19-demethyl C3, 3-disubstituted C21-N-pyrazolylsterols and methods of use thereof

文档序号：883390 发布日期：2021-03-19 浏览：7次中文

阅读说明：本技术 19-去甲基c3,3-二取代的c21-n-吡唑基类固醇及其使用方法 (19-demethyl C3, 3-disubstituted C21-N-pyrazolylsterols and methods of use thereof ) 是由 S.J.卡内斯 J.J.多赫蒂 H.冈杜兹-布鲁斯 J.M.乔纳斯 R.A.拉瑟于 2019-06-12 设计创作，主要内容包括：本文提供的是在有此需要的受试者中治疗抑郁症,例如产后抑郁症或重度抑郁症的方法,其包括向所述受试者施用有效量的化合物1或其药学上可接受的盐：(Provided herein is a need thereforA method of treating depression, e.g., postpartum depression or major depression, in a subject comprising administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt thereof:)

1. A method of treating depression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the formula,

to treat depression in a subject.

2. The method according to claim 1, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 8 weeks.

3. The method according to claim 1, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 6 weeks.

4. The method according to claim 1, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 4 weeks.

5. The method according to claim 1, wherein the duration of the episodic dosing regimen is about 2 weeks or 14 days.

6. The method according to claim 1, wherein the duration of the episodic dosing regimen is 2 weeks.

7. The method of any one of claims 1-6, wherein the subject exhibits a response to the episodic dosing regimen, wherein the response is indicated by a decrease in the HAM-D score greater than or equal to about 50% relative to baseline.

8. The method of any one of claims 1-7, wherein the subject is assessed for recurrence or recurrence of depressive symptoms.

9. The method of any one of claims 1-8, wherein the method comprises multiple episodic dosing regimens.

10. The method of claim 9, wherein the episodic dosing regimen is separated by an interval of at least 6 weeks.

11. A method of treating depression in a subject in need thereof, the method comprising the steps of:

(i) administering to the subject a therapeutically effective amount of a compound having the formula:

for about two weeks; and

(ii) re-administering to the subject a therapeutically effective amount of compound 1 once daily for about two weeks in response to a recurrence of symptoms of depression, provided that the interval between administering compound 1 to the subject and re-administering compound 1 to the subject is at least 6 weeks.

12. The method according to claim 11, wherein the subject is further administered compound 1 for 4 weeks.

13. The method according to claim 11, wherein the subject is further administered compound 1 for 2 weeks.

14. The method according to claim 11, wherein the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 6 weeks.

15. The method according to claim 11, wherein the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 8 weeks.

16. The method according to any one of claims 1-15, wherein the depression is Major Depressive Disorder (MDD).

17. The method according to claim 16, wherein the MDD is moderate major depressive disorder.

18. The method according to claim 16, wherein the MDD is major depressive disorder.

19. The method according to any one of claims 1-15, wherein the depression is bipolar depression.

20. The method according to any one of claims 1-15, wherein the depression is postpartum depression.

21. The method according to any one of claims 1-15, wherein the subject has been diagnosed with depression.

22. The method according to any one of claims 1-15, wherein the depression is major depression or bipolar depression.

23. The method according to any one of claims 1-15, wherein the subject is a female diagnosed with major postpartum depression.

24. The method according to any one of claims 1-15, wherein the subject has experienced a major depressive episode for more than about 1 year.

25. The method according to any one of claims 1-24, wherein the subject is between about 18 and about 75 years of age.

26. The method according to any one of claims 1-24, wherein the subject is between about 18 and about 65 years of age.

27. The method according to any one of claims 1-26, wherein about 10mg of compound 1 is administered to the subject.

28. The method according to any one of claims 1-26, wherein about 20mg of compound 1 is administered to the subject.

29. The method according to any one of claims 1-26, wherein about 30mg of compound 1 is administered to the subject.

30. The method according to any one of claims 1-26, wherein about 40mg of compound 1 is administered to the subject.

31. The method according to any one of claims 1-26, wherein about 10mg of compound 1 is administered to the subject once daily.

32. The method according to any one of claims 1-26, wherein about 20mg of compound 1 is administered to the subject once daily.

33. The method according to any one of claims 1-26, wherein about 30mg of compound 1 is administered to the subject once daily.

34. The method according to any one of claims 1-26, wherein about 40mg of compound 1 is administered to the subject once daily.

35. The method of any one of claims 1-34, wherein the amount of compound 1 administered to the subject is reduced in the event of a severe adverse reaction.

36. The method of any one of claims 1-35, wherein compound 1 is administered at night.

37. The method of any one of claims 1-36, wherein compound 1 is administered with food.

38. The method of any one of claims 1-37, wherein compound 1 is in a capsule.

39. The method of any one of claims 1-38, further comprising administering a second therapeutic agent.

40. A method of treating depression in a subject in need thereof using a kit comprising:

a plurality of individual dosage units comprising compound 1, and

instructions, wherein the instructions describe a method of administering the dosage unit to a subject using a episodic dosing regimen.

41. The method according to claim 40, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 8 weeks.

42. The method according to claim 40, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 6 weeks.

43. The method according to claim 40, wherein the duration of the episodic dosing regimen is from about 2 weeks to about 4 weeks.

44. The method according to claim 40, wherein the duration of the episodic dosing regimen is about 2 weeks.

45. The method according to claim 40, wherein the duration of the episodic dosing regimen is 2 weeks.

46. The method according to any one of claims 40-45, wherein said patient has been diagnosed with depression.

47. The method according to any one of claims 40-45, wherein said depression is Major Depressive Disorder (MDD).

48. The method according to claim 47, wherein the MDD is moderate major depressive disorder.

49. The method according to claim 47, wherein the MDD is major depressive disorder.

50. The method according to any one of claims 40-45, wherein the depression is bipolar depression.

51. The method according to any one of claims 40-45, wherein the depression is postpartum depression.

52. A kit comprising a plurality of therapeutically effective doses of compound 1, and instructions describing a method of administering said doses using a episodic dosing regimen to treat depression.

53. The kit of claim 52, wherein the dose is an individual dosage unit of Compound 1.

54. The kit of claim 52, wherein an individual dosage unit comprises 10mg of Compound 1.

55. The kit of claim 52, wherein an individual dosage unit comprises 15mg of Compound 1.

56. The kit of claim 52, wherein an individual dosage unit comprises 20mg of Compound 1.

57. The kit of claim 52, wherein an individual dosage unit comprises 25mg of Compound 1.

58. The kit of claim 52, wherein an individual dosage unit comprises 30mg of Compound 1.

59. The kit of claim 52, wherein the duration of the episodic dosing regimen is about 2 weeks to about 8 weeks.

60. The kit of claim 52, wherein the duration of the episodic dosing regimen is about 2 weeks to about 6 weeks.

61. The kit of claim 52, wherein the duration of the episodic dosing regimen is about 2 weeks to about 4 weeks.

62. The kit of claim 52, wherein the duration of the episodic dosing regimen is about 2 weeks or 14 days.

63. The kit of claim 52, wherein the duration of the episodic dosing regimen is 2 weeks.

64. The kit according to any one of claims 52-63, wherein said depression is Major Depressive Disorder (MDD).

65. The kit according to claim 64, wherein said MDD is moderate major depressive disorder.

66. The kit according to claim 64, wherein said MDD is major depressive disorder.

67. The kit of any one of claims 52-66, wherein the instructions are printed on a suitable material.

68. The kit of any one of claims 52-67, wherein the individual dosage units are capsules or tablets.

69. The kit according to claim 68, wherein the individual dosage units are capsules.

70. The kit according to claim 68, wherein the individual dosage units are size 1,2, 3 or 4 capsules.

71. The kit according to claim 70, wherein the capsule is a size 1 capsule.

72. The method according to any one of claims 1-52, wherein the method improves cognitive function in the subject.

73. The method according to any one of claims 1-52, wherein said method improves cognitive function in the subject after completion of the episodic dosing regimen.

74. The method according to any one of claims 1-52, wherein said method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein said episodic dosing regimen has a duration of about 2 weeks to about 8 weeks.

75. The method according to any one of claims 1-52, wherein said method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein said episodic dosing regimen has a duration of about 2 weeks to about 6 weeks.

76. The method according to any one of claims 1-52, wherein said method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein said episodic dosing regimen has a duration of about 2 weeks to about 4 weeks.

77. The method according to any one of claims 1-52, wherein said method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein said episodic dosing regimen has a duration of about 2 weeks or 14 days.

78. The method according to one of claims 1-52, wherein said method improves cognitive function in a subject after completion of a episodic dosing regimen, wherein said episodic dosing regimen has a duration of 2 weeks.

79. The method according to any one of claims 1-52, wherein the method does not provide cognitive impairment in the subject.

Technical Field

The present invention relates generally to methods of treating depression, e.g., postpartum depression and major depression, by administering compound 1 described herein.

Technical Field

GABA, gamma-aminobutyric acid, has a profound effect on the global excitability of the brain, as GABA is used as a neurotransmitter by up to 40% of the neurons in the brain. GABA interacts with its recognition site on GRC (GABA receptor complex) to facilitate the flow of chloride ions down the electrochemical gradient of GRC into the cell. This increase in the level of anions within the cell causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory input (i.e., reduced neuronal excitability). In other words, the higher the concentration of chloride ions in neurons, the lower the excitability (level of arousal) of the brain. GRCs are well known to be responsible for the modulation of anxiety, seizures and sedation. Thus, GABA and drugs that act like GABA (e.g., therapeutically useful barbiturates and Benzodiazepines (BZs), e.g.) The therapeutic effects of GRC are produced by interaction with specific regulatory sitesHas the effect of treating the diseases.

There is increasing evidence that GRC contains a unique site for neuroactive steroids (Lan, N.C. et al, New chem. Res.16:347-356 (1991)). Neuroactive steroids may occur endogenously. The most potent endogenous neuroactive steroids are 3 α -hydroxy-5-reduced pregnan-20-one and 3 α -21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the hormones steroid 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-.

Compound 1 (the neuroactive steroids described herein) has been shown to target synapses and extrasynaptic GABA_AGABA of receptors_APositive allosteric modulators of receptors. As GABA_APositive allosteric modulators of the receptor, compound 1, are useful as therapeutic agents for the treatment of CNS-related disorders (e.g., depression, such as postpartum depression and major depression). Current treatments for CNS-related disorders often require prolonged, sometimes long-term, treatment, and patient compliance can be a major problem. Patients with CNS-related diseases would significantly benefit from new treatment regimens that are effective, easy to administer, and/or require fewer administrations and avoid or minimize side effects.

