suicidality, auditory and visual hallucinations, drug and alcohol abuse, and non-compliance. The patients in the placebo group had elevated liver function levels (alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyltransferase). There were no precursors to increased suicidal thoughts / behaviors in patients receiving Compound (1)-50 mg or placebo, as assessed by the C-SSRS observed throughout the study (0% worsening of suicidal thoughts or behaviors in either the Compound (1)-50 mg or placebo groups at day 15). No meaningful differences in the incidence and type of adverse events were observed between patients receiving Compound (1) with or without existing antidepressant therapy (Table 10).

[0551] [Table 10] Data are expressed as n (%).

[0552] Compound (1) produced greater numerical improvement in insomnia symptoms as reflected by greater reductions from baseline in HAMD-17 insomnia individual item scores at Day 15 compared to placebo.

[0553] Insomnia was assessed based on separate items from the HAMD-17 for early insomnia (difficulty falling asleep), mid-stage insomnia (waking up during the night and not being able to fall asleep again), and late-stage insomnia (waking up early in the morning before the sleep cycle is complete).

[0554] The mean reduction from baseline was greater than placebo (nominal P<0.05 * ) were numerically greater for: early insomnia: -1.0 vs. -0.7; mid-stage insomnia: -1.2 vs. -0.8; and late-stage insomnia: -0.8 vs. -0.5.

[0555] There was no indication for an increase in suicidal thoughts or behavior with Compound (1) (Table 11).

[0556] [Table 11] N = number of patients in a particular treatment group with no missing C-SSRS assessments at both baseline and designated visits.

[0557] No precursors of withdrawal were observed as assessed by the PWC-20 (PWC-20 total scores [SD] on day 15 were 7.3 [6.57] and 8.0 [6.57] for Compound (1)-50 mg and placebo, respectively). The mean reductions in PWC-20 total scores (indicating improvement) were similar between treatment groups, suggesting no withdrawal effects following completion of treatment or discontinuation of Compound (1) (Table 12).

[0558] [Table 12] CFFA = change from first assessment after last dose at the time of last dose or within 1 day of last dose. A decrease in PCW-20 total score indicates improvement; n = number of patients on that day.

[0559] conclusion

[0560] There were no clinically meaningful differences in the safety profile of Compound (1)-50 mg monotherapy compared with treatment with existing antidepressant therapy. 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 TEAEs. No TEAEs of weight gain, sexual dysfunction, or elation were reported in the study, suggesting that improvement in depressive symptoms can be achieved without these AEs commonly reported with standard-of-care monoaminergic antidepressants. No evidence of withdrawal symptoms or increased suicidal thoughts / behavior was identified.

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

[0563] ClinicalTrials.gov identification number: NCT02978326

[0564] Primary Efficacy Objective: To determine whether treatment with Compound (1) reduces depressive symptoms compared to placebo in subjects with severe postpartum depression (PPD) as assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15.

[0565] Purpose of secondary effects - To determine whether treatment with Compound (1) capsules 30 mg QD reduces depressive symptoms compared to placebo in subjects with severe PPD, as assessed by change from baseline in HAM-D total score at all other time points. - To determine whether treatment with compound (1) capsules 30 mg QD reduces depressive symptoms compared to placebo at Day 15 and all other time points as assessed by HAM-D response, HAM-D remission, change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score, Clinical Global Impression-Improvement (CGI-I) response, and change from baseline in HAM-D subscale and individual item scores. - To determine whether treatment with Compound (1) capsules 30 mg QD reduces anxiety symptoms compared to placebo, as assessed by change from baseline in Hamilton Anxiety Scale (HAM-A) total score, on Day 15 and at all other time points.

[0566] Safety Objective: To evaluate the safety and tolerability of compound (1) compared to placebo, as assessed by the incidence of adverse events, vital sign measurements, clinical laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0567] Other purposes: - To assess healthcare resource utilization (HCRU) at baseline and day 45. - To determine whether treatment with Compound (1) capsules 30 mg QD reduces subject-reported depressive symptoms compared to placebo, as assessed by change from baseline in Edinburgh Postnatal Depression Scale (EPDS) total score and Patient Health Questionnaire (PHQ-9) total score, at Day 15 and other time points. - To determine whether treatment with Compound (1) capsules 30 mg QD improves maternal behavior compared to placebo as assessed by change from baseline in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores at Day 15 and other time points. - To determine whether treatment with Compound (1) capsules 30 mg QD improves general well-being status compared to placebo, as assessed by change from baseline in Short Form-36 (SF-36) total score, at Day 15 and other time points.

[0568] Pharmacokinetic Objective: To assess the pharmacokinetic (PK) profile of compound (1) in plasma samples and, if possible, concentrations of compound (1) in breast milk following administration of compound (1).

[0569] Research design and methodology

[0570] This was a multicenter, 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. Enrollment was closed after one subject was enrolled and dosed in Part A. The current amendment describes only Part B.

[0572] Screening Period:

[0573] The screening period began with the signing of an informed consent form (ICF). Diagnosis of depression was determined using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) Axis I Disorders (SCID-I). Eligibility was determined by applying 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 close female family members.

[0574] Treatment duration:

[0575] Once subjects were identified as eligible for the study, they were randomized on a 1:1 basis to active investigational drug or placebo.

[0576] Randomized subjects received 30 mg QD of study drug (Compound (1) capsules or placebo). Subjects who were unable to tolerate 30 mg QD would receive 20 mg QD for the remainder of the treatment period. Subjects who experienced intolerable adverse events (AEs) at the 20 mg QD dose level could be discontinued from study treatment at the investigator's discretion. Subjects were instructed to take study drug with food. Study drug was self-administered by subjects in the evening (8:00 pm ± 30 minutes) on an outpatient basis for the entire 14-day treatment period. Study drug administration was monitored by follow-up phone calls from the site each evening on days 1-14 (within approximately 1 hour after the scheduled evening dose).

