CN117098554A

CN117098554A - 19-norC 3, 3-disubstituted C21-N-pyrazolyl steroids for the treatment of major depressive disorder

Info

Publication number: CN117098554A
Application number: CN202280021857.4A
Authority: CN
Inventors: R·A·拉瑟; J·多尔蒂; J·M·乔纳斯; S·J·卡内斯; H·冈杜兹-布鲁斯; J·L·邓巴; B·S·阿迪维贾亚
Original assignee: Sage Therapeutics Inc
Current assignee: Sage Therapeutics Inc
Priority date: 2021-03-17
Filing date: 2022-03-17
Publication date: 2023-11-21

Abstract

The present disclosure relates to a method of treating Major Depressive Disorder (MDD) in a subject in need thereof by: (i) Performing an initial course of treatment on the subject comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, and (ii) performing 0, 1, or 2 subsequent courses of treatment on the subject, wherein each subsequent course of treatment comprises administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof in response to recurrence of symptoms of depression. 0. 1 or 2 subsequent treatment sessions may be performed within a period of 12 months from the beginning of the initial treatment session.

Description

19-norC 3, 3-disubstituted C21-N-pyrazolyl steroids for the treatment of major depressive disorder

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 63/162,501 filed on day 3 and day 17 of 2021 and U.S. provisional application No. 63/284,592 filed on day 11 and day 30 of 2021. The entire contents of the above-mentioned application are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates to a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising: (i) Subjecting the subject to an initial course of treatment comprising administering a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and (ii) subjecting the subject to 0, 1, or 2 subsequent courses of treatment, wherein each subsequent course of treatment comprises administering a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, in response to recurrence of symptoms of depression, wherein 0, 1, or 2 subsequent courses of treatment are performed over a period of 12 months from the beginning of the initial course of treatment.

Background

GABA (gamma-aminobutyric acid) has a profound effect on overall brain excitability, since up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA interacts with its recognition site on the GRC (GABA receptor complex) to promote the electrochemical gradient of chloride ions down the GRC into the cell. This increase in intracellular anion levels results in hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs (i.e., reduced excitability of the neuron). In other words, the higher the chloride ion concentration in the neurons, the lower the brain's excitability (level of arousal). There is sufficient evidence that GRC is responsible for anxietyRegulation of epileptic activity and sedation. Thus, GABA and drugs that act like GABA (e.g., therapeutically useful barbiturates and Benzodiazepines (BZ), e.g.) Producing a therapeutically useful effect thereof by interacting with specific regulatory sites on the GRC.

Accumulated evidence suggests that GRC contains unique sites for neuroactive steroids (Lan, N.C.et al, newchem.Res.16:347-356 (1991)). Neuroactive steroids may be present endogenously. The most potent endogenous neuroactive steroids are 3α -hydroxy-5-reduced pregnan-20-one and 3α -21-dihydroxy-5-reduced pregnan-20-one (the metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al, science 232:1004-1007 (1986); harrison, N.L. et al, J.Pharmacol. Exp. Ther.241:346-353 (1987)).

Summary of The Invention

In one aspect, the disclosure includes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

(i) Subjecting a subject to an initial course of treatment comprising administering a therapeutically effective amount of compound (1):

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering a therapeutically effective amount of compound (1) in response to recurrence of symptoms of depression,

wherein 0, 1 or 2 subsequent treatment sessions are performed within a period of 12 months from the beginning of the initial treatment session.

(i) Subjecting a subject to an initial course of treatment comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of compound (1):

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of compound (1) in response to recurrence of symptoms of depression,

In some embodiments of these aspects, 0 or 1 subsequent treatment session is performed. In some embodiments, 1 subsequent course of treatment is performed.

In some embodiments, there is a gap of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a separation of about 4 weeks, about 6 weeks, or about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session.

In some embodiments, recurrence of depressive symptoms is indicated by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof. In some embodiments, recurrence of symptoms of depression in a subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

In some embodiments, the initial course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, each subsequent course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days during the initial course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days in each subsequent course of treatment.

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

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered once daily in the evening.

In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 11.6 and 12.0 degrees 2-theta and including the end values, between 13.2 and 13.6 degrees 2-theta and including the end values, between 14.2 and 14.6 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, between 21.3 and 21.7 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 22.4 and 22.8 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 14.7 and 15.1 degrees 2 theta and including the end values, between 15.8 and 16.2 degrees 2 theta and including the end values, between 18.1 and 18.5 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, between 20.9 and 21.3 degrees 2 theta and including the end values, between 21.4 and 21.8 degrees 2 theta and including the end values, and between 23.3 and 23.7 degrees 2 theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, and between 21.3 and 21.7 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, and between 21.4 and 21.8 degrees 2 theta and including the end values.

In some embodiments, the subject has not received treatment.

In some embodiments, the subject is already at a stable dose of additional antidepressant for at least 60 days before the initial treatment session begins.

In another aspect, the disclosure includes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

wherein 0, 1 or 2 subsequent treatment sessions are performed within a period of 12 months from the beginning of the initial treatment session, and

wherein the subject has not received treatment.

compound (1); and

wherein the subject has not received treatment.

In some embodiments, recurrence of depressive symptoms is indicated by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof. In some embodiments, recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

In some embodiments, the initial course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, each subsequent course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days during the initial course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days in each subsequent course of treatment. In some embodiments, compound (1) is administered at a dose of about 20mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30mg to about 50 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, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 20mg to about 55mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 30mg to about 50mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 40mg of the free base compound.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily in the evening.

In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 11.6 and 12.0 degrees 2-theta and including the end values, between 13.2 and 13.6 degrees 2-theta and including the end values, between 14.2 and 14.6 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, between 21.3 and 21.7 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 22.4 and 22.8 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2-theta and including the end values, between 10.6 and 11.0 degrees 2-theta and including the end values, between 13.0 and 13.4 degrees 2-theta and including the end values, between 14.7 and 15.1 degrees 2-theta and including the end values, between 15.8 and 16.2 degrees 2-theta and including the end values, between 18.1 and 18.5 degrees 2-theta and including the end values, between 18.7 and 19.1 degrees 2-theta and including the end values, between 20.9 and 21.3 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 23.3 and 23.7 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, and between 21.3 and 21.7 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, and between 21.4 and 21.8 degrees 2 theta and including the end values.

(i) A subject is subjected to an initial course of treatment comprising administering from about 30mg to about 50mg of compound (1):

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 30mg to about 50mg of compound (1) in response to recurrence of symptoms of depression,

(i) A subject is subjected to an initial course of treatment comprising administering a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 30mg to about 50mg of the free base compound:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent amount of about 30mg to about 50mg of the free base compound in response to recurrence of symptoms of depression,

(i) The subject is subjected to an initial course of treatment comprising administering from about 30mg to about 50mg of compound (1), once a day, for about 14 days:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 30mg to about 50mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression,

(i) A subject is subjected to an initial course of treatment comprising administering a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 30mg to about 50mg of the free base compound, once daily, for about 14 days:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 30mg to about 50mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression,

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 30mg to about 50mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is at least about a 6 week interval between the end of the initial treatment session and the beginning of the subsequent treatment session,

Compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 30mg to about 50mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

compound (1); and

Wherein the subject has been at a stable dose of an additional antidepressant for at least 60 days.

compound (1); and

(i) A subject is subjected to an initial course of treatment comprising administering from about 45mg to about 55mg of compound (1):

Compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 45mg to about 55mg of compound (1) in response to recurrence of symptoms of depression,

(i) A subject is subjected to an initial course of treatment comprising administering a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 45mg to about 55mg of the free base compound:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent amount of about 45mg to about 55mg of the free base compound in response to recurrence of symptoms of depression,

(i) The subject is subjected to an initial course of treatment comprising administering from about 45mg to about 55mg of compound (1), once a day, for about 14 days:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 45mg to about 55mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression,

(i) Subjects were subjected to an initial course of treatment comprising administering a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 45mg to about 55mg of the free base compound, once daily, for about 14 days:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 45mg to about 55mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression,

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 45mg to about 55mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is at least about a 6 week interval between the end of the initial treatment session and the beginning of the subsequent treatment session,

Compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 45mg to about 55mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

In some embodiments of these aspects, 0 or 1 subsequent treatment session is performed.

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

In some embodiments, the subject has not received treatment.

Brief Description of Drawings

Fig. 1 is an overview of the clinical study of example 1.

Fig. 2 is a depiction of the qualification criteria for the clinical study of example 1.

Fig. 3 is a flow chart of a dosing group.

Fig. 4A is an overview of the flow of subjects (30 mg group).

Fig. 4B is an overview of the flow of subjects (50 mg group).

FIG. 5 shows the mean LS change over time for HAM-D total score from baseline for the 30mg and 50mg cohorts.

FIG. 6A is a bar graph of HAMD-17 response at a particular time point for 30mg and 50mg groups.

FIG. 6B is a bar graph of HAMD-17 remission at a particular time point for the 30mg and 50mg groups.

FIG. 7 is a bar graph of HAM-D total score over time-study period 1 (safety set).

Figure 8 is a box plot of the change in HAM-D total score at day 15 from the baseline of the specified period during each treatment cycle, based on the use of antidepressant (yes/no) -low dose group at the baseline of the specified period (safety set for cycle 1, full analysis set for C2-5).

FIG. 9 shows a box plot of the change in total HAM-D score at day 15 from baseline during each treatment cycle (safety set for treatment cycle 1, FAS for C2-C5).

Fig. 10 is a box plot of the change in HAM-D total score at day 15 from the baseline of the specified period during each treatment cycle, based on the use of antidepressant (yes/no) -low dose group (FAS of treatment cycle 1, safety set, C2-C5) at the baseline of the specified period.

FIG. 11 is a bar graph of HAM-D response versus time-study period 1 (safety set).

Figure 12 shows a bar graph of HAM-D response over time during study period 1, based on the use of antidepressants at baseline (safety profile).

Fig. 13 is a bar graph of HAM-D response on day 15 of each treatment cycle, based on the use of antidepressant-low dose group (safety) at a specific period baseline.

FIG. 14 is a bar graph of HAM-D remission over time-study period 1 (safety set).

Figure 15 shows a bar graph of HAM-D remission over time during study period 1, based on the use of antidepressants at baseline (safety profile).

Figure 16 shows bar graphs of HAM-D remission on day 15 of each treatment cycle, based on the use of antidepressant-low dose group at a specific period of baseline.

FIG. 17 shows line graph of LS mean (+ -SE) change from baseline for subjects with baseline HAM-D score > 24-study period 1 (safety set).

FIG. 18 is a bar graph of HAM-D response over time for subjects with a baseline HAM-D score of 24 (safety set) during study period 1.

FIG. 19 is a bar graph of HAM-D remission over time for subjects with baseline HAM-D scores ∈24-study period 1 (safety set).

FIG. 20 shows a line graph of LS mean (+ -SE) change from baseline for subjects with baseline HAM-D.gtoreq.26-study period 1 (safety set).

FIG. 21 is a bar graph of HAM-D response over time in study period 1-study period 1 (safety set) for subjects with baseline HAM-D scores.gtoreq.26.

FIG. 22 is a bar graph of HAM-D remission over time for subjects with baseline HAM-D scores.gtoreq.26-study period 1 (safety set).

Figure 23 provides a box plot of the time per re-treatment according to the treatment cycle.

Figure 24 is a bar graph of HAM-D response/no-response versus percentage of responders in the previous cycle-low dose group (FAS).

Figure 25 is a bar graph of HAM-D response/non-responders versus percentage of non-responders in the previous cycle-low dose group (FAS).

Detailed Description

I. Definition of the definition

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

compound (1).

The compound (1), also known as zuranolone, 3α -hydroxy-3β -methyl-21- (4-cyanopyrazol-1-yl) -5β -19-norpregnan-20-one, has the IUPAC name 1- (2- ((3 r,5r,8r,9r,10s,13s,14s,17 s) -3-hydroxy-3, 13-dimethylhexadeca-1H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (CAS registry number 1632051-40-1). Methods of chemically synthesizing compound (1) are described in U.S. patent No. 9,512,165 and PCT application publication No. WO 2014/169833; the entire contents of the above-mentioned application are incorporated herein by reference in their entirety. Several crystalline forms of compound (1) and methods of preparing the forms are described in U.S. patent No. 11,236,121; U.S. patent application publication No. 2019/0177359; and PCT application publication No. WO 2018/039378; the entire contents of the above-mentioned application are incorporated herein by reference in their entirety. Pharmaceutical compositions of compound (1) and methods of preparing the compositions are described in PCT application publication No. WO 2022/020363 and in U.S. application Ser. No. 17/579,541; the entire contents of each of the above applications are incorporated herein by reference in their entirety.