Disclosure of Invention

Provided herein are methods of treating depression in a subject, comprising administering to the subject a therapeutically effective amount of compound 1

Or a pharmaceutically acceptable salt thereof. In a further embodiment, compound 1 is administered using a sporadic dosing regimen (episodic dosing regimen).

In some aspects, provided herein is a episodic dosing regimen comprising administering compound 1 to a subject in need thereof. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to a subject in need thereof. In some embodiments, compound 1 is administered once daily to a subject in need thereof for several weeks, e.g., about 2 weeks to about 6 weeks, e.g., about 2 weeks to about 4 weeks, e.g., about 2 weeks. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered once daily to a subject in need thereof for several weeks.

In a preferred embodiment, administration of compound 1 is with a episodic dosing regimen, wherein the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks (or about 14 days). In another embodiment, the duration of the episodic dosing regimen is 2 weeks, i.e. 14 days.

In some aspects, provided herein is a sporadic dosing regimen for treating depression comprising administering compound 1 to a subject in need thereof. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject. In some embodiments, compound 1 is administered to the subject once daily for several weeks. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject once daily for several weeks. In a preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks. In an even more preferred embodiment, the episodic dosing regimen occurs for about 14 days. In another embodiment, the duration of the episodic dosing regimen is 2 weeks, i.e. 14 days. In an even more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks (or about 14 days), wherein about 30mg of compound 1 is administered to the subject once daily over the 2 week period (or about 14 days). Administering about 20mg of compound 1 to the subject once daily if the subject is unable to tolerate administration of about 30mg of compound 1 once daily.

In some embodiments, the subject exhibits a response to a sporadic dosing regimen, wherein the response is indicated by a greater than or equal to about 50% reduction in HAM-D score relative to baseline. In some embodiments, the response is indicated by alleviation of symptoms of depression.

In some embodiments, the subject is assessed for relapse, i.e., recurrence of depressive symptoms. In some embodiments, the method of treating a subject comprises multiple episodic dosing regimens. In some embodiments, after completion of the episodic dosing regimen, subsequent episodic dosing regimens are administered with a recurrence of depressive symptoms. In some embodiments, the episodic dosing regimen is separated by an interval of at least 6 weeks. In some embodiments, the episodic dosing regimen is 6 weeks apart. In some embodiments, the episodic dosing regimen is 7 weeks apart. In some embodiments, the episodic dosing regimen is 8 weeks apart.

In some aspects, provided herein is a sporadic dosing regimen for treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression, comprising administering compound 1 to a subject in need thereof. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder (severe major depressive disorder). In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject. In some embodiments, compound 1 is administered once daily for several weeks, e.g., from about 2 weeks to about 6 weeks, e.g., from about 2 weeks to about 4 weeks, e.g., about 2 weeks, to treat major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject once daily for several weeks to treat major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression. In a preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In even more preferred embodiments, the episodic dosing regimen occurs for about 2 weeks or about 14 days. In another embodiment, the duration of the episodic dosing regimen is 2 weeks.

In some aspects, provided herein are methods of treating depression in a subject in need thereof, comprising administering to the subject a episodic dosing regimen of compound 1. In some aspects, provided herein are methods of treating post-partum depression in a subject in need thereof, comprising administering to the subject a sporadic dosing regimen of 30mg of compound 1 once daily for 2 weeks (or about 14 days). Administering 20mg of compound 1 to the subject once daily if the subject is unable to tolerate administration of 30mg of compound 1 once daily. In some embodiments, the subject is a human female diagnosed with severe postpartum depression. In some embodiments, the subject has experienced a major depressive episode of about 1 year. In some embodiments, the subject is about 18 to about 75 years old. In some embodiments, the subject is about 18 to about 65 years old.

Unlike current treatments for depression, such as Major Depressive Disorder (MDD), the episodic dosing regimen of the present invention has the advantage of not being a long-term dosing regimen. Thus, according to the present invention, a pharmaceutically effective amount of compound 1 is administered in response to each episode of the onset of symptoms. The advantage of this episodic dosing regimen is that long-term dosing is not required, thus avoiding many of the impairments of current depression therapy.

In another aspect, provided herein is a method of treating depression in a subject in need thereof, the method comprising the steps of:

(i) administering to the subject a therapeutically effective amount of a compound having the formula:

for about two weeks; and

(ii) re-administering to the subject a therapeutically effective amount of compound 1 once daily for about two weeks in response to a recurrence of symptoms of depression;

provided there is a gap between administration of compound 1 to the subject and re-administration of compound 1 to the subject.

In some embodiments, compound 1 is administered to the subject for 2 weeks, i.e., 14 days. In some embodiments, compound 1 is administered to the subject for an additional 2 weeks, i.e., 14 days. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 2-4 weeks. In some embodiments, the interval is 4 weeks. In some embodiments, the interval is 5 weeks. In some embodiments, the interval is 6 weeks. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 7 weeks. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 8 weeks.

In some embodiments, the depression is Major Depressive Disorder (MDD). In some embodiments, the MDD is moderate major depressive disorder. In some embodiments, the MDD is major depressive disorder. In some embodiments, the depression is bipolar depression. In some embodiments, the depression is post-partum depression. In some embodiments, the subject has been diagnosed with depression. In some embodiments, the depression is major depressive disorder or bipolar depression. In some embodiments, the subject is a female diagnosed with severe postpartum depression. In some embodiments, the subject has experienced a major depressive episode of about 1 year. In some embodiments, the subject is about 18 to about 75 years old. In some embodiments, the subject is about 18 to about 65 years old.

In some embodiments, the method of treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression by administering compound 1 improves cognitive function. In other embodiments, the method improves cognitive function in the subject after completing the episodic dosing regimen. In some aspects, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 to about 8 weeks. In other aspects, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 to about 6 weeks. In other embodiments, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 to about 4 weeks. In a further embodiment, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 weeks or 14 days. In other aspects, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of 2 weeks.

In some embodiments, about 10mg of compound 1 is administered to the subject. In some embodiments, about 20mg of compound 1 is administered to the subject. In some embodiments, about 30mg of compound 1 is administered to the subject. In some embodiments, the subject is administered about 40mg of compound 1. In some embodiments, about 10mg of compound 1 is administered to the subject once daily. In some embodiments, about 20mg of compound 1 is administered to the subject once daily. In some embodiments, about 30mg of compound 1 is administered to the subject once daily. In some embodiments, about 40mg of compound 1 is administered to the subject once daily. In some embodiments, the amount of compound 1 administered to the subject is reduced when severe adverse effects occur. In some embodiments, compound 1 is administered at night. In some embodiments, compound 1 is administered with food. In some embodiments, compound 1 is in a capsule. In some embodiments, the method further comprises administering a second therapeutic agent.

In some aspects, provided herein are kits comprising a pharmaceutical composition comprising compound 1 and instructions describing a method of treating depression using a episodic dosing regimen. In some embodiments, the pharmaceutical composition comprises about 10mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 15mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 20mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 25mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 30mg of compound 1. In some embodiments, the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks. In a preferred embodiment, the episodic dosing regimen occurs for 2 weeks. In some embodiments, the depression is major depression, bipolar depression, anxiety, or postpartum depression. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder. In some embodiments, the episodic dosing regimen occurs for about 2 weeks (or about 14 days) for the treatment of postpartum depression. In some embodiments, the instructions are printed on a suitable material. In some embodiments, the individual dosage unit is a capsule or tablet. In some embodiments, the individual dosage unit is a capsule. In some embodiments, the individual dosage unit is a size 1,2, 3, or 4 capsule. In some embodiments, the capsule is a size 1 capsule.

Drawings

FIG. 1 depicts the LS mean change from baseline in the total score of Hamilton (Hamilton) Depression Scale (HAM-D) over time for treatment groups.

Figure 2 depicts a forest map of a subgroup analysis of the primary endpoint at day 15.

FIG. 3 depicts a bar graph of Hamilton (Hamilton) depression scale (HAM-D) relief by time point and treatment group.

FIG. 4 depicts a bar graph of Hamilton (Hamilton) Depression Scale (HAM-D) relief by time point and treatment group

FIG. 5 depicts the change in Montgomery-Asperg (Montgomery-Asperg) Depression Scale (MADRS) total score from baseline in treatment groups over time.

FIG. 6 depicts the change in Hamilton (Hamilton) anxiety Scale (HAM-A) total score from baseline in treatment groups over time.

Fig. 7 depicts a bar graph of Clinical Global Impression (CGI) improved response by time point and treatment group.

Figure 8 depicts an exemplary study design for treatment of MDD with compound 1.

Figure 9 depicts an exemplary study design for treatment of MDD with compound 1.

Detailed Description

As generally described herein, the present invention provides compounds and compositions useful for the treatment of depression, such as postpartum depression and major depressive disorder.

Definition of

The term "unit dosage form" as used herein is defined to mean a form in which compound 1 is administered to a subject. In particular, the unit dosage form may be, for example, a pill, capsule, or tablet. Preferably, the unit dosage form is a capsule. Typical amounts of compound 1 that can be used in unit dosage forms of the invention are about 10mg to about 100mg, preferably about 10mg to about 50mg (e.g., about 10, about 15, about 20, about 25mg, or 30 mg).

In a preferred embodiment of the invention, the unit dosage form comprises about 30mg of compound 1 and is in the form of a capsule. In another preferred embodiment of the invention, the unit dosage form comprises about 45mg of compound 1 and is in the form of a capsule. In another preferred embodiment of the invention, the unit dosage form comprises about 20mg of compound 1 and is in the form of a capsule. In another preferred embodiment of the invention, the unit dosage form comprises about 10mg of compound 1 and is in the form of a capsule. In another preferred embodiment of the invention, the unit dosage form comprises about 15mg of compound 1 and is in the form of a capsule. In another preferred embodiment of the invention, the unit dosage form comprises about 25mg of compound 1 and is in the form of a capsule. Preferably, a capsule containing about 30mg or 45mg of compound 1 is administered to a subject once daily. In some embodiments, three capsules together comprise 30mg of compound 1. In some embodiments, three capsules together comprise 45mg of compound 1.

As used herein, "solid dosage form" refers to a pharmaceutical dosage in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.