[0577] Subjects were not permitted to initiate psychotropic medications or other medications that may have an effect on efficacy or safety endpoints within 30 days prior to informed consent until completion of the Day 15 evaluation. Psychotropic medications initiated at least 30 days prior to informed consent had to be maintained at a stable dose until completion of the Day 15 evaluation.

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

[0579] Follow-up period:

[0580] Follow-up assessments were performed on an outpatient basis on days 21±1 and 45±3 after the start of study drug administration.

[0581] Number of subjects:

[0582] Approximately 140 subjects were randomized in a 1:1 ratio to provide 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 study drug with an effective baseline and at least one post-baseline HAM-D assessment.

[0583] Selection criteria:

[0584] For an individual to be eligible for the study the following inclusion criteria had to be met: 1. Subject has signed the ICF before any study-specified procedures are performed. 2. Subjects will be ambulatory women between the ages of 18 and 45 (inclusive). 3. Subjects are in good physical health and have no clinically significant findings on physical examination, 12-lead ECG or clinical laboratory tests as determined by the Investigator. 4. Subject agrees to comply with study requirements. 5. Subjects must have discontinued breast-feeding at the time of screening or, if still breast-feeding or actively breast-feeding at the time of screening, must agree to temporarily discontinue breast-feeding the subject's infant immediately prior to and through Day 21 of study drug administration, with a 7-day washout period following the last dose of study drug. 6. Subjects must have a negative pregnancy test at screening and 1 day prior to initiating study drug treatment. 7. Subject has a major depressive episode that began after the third trimester of pregnancy and within the first 4 weeks after delivery and meets criteria for a major depressive episode according to DSM-5 as diagnosed by the Structured Clinical Interview for Axis I Disorders (SCID-I). 8. Subject has a HAM-D total score ≧26 at Screening and Day 1 (pre-randomization). 9. Subjects are ≤6 months postpartum. 10. Subject is willing to delay initiation of other antidepressants or anxiolytics and any new pharmacotherapy regimens, including benzodiazepine anxiolytics as needed, until after the end of the treatment period and all Day 15 assessments are completed. 11. Subjects have no detectable Hepatitis B surface antigen (HBsAg), no detectable anti-Hepatitis C virus (HCV), detectable anti-HCV but negative for viral load, and no detectable human immunodeficiency virus (HIV) antibodies at screening. 12. Subject agrees to use one of the following methods of contraception during study participation and for 30 days after the last dose of investigational drug, unless surgically sterile: - Combined oral, intravaginal 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 occlusion. - Vasectomized partner.

[0585] Exclusion criteria

[0586] Subjects were excluded if they met any of the following exclusion criteria: 1. Subject has a recent history or active clinically significant evidence of a metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, cutaneous, genitourinary, neurological, or ocular, ear, nose and pharynx disorder, or any other acute or chronic condition, that, in the opinion of the Investigator, would limit the subject's ability to participate in or complete this clinical study. 2. The subject has a known allergy to Compound (1) capsules or any of its excipients. 3. Subject has an active psychiatric disorder as assessed by the Investigator. 4. Subject has attempted suicide related to a current episode of PPD. 5. Subject has a history of seizures 6. Subject has a history of bipolar disorder, schizophrenia and / or schizoaffective disorder. 7. Subject has a history of active alcohol or drug dependence (including benzodiazepines) in the 12 months prior to screening. 8. Subject has been exposed to another investigational drug or device within 30 days prior to screening. 9. Subject has previously participated in any clinical study of brexanolone or Compound (1). 10. Subjects currently taking psychotropic medications used to treat depression, such as antidepressants and atypical antipsychotics, that have not been taken at the same dose for at least 30 days prior to Day 1. (Subjects who discontinued taking these medications within 30 days prior to the start of the study drug may be eligible if they discontinue the medication for more than 5 half-lives prior to the start of the study drug.) 11. Use of any known strong inhibitor of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives (whichever is longer), or consumption of grapefruit juice, grapefruit, Seville orange, or products containing these within 14 days prior to taking the first dose of investigational drug and throughout the study. 12. Use of any CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital, or St. John's wort, within 14 days or 5 half-lives (whichever is longer) prior to the first dose of investigational drug and throughout the study. 13. Subject has a positive urine drug test at the Screening Visit. 14. Subject is scheduled to undergo elective surgery while participating in the study.

[0587] Test product, dosage and mode of administration:

[0588] Compound (1) capsules were available as hard gelatin capsules containing a white to off-white powder. Active Compound (1) capsules contained the specified amount of Compound (1) drug substance plus excipients croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate. Capsules were available in 10 mg, 20 mg, and 30 mg strengths to provide treatment doses of 20 mg and 30 mg. Subjects received two capsules per dose.

[0589] Reference treatment, dosage and mode of administration:

[0590] Matching placebo capsules were provided containing only the capsule excipients listed above. Subjects received two placebo capsules per day to maintain blinding.

[0591] Participation period:

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

[0593] Randomization:

[0594] Subjects were randomized to receive Compound (1) or matching placebo in a 1:1 ratio. Subjects, clinicians, and the study team were blinded to treatment allocation. Randomization was performed centrally by an interactive response technology (IRT) system.