Compound (1) is a neuroactive steroid, which has been shown to target synaptic and extrasynaptic GABA _A GABA of receptor _A Positive allosteric modulators of receptors. Compound (1) as GABA _A Positive allosteric modulators of receptors are useful as therapeutic agents for the treatment of CNS related disorders, such as depression, post-partum depression and major depressive disorders, and for the treatment of neurological disorders, such as essential tremor, epilepsy and parkinson's disease.

As used herein, "crystallization" refers to a solid phase of a given chemical entity having a well-defined 3-dimensional structural order. Atoms, ions, and/or molecules are arranged in a regular, periodic manner within a repeating 3-dimensional lattice. In various embodiments, the crystalline material may comprise one or more discrete crystalline forms.

As used herein, the terms "crystalline form," "crystalline solid form," "crystalline form," "solid form," and related terms refer to crystalline modifications comprising a given substance (e.g., compound (1)), including single-component crystalline forms and multicomponent crystalline forms, and include, but are not limited to, polymorphs, solvates, hydrates, and salts.

The term "substantially crystalline" refers to a form that may be at least a particular weight percent crystalline. Particular weight percentages 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 specific weight percent of crystallinity is at least 90%. In some embodiments, the specific weight percent of crystallinity is at least 95%. In some embodiments, compound (1) can be any of the crystalline forms described herein (e.g., crystalline forms a and C) and/or a substantially crystalline sample of PCT application publication No. WO 2018/039378; the entire contents of the above-mentioned application are incorporated herein by reference in their entirety.

The term "substantially pure" refers to compositions of a particular crystalline form (e.g., crystalline form of compound (1)), which may be at least a particular weight percent free of impurities and/or other solid forms. The specified weight percentages may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, compound (1) can be a substantially pure sample of any of the crystalline forms described herein (e.g., crystalline forms a and C). In some embodiments, compound (1) may be in substantially pure form a. In some embodiments, compound (1) may be in substantially pure form C.

As used herein, "XRPD" refers to X-ray powder diffraction. XRPD patterns are x-y plots of intensities plotted on the x-axis with 2Q (diffraction angle) plotted on the y-axis. These are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are typically represented and referenced by their position on the x-axis rather than by diffraction peak intensities on the y-axis, as diffraction peak intensities may be particularly sensitive to sample orientation (see Pharmaceutical Analysis, lee & Web, pp.255-257 (2003)). Therefore, the strength is not generally used by those skilled in the art to characterize crystalline materials. As with any data measurement, there may be variability in XRPD data. In addition to variability in diffraction peak intensity, there may be variability in the position of the diffraction peaks on the x-axis. However, this variability can often be explained when the location of the diffraction peaks is reported for characterization purposes. This variability in the position of the diffraction peaks along the x-axis may come from several sources. One such source may be sample preparation. Samples of the same crystalline material prepared under different conditions may produce slightly different diffraction patterns. Factors such as particle size, moisture content, solvent content, temperature and direction may all affect how the sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate with different parameters and may result in slightly different diffraction patterns from the same crystalline material. Likewise, different software packages handle XRPD data differently, and this may also lead to variability. These and other sources of variability are known to those of ordinary skill in the art. Because of such sources of variability, the value of each X-ray diffraction peak may be defined previously by the term "about" or continue to define experimental variability by appropriate ranges (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.).

When the term "characteristic peak" refers to a peak in an XRPD pattern of a crystalline form of a given chemical entity (e.g., the crystalline form of compound (1)), it refers to a collection of specific diffraction peaks whose values span a range of 2θ values (e.g., 0 ° to 40 °), which are unique to that particular crystalline form as a whole.

By "pharmaceutically acceptable" is meant approved or approvable by a regulatory agency of the federal or a state government or a corresponding agency in a country other than the united states, or listed in the united states pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is pharmaceutically acceptable and which has 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 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 organic acids such as 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-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadienedioic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts also include, by way of example only, salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; when the compound contains basic functional groups, non-toxic organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., berge, et al, j.pharm.sci. (1977) 66 (1): 1-79.

Chemical elements are identified according to the periodic table of elements (CAS version, handbook of chemistry and physics, 75ili edition, inner cover) and define specific functional groups generally as described therein. Furthermore, general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, organic Chemistry, university Science Books, sausalato, 1999; smith and March, march's Advanced Organic Chemistry,5ili 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.

When the term "about" is used before a quantitative value, the invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a change of ±10% from the nominal value unless otherwise specified or inferred.

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

As used herein, the term "dose equivalent" refers to a bioequivalent dose. For example, for a 50mg dose of compound (1), the dose equivalent of the pharmaceutically acceptable salt of compound (1) is the amount (by weight) of the desired pharmaceutically acceptable salt that provides a bioequivalent dose to the free base of compound (1) at a 50mg dose.

As used herein, an "effective amount" of a compound (or a pharmaceutically acceptable salt thereof) refers to an amount sufficient to elicit a desired biological response (e.g., to treat depression, e.g., major Depressive Disorder (MDD)). As will be appreciated by one of ordinary skill in the art, the effective amount of a compound of the invention (or a pharmaceutically acceptable salt thereof) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. Effective amounts include therapeutic and prophylactic treatments.

As used herein, an "intermittent dosing regimen" is a dosing regimen in which a compound or composition comprising a compound is administered to a subject for a limited period of time in response to diagnosis of a disorder or symptoms thereof (e.g., diagnosis or symptoms of depression or onset of major depressive disorder). In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a major depressive disorder. In some embodiments, the compounds are formulated as individual dosage units, each unit comprising compound (1) and one or more suitable pharmaceutical excipients. In some embodiments, the intermittent dosing regimen has a duration of weeks, for example about 8 weeks. In contrast to chronic administration as defined herein, intermittent administration of the compound occurs over a limited period of time, e.g., from about 2 weeks to about 8 weeks, in response to diagnosis or recurrence of a disorder (e.g., depression or symptoms thereof). In some embodiments, intermittent dosing occurs once a day over a number of weeks, e.g., from about 2 weeks to about 6 weeks. In one embodiment, intermittent administration has a duration of two weeks. In some embodiments, more than one intermittent dosing regimen is administered to the subject, but no more than 3 intermittent dosing regimens, e.g., two or more intermittent regimens are administered over a period of 12 months.

As used herein, the term "modulate" refers to GABA _A Inhibition or enhancement of receptor function. "modulators" (e.g. modulating GABA) _A A compound of receptor function or a pharmaceutically acceptable salt thereof) may be, for example, GABA _A Agonists, partial agonists, antagonists or partial antagonists of the receptor.

As used herein, "conducting" an initial and/or subsequent treatment session is the act of conducting a treatment session. In some embodiments, performing an initial and/or subsequent course of treatment refers to beginning administration of compound (1) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, performing an initial and/or subsequent course of treatment refers to completing the course of treatment, e.g., administering compound (1) or a pharmaceutically acceptable salt thereof to the subject for a specified period of time (e.g., about 2 weeks or about 14 days).

As used herein, "safety set" refers to all subjects who administered compound (1) in the clinical study of example 1. As used herein, a "full analysis set" refers to all subjects who have had HAM-D responses on day 15 in a safe set at treatment cycle 1 (e.g., initial treatment session), and discontinuation (if present) from the study date is after the end of treatment cycle 1 (e.g., initial treatment session). Responders refer to subjects who showed at least a 50% decrease in HAM-D total score from baseline on day 15 of the treatment cycle. If the total HAM-D score on day 15 of the treatment cycle is absent, the subject is considered to be a non-responder.

As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound (or a pharmaceutically acceptable salt thereof) is an amount sufficient to provide 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 pharmaceutically acceptable salt thereof) refers to an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

In another embodiment, the invention contemplates the administration of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, as a prophylaxis prior to the subject beginning to suffer from a particular disease, disorder, or condition. As used herein and unless otherwise indicated, 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 recurrence thereof. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, "solid dosage form" refers to a dosage of a drug in solid form, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler, and chew.

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

As used herein, unless otherwise indicated, the terms "treatment", "treatment" and "treatment" contemplate actions that occur when a subject has a particular disease, disorder or condition, which actions reduce the severity of the disease, disorder or condition (or any symptom thereof), or hinder or slow the progression of the disease, disorder or condition ("therapeutic treatment"), and also consider preventive actions that occur before the subject begins to have the particular disease, disorder or condition.

As used herein, a "course of treatment" refers to administration of compound (1) or a pharmaceutically acceptable salt thereof to treat Major Depressive Disorder (MDD) in a subject in need thereof for a specific period of time. For example, a course of treatment may administer compound (1) or a pharmaceutically acceptable salt thereof for about 2 weeks or about 14 days. The "course of treatment" starts from the day of the first dose of compound (1) or a pharmaceutically acceptable salt thereof, until the day of the last dose. The first treatment course of the subject within 12 months is the "initial treatment course".

The "course of treatment" may be repeated, provided that there is a time interval between each course of treatment when compound (1) or a pharmaceutically acceptable salt thereof is not administered (e.g., at least 4 weeks, at least 6 weeks, or at least 8 weeks from the end of the initial course of treatment). "subsequent treatment session" refers to a treatment session (e.g., repeated treatment sessions) performed on a subject after the subject has received an initial treatment session. In some embodiments, 0, 1, or 2 subsequent treatment sessions are performed over a period of 12 months from the beginning of the initial treatment session. Thus, in some embodiments, the methods provided herein can be performed on a subject for one, two, or three treatment sessions over a period of 12 months from the beginning of an initial treatment session. In particular embodiments, a course of treatment (e.g., a subsequent course of treatment) may be repeated in response to recurrence of symptoms of depression. Recurrence of depressive symptoms may be indicated by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof. For example, recurrence of depressive symptoms in a subject may be indicated by a PHQ-9 score of greater than or equal to 10 and/or by a HAM-D score of greater than or equal to 20. In some embodiments, the assessment of depression symptoms may be performed every 14 days over a period of 12 months from the end of the initial treatment session.

As used herein, "untreated (treatment)) "refers to a subject that has not been previously treated with additional antidepressants in the current depressive episode. "untreated" also refers to a subject who has not taken any antidepressants for at least 60 days prior to the initial course of treatment. In some embodiments, the subject is a "untreated patientparameter) ". The term "untreated patient" refers to two specific categories: i) Patients who have not been previously therapeutically exposed to the type or class of drug used to treat depression ("first untreated"), and ii) patients who have been previously exposed to the drug used to treat depression, but have a sufficiently long period of clearance ("second untreated") based on the judgment of the practitioner.

As used herein, the term "unit dosage form" is defined as a form that involves administration of compound (1) to a subject. In some embodiments, the unit dosage form may be, for example, a pill, capsule, or tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, typical amounts of compound (1) in unit dosage forms useful in the present disclosure are from about 10mg to about 100mg, from about 20mg to about 55mg, or from about 30mg to about 50mg (e.g., about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, or about 55 mg).

In some embodiments, administration of 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., semantics, context, programming, startup, or work); a direction; language; solving the problem; visual perception, construction and integration; planning; tissue capability; selective attention; inhibition control; and the ability to mentally manipulate information. In one embodiment, the cognitive function is selected from memory (e.g., semantic, contextual, programmatic, start-up, or work); a direction; language; solving the problem; visual perception, construction and integration; planning; tissue capability; selective attention; inhibition control; and manipulating one or more of the information mentally. Measurement of cognitive function includes assessment tools designed to measure, for example: (a) general mental capacity, (b) non-language mental capacity, (c) achievement, (d) attention/executive function, (e) memory and learning, (f) vision-movement and movement function, and (g) language.

Any change in cognitive function (e.g., over time or by treatment) can be monitored by using one or more of these confirmed tests at two or more points in time and comparing the results. The phrase "improving cognitive function" as referred to herein refers to a positive change in a subject's ability to perform a symbological operation (e.g., sense, memory, create mental images, think clarity, awareness, reasoning, thinking, or judgment). The positive change may be measured using any of the above-described tests at two or more times, e.g., a first time to measure baseline cognitive function and a second time to measure cognitive function after a period of time (where treatment may have been administered).

II therapeutic methods

The present disclosure relates to methods of treating Major Depressive Disorder (MDD). The diagnosis and severity of major depressive disorder treated by the methods described herein may be characterized by that defined in the fifth edition of the handbook for diagnosis and statistics of mental disorders (DSM-5).