Where the term "about" is used before a quantitative value, the present teachings also encompass the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" means within ± 10% of the nominal value, unless otherwise indicated or inferred.

The definitions of particular functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table of elements (CAS version, Handbook of Chemistry and Physics, 75 th edition, inner page) and specific functional groups are generally defined as described in the periodic table of elements. Furthermore, the general principles of organic chemistry, as well as specific functional moieties and responsiveness, are described in the following documents: thomas Sorrell, Organic Chemistry, University Science Books, Sausaltito, 1999; smith and March, March's Advanced Organic Chemistry, 5 th edition, John Wiley & Sons, Inc., New York, 2001; larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and carrousers, Some model Methods of Organic Synthesis, 3 rd edition, Cambridge University Press, Cambridge, 1987.

"pharmaceutically acceptable" means having been or may be approved 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 U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, these salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. In particular, these 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, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or a salt formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functional group, is a salt of a non-toxic organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of the acidic functionality. 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.

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

Diseases, disorders, and conditions are used interchangeably herein.

As used herein, and unless otherwise indicated, the term "treating" encompasses actions that occur when a subject is afflicted with a specified disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and actions that occur before the subject begins to be afflicted with the specified disease, disorder, or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is sufficient to elicit a desired biological response, e.g., to treat a CNS-related disorder, e.g., a disorder described herein (e.g., tremor (e.g., essential tremor); depression (e.g., post-partum depression); or anxiety). As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention 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. An effective amount encompasses both therapeutic and prophylactic treatment.

As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound 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 the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the 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" can encompass 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.

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 the disease, disorder or condition, or to prevent relapse thereof. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the treatment of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, a "episodic dosing regimen" is a dosing regimen in which a compound or a composition comprising the compound is administered to a subject over a limited period of time in response to a diagnosis of a disorder or a symptom thereof (e.g., a diagnosis of a symptom of depression, major depressive episode, bipolar depression, anxiety, or postpartum depression). In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder. In some embodiments, the compounds are formulated as separate dosage units, each unit comprising compound 1 and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of several weeks, for example about 8 weeks. In contrast to chronic administration as defined herein, episodic administration of the compound occurs over a limited period of time, e.g., about 2 weeks to about 8 weeks, in response to diagnosis or recurrence of the disorder (e.g., depression or symptoms thereof). In some embodiments, episodic administration occurs once daily for several weeks, e.g., from about 2 weeks to about 6 weeks. In one embodiment, the duration of episodic administration is two weeks. In some embodiments, more than one episodic dosing regimen is administered to the subject, e.g., two or more episodic regimens over the life of the subject.

In some embodiments, administration of compound 1 improves cognitive function. In some embodiments, the cognitive function refers to a collection of psychological tasks and functions, including but not limited to: memory (e.g., semantics, plot, process, priming) or work); direction; a language; the problem is solved; visual perception, construction and integration; planning; (ii) an organizational capacity; selective attention is paid to; suppressive control and the ability to manipulate information psychologically. In one embodiment, the cognitive function is one or more selected from the group consisting of: memory (e.g., semantics, plot, process, priming) or work); direction; a language; the problem is solved; visual perception, construction and integration; planning; (ii) an organizational capacity; selective attention is paid to; suppression control; and the ability to manipulate information psychologically. Measurement of cognitive function includes assessment tools designed to measure, for example: (a) general intelligence, (b) non-verbal intelligence, (c) achievement, (d) attention/performance functions, (e) memory and learning, (f) vision-motion and motion functions, 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 recognized tests at two or more time points and comparing the results. As used herein, "improving cognitive function" refers to a subject performing a symbolic operation, e.g., perceiving, remembering, creating a mental image, being clear in mind, being aware of, making inferences, thinking, or making judgments. Positive changes can be measured at two or more times using any of the above tests, for example, baseline cognitive function at a first time and cognitive function after a period of time (where treatment may have been administered) at a second time. Such assessment tools are well known in the art and include, for example, those described in example 4 herein.

Pharmaceutical composition

In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient"), e.g., compound 1, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral) administration, parenteral (by injection), rectal administration, transdermal administration, intradermal administration, intrathecal administration, Subcutaneous (SC) administration, Intravenous (IV) administration, Intramuscular (IM) administration, and intranasal administration. In a preferred embodiment, compound 1 is administered orally to a subject.

In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent the onset of a CNS disorder, the compounds provided herein will generally be administered to a subject at risk of developing the condition at the dosage levels described above, under the recommendation and supervision of a physician. Subjects at risk of developing a particular disorder typically include those with a family history of the disorder, or those that have been identified by genetic testing or screening as being particularly susceptible to developing the disorder.

The pharmaceutical compositions of the present invention can additionally be delivered using a variety of methods of administration. For example, in certain embodiments, the pharmaceutical composition may be provided as a bolus injection, e.g., to increase the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the desired active ingredient throughout the body, e.g. intramuscular or subcutaneous bolus doses allow a slow release of the active ingredient, while boluses delivered directly to the vein (e.g. by IV drip) allow a faster delivery which quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion (e.g., by IV drip) to provide maintenance of a steady state concentration of the active ingredient in the subject. Furthermore, in other embodiments, the pharmaceutical composition may be administered first in a bolus dose, followed by continuous infusion.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More often, however, the compositions are 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, premeasured ampoules or syringes of liquid composition or, in the case of solid compositions, pills, tablets, capsules and the like. In these compositions, the compound is typically a minor component (about 0.1 to about 50% or preferably about 1 to about 40% by weight), the remainder being various vehicles or excipients and processing aids that assist in forming the desired dosage form.

The above components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17 th edition, 1985, Mack publishing company, Easton, Pennsylvania, section 8, which is incorporated herein by reference.

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

The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the invention. Acids useful for preparing pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate and the like.

Application method

Described herein are methods of treating depression (e.g., postpartum depression, major depression) or anxiety (e.g., generalized anxiety) in a subject, comprising administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt thereof.

Accordingly, in one aspect, provided herein is a method of treating depression (e.g., postpartum depression or major depressive disorder) or anxiety (e.g., generalized anxiety disorder) in a subject, the method comprising administering to the subject a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of compound 1. In some embodiments, the subject is between 18 and 64 years of age, including 18 and 64 years of age. In some embodiments, the subject is between 18 and 75 years of age, including 18 and 75 years of age. In some embodiments, compound 1 is administered with food. In some embodiments, the therapeutically effective amount of compound 1 is 20 mg. In some embodiments, the therapeutically effective amount of compound 1 is 10 mg. In some embodiments, the therapeutically effective amount of compound 1 is 15 mg. In some embodiments, the therapeutically effective amount of compound 1 is 25 mg. In some embodiments, the therapeutically effective amount of compound 1 is about 30 mg. In some embodiments, the therapeutically effective amount of compound 1 is about 45 mg. In some embodiments, compound 1 is administered in one or more capsules. In some embodiments, the therapeutically effective amount is administered via (across) three capsules. In some embodiments, the subject is free of an underlying disorder. In some embodiments, the subject has an underlying disorder.

In some aspects, provided herein are methods for treating a subject suffering from depression or anxiety, comprising administering to the subject a pharmaceutical composition comprising compound 1 using a episodic dosing regimen effective to treat the subject's depression. In some aspects, the duration of the dosing regimen is from about 2 weeks to about 8 weeks. In some other aspects, the duration of the dosing regimen is from about 2 weeks to about 6 weeks. In some other aspects, the duration of the dosing regimen is from about 2 weeks to about 4 weeks. In some other aspects, the duration of the dosing regimen is about 2 weeks. In some other aspects, the duration of the dosing regimen is about 2 weeks or about 14 days.

In some embodiments, about 10mg of compound 1 is administered to the subject once daily for several weeks. In some embodiments, about 15mg of compound 1 is administered to the subject once daily for several weeks. In some embodiments, about 20mg of compound 1 is administered to the subject once daily for several weeks. In some embodiments, about 25mg of compound 1 is administered to the subject once daily for several weeks. In some embodiments, 30mg of compound 1 is administered to the subject once daily. In some embodiments, 30mg of compound 1 is administered to the subject once per day, and if the subject cannot tolerate 30mg of compound 1, 20mg of compound 1 is administered to the subject once per day. In some embodiments, 30mg of compound 1 is administered to the subject once daily for about two weeks. In some embodiments, 30mg of compound 1 is administered to the subject once a day for about two weeks (or about 14 days), and if the subject cannot tolerate 30mg of compound 1, 20mg of compound 1 is administered to the subject once a day for about two weeks (or about 14 days). In some embodiments, 30mg of compound 1 is administered to the subject once daily for two weeks, and if the subject cannot tolerate 30mg of compound 1, 20mg of compound 1 is administered to the subject once daily. In some embodiments, 30mg of compound 1 is administered to the subject once daily for at least two weeks (or about 14 days). In some embodiments, 30mg of compound 1 is administered to the subject once a day for two weeks (or about 14 days), and if the subject cannot tolerate 30mg of compound 1, 20mg of compound 1 is administered to the subject once a day for at least two weeks (or about 14 days). In some embodiments, 30mg of compound 1 is administered to the subject once daily for two weeks.

In some aspects, the methods comprise a episodic dosing regimen, wherein the method comprises administering compound 1 to the subject concurrently with the onset of the disorder being treated (e.g., major depressive disorder, bipolar depression, anxiety disorders (including generalized anxiety disorder) or the onset of postpartum depression). In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder. In some embodiments, the anxiety disorder is generalized anxiety disorder.

In some embodiments, the subject is assessed for recurrence of depressive symptoms. In some embodiments, the method of treatment comprises multiple episodic dosing regimens. In some embodiments, the episodic dosing regimen is separated by an interval of at least 6 weeks. In some embodiments, the episodic dosing regimen is 6 weeks apart. In some embodiments, the episodic dosing regimen is 7 weeks apart. In some embodiments, the episodic dosing regimen is 8 weeks apart.