[0595] Dose adjustments for safety / tolerability reasons:

[0596] During the treatment period, subjects were allowed to receive study drug unless there were dose-limiting safety / tolerability concerns. Dose adjustment criteria are described above.

[0597] Criteria for evaluation:

[0598] Primary Efficacy Endpoint

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

[0600] Secondary Efficacy Endpoints

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

[0602] Safety Endpoints: Safety and tolerability of the study drug were assessed by frequency of adverse events; severity, relatedness, and seriousness of adverse events; clinical laboratory measurements, vital signs, ECGs; and use of concomitant medications. Suicidality was monitored using the C-SSRS.

[0603] Concomitant medications: Doses of all psychotropic medications were recorded throughout the study. No changes and / or additions of antidepressants or anxiolytics were allowed during the treatment period.

[0604] Plasma Concentration Measurements: Plasma samples were collected and assayed for compound (1) concentrations. Pharmacokinetic concentration data were characterized using population PK modeling techniques to estimate individual measures of exposure to compound (1). If consent was given from the subject, breast milk could be collected and samples analyzed for compound (1) as an optional evaluation.

[0605] Other endpoints

[0606] Additional measures of emotional symptoms and functioning related to the current episode 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 health resource utilization data, including medical visits, inpatient visits and medication use, were collected at screening and day 45.

[0607] Total and subscale scores, including change from baseline, were calculated as appropriate. Change from baseline to the end of the treatment period (day 15) and other time points were assessed as other efficacy endpoints. In addition to the scores above, total score categories and individual item scores were assessed as other endpoints.

[0608] Statistical methods:

[0609] General:

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

[0611] Continuous endpoints were summarized using number (n), mean, standard deviation, median, minimum and maximum. In addition, changes from baseline were calculated at each time point and summarized descriptively. For categorical endpoints, descriptive summaries included counts and percentages.

[0612] Analyzed Populations and Methods:

[0613] The total randomized population, defined as all randomized subjects, was used for subject treatment, demographic and baseline characterization summaries. Subjects were classified according to randomization treatment.

[0614] A narrative summary of safety data was obtained using the safety population defined as all subjects who received study drug. Subjects were summarized according to the treatment they received.

[0615] Efficacy data were analyzed using an efficacy population defined as all subjects in the entire randomized population who completed at least 1 day of study medication and had an effective baseline and at least one post-baseline efficacy assessment. Efficacy data were analyzed using appropriate descriptive statistics and pre-specified statistical methods, as well as other data presentation methods, as appropriate. Subject listings were obtained for all efficacy data. Subjects were analyzed according to randomization treatment.

[0616] The PK population consisted of all subjects in the safety population with determined plasma concentrations for Compound (1) and was used for population PK modeling.

[0617] Mixed-effects models for repeated measures (MMRM) were used to analyze the change from baseline in HAM-D total score. The model included center, treatment, baseline HAM-D total score, assessment time point, and time point by treatment as explanatory variables. 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. Unstructured covariance structures were used to model within-subject error. Continuous secondary variables and other variables were analyzed using similar methods.

[0618] Binary efficacy endpoints, including responder and remission endpoints, were summarized and analyzed using generalized estimating equations methods.

[0619] Adverse events were coded using the Medical Dictionary for Regulatory Affairs (MedDRATM) version 19.1 or later. Overall incidence of adverse events was presented by system organ class, preferred term, and treatment. Incidence of adverse events was also presented by maximum severity and relationship to study drug. Vital signs, clinical laboratory measures, ECG, 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 possible relationships between subject characteristics and plasma concentrations of compound (1) were explored, where appropriate. Suicidality data collected using the C-SSRS at baseline and at each visit during the active treatment period were tabulated for all subjects. C-SSRS tabulation included C-SSRS behavior types and / or classifications for suicidal ideation and behavior.

[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 provide 90% power to detect a placebo-adjusted treatment difference in the primary endpoint of approximately 4 points, i.e., change from baseline in HAM-D total score, at Day 15, assuming a standard deviation (SD) of 7 points.