Depressive disorder

Depressive disorders include destructive dysregulated mood disorders, major depressive disorders (including major depressive episodes), persistent depression (dysthymic), premenstrual dysphoric disorders, substance/drug induced depressive disorders, depressive disorders due to another medical condition, other specific depressive disorders, and undefined depressive disorders. A common feature of all these disorders is the presence of sad, empty or restless mood, accompanied by somatic and cognitive changes that significantly affect an individual's ability to function. The difference between them is the problem of duration, timing or presumed etiology.

Major depressive disorder represents a typical condition in this group of disorders. It is characterized by discrete episodes of a duration of at least two weeks (although most episodes are of considerable duration), involving significant changes in emotional, cognitive and autonomic functions and remission between episodes. Discrete episodes of major depressive disorder may be referred to as "major depressive episodes" or "depressive episodes".

Major Depressive Disorder (MDD)

Major depressive disorders are well known in the art.

In some embodiments, MDD is also known as depression or clinical depression, and it is an emotional disorder that results in continued sadness and loss of interest. MDD affects how a subject may feel, think, and behave, and may lead to various emotional and physical problems.

In some embodiments, MDD is defined and diagnosed according to DSM-5, e.g., MDD is diagnosed according to Standard A, as described below.

Standard a. Five (or more) of the following symptoms appear within the same two-week period and represent a change from the previous function; at least one symptom is (1) depressed mood or (2) lost interest or pleasure.

1. Most of the day, almost every day, depressed mood, as indicated by subjective reports (e.g., sad, empty, hopeless) or by what other people observe (e.g., appear tear) (note: a potentially irritating mood in children and adolescents).

2. Most of the time of day, almost every day interest or pleasure in all or almost all activities is significantly diminished (as shown by subjective descriptions or observations).

3. Weight loss or weight gain is significant when not on diet (e.g., weight changes over 5% in one month), or appetite is reduced or increased almost daily (note: in children, consider failure to achieve the desired weight gain.)

4. Insomnia or sleepiness occurs almost every day.

5. Psychomotor agitation or retardation (other people may observe, not just subjective feelings of anxiety or slowness) almost every day.

6. Fatigue or weakness occurs almost every day.

7. Almost every day there is perceived as worthless or excessive or inappropriate feelings of guilt (which may be delusions) (not just self-responsibility or guilt about illness).

8. The ability to think or concentrate is reduced almost every day, or is graceful (whether subjective description or observed by others).

9. Recurrent thoughts of death (not just fear of death), recurrent suicidal ideations without specific plans, suicidal attempts or specific suicidal plans.

The criteria B-E described below are additional descriptions of MDD and are contemplated for describing or diagnosing MDD, but are not required.

Standard B. These symptoms can lead to clinically significant distress or impairment in social, professional, or other important functional areas.

Standard C. The onset is not due to physiological effects of the substance or other medical conditions.

Criteria a-C may represent major depressive episodes.

Standard D. The occurrence of major depressive episodes cannot be better explained by schizoaffective disorders, schizophrenia, schizophreniform disorders, delusional disorders, or other specific and unspecified schizophrenic lineages and other psychotic disorders.

Standard E. Manic or hypomanic episodes never occurred.

In some embodiments, major Depressive Episode (MDE) is a period characterized by MDD symptoms as described above.

In some embodiments, the MDD is a clinical course characterized by one or more Major Depressive Episodes (MDE) of the subject.

In some embodiments, MDD is diagnosed according to criteria A-C as described above. In some embodiments, MDD is diagnosed according to criteria A-E as described above.

Diagnostic features

Standard symptoms of major depressive disorder must appear almost daily to be considered present, except for weight changes and suicidal ideation. Apart from being present almost every day, depressed emotions must also be present for most of the day. Insomnia or fatigue is often a complaint, and failure to explore the accompanying symptoms of depression will lead to under-diagnosis. Sadness may be initially denied, but may be deduced from interviews or from facial expressions and gestures. For individuals who focus on physical discomfort, the clinician should determine whether the affliction caused by the discomfort is associated with a particular depressive symptom. Fatigue and sleep disorders exist in most cases; psychomotor disturbances are less common but indicate a higher overall severity, as is the presence of delusions or paranoid guilt.

The essential feature of major depressive episodes is a period of at least two weeks during which either the mood is low or interest or pleasure is lost in almost all activities (criterion a above). In children and adolescents, the emotion may be annoying rather than sad. Individuals must also experience at least four additional symptoms from changes including appetite or weight, sleep and psychomotor activity; the energy is reduced; a sense of no value or guilt; difficult to think, concentrate on, or make decisions; or recurrent thoughts of death or suicidal ideation or suicidal program or attempt. To account for major depressive episodes, symptoms must be either new or significantly worse than the state of the patient prior to the episode. These symptoms must last for a substantial portion of the day, almost every day, for at least two consecutive weeks. The episode must be accompanied by clinically significant pain or impairment in social, professional or other important functional areas. For some mildly ill individuals, function may appear normal, but require significantly increased effort.

Sleep disorders may take the form of sleep difficulties or hypersomnia (criterion A4). When insomnia is present, it usually manifests as mid-term insomnia (i.e., wakes up at night and then is difficult to fall asleep) or end-stage insomnia (i.e., wakes up prematurely and fails to fall asleep). Incipient insomnia (i.e., difficulty falling asleep) may also occur. Individuals with hypersomnia (somnolence) may experience prolonged episodes of nocturnal sleep or increased daytime sleep. Sometimes, the reason an individual seeks treatment is that sleep is disturbed.

Accordingly, one aspect of the present invention proposes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

Another aspect of the invention proposes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a major depressive disorder.

In some embodiments, 0 or 1 subsequent treatment session is performed. In some embodiments, no (e.g., 0) subsequent treatment sessions are performed. In some embodiments, 1 subsequent course of treatment is performed. In some embodiments, 2 subsequent treatment sessions are performed.

In some embodiments, the method is performed for a total of one, two, or three treatment sessions over a period of 12 months. In some embodiments, the method is performed for a total of two treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session. In some embodiments, the method is performed for a total of three treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session.

In some embodiments, there is a gap of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a gap of at least about 4 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a gap of at least about 6 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a gap of at least about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session.

In some embodiments, there is a separation of about 4 weeks, about 6 weeks, or about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a gap of about 4 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is a gap of about 6 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session. In some embodiments, there is an interval of about 8 weeks between the end of an initial treatment session and the beginning of a subsequent treatment session.

In embodiments where two subsequent treatment sessions are performed, the time interval between each subsequent treatment session is the same as the time interval described above between the initial treatment session and the subsequent treatment session, e.g., there is an interval of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the first subsequent treatment session and the beginning of the second subsequent treatment session. In some embodiments, there is a gap of about 4 weeks, about 6 weeks, or about 8 weeks between the end of the first subsequent treatment session and the beginning of the second subsequent treatment session.

In some embodiments, recurrence of depressive symptoms is indicated by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof. In some embodiments, recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of greater than or equal to 10. In some embodiments, recurrence of depressive symptoms in the subject is indicated by a HAM-D score of greater than or equal to 20. In some embodiments, recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

In some embodiments, the initial course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, the initial course of treatment has a duration of about 2 weeks. In some embodiments, the initial course of treatment has a duration of about 14 days. In some embodiments, the initial course of treatment has a duration of 2 weeks or 14 days.

In some embodiments, each subsequent course of treatment has a duration of about 2 weeks or about 14 days. In some embodiments, each subsequent course of treatment has a duration of about 2 weeks. In some embodiments, each subsequent course of treatment has a duration of about 14 days. In some embodiments, each subsequent course of treatment has a duration of 2 weeks or 14 days.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 2 weeks or about 14 days during the initial course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 2 weeks during the initial course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days during the initial course of treatment.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 2 weeks or about 14 days in each subsequent course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 2 weeks in each subsequent course of treatment. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days in each subsequent course of treatment.

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

In some embodiments, compound (1) is administered at a dose of about 20mg to about 50mg once daily for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 30mg to about 50mg once daily for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 45mg to about 55mg once daily for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 50mg once daily for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50mg once daily for about 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, compound (1) is administered at a dose of about 40mg once daily for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40mg once daily for about 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40mg once daily for about 14 days.

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

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

In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 30mg to about 50mg of the free base compound once daily for about 2 weeks or about 14 days. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 45mg to about 55mg of the free base compound once daily for about 2 weeks or about 14 days. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 50mg of the free base compound once daily for less than 2 weeks. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound once a day for about 2 weeks. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound once a day for about 14 days. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 40mg of the free base compound once daily for less than 2 weeks. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 40mg of the free base compound once daily for about 2 weeks. In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 40mg of the free base compound once daily for about 14 days.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered chronically.

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

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing food. Examples of fat-containing foods include nuts, peanut butter, avocados, eggs, and cheese. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered at night with a fat-containing food (e.g., within 1 hour after a dinner containing fat, or with a fat-containing treat)).

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject at night. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 1 hour before the patient sleeps. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 15 minutes before the patient sleeps. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject once a day at night. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 1 hour before the patient sleeps, once a day. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 15 minutes before the patient sleeps, once a day.

In some embodiments, compound (1) is in crystalline form. In some embodiments, the crystalline form of compound (1) is any of the crystalline forms disclosed in PCT application publication No. WO 2018/039378; the entire contents of the above-mentioned application are incorporated herein by reference in their entirety.

In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 11.6 and 12.0 degrees 2-theta and including the end values, between 13.2 and 13.6 degrees 2-theta and including the end values, between 14.2 and 14.6 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, between 21.3 and 21.7 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 22.4 and 22.8 degrees 2-theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and inclusive, between 14.6 and 15.0 degrees 2-theta and inclusive, between 16.8 and 17.2 degrees 2-theta and inclusive, between 20.5 and 20.9 degrees 2-theta and inclusive, and between 21.3 and 21.7 degrees 2-theta and inclusive.

In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 14.7 and 15.1 degrees 2 theta and including the end values, between 15.8 and 16.2 degrees 2 theta and including the end values, between 18.1 and 18.5 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, between 20.9 and 21.3 degrees 2 theta and including the end values, between 21.4 and 21.8 degrees 2 theta and including the end values, and between 23.3 and 23.7 degrees 2 theta and including the end values. In some embodiments, compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, and between 21.4 and 21.8 degrees 2 theta and including the end values.

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

In some embodiments, the subject has not received treatment. In some embodiments, the subject does not receive any antidepressant treatment for at least 30 days before the beginning of the initial treatment course. In some embodiments, the subject does not receive any antidepressant treatment for at least 60 days before the initial treatment session begins.

Another aspect of the present disclosure includes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

Wherein the subject has not received treatment.

compound (1); and

wherein the subject has not received treatment.

In some embodiments, the method is performed for a total of one, two, or three courses of treatment over a period of 12 months. In some embodiments, the method is performed for a total of two treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session. In some embodiments, the method is performed for a total of three treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session.

In embodiments where two subsequent treatment sessions are performed, the time interval between each subsequent treatment session is the same as the time interval described above between the initial treatment session and the subsequent treatment session, e.g., there is an interval of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the first subsequent treatment session and the beginning of the second subsequent treatment session. In some embodiments, there is a separation of about 4 weeks, about 6 weeks, or about 8 weeks between the end of the first subsequent treatment session and the beginning of the second subsequent treatment session.

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

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

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 30mg to about 50mg of the free base compound, in response to recurrence of symptoms of depression,

compound (1); and

Compound (1); and

Another aspect of the disclosure includes a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

(i) The subject is subjected to an initial course of treatment comprising administering from about 45mg to about 55mg of compound (1):

Compound (1); and

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) in a dose equivalent of about 45mg to about 55mg of the free base compound, in response to recurrence of symptoms of depression,

compound (1); and

(i) The subject is subjected to an initial course of treatment comprising administering the pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 45mg to about 55mg of the free base compound, once daily, for about 14 days:

Compound (1); and

In some embodiments, the method is performed for a total of one, two, or three treatment sessions over a period of 12 months. In some embodiments, the method performs a total of two treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session. In some embodiments, the method is performed for a total of three treatment sessions over a period of 12 months from the beginning of the initial (first) treatment session.

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

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a fat-containing food. Examples of fat-containing foods include nuts, peanut butter, avocados, eggs, and cheese. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered at night with a fat-containing food (e.g., within 1 hour after a fat-containing dinner, or with a fat-containing treat).

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject at night. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 1 hour before the patient sleeps. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered to the subject no later than 15 minutes before the patient sleeps.

In some embodiments, the subject has not received treatment. In some embodiments, the subject has not received any antidepressant treatment for at least 30 days before the beginning of the initial treatment regimen. In some embodiments, the subject has not received any antidepressant treatment for at least 60 days prior to the initiation of the initial treatment regimen.