In some aspects, provided herein are methods of treating post-partum depression in a subject in need thereof, comprising the steps of: a sporadic dosing regimen of 30mg of compound 1 to the subject once daily for about 2 weeks (or about 14 days), and if the subject is unable to tolerate administration of 30mg of compound 1 once daily, administering 20mg of compound 1 once daily to the subject.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in Hamilton (Hamilton) depression score (HAM-D)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a decrease in HAM-D score relative to baseline at the end of a treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration or episodic dosing). In some embodiments, the decrease in HAM-D score relative to baseline is from severe (e.g., a HAM-D score of 24 or greater; or a score of 26 or greater) to asymptomatic, i.e., reduced in depression (e.g., a HAM-D score of 7 or less). In some embodiments, the decrease from baseline in the HAM-D score is from severe (e.g., a HAM-D score of 24 or greater; or a score of 26 or greater) to normal or mild depression (e.g., a HAM-D score of 7 or less; or a HAM-D score of 18-13).

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in Montgomery-asperg depression rating scale (MADRS)) in about 45, about 21, about 15, about 8, or about 3 days or less. The Montgomery-asperger (Montgomery-asperg) depression rating scale (MADRS) is a ten diagnostic questionnaire used by psychiatrists to measure the severity of a depressive episode in a mood disorder patient (regarding overt sadness, reported sadness, intrinsic tension, insufficient sleep, decreased appetite, inattention, tiredness, feelings of weakness, pessimistic thoughts, and suicidal thoughts). 0-6 indicates normal/asymptomatic; 7-19 indicate mild depression; 20-34 indicate moderate depression; >34 for major depression. In some embodiments, the therapeutic effect is a decrease in the MADRS score relative to baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days or less). In some embodiments, the decrease from baseline in the MADRS score is from severe (e.g., a MADRS score of 30 or higher) to asymptomatic (e.g., a MADRS score of 20 or lower). For example, the average change from baseline in the MADRS total score for treatment with the compounds described herein is about-15, -20, -25, -30, while the average change from baseline in the MADRS total score for treatment with placebo is about-15, -10, -5.

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

In some embodiments, the methods provide a therapeutic effect (e.g., as measured by a decrease in Hamilton Anxiety Score (HAM-a)) within about 45, about 21, about 15, about 8, or about 3 days. HAM-a was scored where <17 indicates mild severity, 18-24 mild to moderate, 25-30 moderate to severe. In some embodiments, the therapeutic effect is a decrease in HAM-a score relative to baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration or episodic dosing). In some embodiments, the decrease in HAM-a score relative to baseline is from severe (e.g., a HAM-a score of 25 or higher) to asymptomatic (e.g., a HAM-a score of 17 or lower). In some embodiments, the decrease in HAM-a score relative to baseline is from severe (e.g., a HAM-a score of 25 or greater) to mild (e.g., a HAM-a score of 24 or less).

In some embodiments, the instructions describe a method comprising a episodic dosing regimen, wherein the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In some embodiments, the instructions describe a method comprising a episodic dosing regimen, wherein the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In some embodiments, the instructions describe a method comprising a episodic dosing regimen, wherein the episodic dosing regimen occurs for about 2 weeks or about 14 days. In some embodiments, the instructions describe a method comprising a episodic dosing regimen, wherein the episodic dosing regimen occurs for 2 weeks.

In one embodiment, the instructions are printed instructions.

In a further embodiment, the instructions describe a method comprising a episodic dosing regimen, wherein the method comprises administering compound 1 to the subject at the same time as the onset of the disorder being treated. In some aspects, the instructions describe a method comprising a episodic dosing regimen, wherein the method comprises administering compound 1 to the subject concurrently with the onset of the disorder being treated (e.g., the onset of depression). In some aspects, the instructions describe a method comprising a episodic dosing regimen, wherein the method comprises administering compound 1 to the subject concurrently with the onset of the disorder being treated (e.g., the onset of depression). In some aspects, the instructions describe a method comprising a episodic dosing regimen, wherein the method comprises administering compound 1 to the subject concurrently with the onset of the disorder being treated (e.g., the onset of major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression). In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder.

In one aspect, provided herein is a method of treating depression in a subject in need thereof, the method comprising the steps of:

(i) administering to the subject a therapeutically effective amount of a compound having the formula:

for about two weeks; and

(ii) in response to a recurrence of symptoms of depression, the subject is re-administered a therapeutically effective amount of compound 1 once daily for about two weeks, provided there is an interval of at least six weeks between the administration of compound 1 to the subject and the re-administration of compound 1 to the subject.

It will be appreciated that, as described above, the six week interval is the duration between the last dose of compound 1 administered to the subject and the first dose of compound 1 re-administered to the subject.

In some embodiments, compound 1 is administered to the subject for 2 weeks. In some embodiments, compound 1 is further administered to the subject for 2 weeks. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 6 weeks. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 7 weeks. In some embodiments, the interval between administration of compound 1 to the subject and re-administration of compound 1 to the subject is 8 weeks.

In one aspect, provided herein is a method of treating major depressive disorder in a subject in need thereof, the method comprising the steps of:

(i) a first administration of a therapeutically effective amount of a compound of formula (I) to a subject once daily for 14 days:

and

In one aspect, provided herein is a method of treating post-partum depression in a subject in need thereof, the method comprising the steps of:

(i) a first administration of a therapeutically effective amount of a compound of formula (I) to a subject once daily for 14 days:

and

In one aspect, provided herein is a method of treating generalized anxiety disorder in a subject in need thereof, the method comprising the steps of:

(i) a first administration of a therapeutically effective amount of a compound of formula (I) to a subject once daily for 14 days:

and

In one aspect, provided herein is a method of treating bipolar depression in a subject in need thereof, the method comprising the steps of:

(i) a first administration of a therapeutically effective amount of a compound of formula (I) to a subject once daily for 14 days:

and

(ii) a second administration of a therapeutically effective amount of compound 1 to the subject once daily in response to a recurrence of symptoms of major depressive disorder, with the proviso that there is at least a six week interval between the last dose of the first administration of compound 1 to the subject and the first dose of the second administration of compound 1 to the subject. In some aspects, provided herein are kits, wherein the kits comprise instructions describing a method of treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression by administering compound 1, wherein the method comprises a episodic dosing regimen. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is major depressive disorder. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject. In some embodiments, compound 1 is administered to the subject once daily for several weeks, e.g., about 2 weeks to about 6 weeks, e.g., about 2 weeks to about 4 weeks, e.g., about 2 weeks. In some embodiments, about 10mg, about 15mg, about 20mg, about 25mg, or about 30mg of compound 1 is administered to the subject once daily for several weeks. In a preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen occurs for about 2 weeks to about 4 weeks. In even more preferred embodiments, the episodic dosing regimen occurs for about 2 weeks or about 14 days. In another embodiment, the episodic dosing regimen occurs for 2 weeks.

Also provided herein is a method of treating anxiety in a subject, the method comprising administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt thereof. Accordingly, in one aspect, provided herein is a method of treating anxiety in a subject, the method comprising administering to the subject a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of compound 1. In some embodiments, the subject is between 18 and 64 years of age, including 18 and 64 years of age. In some embodiments, the compound is administered with food. In some embodiments, the therapeutically effective amount is 20 mg. In some embodiments, the therapeutically effective amount is 10 mg. In some embodiments, the therapeutically effective amount is 15 mg. In some embodiments, the therapeutically effective amount is 25 mg. In some embodiments, the therapeutically effective amount is about 30 mg. In some embodiments, the therapeutically effective amount is about 45 mg. In some embodiments, compound 1 is administered in one or more capsules. In some embodiments, the therapeutically effective amount is via (across) three capsules.

In some embodiments, the anxiety disorder is generalized anxiety disorder. Generalized Anxiety Disorder (GAD) is characterized by persistent and excessive concerns over many different things. People with GAD may anticipate disasters and may be overly worried about money, health, family, work, or other issues. People with GAD have difficulty controlling their own anxiety. They may worry about things more than necessary or even without obvious reasons to expect the worst case.

In other embodiments, the anxiety disorder is Obsessive Compulsive Disorder (OCD); panic disorder, Post Traumatic Stress Disorder (PTSD) or social anxiety disorder. Obsessive Compulsive Disorder (OCD) is an anxiety disorder characterized by recurrent episodes, unwanted thoughts (obsessive compulsive) and/or repetitive behaviors (obsessive compulsive). Repetitive activities (e.g., hand washing, counting, inspection, or cleaning) are often performed in hopes of preventing compulsive thoughts or disappearing them. However, performing these so-called "ceremonies" provides only temporary relief, and not performing these enhances anxiety. Panic disorder is an anxiety disorder characterized by sudden, repeated episodes of intense fear accompanied by physical symptoms which may include chest pain, palpitations, shortness of breath, dizziness or abdominal discomfort. Post-traumatic stress disorder (PTSD) is an anxiety disorder that may be manifested in the occurrence of serious physical injury or a threatening terrorist event or affliction. Traumatic events that may trigger a PTSD include a violent physical attack, a natural or man-made disaster, an accident, or a military battle. Social phobia or social anxiety disorder is an anxiety disorder characterized by uncontrollable anxiety and excessive self-absence in everyday social situations. Social phobia can be limited to only one type of situation-for example, fear of talking in a formal or informal situation, or eating, drinking, or in the most severe form in front of others-and so widely as to cause symptoms in almost any situation where there are others around them.

Provided herein are methods of treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression with a episodic dosing regimen comprising administering compound 1 to a subject in need thereof. In some embodiments, the method improves cognitive function in the subject after completion of the episodic dosing regimen. In some aspects, the method improves cognitive function in a subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 to about 8 weeks. In other aspects, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen lasts from about 2 to about 6 weeks. In other embodiments, the method improves cognitive function in a subject upon completion of a episodic dosing regimen, wherein the duration of the episodic dosing regimen is about 2 to about 4 weeks. In other embodiments, the method improves cognitive function in a subject after completion of a episodic dosing regimen, wherein the duration of the episodic dosing regimen is about 2 weeks or 14 days. In other aspects, the method improves cognitive function in the subject upon completion of a episodic dosing regimen, wherein the episodic dosing regimen lasts for 2 weeks.

In some other aspects, described herein are kits comprising a plurality of individual dosage units of a pharmaceutical composition comprising compound 1 described herein and instructions. In some embodiments, the instructions describe a method for administering the pharmaceutical composition to a patient, wherein the method comprises a episodic dosing regimen. In another embodiment, the present invention provides a kit comprising:

1. a plurality of individual dosage units comprising a pharmaceutical composition of compound 1; and

2. instructions for administering said dosage unit to a patient in need thereof using a episodic dosing regimen.