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

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

[0624] [Table 13-1] [Table 13-2] BIMF=Barkin Index of Maternal Functioning;CGI-I=Clinical Global Impression of Improvement;CGI-S=Clinical Global Impression-Severity;C-SSRS=Columbia Suicide Severity Rating Scale;ECG=Electrocardiogram;EPDS=Edinburgh Postnatal Depression Scale;ET=Early Discontinuation;HAM-A=Hamilton Anxiety Rating Scale;HAM-D=Hamilton Rating Scale for Depression, 17 items;HCRU=Healthcare Resource Utilization;HIV=Human Immunodeficiency Virus; MADRS=Montgomery-Asberg Depression Rating Scale; O=as needed; PHQ-9=Patient Health Questionnaire; PK=pharmacokinetics; QD=once daily; SCID-I=Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Axis I Disorders; SF-36: Short Form-36 * All DI procedures should be completed prior to dosing. a An unscheduled visit may be required at any time during the treatment period to return the current remaining dose and dispense the adjusted dose if a dose adjustment is deemed necessary by the Investigator. b Subjects will be specifically asked about their depression and anxiety diagnoses. c Conducted / collected in the morning at the clinic. d Weight only. e Safety laboratory tests will include hematology, serum chemistry, coagulation, selected hormonal parameters and urinalysis. f Urine toxicology for selected drugs of abuse and serum (screening only) or breath testing for alcohol. g Serum pregnancy test at screening and urine pregnancy test on days 1 and 45. Urine pregnancy tests will also be collected as part of the early discontinuation evaluation for subjects who discontinue the study early. hIf consent is given, blood samples as required for stress hormone levels, kynurenine biochemistry, and markers of inflammation. i Genetic samples as needed for biomarker studies, if consent has been obtained. j Vital signs include respiratory rate, oral temperature, and supine (for at least 5 minutes prior to measurement) and standing systolic and diastolic blood pressure and heart rate. Vital signs may be repeated at the discretion of the investigator if clinically indicated. k At the time of screening and within ±60 minutes of the scheduled 9:00 AM time point. l The "Baseline / Screening" C-SSRS form will be completed at screening. The "Since Last Visit" C-SSRS form will be completed at all subsequent time points. m The HAM-D is completed at a scheduled clinic visit 12 hours (± 1 hour) after the evening dose. n HCRU will be administered at screening (screening version). HCRU (log post-screening) will be administered on days 1-45 to collect cumulative assessments of HCRU over 45 days. o Plasma samples for PK analysis will be collected in the morning at each clinic visit. In the event of a dose adjustment, unscheduled PK samples should be collected immediately prior to the dose change, if possible. p For subjects who provide consent as required for collection of breast milk and measurement of SAGE-217 concentrations, additional samples will be collected on the day of titration, as appropriate. For all samples, start and end times, days of pumping, and amount of breast milk will be recorded. q At the discretion of the Investigator, an additional visit may be conducted to dispense the study drug. The only procedure planned for this visit is the dispensing of the study drug. rDosing will occur daily at 8:00 PM ± 30 minutes with food. If a dose is not administered within < 60 minutes after the scheduled dose, subjects will skip that dose and take the next scheduled dose the next day (doses administered > 30 minutes before / after but < 60 minutes before / after the scheduled time are considered protocol deviations). s Treatment adherence calls will be made within approximately 1 hour after the scheduled evening dose on days 1-14. t To include investigational medication taken before the first dose and throughout the study, as well as antidepressant medication and treatment history.

[0625] Example 5 Rapid and sustained improvement in concurrent symptoms of depression and anxiety in a post-hoc analysis of compound (1) treatment 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, estimates of women with self-reported symptoms of PPD vary from 9.7% to 23.5% yearly by state, with an overall prevalence of 13.2%. PPD symptoms may be associated with significant impairment of maternal-infant bonding and maternal functioning, including breastfeeding and child care, affecting the child's health and development. Multiple environmental and biological risk factors have been proposed to play a role in the development 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 GABAA receptors, and activity at these receptors may play a role in restoring adaptive signaling in the brain. Dysregulation of adaptive signaling in neuronal networks has been implicated as an important mechanism in depression.

[0629] In a double-blind, randomized, placebo-controlled Phase 3 study (NCT02978326; Clinical Trial in Example 4) in adult women with PPD, Compound (1) achieved the primary endpoint of a statistically significant reduction in depressive symptoms compared to placebo as assessed by the 17-item clinician-rated Hamilton Rating Scale for Depression (HAMD-17) at day 15. This example investigated concurrent improvement in depressive and anxiety symptoms at days 15 and 45 (study follow-up) with post-hoc analyses. The study protocol is presented in Example 4.

[0630] method

[0631] As shown in Example 4, women (N=151) aged 18-45 years with a diagnosis of PPD (defined as a major depressive episode with onset in the third trimester or ≤4 weeks postpartum) ≤6 months postpartum and a baseline HAMD-17 total score ≥26 were randomized to study medication in an outpatient setting.

[0632] Patients were randomized 1:1 to receive Compound (1) 30 mg or placebo orally once daily for 14 days with 4 weeks of follow-up. Change from baseline vs. placebo (CFB) on HAMD-17 at day 15 was the primary endpoint. Treatment-emergent adverse events (TEAEs) were assessed throughout the study.

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

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

[0635] CFB for HAMD-17 total score was assessed using least squares means from a mixed effects model for repeated measures. Concurrent improvement rates were assessed using Fisher's exact test, while estimates for odds ratios (ORs) and 95% confidence intervals (CIs) for ORs were derived using a generalized estimating equation model for repeated measures, adjusting for baseline covariates (Table 14).

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

[0637] result

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

[0639] Compound (1) demonstrated a statistically significant Day 15 CFB versus placebo in 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 occurring in ≥5% of patients receiving 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. No loss of consciousness or fainting was reported in either group.

[0641] The likelihood of achieving concurrent improvement in depression and anxiety symptoms (Days 15 and 45), as well as sustained concurrent improvement, was significantly higher for Compound (1)-treated patients (Table 14).

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

[0643] Using a combination of the HAMD-17 and HAM-A scales (model-adjusted p-values), a significantly higher proportion of Compound (1)-treated patients achieved simultaneous improvement in depression and anxiety symptoms at days 3 (p=0.003), 15 (p=0.007), and 45 (p<0.001) ( FIG. 20A ).

[0644] Similarly, using a combination of the MADRS and HAM-A scales (model-adjusted p-values), a significantly higher proportion of Compound (1)-treated patients achieved simultaneous improvement in depression and anxiety symptoms at days 3 (p=0.010), 15 (p=0.014), and 45 (p=0.001) ( FIG. 20B ).

[0645] A significantly higher percentage of Compound (1)-treated patients achieved sustained simultaneous improvement in anxiety and depression at days 15 and 45 using HAMD-17 / HAM-A (p<0.001). Similarly, a significantly higher percentage of Compound (1)-treated patients achieved sustained simultaneous improvement in anxiety and depression at days 15-45 using MADRS / HAM-A (p=0.003) (FIG. 21).

[0646] conclusion

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

[0648] In post hoc analyses, sustained concurrent improvements in depression and anxiety symptoms were seen from days 15 to 45.