III pharmaceutical composition

Another aspect of the present disclosure provides a pharmaceutical composition for use in the methods described herein, comprising compound (1) (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a pharmaceutical composition for use in the methods described herein, comprising a pharmaceutically acceptable salt of an active ingredient and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient. In some embodiments, the pharmaceutical composition of compound (1) is any of the pharmaceutical compositions disclosed in PCT application publication No. WO 2022/020363; the entire contents of the above-mentioned application are incorporated herein by reference in their entirety.

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

The pharmaceutical compositions of the present invention may be further delivered using a variety of methods of administration. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. The location of the bolus dose depends on the desired systemic level of the active ingredient throughout the body, e.g., intramuscular or subcutaneous bolus doses allow slow release of the active ingredient, while direct bolus delivery to the vein (e.g., by IV infusion) allows faster delivery, thereby rapidly increasing 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, e.g., by IV drip, to provide maintenance of steady state concentration of the active ingredient in the subject. In addition, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose, followed by continuous infusion.

Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. More often, however, the composition is presented in unit dosage form to facilitate accurate administration. 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 quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or, for solid compositions, pills, tablets, capsules, and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), the remainder being various vehicles or excipients and processing aids that aid in forming the desired dosage form.

The components of the compositions described above for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, among others, are set forth in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, which is incorporated herein by reference.

The compositions of the present invention may also be administered in a sustained release form or by a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

Although the description of pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to a wide variety of animals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to a variety of animals is well understood, and such modifications can be designed and/or made by routine experimentation by the ordinarily skilled veterinary pharmacologist. 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.

In another aspect, the disclosure includes a method of treating major depressive disorder in a subject in need thereof, the method comprising administering to the subject a daily dose comprising 45mg to 55mg of compound (1) using an intermittent dosing regimen to treat the major depressive disorder in the subject.

In one embodiment of this aspect, the intermittent dosing regimen has a duration of about 2 to about 8 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 to about 6 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 to about 4 weeks. In further embodiments, the intermittent dosing regimen has a duration of about 2 weeks or 14 days. In yet another embodiment, the intermittent dosing regimen has a duration of 2 weeks.

In one embodiment, the subject exhibits a response to an intermittent dosing regimen, wherein the response is indicated by a decrease in HAM-D score of greater than or equal to about 50% relative to baseline. In one embodiment, the subject is assessed for recurrence or reproduction of symptoms of depression.

In some embodiments, the method comprises a plurality of intermittent dosing regimens. In one embodiment, the intermittent dosing regimen is separated by intervals of at least 8 weeks. In another embodiment, the daily dose comprises 45mg to 55mg of compound (1). In another embodiment, the daily dose comprises 48mg to 52mg of compound (1). In a further embodiment, the daily dose comprises 50mg of compound (1).

In one embodiment, the daily dose is administered to the subject at night. In another embodiment, the daily dose is administered to the subject concurrently with or immediately after ingestion of the food.

In another aspect, the present disclosure includes a method of treating major depressive disorder in a subject in need thereof, the method comprising the steps of:

(i) Administering to the subject a daily dose comprising 45mg to 55mg of compound (1), once daily, for about two weeks; and is also provided with

(ii) Re-administering to the subject a daily dose comprising 45mg to 55mg of compound (1) once daily for about two weeks in response to recurrence of symptoms of depression, provided that there is a gap of at least 8 weeks between administration of compound (1) to the subject and re-administration of compound (1) to the subject.

In one embodiment of this aspect, compound (1) is reapplied to the subject for 2 weeks. In another embodiment, the interval between administration of compound (1) to a subject and re-administration of compound (1) to a subject is 8 weeks. In further embodiments, the major depressive disorder is a moderate major depressive disorder. In another embodiment, the major depressive disorder is major depressive disorder. In one embodiment, the subject has experienced a major depressive episode in a period of about 1 year. In another embodiment, the subject is between about 18 years old and about 75 years old. In another embodiment, the subject is between about 18 years old and about 65 years old. In one embodiment, the daily dose comprises 48mg to 52mg of compound (1). In a further embodiment, the daily dose comprises 50mg of compound (1). In another embodiment, the daily dose is administered to the subject at night. In another embodiment, the daily dose is administered to the subject concurrently with or immediately after ingestion of the food. In one embodiment, the daily dose comprising compound (1) is in the form of a capsule. In one embodiment, the method further comprises administering a second therapeutic agent to the subject.

In another aspect, the disclosure includes a method of treating major depressive disorder in a subject in need thereof using a kit (kit) comprising:

a plurality of individual dosage units, each dosage unit comprising 45mg to 55mg of compound (1), and

a set of instructions, wherein the set of instructions describes a method of administering a dosage unit to a subject using an intermittent dosing regimen.

In another aspect, the disclosure includes a method of treating major depressive disorder in a subject in need thereof using a kit comprising:

a plurality of individual dosage units, each dosage unit comprising from 30mg to 50mg of compound (1), and

In embodiments of these aspects, the intermittent dosing regimen has a duration of about 2 to about 8 weeks. In one embodiment, the intermittent dosing regimen has a duration of about 2 to about 6 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 to about 4 weeks. In a further embodiment, the intermittent dosing regimen has a duration of about 2 weeks. In yet another embodiment, the intermittent dosing regimen has a duration of 2 weeks. In one embodiment, the subject has been diagnosed with major depressive disorder. In further embodiments, the major depressive disorder is a moderate major depressive disorder. In another embodiment, the major depressive disorder is major depressive disorder. In one embodiment, each dosage unit contains 45mg to 55mg of compound (1). In one embodiment, each dosage unit contains 48mg to 52mg of compound (1). In a further embodiment, each dosage unit contains 50mg of compound (1). In a further embodiment, each dosage unit contains 40mg of compound (1). In one embodiment, the instruction set describes a method comprising instructions for administering a dosage unit at night. In another embodiment, the instruction set describes a method comprising instructions for administering a dosage unit simultaneously with or immediately after ingestion of food.

In another aspect, the disclosure includes a kit comprising a plurality of doses, each dose comprising 45mg to 55mg of compound (1), and a set of instructions describing a method of administering the dose using an intermittent dosing regimen to treat major depressive disorder. In one embodiment of this aspect, the dose is a single dosage unit of compound (1). In a further embodiment, the individual dosage units comprise 48mg to 52mg of compound (1). In yet another embodiment, the individual dosage units comprise 50mg of compound (1). In one embodiment, the intermittent dosing regimen has a duration of about 2 to about 8 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 to about 6 weeks. In further embodiments, the intermittent dosing regimen has a duration of about 2 to about 4 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 weeks or 14 days. In yet another embodiment, the intermittent dosing regimen has a duration of 2 weeks. In one embodiment, the major depressive disorder is a moderate major depressive disorder. In another embodiment, the major depressive disorder is major depressive disorder. In one embodiment, the instruction set is printed on a suitable material. In another embodiment, the individual dosage units are capsules or tablets. In a further embodiment, the individual dosage units are capsules. In some embodiments, the individual dosage units are capsules of size 1, 2, 3 or 4. In one embodiment, the capsule is size 1.

In another aspect, the disclosure includes a kit comprising a plurality of doses, each dose comprising 30mg to 50mg of compound (1), and a set of instructions describing a method of administering the dose using an intermittent dosing regimen to treat major depressive disorder. In one embodiment of this aspect, the dose is a single dosage unit of compound (1). In a further embodiment, the individual dosage units comprise 45mg to 55mg of compound (1). In a further embodiment, the individual dosage units comprise 48mg to 52mg of compound (1). In yet another embodiment, the individual dosage units comprise 50mg of compound (1). In yet another embodiment, the individual dosage units comprise 40mg of compound (1). In one embodiment, the intermittent dosing regimen has a duration of about 2 to about 8 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 to about 6 weeks. In further embodiments, the intermittent dosing regimen has a duration of about 2 to about 4 weeks. In another embodiment, the intermittent dosing regimen has a duration of about 2 weeks or 14 days. In yet another embodiment, the intermittent dosing regimen has a duration of 2 weeks. In one embodiment, the major depressive disorder is a moderate major depressive disorder. In another embodiment, the major depressive disorder is major depressive disorder. In one embodiment, the instruction set is printed on a suitable material. In another embodiment, the individual dosage units are capsules or tablets. In a further embodiment, the individual dosage units are capsules. In some embodiments, the individual dosage units are capsules of size 1, 2, 3 or 4. In one embodiment, the capsule is size 1.

In some embodiments, the method improves cognitive function in the subject. In some embodiments, the method improves cognitive function in the subject after completion of the intermittent dosing regimen. In some embodiments, the method does not cause cognitive impairment in the subject.

In another aspect, the invention includes a method of treating major depressive disorder in a subject in need thereof, the method comprising the steps of:

(i) Subjecting a subject to an initial administration period, wherein the initial administration period consists essentially of a dosing period comprising administering to the subject a daily dose comprising about 30mg or about 50mg of compound (1), once a day:

compound (1)

A period of two weeks followed by a non-dosing period comprising a period of at least 8 weeks, wherein compound (1) is not administered to the subject; and

(ii) The subject is subjected to 0, 1, 2, 3 or 4 subsequent administration cycles, wherein each subsequent administration cycle consists essentially of a dosing period comprising administering to the subject a daily dose comprising about 30mg or about 50mg of compound (1), once a day, for a period of two weeks followed by a non-dosing period comprising a period of at least 8 weeks, wherein compound (1) is not administered to the subject.

In one embodiment of this aspect, the total time of the initial administration period and all subsequent administration periods does not exceed one year. In another embodiment, there are no more than four subsequent administration periods within the year. In some embodiments, there is an 8 week interval between the administration of compound (1) to the subject and the re-administration of compound (1) to the subject. Administration of one or more subsequent administration cycles to a subject that has received an initial administration cycle is interchangeably referred to as re-administration of compound (1), also interchangeably referred to as re-treatment. In one embodiment, each subsequent administration cycle is performed after the non-administration period of the previous administration cycle in response to recurrence of symptoms of depression. In another embodiment, recurrence of depressive symptoms requiring subsequent administration periods is determined by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof. In another embodiment, recurrence of depressive symptoms requiring subsequent administration cycles is determined by a HAM-D score of ≡20. In a further embodiment, recurrence of depressive symptoms requiring subsequent administration cycles is further determined by a PHQ-9 score of ≡10. In yet another embodiment, recurrence of depressive symptoms requiring subsequent administration cycles is further determined by MADRS score of 28 or more. In one embodiment, the non-dosing period is at least 10 weeks and the subject is subjected to no more than 3 subsequent administration cycles. In another embodiment, the non-dosing period is at least 12 weeks and the subject is subjected to no more than 2 subsequent administration cycles. In another embodiment, the non-dosing period is at least 16 weeks and the subject is subjected to no more than 1 subsequent administration period. In another embodiment, the non-dosing period is at least 24 weeks and no subsequent administration cycles are performed to the subject. In some embodiments, the depressive symptoms do not recur. In some embodiments, the initial administration period comprises a daily dose of 30mg of compound (1). In a further embodiment, each subsequent administration cycle comprises a daily dose of 30mg of compound (1). In another embodiment, one or more subsequent administration periods comprise a daily dose of 50mg of compound (1), and the remaining subsequent administration periods comprise a daily dose of 30mg of compound (1). In another embodiment, each subsequent administration cycle comprises a daily dose of 50mg of compound (1). In some embodiments, the initial administration period comprises a daily dose of 50mg of compound (1). In a further embodiment, each subsequent administration cycle comprises a daily dose of 50mg of compound (1). In another embodiment, one or more subsequent administration periods comprise a daily dose of 30mg of compound (1), and the remaining subsequent administration periods comprise a daily dose of 50mg of compound (1). In another embodiment, each subsequent administration cycle comprises a daily dose of 30mg of compound (1). In one embodiment, the subject is not receiving any form of treatment with a drug for treating depression. In further embodiments, the subject is first untreated. In further embodiments, the subject is twice untreated. In one embodiment, the subject is currently taking or has recently taken antidepressants. In further embodiments, the subject is at a stable dose of the antidepressant drug for at least 60 days prior to the beginning of the initial administration period. In one embodiment, the major depressive disorder is a moderate major depressive disorder. In another embodiment, the major depressive disorder is major depressive disorder. In one embodiment, the subject has experienced a major depressive episode in a period of about one year. In one embodiment, the subject is between about 18 years old and about 75 years old. In further embodiments, the subject is between about 18 years old and about 65 years old. In one embodiment, the daily dose of compound (1) is administered to the subject at night. In another embodiment, the daily dose is administered to the subject concurrently with or immediately after ingestion of the food. In one embodiment, the daily dose comprising compound (1) is in the form of a capsule. In another embodiment, the method further comprises administering a second therapeutic agent to the subject.