In some embodiments, the instructions are printed on a suitable material, such as paper. In some embodiments, the dosage unit is a capsule. In some embodiments, the unit dose or dosage unit comprises a prefilled, predetermined amount of ampoule or syringe of a liquid composition, or in the case of a solid composition, a pill, tablet, capsule, or the like. In some embodiments, the dosage unit is a size 1 capsule. In other embodiments, the capsule has a size of 000, 00, 0, 1,2, 3, or 4, as known in the art.

Examples

Example 1 Compound 1 and postpartum depression

The use of compound 1 in depression patients was investigated. The study used female subjects (18-65 years) with severe postpartum depression (PDD) with a total HAM-D score greater than or equal to 26 at screening and day 1. A capsule containing 30mg of compound 1 was administered to the subject once daily. If a 30mg dose is not tolerated, the dose can be adjusted to a capsule containing 20mg of compound 1. Subjects not administered compound 1 were administered a placebo. A total of 78 subjects were treated with 30mg of compound 1 and 73 subjects were treated with placebo.

Statistics of

Assuming a 2-plane test with an alpha level of 0.05, a sample size of approximately 65 evaluable subjects per treatment group provided 90% efficacy to detect placebo-adjusted treatment differences at approximately 4 points in the primary endpoint, the change in HAM-D total score from baseline at day 15, assuming a Standard Deviation (SD) of 7 points. The change in HAM-D total score relative to baseline was analyzed using a repeatedly measured mixed effects model (MMRM). The model includes the relative baseline change at each visit as a dependent variable. The main comparison was between compound 1 capsules and placebo at the 15 day time point (minimum mean square error LSMEAN).

For model-based point estimates (i.e., LSMEAN, 95% confidence interval, and p-value), unstructured covariance structure was used to model the subject internal errors. If the unstructured covariance model has convergence problems, then Toeplitz, a compound symmetric or autoregressive (1) (AR [1]) covariance structure is used, in this order, until convergence is achieved. If the model still does not converge with the AR (1) structure, no results are reported. When the covariance structure is not UN, the EMPIRICAL option in the PROC MIXED statement of SAS is used to derive a sandwich variance estimate (sandwich estimator) of the variance-covariance matrix.

Also, MMRM was used for the analysis of the following variables: MADRS total score and HAM-a total score change from baseline, and individual items and sub-scale scores were selected. For each model, the comparison of interest was between compound 1 capsules and the matched placebo at a 15 day time point. Model-based point estimates (i.e., LS mean), 95% confidence intervals, and p-values are reported.

Results

The results indicate that the primary endpoint is satisfied. The average decrease from baseline in the sum HAM-D score at day 15 was: compound 1(30mg) treated subjects were-18.0 (8.36) relative to mean baseline 28.4(2.09) and placebo treated subjects were-13.6 (8.31) relative to mean baseline 28.8 (2.32). The difference between the model-based treatment groups at day 15 with the corresponding 95% Confidence Interval (CI) was-4.2 (-6.9, -1.5), compound 1 was preferred, and the p-value was 0.0029. FIG. 1 depicts the mean change in LS of the total score of Hamilton (Hamilton) Depression Scale (HAM-D) versus baseline for the treatment groups over time. Figure 2 depicts a forest map of a subgroup analysis of the primary endpoint at day 15. FIG. 3 depicts a bar graph of Hamilton (Hamilton) depression scale (HAM-D) relief by time point and treatment group. Fig. 4 depicts a bar graph of Hamilton (Hamilton) depression scale (HAM-D) relief by time point and treatment group.

HAM-D response and remission rates were significantly higher in subjects treated with compound 1 than in placebo-treated subjects:

answering: compound 1 treated subjects (30mg) were 53/74 (71.6%), while placebo treated subjects were 35/73 (47.9%). The model-based odds ratio and corresponding (95% CI) was 2.63(1.34, 5.16), with a p-value of 0.0050.

Mitigation: compound 1 treated subjects (30mg) were 33/74 (44.6%) compared to placebo treated subjects 17/73 (23.3%). The model-based odds ratio and corresponding (95% CI) was 2.50(1.22, 5.11), with a p-value of 0.0122.

Change in MADRS total score from baseline on day 15 and all other time points:

mean reduction of MADRS total score from baseline at day 15: compound 1-treated subjects (30mg) were-22.0 (11.64) relative to baseline 34.9(4.41), while placebo-treated subjects were-17.7 (11.72) relative to baseline 36.3 (4.68). The difference between the model-based treatment groups and the corresponding 95% Confidence Interval (CI) was-4.6 (-8.3, -0.8), compound 1 was preferred, and the p-value was 0.0182. The results of the study are shown in FIG. 5.

Change in HAM-a total score from baseline at day 15 and all other time points:

mean decrease in HAMA total score from baseline at day 15: compound 1(30mg) treated subjects were-16.5 (9.51) relative to mean baseline 26.1(5.88) and placebo treated subjects were-12.9 (8.57) relative to baseline 27.2 (5.45). The difference between the model-based treatment groups and the corresponding 95% Confidence Interval (CI) was-3.90 (-6.7, -1.1), compound 1 was preferred, p-value 0.0063. The results of the study are shown in FIG. 6.

CGI-I response at day 15:

compound 1(30mg) treated subjects were 53/74 (71.6%), while placebo treated subjects were 38/73 (52.1%). The odds ratio based on the model and corresponding (95% CI) was 2.15(1.09, 4.27), compound 1 was preferred, and the p value was 0.0280. The results of the study described herein are shown in figure 7.

This study shows that compound 1, administered once daily at 30mg for 15 days (an exemplary episodic dosing regimen) is effective in treating postpartum depression as compared to placebo.

Example 2: phase 3, open-label, phase 1 year study of safety, tolerability, and need for retreatment with Compound 1 in adult subjects with major Depression (MDD)

Abbreviation list

ADT antidepressant therapy

AE adverse events

CGI-I Total clinical efficacy Scale-improvement

CGI-S Total clinical efficacy Scale-severity

Clinically significant CS

C-SSRS Columbia (Columbia) suicide severity rating Scale

CYP cytochrome P450

DSM-5 diagnostic and statistical Manual of mental disorders, fifth edition

ECG electrocardiogram

eCRF electronic case report form

End of EOT treatment

ET early termination

FSH follicle stimulating hormone

GABA gamma-aminobutyric acid

HAM-D Hamilton (Hamilton) Depression Scale

HCV hepatitis C virus

HIV human immunodeficiency virus

ICF informed consent

IRB institutional review Board

IRT interactive response technology

Severity index of ISI insomnia

MADRS Montgomery-Aberg Depression Scale

MDD major depressive disorder

Major depressive episode of MDE

NCS is clinically insignificant

PHQ-99 patient health questionnaire

PK pharmacokinetics

PSQ patient status questionnaire

QTcF QT corrected according to Fridericia's formula

SAE Severe adverse events

SAP statistical analysis plan

SCID-5-CT for diagnostic and DSM-5 clinical trial versions of structured clinical interview

Standard deviation of SD

SDS xi En Disability Scale (Sheehan Disability Scale)

SUSAR suspects, accidents, severe adverse responses

TEAE emergency treatment of adverse events

WHO world health organization

Overall study design

Compound 1 was studied in an open-label, long-term, longitudinal study in adults with Major Depressive Episode (MDE) who currently experienced MDD. See figure 8 for a schematic of the study design.

Diagnosis of MDD is based on a structured clinical interview with DSM-5 clinical trial version (SCID-5-CT) conducted by qualified healthcare professionals. Subjects were evaluated at the screening visit in a preliminary screening program to determine eligibility, including completion of MADRS and CGI-S.

The main goal of this study was to determine the safety and tolerability of initial and re-treatment with compound 1 in adults with MDD during 1 year and currently experiencing Major Depressive Episodes (MDE).

A secondary objective of this study was to assess the need for re-treatment with compound 1 after initial treatment in adults with MDD during 1 year and currently undergoing MDE, and to assess the response to initial and re-treatment with compound 1 after an initial 2-week treatment period (exemplary episodic dosing regimen) in adults with MDD during 1 year and currently undergoing MDE.

The exploratory goal of this study was to develop a digital phenotype of adults with MDD who are currently experiencing MDE and assess potential relevance to clinical endpoints; assessing the effect of compound 1 on sleep; and evaluating the patient's reported outcome measures as they relate to the impact of depression on the subject's life, the severity of depression, function, the subject's opinion of the symptoms, and the subject's satisfaction with compound 1.

The primary endpoint of this study was the safety and tolerability of the initial treatment with compound 1 and the re-treatment with compound 1, as determined by the incidence and severity of AEs/SAEs included; changes from baseline in clinical laboratory measurements, vital signs and Electrocardiogram (ECG); suicidal ideation and behavior (using Columbia suicide severity scoring Table (C-SSRS)) were evaluated.

The secondary endpoints of this study were: the need for retreatment of compound 1, as assessed by: time to first re-treatment (Kaplan-Meier curve); the number of subjects who meet the retreatment requirement; and the number of retreatment cycles per subject. Response to initial treatment and/or retreatment, as assessed by: change from baseline in HAM-D total score for 17 items at the end of each 14 day treatment (initial and/or retreatment) period; HAM-D response at the end of each 14-day treatment (initial and/or retreatment) period, defined as a > 50% reduction in HAM-D score relative to baseline; HAM-D remission at the end of each 14-day treatment (initial and/or retreatment) period, defined as a total HAM-D score of < 7; at the end of each 14-day treatment (initial and/or retreatment) period, CGI-I response, defined as "major improvement" or "major improvement"; and changes from baseline in the clinical global impression-severity (CGI-S) score at the end of each 14 day treatment (initial and/or retreatment) period (also referred to as an exemplary episodic dosing regimen).

The exploratory endpoints of this study were: digital phenotypes, as developed by passively collecting basic behavioral data, such as GPS, text/phone usage, motor/sleep patterns in subjects who agree to use a cell phone-supported software application; the effect of compound 1 on sleep as assessed by the Insomnia Severity Index (ISI); the time of first use of new ADT (Kaplan-Meier curve) and the number of new ADTs used; patient reported symptoms of depression as assessed by the 9 patients health questionnaire (PHQ-9); patient reported function as assessed by the Sheehan Disability Scale (SDS); as well as the patient reported depressive effects and patient opinion of symptoms and satisfaction, as assessed by the Patient Status Questionnaire (PSQ).