[0649] Taken together, 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 and sustained improvement of depressive symptoms, residual symptoms, and patient-reported outcomes in postpartum depression

[0651] Quick summary

[0652] This study evaluated the effect of Compound (1) on depressive, anxiety, and sleep-related symptoms and patient-reported outcomes (PROs) in women with postpartum depression (PPD). This was a phase 3, double-blind, randomized, outpatient, placebo-controlled trial, a post-hoc analysis of study 4 (NCT02978326), conducted at 33 US sites from January 2017 to December 2018. Participants included women aged 18-45 years, ≤6 months postpartum, with PPD and a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score ≥26. Participants were randomized 1:1 to receive placebo (n=76) or Compound (1) 30 mg (n=77), administered nightly for 2 weeks. A significantly higher proportion of patients in the compound (1) group achieved HAMD-17 response (P=.0042) and remission (P=.0088) at day 15 versus placebo. Single-digit numbers needed to treat (NNT) were found for HAMD-17 response and remission beginning at day 15 and maintained through day 45. Compound (1) demonstrated a statistically significant reduction in least squares mean HAMD-17 anxiety / somatization change from baseline compared to placebo beginning at day 3 (P=.0073) through day 45 (P=.0033). A significantly higher proportion 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 at days 15 and 45. Compound (1) also demonstrated improvement in patient-reported depressive symptoms compared to placebo. Thus, compound (1) provides a range of beneficial effects on depressive symptoms, as well as improvement of 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; DeSisto CL, et al. Prev Chronic Dis. 2014;11:E104; Centers for Disease Control and Prevention. Diabetes During Pregnancy. Updated June 12, 2018; Centers for Disease Control and Prevention. Data on Selected Pregnancy Complications in the United States. Updated February 28, 2019; Executive summary: hypertension in pregnancy. American College of Obstetricians and Gynecology. Obstet Gynecol. 2013;122(5):1122-1131; Callaghan WM, et al. Am J Obstet Gynecol. 2010;202(4):353.e1-e6).Expert opinions vary regarding the timing and occurrence of PPD symptoms (ACOG Committee Opinion No. 757: Screening for perinatal depression. Obstet Gynecol. 2018;132(5):e208-e212; Stewart DE, et al. Postpartum depression: literature review of risk factors and interventions. University Health Network Women's Health Program; 2003; American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. American Psychiatric Association; 2013; National Institutes of Mental Health. Perinatal depression). PPD is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a major depressive episode of perinatal onset occurring during pregnancy or within the first 4 weeks after delivery. In the United States, estimates of new mothers who self-report symptoms of PPD annually vary by state, ranging from 9.7% to 23.5%, with an overall prevalence of 13.2%. PPD symptoms can be associated with significant impairments in maternal-infant bonding and maternal functioning, including breastfeeding and child care, all of which impact child health and development (Kerstis B, et al. Arch Womens Ment Health. 2016;19(1):87-94; Posmontier B. J Midwifery Womens Health. 2008;53(4):310-318; Barkin JL, et al. J Womens Health (Larchmt). 2016;25(7):707-713; Gagliardi L, et al. Arch Dis Child. 2012;97(4):355-357).Multiple environmental and biological risk factors have been proposed to play a role in the development of PPD, including a history of depression and more recently the COVID-19 pandemic (McLearn KT, et al. Arch Pediatr Adolesc Med. 2006;160(3):279-284; Moore Simas TA, et al. J Med Econ. 2020;23(2):174-183).

[0655] The pathophysiology of PPD is likely multifactorial (Robertson E, et al. Gen Hosp Psychiatry. 2004;26(4):289-295; Biaggi A, et al. J Affect Disord. 2016;191:62-77), and evidence supports a role for perinatal disruption of gamma-aminobutyric acid (GABA) signaling, a major inhibitory signaling pathway in the central nervous system (Yim IS, et al. Annu Rev Clin Psychol. 2015;11:99-137). Compound (1), an investigational oral neuroactive steroid under clinical investigation as a once-daily, 2-week treatment for major depressive disorder and PPD, inhibits GABA signaling. A It is a positive allosteric modulator of the GABA receptor, which may play a role in restoring adaptive signaling in the brain. Restoration of homeostasis through the interplay between excitatory and inhibitory drives and regulatory signaling can be referred to as adaptive signaling. Dysregulation of adaptive signaling in neuronal networks has been implicated as an important mechanism of depression. In vitro, compound (1) inhibited synaptic and extrasynaptic GABA receptors. A Compound (1) was also shown to bind to both phasic and tonic GABA receptors in vitro and potentiate both phasic and tonic currents, respectively. A Receptor activity was demonstrated, indicating that compound (1) has a binding site distinct from that of benzodiazepines.

[0656] The ROBIN study (NCT02978326; Study of Example 4) was a randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of Compound (1) in adult women with PPD. The primary endpoint and safety results from the ROBIN study have been previously published. Briefly, the study reported that Compound (1) achieved its primary endpoint of a statistically significant reduction from baseline in depressive symptoms compared to placebo, as assessed by the 17-item Hamilton Rating Scale for Depression total score (HAMD-17) total score at day 15 (-17.8 vs. -13.6, respectively, P=.0029). Treatment with Compound (1) was generally well tolerated. The most common treatment-emergent adverse events (TEAEs) occurring in ≥5% of patients receiving Compound (1) were somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, and sedation.

[0657] Given the substantial negative impact of PPD on patients, we now evaluate the impact of treatment on various aspects of patients' lives and well-being in this post-hoc analysis.Thus, we evaluate the effect of compound (1) on clinician-reported outcomes of depression, anxiety and sleep-related symptoms, and patient-reported outcomes (PROs) of depression, and health-related quality of life (QoL) in women with PPD.