Examples

Example 1. Safety, tolerability and necessity of retreatment with compound (1) in adult subjects with major depressive disorder phase 3, open, 1 year study.

Abbreviations (abbreviations)	Definition or description
		AE	Adverse events
CGI-I	Clinical global impression-improvement
		CGI-S	Clinical global impression-improvement
C1	Cycle 1
		CI	Confidence interval
C-SSRS	Columbia suicide severity rating scale
		ECG	Electrocardiogram
FAS	Full analysis set
		HAM-D	Hamilton depression scale
HAM-A	Hamilton anxiety rating scale
		HSV	Herpes simplex virus
ICF	Informed consent form
		LS Mean	Least squares mean
MADRS	Montgomery-osberg depression scale
		MDD	Major depressive disorder
MedDRA	Supervision activity medical dictionary
		MMRM	Hybrid effect model repeat measurement
PT	Preferred terminology
		SAE	Serious adverse events
SE	Standard error of
		SOC	Systematic organ classification
TEAE	Adverse events occurring during the treatment period

The main purpose is as follows: the safety and tolerability of initial and retreatment with compound (1) for adults suffering from Major Depressive Disorder (MDD) that currently experienced Major Depressive Episode (MDE) over a period of 1 year was determined.

Secondary objective: the need for retreatment with compound (1) after the initial treatment of an adult with MDD who is currently experiencing MDE during the 1 year period was evaluated, and the response of initial treatment and retreatment with compound (1) after the initial 2-week treatment period of an adult with MDD who is currently experiencing MDE during the 1 year period was evaluated.

The main end point is: safety and tolerability of initial treatment with compound (1) and retreatment with compound (1) as assessed by incidence and severity of adverse events/severe adverse events; changes from baseline in clinical laboratory measurements, vital signs, and Electrocardiography (ECG); and suicidal ideation and behavior between 1 year using the columbia suicide severity rating scale (C-SSRS). Safety and tolerability of initial treatment with compound (1) and retreatment with compound (1) as assessed by incidence and severity of adverse events/severe adverse events; changes from baseline in clinical laboratory measurements, vital signs, and Electrocardiography (ECG); suicidal ideation and behavior using the columbia suicide severity rating scale (C-SSRS).

Secondary endpoint: the necessity of retreatment with compound (1) was evaluated as follows: time to first retreatment (Kaplan-Meier curve), number of subjects meeting retreatment requirement, number of retreatment cycles for US subjects, response to initial treatment and/or retreatment, as assessed by: the sum score of the HAM-D scale (HAM-D) at the end of each 14-day treatment (initial and/or retreatment) period was varied from baseline at 17 hamilton depression levels, the HAM-D response at the end of each 14-day treatment (initial and/or retreatment) period was defined as a decrease of ∈50% from baseline, the sum-D remission at the end of each 14-day treatment (initial and/or retreatment) period was defined as a sum-D score of ∈7, the clinical overall impression-improvement (CGI-I) response was defined as a "large improvement" or "very large improvement", the change of the clinical overall impression-severity (CGI-S) score from baseline at the end of each 14-day treatment (initial and/or retreatment) period.

Study population: subjects were 18-75 years old, were diagnosed with Major Depressive Disorder (MDD), and had a total MADRS score of 28 and HAM-D score of 20 at screening and day 1 (pre-dose).

Treatment group: the 30mg and 50mg dose groups were separated by the time of entry. The study included two groups: one starting with 30mg of compound (1) (30 mg group; n=725), one starting with 50mg of compound (1) (50 mg group; n=199). Patients receiving 30mg of compound (1) can reduce the dose to 20mg, and patients receiving 50mg of compound (1) can reduce the dose to 40mg (based on tolerability). In all groups, compound (1) was self-administered by the patient as an oral regimen, taken once a night with food, for 14 days.

Study design

The study had a screening period of up to 28 days, a treatment period of 14 days and a follow-up period of up to 1 year. Fig. 1 is an overview of the study.

The screening period begins with signing Informed Consent (ICF) at the screening visit; the ICF must be signed before any screening activity is started. The diagnosis of MDD must be made by qualified healthcare professionals according to the structured clinical interview for mental disease diagnosis and statistics Manual, fifth edition (DSM-5) clinical trial version (SCID-5-CT). The subject will undergo a preliminary screening procedure at screening visit to determine eligibility, including completion of MADRS, HAM-D and CGI-S.

Provided that the subject is at a stable dose at least 60 days prior to day 1 and agrees to continue at the stable dose during the follow-up period (day 42), then the use of antidepressant drugs is allowed. The start of new antidepressants or any other drug that may have an impact on efficacy or safety endpoints is not allowed between screening and completion of the day 42 evaluation.

The eligible subjects were given compound (1) -taken at home with meals at night. Subjects with at least 50% decrease in HAM-D total score at day 15, i.e., responders in treatment cycle 1 were allowed to continue to participate in the study; others were terminated after a follow-up of 14 days (day 28).

Subjects who continued in the observation period were monitored remotely by PHQ-9 evaluation every two weeks. If PHQ-9 score > =10 in any of the assessments, the PHQ-9 assessment is switched to once a week until the score drops below 10 or compound (1) is administered to the subject in a subsequent cycle, whichever is earlier. Subjects were asked to return to the point for HAM-D assessment within one week of PHQ-9 score > =10; if HAM-D total score > =20 and at least 56 days have elapsed since the last administration of compound (1), another administration cycle of compound (1) is started. If either of these criteria is not met, the subject cannot be treated with compound (1) at that time. Subjects were followed out every 8 weeks without triggering PHQ-9> =10. Subjects can receive a maximum of 5 treatment cycles in a year. Fig. 2 is a depiction of the qualification criteria for this study.

Fig. 3 is a flow chart of a dosing group.

At the time of 50mg introduction, subjects treated with 30mg in the past cycle were turned to 50mg in the next treatment cycle.

If safety and/or tolerability of the subject is warranted, a dose reduction from 30mg to 20mg or from 50mg to 40mg is allowed during any treatment cycle. Furthermore, if the subject dose is reduced from 50mg to 40mg during any cycle, the researcher may choose to have the subject start at 50mg or 40mg for the next treatment cycle. Subjects whose dose was reduced from 30mg to 20mg still began with 30mg in the next treatment cycle.

The use of antidepressants may be modified between treatment cycles according to specific rules specified in the protocol.

Main inclusion criteria: female and male patients, aged 18-75 years and diagnosed with MDD, with symptoms occurring for > 4 weeks, and HAM-D17 total score > 20 and MADRS total score > 28 on screening and day 1 (pre-dosing). Patients taking antidepressants must take these drugs at the same dose for at least 60 days before day 1 and intend to continue to complete the first treatment cycle.

The main exclusion criteria: active psychosis, suicidal paralysis or suicidal risk associated with current MDD episodes, history of bipolar disorder, schizophrenia and/or schizoaffective disorder, or treatment resistant depression, defined as the presence of symptoms of persistent depression despite treatment within the current MDE with sufficient doses of antidepressants from 2 different classes (excluding antipsychotics) for at least 4 weeks

Determination of sample size: the sample size is not calculated based on the formal sample size. The sample size of 900 subjects was selected so that at least 450 subjects completed a 24 week study, and at least 150 subjects completed a thorough 56 week study.

The groups associated with the different doses received by the subjects are defined as follows:

50mg group: the group included subjects who had begun treatment with 50mg and received only 50mg of retreatment.

30mg group: the cohort included subjects who had begun to be treated with 30mg, regardless of the dose they received in the retreatment.

Low dose group: the cohort included subjects who had begun to receive treatment with 30mg and who received only 30mg retreatment.

Dose-conversion group: the group included subjects who had begun to receive treatment with 30mg and at least one subsequent re-treatment with 50 mg.

Study period X: starting from the date of the first dose of compound (1) in cycle X until the day before the first dose of the next cycle. In some embodiments, X is any number from 1 to 5.

Treatment period X: starting from the date of the first dose of compound (1) in cycle X, up to the day after the last dose in cycle X. In some embodiments, X is any number from 1 to 5.

Treatment period X: starting from the date of the first dose of compound (1) in cycle X up to 14 days after the last dose in cycle X. The treatment cycle may be expressed as C1-C5.

Observation period X: starting on the second day after the end of treatment cycle X and starting on the day before the start of the next treatment cycle. In some embodiments, X is any number from 1 to 5.

Using the foregoing, for study period 1, the 30mg group was essentially identical to the combined group of the low dose group and the dose-converted group. 725 subjects received dosing in the 30mg group (n=645 in the low dose group and n=80 in the dose-converted group), and 199 subjects received dosing in the 50mg group. The 30mg group completed one year follow-up.

Analysis set: safety set is defined as all subjects administered study drug. The safety set for a particular period includes subjects who have administered study medication in the safety set in the corresponding treatment cycle. The Full Analysis Set (FAS) was defined as all subjects with HAM-D response on day 15 in treatment cycle 1 in safety concentrations, and discontinuation from the study date (if present) was after the end of treatment cycle 1. ( Treatment cycle X responders were safety group subjects whose HAM-D total score on day 15 of treatment cycle X showed at least a 50% decrease from baseline. If the total HAM-D score was absent on day 15 of treatment cycle X, the subject was considered to be a non-responder. )

Dose-shift groups were defined as all subjects who received 30mg of treatment on day 1 of the treatment cycle and 50mg of treatment on day 1 of the subsequent re-treatment cycle, with safety focus.

Statistical analysis

The data of all groups are presented separately, except that all groups are taken together as an overall group of compound (1), whenever possible. For the dose-shift group, the data is presented by study period, treatment period X, day 1 dose received in terms of dose distribution over a specified period, and the population of compound (1), regardless of the dose received. All displays are presented according to the received treatment, without regard to the planned treatment.

Treatment of subjects has been provided, including the number of subjects dosed in each cycle and the number of subjects dosed in exactly X treatment cycles. Descriptive statistics of sum-D score, sum-D response and relief of treatment cycle 1 have been provided for subjects dosed in treatment cycle 1 (safety set). The remaining analysis of HAM-D total scores used FAS administered to subjects in each treatment cycle. A plot of mean change in LS of HAM-D total score from baseline for each study period is provided, based on a mixed effect model (MMRM) of repeated measurements for each study period and each dose group, respectively; the model will include baseline scores for each particular period, antidepressant usage (yes or no) at baseline, evaluation time points, as explanatory variables. A sum-D summary of the dose-converted cohort for the first dose in each cycle has been provided. In addition, a summary of the total HAM-D score for subjects dosed during period X for the current and past treatment periods is provided. The response of the past period of the subject without the response in the current period on day 15 is provided. Bar graphs of HAM-D response and remission during the study have been provided.

For safety analysis, a safety set of specific time periods was used in addition to the dose-shift cohort when appropriate. The treatment period is defined as the first dose up to the last dose date+1 day of the study period. The treatment period was defined as the first dose date of the study period until 14 days after the last dose date. Adverse events have been analyzed by dose cohort:

1. summary of adverse events occurring during the treatment period, including the number and percentage of subjects with TEAE, TEAE during the treatment period, during the post-treatment period, TEAE of greatest severity, TEAE resulting in study drug withdrawal or dose reduction, severe TEAE-population, and according to study period.

2. AE during the treatment period according to SOC and PT-first dose according to study period and study period using dose-shift group.

3. Treatment period according to SOC/PT and maximum severity AE-first dose according to study period and study period using dose shift group.

4. TEAE (in terms of SOC/PT) resulting in drug withdrawal of the study.

5. TEAE (in terms of SOC/PT) resulting in reduced dose of study drug.

6. Severe TEAE during the treatment period according to SOC/PT-first dose according to study period and study period using dose-shift group.

Example 2. Results from example 1-the most important results.

The data used in this example 2 is data with an expiration date, which is the date the study was completed for the last subject to begin the study at a dose of 30 mg. By this expiration date, all subjects in the 50mg group completed a 28 day treatment cycle 1, but some subjects were under study for insufficient time to qualify for any retreatment. By the date of expiration of this data, only 1 subject in the 50mg group had been dosed during treatment cycle 3 (including the initial cycle).

An overview of the subject procedure is provided in fig. 4A and 4B.

Results

Primary endpoint-security

A similar proportion of subjects have reported adverse events (TEAE) occurring during the treatment period across dose groups: 50mg group: 62.8% (125/199); 30mg group: 68.0% (493/725); low dose group: 67.6% (436/645); dose-conversion group: 71.3% (57/80)

TEAE occurring in more than 5% of subjects in any dose group is provided in the table below.