The duration of subject participation was approximately 56 weeks: a screening period (28 days), an initial treatment period (14 days, or an exemplary episodic dosing regimen), a follow-up period (14 days), and an observation period (48 weeks). An additional 14-day retreatment period (or episodic dosing regimen) with compound 1 may also occur within the 48-week observation period.

All subjects received daily doses of oral compound 1 from day 1 to day 14 of the first treatment cycle. Compound 1 is administered (re-administration or further episodic dosing regimen) during the subsequent 14 day treatment period, depending on the recurrence, recurrence or reoccurrence of the depressive symptoms.

Subjects responding to Compound 1 were followed up for 48 weeks

Starting on day 1, eligible subjects orally take 30mg of compound 1 themselves once a day in the evening for 14 days. Follow-up was performed for 14 days (± 1 day) after the end of the 14-day treatment period.

If the subject did not exhibit a response to compound 1 at day 15 of initial treatment (defined as a > 50% reduction from baseline), the study was terminated for that subject after completing the 14 day follow-up.

Subjects were naturally followed up for 48 weeks after the initial treatment period. Subjects returned to the study site for clinical evaluation every 8 weeks (beginning after the first follow-up) during the 48-week observation period.

Compound 1 treatment cycle

Each 14-day treatment period and the corresponding 14-day follow-up period for compound 1 were considered a cycle (day 28). Initial treatment was cycle 1, and re-treatment sequence was numbered. Each cycle begins on day 1 (e.g., the first day of the first retreatment period is day 1 of cycle 2). A maximum of 5 treatment cycles is allowed; no new re-treatment cycle was started after week 48. Subjects who began a new compound 1 treatment cycle between weeks 45 and 48 were followed up to the end of the treatment cycle (day 28, the end of the follow-up phase of the treatment cycle).

Assessing whether re-treatment is required by remote assessment every 14 days based on the subject's reported results for PHQ-9 over an observation period of 48 weeks; if the PHQ-9 score is ≧ 10, the subject returns to the study site for evaluation by HAM-D administered by the clinician. Subjects with a HAM-D score of 20 or greater begin a new compound 1 cycle, which is assessed at about 1 week from a PHQ-9 score of 10 or greater.

A time period or interval of at least 8 weeks (56 days) was required between cycles of compound 1 treatment. This is based on establishing a "complete remission" of the depressive episode for a period of 8 weeks (american psychiatric association, 2013) and is consistent with the treatment period required for any available Antidepressant (ADT) to exert maximum efficacy.

Since this was the first study to be conducted on compound 1 for longitudinal retreatment testing, and the likelihood of withdrawal-related events (including seizures) was monitored based on known withdrawal symptoms of other GABAergic drugs and non-clinical findings of compound 1 studies in dogs for a period of 9 months.

Research drug packaging and labeling

Compound 1 is provided to a clinical pharmacist and/or designated study site staff responsible for dispensing study medication (in a subject-specific kit containing sealed unit doses with appropriate labeling). Each unit dose consists of 1 capsule.

Study drug administration

Compound 1 was orally administered with food once daily in the evening. The actual choice involves taking compound 1 within 1 hour after the evening meal or taking compound 1 with solid food during the evening. If a subject misses a dose, the subject skips the dose (i.e., they should not take the dose in the morning) and takes the next scheduled dose in the evening the following day.

Since this was the first longitudinal retreatment study with compound 1 and the likelihood of withdrawal-related events (including seizures) was monitored based on known withdrawal symptoms of other GABAergic drugs and non-clinical findings of compound 1 studies in dogs for a period of 9 months (investigator manual), including study drug withdrawal or dose reduction.

If the subjects showed suicidal tendencies at any time, they returned to the study site as soon as possible for evaluation by the investigator.

Table 1 summarizes the assessment of the screening, treatment and follow-up periods; table 2 summarizes the observation period and the evaluation of any unplanned visits.

Table 1.

CGI-I is a clinical global impression-improvement scale; CGI-S-clinical global impression-severity scale; the C-SSRS ═ Columbia (Columbia) suicide severity scale; d ═ day; ET-early termination; ECG as an electrocardiogram; EOT-end of treatment; FSH ═ follicle stimulating hormone; HAM-D ═ Hamilton (Hamilton) depression scale, item 17; HIV ═ human immunodeficiency virus; ICD-10, version 10 of the international statistical classification of disease and related health problems; ISI, which is an index of severity of insomnia; MADRS ═ Montgomery-asperger (Montgomery-Asberg) depression scale; MGH ATRQ ═ massachusetts general hospital antidepressant treatment response questionnaire; o ═ is optional; SCID-5 structural clinical interview of a manual for diagnosis and statistics of mental disorders, fifth edition; PHQ-9 ═ 9 patient health questionnaire; PSQ ═ patient status questionnaire; SAE is a serious adverse event;

SDS-the schin Disability Scale (Sheehan Disability Scale); weight ratio of wt ═ weight

^aThe screening procedure was only performed prior to the initial (cycle 1) treatment period.

^bScreening was required for at least 14 days for subjects who agreed to use a mobile phone-supported software application for digital phenotypic analysis.

^cEach cycle was 28 days (± 1 day) including a 14 day treatment period and a 14 day follow-up period. Initial treatment is considered cycle 1 and retreatment will be numbered in order. Each re-treatment cycle will start on day 1 (e.g., the first day of the first re-treatment will be day 1 of cycle 2).

^dSubjects who discontinued treatment early should return to the study site as soon as possible for end of treatment (EOT) visits, preferably the next day of treatment discontinuation. The follow-up should be performed 14 days after the last dose treatment. If at any time after an EOT visit, the subject decides to terminate the study, the subject should return for an Early Termination (ET) visit. EOT and ET visits may be made on the same day if the subject discontinues study medication during the clinical visit and terminates the study on the same day; in this case, all events scheduled for EOT access will be scheduled.

^eSubject authorization will be required to enter their unique subject identifier into a registry (www.subjectregistry.com) to identify subjects who may meet exclusion criteria for participation in another clinical study.

^fFemale subjects without surgical sterilization will be subjected to a serum FSH test at screening to confirm whether female subjects with spontaneous amenorrhea ≧ 12 months meet the criteria defined by the post-menopausal protocol.

^gA comprehensive physical examination will be performed at screening, after which a brief physical examination will be performed. A comprehensive physical examination includes an assessment of the body system (e.g., head, eyes, ears, nose and throat; heart; lungs; abdomen and limbs).

^hSecureLaboratory tests will include hematology, serum chemistry, coagulation and urinalysis.

ⁱUreology (according to the laboratory manual) and alcohol breath test of selected drugs of abuse.

^jSerum pregnancy tests were performed at screening, followed by urine pregnancy tests.

^kFemale subjects who abort prematurely will undergo pregnancy tests at EOT visit.

^lAfter consent was obtained, an optional blood sample for hormonal and exploratory biochemical testing was given.

^mOptional genetic samples for biomarker testing were given with consent.

ⁿVital signs include oral temperature (deg.C), respiratory rate, heart rate, and blood pressure (supine and standing). After the subjects had rested for 5 minutes, heart rate and blood pressure were again collected in the supine position at all the planned time points for the standing position. Clinical researchers can decide whether to repeat vital signs as appropriate.

^oTriplicate ECGs will be collected.

^pThe "Baseline/Screen" C-SSRS form will be filled out at the time of screening. The "C-SSRS table will be filled out at any time of day at all subsequent time points since the last access.

^qHAM-D will complete as early as possible during the access.

^rThe evaluation time box for the HAM-D scale refers to the past 7 days (1 week).

^sSubjects who did not respond to compound 1 on day 15 of initial treatment (defined as > 50% reduction in HAM-D score relative to baseline) will terminate the study after the end of follow-up.

^tIndicating that the consenting subjects will have used a cell phone supported software application for the duration of the study since screening.

^uThe collection of adverse events will be knownThe time of the informed consent began and was throughout the subject's participation in the study.

^vPrevious medications will be collected at the time of screening and accompanying medications will be collected at each subsequent visit.

Table 2.

ECG as an electrocardiogram; ET-early termination; HAM-D ═ Hamilton (Hamilton) depression scale, item 17; ISI, which is an index of severity of insomnia; o ═ is optional; PHQ-9 ═ 9 patient health questionnaire; PSQ ═ patient status questionnaire; Q2W once every 2 weeks; Q8W once every 8 weeks; SDS-the schin Disability Scale (Sheehan Disability Scale); SAE ═ Severe adverse events

^aThe assessment schedule in the observation period should be based on the last day of the previous treatment period (e.g., the first day in the Q2W remote assessment would be on day 42 (± 1 day), while the first day of Q8W visits would be on day 84 (± 3 days)).

^bIf the PHQ-9 score is greater than or equal to 10 and/or there are any suicidal thoughts or behaviors, the subject will return to the study site outside the Q8W visit schedule.

^cAll PHQ-9 evaluations will be performed by the handset supported software application.

^dThe subject will do PHQ-9 once every 14 days; if the PHQ-9 score is ≧ 10, the subject will return to the study site for HAM-D assessment administered by the clinician in about one week. If HAM-D score<20, the subject will do PHQ-9: subjects with a PHQ-9 score still ≧ 10 will return to the site receiving the HAM-D assessment weekly; if PHQ-9 scores<10, the subject will do PHQ-9 every two weeks thereafter.

^eIf the HAM-D score is ≧ 20 (assessed about one week after PHQ-9 score ≧ 10), and at least 8 weeks from the last treatment day of the last compound 1 treatment cycle (i.e., day 70 or later), the subject will begin a 14-day retreatment period and have a 14-day follow-up (see table 1). If the HAM-D score is greater than or equal to 20, but less than 8 weeks from the last treatment day of the previous Compound 1 treatment cycle (i.e., day 69 or earlier); the subject will do PHQ-9 weekly until a period of 8 weeks has elapsed, at which time the subject can begin retreatment with compound 1 (see table 1), or until a PHQ-9 score is reached<10。

^fConcomitant medications are collected at each clinical visit.

^gSubjects who agree to digital phenotypic analysis will use a cell phone supported software application from a screening visit during the study.

^hThe collection of adverse events will begin with informed consent and throughout the course of the subject's participation in the study.

Demonstration of dose

In this study, a dose level of 30mg per day was an effective and well tolerated dose level in a phase 2 study with MDD. Compound 1, the dose allowed to adjust to 20 mg; it is expected that 20mg of compound 1 would be well tolerated as it is below the maximum tolerated dose. Compound 1 was administered in the evening in this study due to the sedation/lethargy observed in previous clinical trials when administered in the morning, while improving tolerability when administered in the evening.