[0658] method

[0659] Test Design

[0660] The ROBIN study design and patient inclusion / exclusion criteria are discussed in Example 4. The study enrolled women aged 18-45 years, ≦6 months postpartum, diagnosed with PPD (defined as occurrence in the third trimester or ≦4 weeks postpartum) and a baseline HAMD-17 total score of ≧26 (n=151). Patients were randomized 1:1 to receive Compound (1) 30 mg or placebo orally once daily for 14 days as outpatients, with follow-up until day 45. The primary endpoint was the change from baseline (CFB) in the HAMD-17 total score versus placebo at day 15. TEAEs were assessed throughout the study.

[0661] Post-test outcome measures

[0662] Secondary endpoints included the HAMD-17 at all other measurement time points (apart from the primary endpoint at day 15), as well as the Hamilton Rating Scale for Anxiety (HAM-A), and the CFB of the Montgomery-Asberg Depression Rating Scale (MADRS). Safety and tolerability were assessed by adverse events (AEs), vital signs, clinical laboratory assessments, electrocardiogram parameters, and the Columbia Suicide Severity Scale (C-SSRS). Exploratory patient-reported endpoints included the 9-item Patient Health Questionnaire (PHQ-9, with scores of 1–4=mild depression, 5–9=mild depression, 10–14=moderate depression, 15–19=moderately severe depression; and 20–27=severe depression) as a global measure of general health status, the total Edinburgh Postnatal Depression Score (EPDS; a commonly used screening instrument for PPD, with cut-off scores <7, <10, and <13 assessed), and the Medical Outcomes Study 36-Item Short Form Questionnaire Table Bar. included depression measured by two commonly used screening instruments in real-world settings, including the John 2 (SF-36v2, defined as individual meaningful change in each domain: physical health score [PCS]: >3.4; mental health score [MCS]: >4.6; physical functioning: >4.3; role functioning (physical): >3.4; bodily pain: >6.2; general well-being: >7.2; vitality: >6.2; social functioning: >6.9; role functioning (mental): >4.5; and mental health: >6.2).

[0663] Response definition and analysis outcomes

[0664] The proportion of individual patients demonstrating HAMD-17 response, remission, sustained response, or sustained remission was examined across treatment groups to calculate the number needed to treat (NNT). Sustained response or remission was defined as a continuous classification of responders / remitters at both days 15 and 45. Tolerability and safety outcomes included the number needed to harm (NNH) to discontinue due to AEs, and individual safety events of interest. NNH was calculated for (1) AEs with a rate of ≥2% for compound (1) and higher than placebo, and (2) the proportion of patients in each treatment group who discontinued the study drug due to AEs. 95% confidence intervals (CI) were calculated based on Wilson score intervals.

[0665] Post hoc analyses were performed using CFBs of the HAMD-17 Anxiety / Somatization (A / S) subscale and the EPDS Anxiety subscale (EPDS-3A), HAMD-17A / S and HAM-A response rates (≥50% reduction in score), and HAM-A remission rates (score ≤7). Post hoc analyses explored simultaneous improvement in anxiety and depression at days 15 and 45 using combinations of scales: (1) HAMD-17 ≤7 + HAM-A ≤7 or (2) MADRS ≤10 + HAM-A ≤7. Improvement in depression was defined as either a HAMD-17 total score ≤7 or a MADRS total score ≤10. Improvement in anxiety symptoms was defined as a HAM-A total score ≤7. Sustained improvement was defined as meeting remission criteria simultaneously at both days 15 and 45. Adjusted odds ratios (ORs) were calculated using generalized estimating equation models. Scores on the HAM-D Insomnia subscale (HAM-D-Ins, which consists of three questions rating problems with falling asleep and maintaining sleep during three periods of the night) and the MADRS individual insomnia item (MADRS-Ins, which consists of a single question about reduced sleep duration or depth compared to usual) were assessed in post hoc analyses.

[0666] statistical analysis

[0667] CFB of HAMD-17 total score was assessed using least squares means from a mixed effects model for repeated measures. Concurrent improvement rates were derived using a generalized estimating equation model for repeated measures and adjusted for baseline covariates, while estimates and 95% CIs for ORs were assessed using Fisher's exact test. Least squares means ± standard errors and adjusted ORs were reported by treatment group. Secondary and post hoc endpoints were not adjusted for multiplicity.

[0668] result

[0669] Of the 275 women enrolled, 150 were randomized (placebo, n=74; compound (1), n=76) and included in the efficacy analysis. Baseline demographics and patient characteristics were well balanced between the two treatment groups (Table 15). A significantly higher proportion of patients in the compound (1) group achieved HAMD-17 response (72% vs. 48%; P=.0005) and remission (45% vs. 23%; P=.011) at day 15 compared with the placebo group (Figure 22A). At day 45, the compound (1) group had significantly higher sustained HAMD-17 response rates (59% vs. 39%; P=.0200) and remission rates (37% vs. 13%, P=.0006) compared with the placebo group (Figure 22B). The NNT for sustained response and remission was similar to that observed at day 15 (Figure 22B). The estimated NNH for compound (1) versus placebo was not significant at the P<.05 threshold (Table 16).

[0670] At day 15, 73.0% of patients treated with compound (1) demonstrated a response as assessed by MADRS total score compared to 47.9% of patients in the placebo group. Similarly, at day 15, 54.1% of patients treated with compound (1) demonstrated remission as assessed by MADRS total score compared to 30.1% of patients in the placebo group.