TABLE 1 TEAE occurring in more than 5% of subjects

To date, the overall safety observations in subjects receiving 50mg of compound (1) were comparable to those observed with 30mg, and neither dose deviated from the known safety profile of compound (1).

Most TEAEs were mild to moderate in all dose groups, with similar incidence for all dose groups.

TABLE 2 TEAE severity in all dose groups

The percentage of subjects reporting TEAE resulting in withdrawal of study drug was 6.5% (13/199) in the 50mg group, 2.8% (18/645) in the low dose group, and 1.3% (1/80) in the dose-shift group.

TEAE was reported to result in a percentage of subjects who were withdrawn from the study of 7.0% (14/199) in the 50mg group, 4.8% (31/645) in the low dose group, and 1.3% (1/80) in the dose-shift group.

The percentage of subjects reporting TEAE to result in dose reduction is in the 50mg group: 17.1% (34/199), all in cycle 1, 2/26 in cycle 2, except for 2. In the low dose group: overall 5.0% (32/645): respectively, 3.4% (22/645) in cycle 1, 4.4% (9/206) in cycle 2, 2.3% (2/86) in cycle 3, 0 (0/43) in cycle 4, and 10% (2/20) in cycle 5. In the dose-shift group: overall 15.0% (12/80): when at 30mg, 2.5% (3/80) in each of cycle 1 and cycle 2; when switching to 50mg, 4.2% (3/71) in cycle 3, 3.8% (2/53) in cycle 4, and 17.4% (4/23) in cycle 5. Somnolence, dizziness, sedation and headache are the most common AEs resulting in dose reduction.

Secondary endpoint-therapeutic effect

TABLE 3 variation of HAM-D total score on day 15 (safety set)

* All enrolled (HAM-D > =20, madrs > =28) and dosed subjects

On day 15, for the 30mg group, the mean change from baseline was-15.2±7.1 (n=687); 505 (73.5%) patients obtained responses and 276 (40.2%) patients obtained remissions (HAM-D.ltoreq.7). On day 15 of the initial treatment course in the 50mg group, the mean HAM-D change from baseline was-16±6.0;149/185 (80.5%) gave a response and 80/185 (43.2%) gave relief. Changes in HAM-D total score over time-study period 1 (safety set) is shown in fig. 5. Initial HAM-D response and mitigation are shown in fig. 6A and 6B, respectively.

Table 4 shows a summary of safe and focused retreatment.

Table 4. Remaking summary (safety set)

[1] Meeting the re-treatment condition means that the subject completed treatment cycle 1 and did not discontinue the study within 56 days after the last dose date.

[2] Qualification for retreatment means that the subject meets retreatment conditions and HAM-D total score > = 20 points prior to retreatment.

[3] The percentages use the denominator from the number of subjects meeting the re-treatment conditions.

TABLE 5 number of subjects according to the retreatment cycle (%)

As shown in table 5, most patients (68.5%) received only 1 or 2 treatments of compound (1) during the 30mg group over the 12 month follow-up period.

During the 1 year follow-up, the average (range) number of retreatments per subject was 0.8 (0-4) for the low dose group, and 2.8 (1-4) for the dose-shift group. In summary, the average number of retreatments in the 30mg group was 1.2 (0-4). The retreatment rate was similar with and without the existing antidepressant treatment. At the time of the report, no subjects in the 50mg group were on study for more than 6 months, with most subjects (n=114) having a follow-up time of less than 3 months, and only 1 subject received more than one re-treatment.

TABLE 6 time interval between retreatment (days)

The time intervals (days) between retreatments by using antidepressants at baseline in the previous treatment cycle are shown in table 7. The use of antidepressants has no significant effect on the length of time between retreatments.

Table 7 antidepressant drug use at baseline in the previous cycle (low dose cohort)

The response rate of the treatment cycle in the low dose group is as follows: treatment cycle 2:59.3% (118/199) of total response rate. Treatment cycle 3:57.8% (48/83) total response rate, with 75% (36/48) of the subjects being responders in treatment cycle 2 and still responders in treatment cycle 3. 25% (12/483) of treatment cycle 2 was non-responders to retreatment. Treatment cycle 4:51.2% (22/43) total response rate, where 81.8% (18/22) subjects were responders in treatment cycle 3, 63.6% (14/22) subjects were responders in treatment cycle 2 and still be responders in treatment cycle 4. 18.2% (4/22) of the subjects were non-responders during treatment cycle 3 and 36.4% (8/22) were non-responders to retreatment during treatment cycle 4 during treatment cycle 2. Treatment cycle 5:50.0% (10/20) total response rate, with 90% (9/10) in treatment cycle 4, 80% (8/10) in treatment cycle 3, and 70% (7/10) of the subjects being responders in treatment cycle 2 and still responders in treatment cycle 5. 1% (1/10), 20.0% (2/10) and 30% (3/10) subjects were non-responders to retreatment in treatment cycle 5 in treatment cycle 4, treatment cycle 3 and treatment cycle 2, respectively.

Figure 7 provides a bar graph of HAM-D response/no response at day 15 for low dose group (FAS) alone according to treatment cycle. The inner bar represents the percentage of respondents in the previous cycle.

Figure 8 provides a box plot of the change in HAM-D total score from the baseline for the specified period on day 15 of each treatment cycle, based on antidepressant use (yes/no) at the baseline for the specified period—low dose group (safe set for treatment cycle 1, FAS for treatment cycles 2-5).

Example 3. Results from example 1-full results set.

Subject treatment

The data used in this example 3 is data from the study of example 1 with an expiration date, which is the date on which the study was completed for the last subject to begin the study at a dose of 30 mg. This example demonstrates additional results from example 2.

A total of 924 subjects were treated with compound (1) in treatment cycle 1 (C1), with 725 subjects in the 30mg group receiving treatment (645 subjects in the low dose group and 80 subjects in the dose-converted group), and 199 subjects in the 50mg group receiving treatment.

Of 725 subjects initially treated with 30mg, 202 (31.3%) subjects were withdrawn in advance or from the study during treatment cycle 1. Of 202 subjects, 146 (72.3%) discontinued the study due to a 50% decrease in HAM-D not being reached on day 15. 523 (72.1%) of the subjects completed treatment cycle 1.

As shown in table 8, of 725 subjects initially treated with 30mg, 413 (57%) subjects were withdrawn from the study in the 30mg group in advance of one year completion. Of these 413 subjects, 173 (41.9%) were withdrawn due to failure to meet the responder criteria in treatment cycle 1. Of these 173 subjects, 146 discontinued during treatment cycle 1 because they should follow the regimen, and another 27 subjects discontinued the study after treatment cycle 1 was completed because they were non-responders during treatment cycle 1, bringing the total to 173).

Of 725 subjects initially treated with 30mg, 489 (67.4%) of 725 subjects (409 subjects in the low dose group and 80 subjects in the dose-converted group) were responders in treatment cycle 1 and completed treatment cycle 1, and were therefore in FAS.

Of the 80 subjects in the dose-shift group, 10 subjects were in treatment cycle 2, 21 subjects were in treatment cycle 3, 38 subjects were in treatment cycle 4, and 11 subjects were shifted to 50mg in treatment cycle 5. Two subjects who switched to 50mg in treatment cycle 3, treatment cycle 4 was started with a reduced dose of 40 mg. The 4 subjects in this group withdrawn-1 from the periodic study when they switched to 50mg stopped study treatment during treatment period 2 and withdrawn as decided by the doctor; 1 stopped treatment during treatment cycle 5 and exited due to adverse events; 1 withdraw consent during treatment cycle 4, and one withdraw after completion of cycle 5 treatment but failing to complete the last part of study visit due to calendar conflicts.

Of 199 subjects dosed in the 50mg group, 64 (32.2%) subjects were withdrawn from the study prior to the data expiration date. Of the 64 subjects who were withdrawn from the study, 35 (54.7%) were withdrawn by 50% of the HAM-D reduction not reached on day 15, and 14 (21.9%) were withdrawn by adverse events. Of 199 subjects initially treated with 50mg, 146 (73.4%) were counted in FAS (responders in treatment cycle 1 and did not stop the study in treatment cycle 1).

TABLE 8 treatment-therapy cycle 1

Demographic and baseline characteristics

Demographic and baseline characteristics of subjects entering the study were very balanced between the 30mg group and the 50mg group. Overall, about 68% are females, 81% are white, and the average age is 45 years (SD: 14.13 years). About 42% of subjects use antidepressants at baseline. 82% of subjects have a baseline HAMD of greater than or equal to 22.

TABLE 9 demographic and baseline characteristics (safety set)

TABLE 10 completion of treatment and participation in the study

Efficacy results

HAM-D Total score

TABLE 11 mean and percent changes in HAM-D total score for study period 1 only (safety set)

[1] The baseline row represents the mean value of HAM-D total score.+ -. SD

FIG. 5 provides a line graph of changes in the total HAM-D score from baseline LS mean (+ -SE) for study period 1.

FIG. 9 provides a box plot of the change in total HAM-D score at day 15 of each treatment cycle (safety set for treatment cycle 1, FAS for C2-C5).

Figure 10 provides a box plot of the change in HAM-D total score from the baseline for the specified period on day 15 of each treatment cycle, based on antidepressant use (yes/no) -low dose group at the baseline for the specified period (FAS for treatment cycle 1, C2-5).

ham-D response

TABLE 12 HAM-D response of study period 1 alone (safety set)

FIG. 11 provides a bar graph of HAM-D response over time-study period 1 (safety set). Figure 12 provides a bar graph of HAM-D response over time during study period 1, based on antidepressant use at baseline (safety profile). Figure 13 provides a bar graph of HAM-D response at day 15 of each treatment cycle, based on antidepressant usage-low dose group (safety set) at a baseline for a specific period.

HAM-D mitigation

Table 13 HAM-D remission (safety set) for study period 1 only.

Fig. 14 provides a bar graph of HAM-D remission over time-study period 1 (safety set). Figure 15 provides a bar graph of HAM-D remission over time during study period 1, based on antidepressant use at baseline (safety set). Figure 16 provides a bar graph of HAM-D remission on day 15 of each treatment cycle, based on antidepressant usage-low dose group at a baseline for a specific period.

4. Subjects with baseline HAM-D scores ∈24 (total score, response, and remission)

Tables 14, 15 and 16 show the sum-score, response and remission, respectively, of HAM-D at various time points for subjects with a baseline HAM-D score of ∈24. FIG. 17 provides a line graph of LS mean (. + -. SE) change from baseline for subjects with a baseline HAM-D score of 24-study period 1 (safety set). FIGS. 18 and 19 provide bar graph-study period 1 (safety set) of HAM-D response and remission, respectively, for subjects with baseline HAM-D scores of > 24.

TABLE 14 mean change and percent change in HAM-D total score for subjects with baseline HAM-D score > 24-study period 1 (safety set)

[1] The baseline row represents the mean value of HAM-D total score.+ -. SD

Table 15 HAM-D response (safety set) for subjects with baseline HAM-D score > 24 during study period 1 alone.

Table 16. HAM-D remission (safety set) for subjects with baseline HAM-D score > 24 in study period 1 alone.

5. Subjects with a baseline HAM-D score of > 26 (total score, response, and remission)

Tables 17, 18 and 19 show the sum-score, response and remission, respectively, of HAM-D at various time points for subjects with baseline HAM-D score ∈26. FIG. 20 provides a line graph of changes in LS mean (+ -SE) from baseline for subjects with a baseline HAM-D score of > 26-study period 1 (safety set). FIGS. 21 and 22 provide bar graph-study period 1 (safety set) of HAM-D response and remission, respectively, for subjects with baseline HAM-D scores of > 26.

TABLE 17 mean change and percent change in HAM-D total score for subjects with baseline HAM-D score > 26-study period 1 (safety set)

[1] The baseline row represents the mean value of HAM-D total score.+ -. SD

TABLE 18 HAM-D response (safety set) for subjects with baseline HAM-D score.gtoreq.26 for study period 1 alone.

Table 19. HAM-D remission (safety set) was only observed for subjects with baseline HAM-D scores > 26 in study period 1.

6. Retreatment

The average (range) number of retreatments per subject was 0.8 (0-4) for the low dose group and 2.8 (1-4) for the dose-converted group. In summary, in the 30mg group, the average number of retreatments was 1.2 (0-4). At the time of the report, no subjects in the 50mg group were in the study for more than 6 months, most (n=114) of the follow-up time was less than 3 months, and only 1 subject received more than 1 re-treatment.