According to DSM-5, it takes 8 weeks (american psychiatric association, 2013) to establish "complete relief" of the onset of depression. In addition, available antidepressant therapy (ADT) typically takes up to 8 weeks to exert maximum efficacy. Thus, at least 8 weeks (56 days) were required between the end of the 14 day treatment period and the start of the new compound 1 treatment cycle.

Dose adjustment criteria

If 30mg of compound 1 is not tolerated at any time (as assessed by the investigator's judgment of the occurrence of a severe AE in relation to the study drug) the dose should be reduced as quickly as possible to 20mg and maintained for the remainder of the time. Dose adjustments associated with moderate AEs were judged by the investigator. If the investigator believes that the dose needs to be adjusted from 30mg to 20mg, the subjects return to the study site to adjust the dose dispensed. Any re-treatment period begins with a dose of 30mg, regardless of whether the subject needs to adjust the dose in a previous treatment period. Study medication was discontinued for subjects who were not tolerant to a 20mg dose at any time, and the study was terminated for this subject after the end of the subsequent 14-day follow-up period.

Subject enrollment criteria

Eligible subjects met all of the following conditions:

1. the subject has signed the ICF prior to performing any study-specific procedures.

2. The subject is male or female between 18 and 75 years of age, inclusive.

3. The subjects were in good physical health and had no clinically significant findings from investigator physical examination, twelve lead ECG, or clinical laboratory testing.

4. Subjects agreed to comply with the study requirements.

5. The subject had an MDD diagnosis diagnosed by SCID-5-CT, and symptoms had been present for at least 4 weeks.

6. Subjects had a MADRS score of 28 or more on screening and day 1 (pre-dose).

7. Subjects taking antidepressants for the treatment of major depression must take these drugs at the same dose at least 60 days before day 1.

8. Female subjects agreed to use the following contraceptive method during participation in the study and within 30 days after the last study medication, except post-menopause (defined as no menstruation within 12 months without other medical reasons and confirmed by follicle stimulating hormone [ FSH ] >40 mIU/mL), surgical sterilization (hysterectomy or bilateral ovariectomy) or no sexual relationship that could lead to pregnancy occurred: combined with oral (containing estrogen and progestin), intravaginal or transdermal hormonal contraception associated with ovulation inhibition; hormonal contraception with ovulation inhibition in connection with progestin, either oral, injectable or implantable; an intrauterine device; an intrauterine hormone release system; ligation/occlusion of the fallopian tubes on both sides; a partner for vasectomy; sexual desire (no sexual intercourse).

9. Male subjects agreed to use an acceptable effective contraceptive method during the study and within 5 days after receiving the last dose of study medication, unless the subject did not develop a sexual relationship that could lead to pregnancy. Effective contraceptive methods acceptable for men include sexual desire, vasectomy or if the female partner is fertile, use of condoms with spermicides along with highly effective female contraceptive methods (see entry criteria 8 for acceptable contraceptive methods).

10. Male subjects were willing to avoid donation of sperm during the study period and 5 days after receiving the final dose of study drug.

11. Subjects agreed to avoid abuse of drugs and alcohol during the study.

Subject exclusion criteria

Subjects meeting any of the following criteria will be disqualified from the study:

1. the subject has attempted suicide associated with the current onset of MDD.

2. The subject has a recent history of or has an active clinically significant manifestation of metabolic, liver, kidney, blood, lung, cardiovascular, gastrointestinal tract, musculoskeletal, skin, urogenital, nervous system or eye, ear, nose and throat disorders or any other acute or chronic condition that the researcher believes will limit the subject's ability to complete or participate in this clinical study.

3. The subject has treatment-resistant depression, which is defined as persistent depressive symptoms despite treatment with adequate doses of two different classes of antidepressants for at least 4 weeks within the current major depressive episode (excluding antipsychotics). For this purpose, the massachusetts state general hospital antidepressant therapy response questionnaire was used.

4. The subjects received vagal stimulation, electroconvulsive therapy, or ketamine administered during the current major depressive episode.

5. Subjects were either taking benzodiazepines, barbiturates or GABAA modulators (e.g., eszopiclone, zopiclone, zaleplon and zolpidem) on day 28 or the subjects used these drugs daily or nearly daily (4 times weekly) for more than one year.

6. The subject takes on day 14 a non-GABA anti-insomnia drug (e.g., melatonin, diphenhydramine (Benadryl) [ antihistamine ], trazodone, low dose quetiapine, mirtazapine (mirtazapine), etc.) and/or an atypical antipsychotic drug (e.g., aripiprazole, quetiapine).

7. The subject is allergic to compound 1, allopregnanolone (allopregnanolone) or a related compound.

8. During any treatment cycle, subjects had a positive pregnancy test on day 1 prior to screening or initiation of study drug administration.

9. Subjects breastfeeding at screening or on day 1 (prior to study medication administration) did not agree that breastfeeding of children was temporarily discontinued from the day 1 on study medication until day 7 after the last dose of study medication in each treatment cycle.

10. The subject has detectable hepatitis b surface antigen, anti-Hepatitis C Virus (HCV) and positive HCV viral load (load) or Human Immunodeficiency Virus (HIV) antibodies at the time of screening.

11. Subjects had clinically significant abnormal twelve lead ECGs at screening or baseline visit. Note that: the average QT interval calculated using the frigericia method (QTcF), was >450 milliseconds in men and >470 milliseconds in women, which was the basis for exclusion from this study.

12. The subject had active psychosis, as assessed by the investigator.

13. The subject had a history of epilepsy.

14. The subject has a history of bipolar depression, schizophrenia, and/or schizophrenic affective disorder.

15. The subject had a history of mild, moderate or severe substance use disorders (including benzodiazepines) diagnosed using DSM-5 criteria during the 12 months prior to screening.

16. Subjects took chronic or on-demand psychostimulants (e.g., methylphenidate, amphetamine) or opioids on day 28.

17. The subject was exposed to another study drug or device within 30 days prior to screening.

18. The subjects had previously participated in a clinical trial of compound 1 or brexanolone.

19. Any known strong inhibitor of cytochrome P450(CYP)3a4 was used within 28 days or 5 half-lives (whichever is longer), or grapefruit juice, grapefruit or Seville orange juice (Seville) or products containing these were consumed within 14 days prior to the first dose of study drug for any compound 1 treatment cycle.

20. The following potent CYP3a4 inducer was used 28 days prior to the first dose of study drug for any cycle of compound 1 treatment: rifampin (rifampin), carbamazepine (carbamazepine), enzalutamide (enzalutamide), mitotane (mitotane), phenytoin (phenytoin) and hypericum (St John's Wort).

21. Subjects were positive for drug and/or alcohol screening at screening or day 1 prior to administration of the initial treatment cycle.

22. The subjects planned to undergo phase selective surgery during initial treatment and follow-up.

23. During the year preceding the screening, the subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell carcinoma and melanoma in situ).

24. The subject had a history of sleep apnea.

25. The subject has undergone gastric bypass surgery, either with gastric cuffs (gastric sleeve) or gastric bands or any related surgery that interferes with gastrointestinal transit.

Subject withdrawal criteria

The subject may withdraw the study drug or terminate the study at any time for any reason. The investigator may withdraw the subject from the study drug or study for any of the following reasons: the subject is unwilling or unable to comply with the protocol; the subject experienced an intolerable AE; other medical or safety reasons, as appropriate by the researcher and/or medical monitor.

When the subject withdraws from the study drug or terminates the study for any reason, the investigator immediately notifies the sponsor and/or medical guardian. The cause is recorded in the electronic case report form (eCRF) of the subject.

If the subject continues to be out of compliance, the researcher will discuss with the sponsor the possibility of discontinuation of the subject. Any reason why the protocol is not desired or followed is documented in the eCRF of the subject, including: missed visits, interruption of study drug administration schedules, unauthorized drugs.

Subjects who discontinued the study due to AE should be followed up, regardless of the causal relationship established by the investigator, until the event resolved, was considered stable or the investigator determined that the event was no longer clinically significant.

Subjects who discontinued study medication early during treatment should return to the study site for end of treatment (EOT) visits as soon as possible, preferably the second day after treatment termination. Follow-up telephone calls and remote assessments were performed 14 days after the last dose treatment. Thereafter, the subjects continued the observation period as planned (table 2).

If at any time during the follow-up or observation period the subject decides to terminate the study, the subject should contact the study site and complete their remote assessment as an Early Termination (ET) visit. An ET visit was made on the same day as the EOT visit if the subject discontinued study medication during treatment and terminated the study on the same day; in this case, all plans for EOT access events will be made.

Upon failure to attempt to contact the subject, the subject is considered to have lost follow-up.

Individual subject stopping criteria

This was the first study to conduct a longitudinal retreatment test with compound 1 and based on the known withdrawal symptoms of other GABAergic drugs and non-clinical findings (investigator manual) of a 9 month study of compound 1 in dogs, there was a possibility of withdrawal-related events, including seizures. The following study drug discontinuation or dose reduction guidelines were proposed to protect subject safety: (1) subjects who report a diagnosed or suspected seizure at any time are discontinued from treatment and are not eligible for other treatment cycles, but continue to be of interest in the study; (2) after the first treatment period, researchers monitored the processes of CNS-based signs and symptoms suggestive of seizures, which were not caused by comorbid psychiatric or medical conditions. Reported events may reflect significant or serious events that would be indicative of seizures and/or increased risk, such as temporary confusion, tremors, involuntary muscle contractions or twitching movements or paresthesias in the arms or legs. If such symptoms occur, the investigator should negotiate with a Sage Medical Monitor, consider reducing the dose of study drug to 20mg, withholding treatment to assess the effect on symptoms (e.g., remission, improvement, etc.), or withholding treatment of the subject. Subjects who stopped treatment were still in the study and continued to evaluate protocol requirements until the end of the study.

Since this is an open label study, the assessment of any major or severe event will continue to be conducted, including the assessment of the benefit/risk profile of compound 1 in the context of the current study. As a result, the sponsor modifies or aborts the study.

Previous and concomitant medications and/or supplements

The start and end dates, routes, doses/units, frequency and indications for all drugs and/or supplements were recorded 30 days prior to screening and throughout the study period. In addition, antidepressants taken within three years prior to screening were also recorded.