[0671] [Table 15-1] [Table 15-2] BMI = body mass index; SD = standard deviation

[0672] [Table 16] AE = adverse event; CI = confidence interval; NNH = number needed to harm; ns = not statistically significant at the P < .05 threshold.

[0673] The change from baseline in HAMD-17A / S and EPDS-3A scores is shown in Figures 23A-23B. Compound (1) demonstrated a statistically significant reduction in least squares mean HAMD-17A / S CFB compared to placebo beginning on day 3 (-3.8 vs. -2.7; P=.0073; Figure 23A) and sustained at all measurement time points through day 45 (-5.7 vs. -4.3; P=.0033). Compound (1) also demonstrated a statistically significant reduction in least squares mean EPDS-3A change from baseline beginning on day 8 compared to placebo (-2.2 vs. -1.5; p=0.0315; Figure 23B). Statistically significant differences were also sustained at all measurement time points from day 8 through day 45 (-3.6 vs. -2.1; P=.0001). Compound (1) demonstrated significantly higher HAM-A remission rates compared to placebo at day 3 (27.0% vs. 12.2%), HAM-A response rates compared to placebo at day 8 (69.3% vs. 43.2%), and HAMD-17A / S response rates compared to placebo at day 15 (68.9% vs. 46.6%; Figures 24A-24C).

[0674] A significantly higher proportion of Compound (1)-treated patients achieved simultaneous improvement in remission of anxiety and depression symptoms as early as day 3 (all P<.05), which was sustained at the group level at days 15 and 45 using a combination of the HAMD-17 and HAM-A scales (model-adjusted p-values; Figures 20A-20B; Figure 21). Similarly, a significantly higher proportion of Compound (1)-treated patients achieved simultaneous improvement in depression and anxiety symptoms at days 3 (P=.010), 15 (P=.014), and 45 (P=.001) using a combination of the MADRS and HAM-A scales (model-adjusted p-values; Figures 20A-20B). A significantly higher proportion of Compound (1)-treated patients achieved sustained simultaneous improvement in anxiety and depression at days 15 and 45 using HAMD-17 / HAM-A (P<.001). Similarly, a significantly higher percentage of Compound (1)-treated patients achieved sustained concurrent improvements in anxiety and depression from days 15 to 45 using the MADRS / HAM-A (P=.003; FIG. 21).

[0675] Patients treated with Compound (1) achieved significantly greater reductions in CFB of HAMD-17-Ins compared to placebo (Compound (1)-Placebo difference=-0.841; P=0.0142) beginning on day 3 and continuing through all other time points measured during the study, including day 45 (30 days after cessation of treatment: P=0.0207; Figure 25A). Figure 25B shows the CFB of MADRS-Ins scores compared to placebo.

[0676] Insomnia was assessed based on separate items from the HAMD-17 for early insomnia (difficulty falling asleep), mid-stage insomnia (waking up during the night and not being able to fall asleep again), and late-stage insomnia (waking up early in the morning before the sleep cycle is complete).

[0677] The mean reduction from baseline was greater than placebo (nominal P<0.05 * ) were numerically greater for: early insomnia: -1.3 vs. -0.9; mid-stage insomnia: -1.3 vs. -0.9; and late-stage insomnia: -1.3 vs. -0.8.

[0678] Compound (1) demonstrated a statistically significant reduction in least squares mean PHQ-9 depression total scores (-11.8 vs. -9.0, P=.009) compared to placebo at Day 45, and numerically greater reductions in PHQ-9 total scores at all post-baseline time points (Figure 26A). HAM-D and PHQ-9 total scores were significantly and moderately (0.5-0.7) correlated at Day 45 (r=.70, R2=.49, P<.001; Figure 26B).

[0679] At day 15, there were no significant differences between patients treated with compound (1) versus placebo for the definitions of remission of EPDS<7 and <10, although significance w...

Claims

1. 1. A composition for use in a method for treating depression with elevated anxiety in a subject in need thereof, the composition comprising compound (1): 【Chemistry 48】 Or a composition comprising a pharma- ceutically acceptable salt of compound (1).

2. 2. The composition of claim 1, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days or about two weeks.

3. Compound (1) is (a) about 20 mg to about 55 mg; (b) about 50 mg; or (c) about 30 mg or about 40 mg The composition according to claim 1 or claim 2, characterized in that it is administered in a dose of

4. The pharma- ceutically acceptable salt of compound (1) is (a) about 20 mg to about 55 mg of a free base compound; (b) about 50 mg of the free base compound; or (c) about 30 mg or about 40 mg of the free base compound 3. The composition according to claim 1 or 2, characterized in that it is administered in a dose equivalent to

5. Compound (1) is (A) peaks between 9.7 and 10.1 degrees 2θ [endpoints included], between 11.6 and 12.0 degrees 2θ [endpoints included], between 13.2 and 13.6 degrees 2θ [endpoints included], between 14.2 and 14.6 degrees 2θ [endpoints included], between 14.6 and 15.0 degrees 2θ [endpoints included], between 16.8 and 17.2 degrees 2θ [endpoints included], between 20.5 and 20.9 degrees 2θ [endpoints included], between 21.3 and 21.7 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 22.4 and 22.8 degrees 2θ [endpoints included]; (B) peaks between 9.3 and 9.7 degrees 2θ [endpoints included], between 10.6 and 11.0 degrees 2θ [endpoints included], between 13.0 and 13.4 degrees 2θ [endpoints included], between 14.7 and 15.1 degrees 2θ [endpoints included], between 15.8 and 16.2 degrees 2θ [endpoints included], between 18.1 and 18.5 degrees 2θ [endpoints included], between 18.7 and 19.1 degrees 2θ [endpoints included], between 20.9 and 21.3 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 23.3 and 23.7 degrees 2θ [endpoints included]; (C) peaks between 9.7 and 10.1 degrees 2θ [endpoints included], between 14.6 and 15.0 degrees 2θ [endpoints included], between 16.8 and 17.2 degrees 2θ [endpoints included], between 20.5 and 20.9 degrees 2θ [endpoints included], and between 21.3 and 21.7 degrees 2θ [endpoints included]; or (D) peaks between 9.3 and 9.7 degrees 2θ [endpoints included], between 10.6 and 11.0 degrees 2θ [endpoints included], between 13.0 and 13.4 degrees 2θ [endpoints included], between 18.7 and 19.1 degrees 2θ [endpoints included], and between 21.4 and 21.8 degrees 2θ [endpoints included] 2. The composition of claim 1, in a crystalline form having an XRPD pattern comprising:

6. 1. A composition for use in a method for treating depression with elevated anxiety in a subject in need thereof, the composition comprising compound (1): 【Chemistry 52】 or a pharma- ceutically acceptable salt of compound (1), The method comprises administering a dose of about 30 mg to about 50 mg of compound (1) or a dose of said pharma- ceutically acceptable salt of compound (1) equivalent to about 30 mg to about 50 mg of the free base compound.

7. The composition of claim 6, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once daily for about 14 days, i.e., about two weeks.

8. 1. A composition for use in a method for treating depression with elevated anxiety in a subject in need thereof, the composition comprising compound (1): 【Chemistry 60】 or a pharma- ceutically acceptable salt of compound (1), The method includes administering compound (1) at a dose of about 30 mg to about 50 mg once daily for about 14 days or about 2 weeks, or a pharma- ceutically acceptable salt of compound (1) at a dose equivalent to about 30 mg to about 50 mg of the free base compound, once daily for about 14 days or about 2 weeks; The composition, wherein the subject has not been previously treated.

9. 1. A composition for use in a method for treating depression with elevated anxiety in a subject in need thereof, the composition comprising compound (1): 【Chemistry 64】 or a pharma- ceutically acceptable salt of compound (1), The method includes administering compound (1) at a dose of about 30 mg to about 50 mg once daily for about 14 days or about 2 weeks, or a pharma- ceutically acceptable salt of compound (1) at a dose equivalent to about 30 mg to about 50 mg of the free base compound, once daily for about 14 days or about 2 weeks; (A) 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 pharma- ceutical acceptable salt of compound (1); or (B) The composition, wherein 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 pharma- ceutical acceptable salt of compound (1).

10. The composition according to any one of claims 6 to 9, characterized in that compound (1) is administered in a dose of about 50 mg or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound.

11. The composition according to any one of claims 6 to 9, characterized in that compound (1) is administered in a dose of about 40 mg or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

12. The composition according to any one of claims 6 to 9, wherein compound (1) is administered in a dose of about 30 mg or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

13. Compound (1) or the pharma- ceutically acceptable salt of compound (1) is (A) administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally; (B) orally; (C) with food; and / or (D) At night, once a day The composition according to any one of claims 1, 6, 8 and 9, characterized in that it is administered.

14. The composition of claim 1 or claim 6, wherein the subject is treatment naive.

15. The composition of claim 1 or claim 6, wherein 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 pharma- ceutical acceptable salt of Compound (1).

16. The composition of any one of claims 1, 6, 8, and 9, wherein the composition is administered in combination with a second therapeutic agent.

17. Compound (1) or the pharma- ceutically acceptable salt of compound (1) is re-administered to the subject upon recurrence of depressive symptoms after completion of the initial treatment; Optionally, an interval of at least 6 weeks is provided between the last dose of said initial treatment and the first dose of said re-administration; and 10. The composition of any one of claims 1, 6, 8 and 9, wherein the re-administration, as needed, is performed for about 14 days or about 2 weeks.

18. PPD accompanied by elevated anxiety is (A) a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher, prior to administration of compound (1) or said pharmacologic acceptable salt of compound (1); (B) a HAM-D total score of 24 or greater and a HAM-A total score of 17 or greater prior to administration of compound (1) or the pharma- ceutical acceptable salt of compound (1); (C) a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of compound (1) or the pharma- ceutical acceptable salt of compound (1); (D) optionally, a HAM-D total score of 26 or greater and a HAM-A total score of 17 or greater prior to administration of compound (1) or said pharma- ceutical acceptable salt of compound (1); or (E) optionally, a HAM-D total score of 26 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of compound (1) or said pharma- ceutical acceptable salt of compound (1); 10. The composition of any one of claims 1, 6, 8, and 9, characterized by:

19. the subject exhibits a reduction from baseline in a HAM-D total score, a HAM-A total score, a HAM-D anxiety / somatization subscale score, or a combination thereof; Optionally, the subject exhibits at least a 14 point reduction in HAM-D total score 15 days after administration of Compound (1) or said pharmacologic acceptable salt of Compound (1); or 10. The composition of any one of claims 1, 6, 8, and 9, wherein, optionally, the subject exhibits at least a 12 point reduction in HAM-A total score 15 days after administration of compound (1) or the pharma- ceutically acceptable salt of compound (1).

20. A composition described in any one of claims 1, 6, 8, and 9, wherein the depression accompanied by elevated anxiety is postpartum depression (PPD) accompanied by elevated anxiety.

21. The composition described in any one of claims 1, 6, 8, and 9, wherein the depression accompanied by elevated anxiety is major depressive disorder (MDD) accompanied by elevated anxiety.

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