TABLE 20 retreatment from treatment cycle 1

TABLE 21 crowd (safety set) according to dosing cycle

[1] Percentage based on the number of subjects dosed in C1

[2] Based on the percentage of the number of subjects in FAS

TABLE 22 number of subjects (%)

TABLE 23 summary of time (days) for each retreatment since last dose in previous treatment cycle according to treatment cycle (FAS)

[1] N = number of FAS subjects meeting dosing conditions in X cycles; n = number of FAS subjects eligible and dosed in X cycles.

Table 24. Summary of time per retreatment (days) based on baseline antidepressant use in previous treatment cycle-Low dose group (FAS)

7. Therapeutic effects in responders versus non-responders

TABLE 25 summary of non-responsive status of responders at D15 in the current treatment cycle at D15 in the past treatment cycle-Low dose group (FAS)

The denominator of the +% is the number of subjects dosed in the current cycle

* The denominator of the percentages is the number of respondents or non-respondents for the current period.

Figure 24 provides a bar graph of HAM-D response/no responders, and percentage of responders in the previous treatment cycle-low dose (FAS) [ inner bars represent percentage of responders in the previous cycle ].

Fig. 25 provides a bar graph of HAM-D response/no responders, and percent no responders in the previous treatment cycle-low dose (FAS) [ inner bars represent percent no responders in the previous cycle ].

8. Total score of HAM-D in current and past cycles

Low dose cohort

Table 26 average change/percent change from baseline for a particular period of time in total HAM-D score in current and past treatment cycles in subjects dosed during the treatment cycle-low dose group (FAS).

* n = number of subjects on which the calculation is based.

Dose conversion group

TABLE 27 HAM-D Total score-dose conversion group (FAS)

* n = number of subjects on which the calculation is based.

The dose shift cohort included subjects who began the study at a dose of 30mg but shifted to 50mg in the subsequent treatment cycle.

Safety results (adverse events)

Subjects of similar proportion reported adverse events (TEAE) occurring during the treatment period across three dose groups: 60.5% (46/76) in the 50mg group, 66.6% (451/677) in the low dose group, and 77.1% (37/48) in the dose-converted group subjects.

TABLE 28 general summary of adverse events (safety set)

Treatment period TEAE are those that begin between the first dose and the last dose of compound (1) for +1 day. TEAE during the treatment period are those that begin between the first dose of compound (1) and 14 days after the last dose.

TEAE occurring in more than 5% of subjects in any dose group is provided in table 29.

TABLE 29 TEAE (safety set) occurring in more than 5% of subjects in any dose group to date

Table 30. Overview of teae intensity

The overall safety observations in subjects receiving 50mg of compound (1) were comparable to those observed with 30mg, and did not deviate from the known safety profile of compound (1). Similar adverse events were reported regardless of the presence or absence of existing antidepressant therapies. By the expiration date, no loss of consciousness events are reported.

During treatment cycle 1, 2.5% (5/199) of the subjects in the 50mg group reported SAE and 0.9% (6/645) in the low dose group. In the 50mg group, three of the five SAE were considered likely to be related to study drug; withdrawal, and in each case subjects discontinued from the study: one subject had confusion, one subject had frailty, and one subject had delirium. Of the 5 cases of SAE considered unrelated to study drug, 2 were suicidal and deliberate self-disability in the 50mg group; both resolved within 7 days.

In the low dose group (only 30 mg), no SAE are considered presumably or possibly related to the study drug. Although 5 out of 6 SAE's were considered severe in intensity, only one (intracranial aneurysm) resulted in discontinuation from the study.

TABLE 31 SAE of approximate or probable relevance

The percentage of subjects reported to result in TEAE that was withdrawn from the study in the 50mg group was 7.0% (14/199), 4.8% (31/645) in the low dose group, and 1.3% (1/80) in the dose-shift group.

The percentage of subjects reporting TEAE resulting in dose reduction is: 17.1% (34/199), all in cycle 1, 2/26 in cycle 2, except for 2. In the low dose group: overall 5.0% (32/645): respectively, 3.4% (22/645) in cycle 1, 4.4% (9/206) in cycle 2, 2.3% (2/86) in cycle 3, 0 (0/43) in cycle 4, and 10% (2/20) in cycle 5. In the dose-shift group: overall 15.0% (12/80): 2.5% (3/80) in each of cycle 1 and cycle 2; and when switching to 50mg, 4.2% (3/71) in cycle 3, 3.8% (2/53) in cycle 4, and 17.4% (4/23) in cycle 5. Somnolence, dizziness, sedation and headache are the most common AEs resulting in dose reduction.

TABLE 32 adverse event summary of antidepressant drug use during the study period-Low dose group (safety Congress)

The treatment period is defined as the first dose to the last dose +1 day. The treatment period was defined as the end of the follow-up 14 days after the first dose to the last dose.

Conclusion(s)

The first course of treatment of 30mg of compound (1) is generally well tolerated and the safety results are consistent with previous studies. In the 30mg group, 68.5% of subjects did not receive more than 1 re-treatment. In the low dose group (treated with only 30 mg), subjects received an average of 0.8 retreatment (or 1.8 treatments total). In the 30mg group, subjects received an average of 1.2 times (or 2.2 treatments in total). A maximum of 1 additional course of treatment is used in about 70% of patients in the 30mg group who respond to the initial course of treatment.

Initial response rates for the 30mg and 50mg groups were 73.5% and 80.5%, respectively.

The safety and tolerability profiles of 30mg of compound (1) and 50mg of compound (1) were consistent with those seen in the early test. To date, no conscious loss event has been reported in either group. Most TEAEs in the 30mg group and the 50mg group were mild or moderate.

Example 4.50 annual follow-up for mg group

Introduction to the invention

Example 4 provides additional data from the study described in example 1 (a phase 3, open, 1 year study of safety, tolerability and necessity of retreatment with compound (1) in adult subjects with major depressive disorder). Examples 2-3 present data for a period of time ending when the 30mg group (n=725) completed a year follow-up. Some early data for the 50mg group is provided in examples 2-3, which are available when the 30mg group completes a year of follow-up. Example 4 presents data for a later period until the 50mg group (n=199) ended when the one year follow-up was completed. Example 4 provides additional data that has now been collected and analyzed for the 50mg group, but does not alter the data, results or conclusions described for the 30mg group in examples 2-3.

The data used in example 4 is data with an expiration date, which is the study completion date of the last subject (n=199) in the 50mg group starting the study. In examples 2-3, all subjects in the 50mg group completed treatment cycle 1, but some subjects were under study for insufficient time to qualify for any retreatment. By the date of expiration of the data of examples 2-3, only 1 subject in the 50mg group had been dosed during treatment cycle 3. By the date of expiration of the data of example 4, all subjects in the 50mg cohort completed one year follow-up.

Results

The average baseline HAMD score (±sd) for the 50mg cohort at the time of study entry was 25.1±3.29 (n=199). At baseline, 81 (40.7%) patients were on existing antidepressant therapy (ADT) and continued, while 118 (59.3%) patients were not on ADT.

For 50mg group subjects who received one or more treatment cycles for a year, 50mg of compound (1) was generally well tolerated and no new safety findings or trends were found in the available data by the expiration date of example 4. Safety was assessed during, between, and over multiple treatment cycles to understand tolerance over time. At least one adverse event was reported in 137 (68.8%) of 199 50mg subjects, similar to 30mg (68.0%). Most 50mg group subjects reported adverse events (TEAE) occurring during the treatment period with the greatest severity being mild to moderate. The most common adverse events (TEAE) occurring during treatment (reporting at least 5%) were somnolence (32; 16.1%), dizziness (30; 15.1%), headache (25; 12.7%), sedation (20; 10.1%), insomnia (14; 7.0%), nausea (13; 6.5%) and tremors (11; 5.5%).

The TEAE types reported by the 50mg group subjects were similar to those reported by the 30mg group subjects. Adverse drug reactions such as somnolence, dizziness, sedation and tremors were more frequent in the 50mg group; however, the severity and outcome of TEAE was consistent with the overall safety profile of the 30mg group and compound (1). The percentage of 50mg group subjects reporting to discontinue study drug and TEAE withdrawn from the study was 6.5% (13/199) and 8.0% (16/199), respectively.

No sign of suicidal ideation or increase in suicidal behavior compared to baseline was seen in any study period or dose group as measured by the columbia suicide severity rating scale (C-SSRS). The overall adverse event profile from the 50mg cohort was substantially consistent with the previously reported data, and the TEAE type reported was similar to that already reported in the compound (1) clinical program.

On day 15 (treatment cycle 1), the mean change in HAM-D from baseline for the 50mg group was-16.0±6.04 (n=185). About 149 subjects (74.9%) obtained responses (at least 50% decrease in HAM-D from baseline), and 80 subjects (40.2%) obtained remissions (less than or equal to 7). Of the 149 responders, 3 subjects were withdrawn from the study prior to day 28, leaving 146 subjects under study after day 28 (i.e., 146 or about 73.4% of 199 subjects initially treated with 50mg of compound (1) were included in FAS). Of the 146 subjects under study, 79.5% received at most one additional treatment cycle with compound (1) after day 28. 54.8% (n=80) received a total of 1 treatment course; 24.7% (n=36) received a total of 2 treatment sessions; 10.3% (n=15) received a total of 3 treatment sessions; 6.8% (n=10) received a total of 4 treatment sessions; and 3.4% (n=5) received a total of 5 treatment sessions. Approximately 79.5% of FAS subjects in the 50mg group did not receive more than 1 re-treatment.

The proportion of subjects receiving zero or up to 1 additional cycles of compound (1) treatment in the 50mg group was similar, regardless of whether or not antidepressant treatment was used at baseline.

Example 5 patient subpopulations in the study of example 1

EXAMPLE 5.1 MDD and Metabolic complications

Example 5.1 provides data for MDD patients with metabolic complications of the study described in example 1.

Introduction to the invention

MDD patients with metabolic complications face additional adverse events (e.g., weight gain, metabolic abnormalities) associated with antidepressants and often respond poorly. This example presents the results of a post hoc analysis of the clinical study of example 1 for patients with MDD and metabolic complications.

Method

The clinical study of example 1 was enrolled with 1 of 2 groups of patients with MDD, age 18-75 years, HAMD-17 score > 20 and MADRS total score > 28: 30mg group and 50mg group. HAMD-17 responders on day 15 (50% or more decrease from baseline) continued to study and assess re-treatment eligibility.

Patients with metabolic complications are identified by the following coded terms in the patient history: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, type 1 diabetes, impaired glucose tolerance, hypertriglyceridemia, dyslipidemia, metabolic syndrome and/or diabetic dyslipidemia.

Results

The study of example 1 recruited 924 patients (30 mg group n=725; 50mg group n=199). Of these, 253/924 (27.4%) had metabolic complications (30 mg group 197/725;27.2%;50mg group 56/199; 28.1%). Baseline demographics relative to the general population: average (SD) age 52.2 (12.4) versus 45.0 (14.1); spanish 30.4% versus 23.8%; the use of antidepressants was 54.2% versus 41.8%; average (SD) kg/m ² BMI 33.4 (6.7) versus 30.0 (6.54).

The average (SD) CFB of HAMD-17 at day 15 for the first treatment cycle (metabolic syndrome subpopulation versus population overall) was-14.8 (7.10) vs-15.4 (6.9), respectively; HAMD-17 response rate was 67.3% versus 75.0%; the HAMD-17 remission rate was 37.1% versus 40.8%.

For 161/253 patients in the metabolic syndrome subpopulation that responded to and completed the first treatment cycle, 90 (55.9%) did not require additional treatment sessions (43.7% relative to total) during their study; the average (range) number of total treatment sessions was 1.9 (1-5) relative to the total 1.8 (1-5).

The number of patients with > 1TEAE in the metabolic syndrome subgroup during the duration of the study was 167/253 (66.0%); most are mild/moderate (148/167; 88.6%). TEAE common (. Gtoreq.5%) in this subgroup was relative to the population, including headache (14.2% relative to 13.9%), somnolence (13.8% relative to 12.8%), dizziness (9.1% relative to 9.1%), diarrhea (6.7% relative to 6.3%), upper limb respiratory tract infection (5.9% relative to 6.3%), dry mouth (5.5% relative to 5.5%) and sedation (5.1% relative to 8.7%). TEAE resulted in 8/253 (3.2%) patients disabling study drug; 19/253 (7.5%) patients reduced dose; 11/253 (4.3%) patients were withdrawn from the study.

Conclusion(s)

Compound (1) was generally well tolerated in patients with MDD and metabolic complications, showing safety and efficacy outcomes similar to the overall study population. These results support the further development of compound (1) as a potential on-demand treatment for MDD patients, including patients with metabolic complications.

EXAMPLE 5.2 postmenopausal women with MDD

Example 5.2 provides data for postmenopausal women classified as having MDD in the study described in example 1.

Introduction to the invention

Hormonal changes in the early menopause often affect the metabolism of Antidepressants (ADT). Postmenopausal/geriatric women may respond poorly to ADT. This example a post-menopausal female with MDD was analyzed post-operatively for the study described in example 1.

Method

The study described in example 1 will have MDD, age 18-75 years, patients with HAMD-17. Gtoreq.20 and MADRS total score. Gtoreq.28 recruited to 1 of 2 groups: 30mg group and 50mg group. HAMD-17 responders on day 15 (50% or more from baseline) continued to study and assess eligibility for retreatment. Postmenopausal women of an age > 45 are identified based on whether follicle stimulating hormone >40 (central laboratory data) at baseline and medical history encoding terms include "menopause".

Results

The study described in example 1 recruited 924 patients (30 mg group n=725; 50mg group n=199); in the first 14-day course of treatment, 152/924 (16.5%) postmenopausal women received either 30mg (110/725; 15.2%) of compound (1) or 50mg (42/199; 21.1%) of compound (1). In addition to age and gender, the baseline demographics of patients in this subpopulation were substantially identical to the overall study population, with: average (SD) age, 58.7 (6.72) years old relative to 45.0 (14.1) years old; average (SD) HAMD-17, 25.7 (3.92) versus 25.3 (3.9); the antidepressant is used in an amount of 52.6% versus 41.7%.

The average (SD) CFB of HAMD-17 on day 15 (last day of first treatment period) in postmenopausal patients was-16.0 (7.00) versus-15.4 (6.9) for the total study population. The HAMD-17 response rate at day 15 was 75.7% relative to 75.0% of the total study population. The HAMD-17 remission rate at day 15 was 39.6% versus 40.8% for the total study population.

For 106/152 postmenopausal patients who responded to treatment cycle 1 and completed treatment cycle 1, 45 (42.5%) did not require additional courses of treatment during their study; the average number of total treatment courses was 2.2 (1-5).

The number of postmenopausal patients with at least 1 TEAE during the duration of the study was 102/152 (67.1%). Most experienced mild or moderate TEAE (90/102; 88.2%). TEAE, which is most common (5% or more) in postmenopausal patients (relative to the population as a whole), includes headache (13.2% versus 13.9%), somnolence (12.5% versus 12.8%), dizziness (11.8% versus 9.1%), diarrhea (7.9% versus 6.3%), upper respiratory tract infections (7.9% versus 6.3%), dry mouth (7.2% versus 5.5%), sedation (6.6% versus 8.7%), and insomnia (6.6% versus 5.4%). TEAE resulted in 8/152 (5.3%) patients discontinuing study drug; 16/152 (10.5%) patients reduced dose; 9/152 (5.9%) of the patients were withdrawn from the study.

Conclusion(s)

Compound (1) was generally well tolerated in postmenopausal women, showing similar safety and efficacy outcomes as the overall study population. These results support the further development of compound (1) as a potential on-demand treatment for MDD patients, including refractory postmenopausal women.

Equivalent forms and scope

In the claims, articles such as "a" and "the" may refer to one or more than one unless indicated to the contrary or clear from the context. Unless indicated to the contrary or apparent from the context, claims or descriptions that include "or" between "one or more group members are considered satisfactory if one, more than one, or all group members are present, used, or otherwise associated with a given product or process. The present invention includes embodiments in which exactly one group member is present, used, or otherwise associated with a given product or process. The present invention includes embodiments in which more than one or all of the group members are present, employed, or otherwise associated with a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same underlying claim. Where elements are presented in a list (e.g., in Markush group format), each sub-group of the elements is also disclosed, and any elements may be removed from the group. It should be understood that, in general, certain embodiments of the invention or aspects of the invention consist of or consist essentially of the particular elements and/or features when referred to as comprising those elements and/or features. For simplicity, those embodiments are not explicitly set forth in these words herein. It is further noted that the terms "comprising" and "comprises" are intended to be open-ended and to allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understood by those of ordinary skill in the art, values expressed as ranges in different embodiments of the invention may take any particular value or subrange within the range to one tenth of the unit of the lower limit of the range unless the context clearly indicates otherwise.

The present application is directed to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If a conflict exists between any of the incorporated references and this specification, the present specification will control. In addition, any particular embodiment of the application that falls within the prior art may be expressly excluded from any one or more of the claims. Because these embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly set forth herein. Any particular embodiment of the application may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Other embodiments

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited by the foregoing description, but rather is set forth in the following claims. It will be understood by those skilled in the art that various changes and modifications may be made to the present description without departing from the spirit or scope of the application as defined in the following claims.

Claims

1. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

wherein the 0, 1, or 2 subsequent treatment sessions are performed over a period of 12 months from the beginning of the initial treatment session.

2. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

3. The method of claim 1 or 2, wherein 0 or 1 subsequent treatment session is performed.

4. The method of claim 1 or 2, wherein 1 subsequent treatment session is performed.

5. The method of any one of claims 1-4, wherein there is a gap of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session.

6. The method of any one of claims 1-4, wherein there is a gap of about 4 weeks, about 6 weeks, or about 8 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session.

7. The method of any one of claims 1-6, wherein recurrence of symptoms of depression is indicated by an assessment of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof.

8. The method of any one of claims 1-7, wherein recurrence of the depressive symptom in the subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

9. The method of any one of claims 1-8, wherein the initial course of treatment has a duration of about 2 weeks or about 14 days.

10. The method of any one of claims 1-9, wherein each subsequent course of treatment has a duration of about 2 weeks or about 14 days.

11. The method of any one of claims 1-10, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days during the initial course of treatment.

12. The method of any one of claims 1-11, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days in each subsequent course of treatment.

13. The method of claim 1, wherein compound (1) is administered at a dose of about 20mg to about 55 mg.

14. The method of claim 1, wherein compound (1) is administered at a dose of about 50 mg.

15. The method of claim 1, wherein compound (1) is administered at a dose of about 40 mg.

16. The method of claim 2, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 20mg to about 55mg of the free base compound.

17. The method of claim 2, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound.

18. The method of claim 2, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 40mg of the free base compound.

19. The method of any one of claims 1-18, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally.

20. The method of claim 19, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

21. The method of any one of claims 1-20, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a food.

22. The method of any one of claims 1-21, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered at night, once a day.

23. The method of claim 1, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 11.6 and 12.0 degrees 2-theta and including the end values, between 13.2 and 13.6 degrees 2-theta and including the end values, between 14.2 and 14.6 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, between 21.3 and 21.7 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 22.4 and 22.8 degrees 2-theta and including the end values.

24. The method of claim 1, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 14.7 and 15.1 degrees 2 theta and including the end values, between 15.8 and 16.2 degrees 2 theta and including the end values, between 18.1 and 18.5 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, between 20.9 and 21.3 degrees 2 theta and including the end values, between 21.4 and 21.8 degrees 2 theta and including the end values, and between 23.3 and 23.7 degrees 2 theta and including the end values.

25. The method of claim 1, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, and between 21.3 and 21.7 degrees 2-theta and including the end values.

26. The method of claim 1, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, and between 21.4 and 21.8 degrees 2 theta and including the end values.

27. The method of any one of claims 1-26, wherein the subject has not received treatment.

28. The method of any one of claims 1-26, wherein the subject has been at a stable dose of additional antidepressant for at least 60 days prior to the start of the initial treatment session.

29. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

wherein the 0, 1 or 2 subsequent treatment sessions are performed within a period of 12 months from the beginning of the initial treatment session, and

wherein the subject has not received treatment.

30. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

wherein the subject has not received treatment.

31. The method of claim 29 or 30, wherein 0 or 1 subsequent treatment session is performed.

32. The method of claim 29 or 30, wherein 1 subsequent treatment session is performed.

33. The method of any one of claims 29-32, wherein there is a gap of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session.

34. The method of any one of claims 29-32, wherein there is a gap of about 4 weeks, about 6 weeks, or about 8 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session.

35. The method of any one of claims 29-34, wherein the recurrence of depression symptoms is indicated by an assessment of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof.

36. The method of any one of claims 29-35, wherein recurrence of the depressive symptom in the subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

37. The method of any one of claims 29-36, wherein the initial course of treatment has a duration of about 2 weeks or about 14 days.

38. The method of any one of claims 29-37, wherein each subsequent course of treatment has a duration of about 2 weeks or about 14 days.

39. The method of any one of claims 29-38, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days during the initial course of treatment.

40. The method of any one of claims 29-39, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once daily for about 14 days in each subsequent course of treatment.

41. The method of claim 29, wherein compound (1) is administered at a dose of about 20mg to about 55 mg.

42. The method of claim 29, wherein compound (1) is administered at a dose of about 50 mg.

43. The method of claim 29, wherein compound (1) is administered at a dose of about 40 mg.

44. The method of claim 30, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 20mg to about 55mg of the free base compound.

45. The method of claim 30, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound.

46. The method of claim 30, wherein the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 40mg of the free base compound.

47. The method of any one of claims 29-46, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally.

48. The method of claim 47, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

49. The method of any one of claims 29-48, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with food.

50. The method of any one of claims 29-49, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered at night, once daily.

51. The method of claim 29, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 11.6 and 12.0 degrees 2-theta and including the end values, between 13.2 and 13.6 degrees 2-theta and including the end values, between 14.2 and 14.6 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, between 21.3 and 21.7 degrees 2-theta and including the end values, between 21.4 and 21.8 degrees 2-theta and including the end values, and between 22.4 and 22.8 degrees 2-theta and including the end values.

52. The method of claim 29, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 14.7 and 15.1 degrees 2 theta and including the end values, between 15.8 and 16.2 degrees 2 theta and including the end values, between 18.1 and 18.5 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, between 20.9 and 21.3 degrees 2 theta and including the end values, between 21.4 and 21.8 degrees 2 theta and including the end values, and between 23.3 and 23.7 degrees 2 theta and including the end values.

53. The method of claim 29, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.7 and 10.1 degrees 2-theta and including the end values, between 14.6 and 15.0 degrees 2-theta and including the end values, between 16.8 and 17.2 degrees 2-theta and including the end values, between 20.5 and 20.9 degrees 2-theta and including the end values, and between 21.3 and 21.7 degrees 2-theta and including the end values.

54. The method of claim 29, wherein compound (1) is in crystalline form having an XRPD pattern comprising the following peaks: between 9.3 and 9.7 degrees 2 theta and including the end values, between 10.6 and 11.0 degrees 2 theta and including the end values, between 13.0 and 13.4 degrees 2 theta and including the end values, between 18.7 and 19.1 degrees 2 theta and including the end values, and between 21.4 and 21.8 degrees 2 theta and including the end values.

55. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

56. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

57. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

58. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

59. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 30mg to about 50mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is a gap of at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

60. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

Compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 30mg to about 50mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is a gap of at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

61. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

62. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

63. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

Compound (1); and

64. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

65. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

Compound (1); and

66. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

67. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject from about 45mg to about 55mg of compound (1), once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is a gap of at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

68. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising:

compound (1); and

(ii) Subjecting the subject to 0, 1 or 2 subsequent treatment sessions, wherein each subsequent treatment session comprises administering to the subject a pharmaceutically acceptable salt of compound (1) at a dose equivalent of about 45mg to about 55mg of the free base compound, once daily, for about 14 days, in response to recurrence of symptoms of depression, provided that there is a gap of at least about 6 weeks between the end of the initial treatment session and the beginning of the subsequent treatment session,

69. The method of any one of claims 55-68, wherein 0 or 1 subsequent treatment session is performed.

70. The method of any one of claims 55-68, wherein recurrence of symptoms of depression is indicated by evaluation of the subject using the hamilton depression scale (HAM-D), montgomery-osberg depression scale (MADRS), patient health questionnaire (PHQ-9), or a combination thereof.

71. The method of any one of claims 55-68, wherein recurrence of symptoms of depression in the subject is indicated by a PHQ-9 score of greater than or equal to 10 or a HAM-D score of greater than or equal to 20.

72. The method of any one of claims 55-68, wherein compound (1) is administered at a dose of about 50mg or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 50mg of the free base compound.

73. The method of any one of claims 55-68, wherein compound (1) is administered at a dose of about 40mg or the pharmaceutically acceptable salt of compound (1) is administered at a dose equivalent of about 40mg of the free base compound.

74. The method of any one of claims 55-68, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally.

75. The method of claim 74, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered orally.

76. The method of any one of claims 55-68, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered with a food.

77. The method of any one of claims 55-68, wherein compound (1) or a pharmaceutically acceptable salt of compound (1) is administered at night, once daily.

78. The method of any one of claims 55-60 and 63-68, wherein the subject is not receiving treatment.