At any time during the study, the investigator will decide, as appropriate, to administer any medication and/or supplement necessary for welfare to the subject.

If the subject intends to continue taking a stable dose of medication during initial treatment and follow-up (up to day 28 of cycle 1), the antidepressant is allowed to take at least 60 days before day 1 at the same dose.

Concomitant psychotropic drugs allowed for use during each study period are shown in table 3.

Use of Compound 1 for the treatment of post-cycle exacerbation of Depression symptoms

For subjects who achieved remission or response on day 15 (78.6%), subjects with HAM-D ≧ 22 on day 42 were 6.1%; another 18.2% had-D scores at day 42 ranged from 16 to 21. This suggests that most subjects who may experience a new MDE will have this experience after reaching the minimum required time (8 weeks or 56 days) before the new compound 1 treatment cycle. Thus, most subjects were eligible for a treatment cycle of Compound 1 when needed (i.e., PHQ-9 ≧ 10 and HAM-D ≧ 20 were confirmed within 2 weeks); it took 2 weeks to set up a new MDE (DSM-5).

For subjects who developed an exacerbation of depression symptoms after day 28 and who still failed to meet the conditions of the new cycle of compound 1 treatment, there were 2 intervention options: on demand (limited to up to 4 days per week) and/or with new ADT or increasing the current ADT dose (table 3). In order to maintain an equivalent clinical status (i.e., new compound 1, new ADT or increasing the current dose of ADT) throughout all ADT use, it must be confirmed that the requirements of PHQ-9 ≧ 10 and HAM-D ≧ 20 are met within 2 weeks in all ADT use conditions. If subjects undergoing stable ADT develop an exacerbation of depressive symptoms (PHQ-9 ≧ 10), then use of medications only as needed is recommended only at HAM-D scores < 20; if the HAM-D score is greater than or equal to 20, then the current dose is increased or a new ADT is introduced. In addition, the clinician considered the initial experience of the individual subject with compound 1 when initiating any new ADTs, as it could greatly reduce the likelihood of the subject meeting the conditions of the cycle of receiving a new compound 1 treatment once time allowed (i.e. HAM-D could be < 20). There is no PHQ-9 or HAM-D score requirement for on-demand drug use.

Allowable on-demand drugs for symptom management include benzodiazepines, GABA modulators for insomnia (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem), and non-GABA for insomnia treatment; the upper limit of use for such treatment should be up to 4 days per week.

If an on-demand drug and/or a new ADT is introduced or the current dose of ADT is increased and the subject continues to exhibit HAM-D ≧ 20, a new cycle of compound 1 treatment can be initiated on day 70 or later. After completion of the new compound 1 cycle, the investigator may consider any intervention used during the previous observation period to continue use, as appropriate.

7 days prior to any new compound 1 treatment cycle, any benzodiazepine and/or GABA modulating drugs were discontinued from use during the observation period. The use of non-GABA modulating drugs as needed was discontinued 1 day prior to the start of any new compound 1 treatment cycle.

Female subjects may use contraceptives.

Table 3.

^aOn demand drugs (benzodiazepines, GABA-modulators for insomnia [ e.g., eszopiclone, zopiclone, zaleplon, and zolpidem)]And for non-GABA-mediated treatment of insomnia [ e.g., melatonin, diphenhydramine (Benadryl) [ antihistamines]Trazodone, mirtazapine (mirtazapine), and the like]) Should be limited to a maximum of 4 days per week.

^bIf subjects undergoing stable ADT are experiencing an exacerbation of depressive symptoms (PHQ-9 ≧ 10), a recommendation is made to score HAM-D<20, only using the required medicine; if the HAM D score is 20 or greater, the current ADT dose may be increased or a new ADT may be introduced.

Time relative to initial/previous cycle of compound 1

ADT ═ an antidepressant; stable ADT-ADT started before the study and continued at baseline, or any new ADT started within the observation period and continued throughout the new compound 1 cycle.

Example 3: phase 3, randomized, double-blind, placebo-controlled study of efficacy and safety of relapse prevention in adults with Major Depressive Disorder (MDD) with fixed, repeated treatment regimen of compound 1

This is a study of the first open label phase followed by a randomized, double-blind, placebo-controlled phase to evaluate the effect of compound 1 monotherapy in preventing relapse in adult subjects with MDD (Montgomery-asperger) depression scale [ MADRS ] > 32, HAM-D > 22) who are currently not taking antidepressants compared to placebo in a fixed, repeat treatment regimen. See figure 9 for a schematic of the study design.

The duration of the program in which subjects participated was up to 52 weeks, including the screening phase (up to 4 weeks), Open Label (OL) phase (8 weeks) and Double Blind (DB) phase (40 weeks).

The screening period (table 4) began with the signing of an Informed Consent Form (ICF); the ICF endorsements are prior to the start of any screening activities. Diagnosis of MDD was performed by qualified medical professionals according to the structured clinical interview of the mental illness diagnostic and statistics manual, fifth edition (DSM-5) clinical trial edition (SCID-5-CT). Subjects received a preliminary screening procedure in a screening visit to determine eligibility, including completion of MADRS and CGI-S.

Starting on day 1 of the OL phase, eligible subjects self-took a single dose of study medication with food in the evening every day for 14 consecutive days on an outpatient basis. The actual choice involves taking compound 1 within 1 hour after the evening meal or taking compound 1 with solid food during the evening. Subjects returned to the study center during OL treatment and during follow-up as described in table 5.

Subjects who did not develop significant tolerability problems at the investigator's discretion upon completion of the OL phase (by day 56), and subjects who exhibited HAM-D responses (defined as a ≧ 50% decrease in the total HAM-D score at visits 4, 6, 7, and 8 relative to baseline) (see Table 5) met the criteria for the DB phase. At visit 6, 7 or 8, one shift of < 50% reduction in HAM-D total score from baseline was allowed to enter the DB phase.

Starting on day 1 of the DB phase, eligible subjects were randomized to 1: ratio of 1 received 30mg of compound 1 or matched placebo. The 40-week DB phase comprises five 14-day treatment periods, each with a 6-week follow-up period between treatment periods; the end of each follow-up session coincides with the first visit of the next treatment session. Subjects self-administered a single dose of study medication with food once daily overnight on an outpatient basis over a 14 day treatment period. Subjects returned to the study center during DB treatment and during follow-up as described in table 5.

During follow-up in the DB phase, depression symptoms were monitored every 7 days by remote PHQ-9; if the PHQ-9 score is ≧ 10, the subject should be returned to the study site as soon as possible for evaluation by the clinician under the management of HAM-D (Table 6). If the HAM-D of this visit is ≧ 18, the subject returns to the study site within 7 to 14 days for re-evaluation by HAM-D (Table 6); if HAM-D is still ≧ 18, the subject is considered to have relapsed. The subject is considered to have relapsed in the event of any worsening of depression requiring hospitalization, any risk of suicide determined by the investigator, and/or any other clinically relevant event not requiring hospitalization. Subjects who relapse in the DB stage, as determined by the investigator, terminated the study after completion of the Early Termination (ET) visit; if a subject is determined to have relapsed within the treatment period, the subject is given an end of treatment (EOT) visit as soon as possible, and an ET visit 7 days after the EOT visit. The final determination of Relapse was performed by the Independent Relapse Assessment Committee (IRAC).

If 30mg of compound 1 is not tolerated at any time during the study (as assessed by the investigator's judgment of the occurrence of a severe AE in relation to the study drug), the dose is reduced to 20mg and maintained for the remainder of the treatment period. Dose adjustments associated with moderate AEs were determined by the investigator. Subsequent treatment periods began with a 30mg dose, regardless of whether the subject required dose adjustments during the previous treatment period. Subjects who did not tolerate a 20mg dose at any time were terminated after completing EOT visits as soon as possible and ET visits made 7 days later.

The primary goal of this study was to assess the efficacy of compound 1 in preventing relapse in subjects with major depression (MDD) who responded to OL treatment with compound 1 using a fixed, repeated treatment regimen.

A secondary objective of this study was to evaluate the long-term safety and tolerability of fixed, repeated treatment regimens of compound 1 for up to 1 year.

Other objectives of the study were to evaluate the efficacy of compound 1 of a fixed, repeated treatment regimen compared to placebo in terms of work and activity impairment and health-related quality of life in subjects with MDD, and to evaluate the Pharmacokinetics (PK) of compound 1 using a population PK approach.

The primary endpoint of this study was the time of first recurrence of the DB phase (days; recurrence during the DB phase from the first dose of study drug in DB phase [ date ]).

Secondary endpoints of this study were: percent of subjects who had relapsed in DB phase, change in HAM-D score relative to baseline in 17 total scores at the end of DB phase every 14 days of treatment period, HAM-D response at the end of DB phase every 14 days of treatment period, defined as a decrease in HAM-D score of > 50% relative to baseline, HAM-D remission at the end of DB phase every 14 days of treatment period, defined as a total score of HAM-D of < 7, CGI response, defined as "substantial improvement" or "great improvement" at the end of DB phase every 14 days of treatment period, change in clinical global impression-severity scale (CGI-S) score relative to baseline at the end of DB phase every 14 days of treatment period, change in health questionnaire (PHQ-9) score of 9 patients relative to baseline at the end of DB phase, time (days; first dose from DB in DB for subjects who reached HAM-D remission in OL phase, time (days; first dose from DB; day; first dose from DB) Study drug to DB phase relapse [ date ]), as well as the incidence and severity of Treatment Emergency Adverse Events (TEAEs).

Other endpoints of this study were: changes from baseline in clinical laboratory measurements, vital signs and Electrocardiogram (ECG), suicidal ideation and behavior using the Columbia (Columbia) suicide severity scale (C-SSRS); assessing withdrawal symptoms by physician withdrawal checklists (PWC-20); PRO measurements of work and activity impairment as assessed by changes from baseline in the work production and activity impairment questionnaire (WPAI) specific health problem V2.0 (absenteeism, overtime work, overall work impairment, and overall activity impairment); PRO measurement of health-related quality of life as assessed by changes from baseline in a 5-dimensional, 5-level questionnaire developed by the EuroQol Group (EQ-5D-5L); PK parameters (e.g., clearance) and exposure estimates (e.g., area under the curve, maximum plasma concentration within the dosing interval) as assessed by the population PK method.

And (3) inclusion standard:

eligible subjects met all of the following conditions:

1. the subject has signed the ICF prior to performing any study-specific procedures.

2. The subject is male or female between 18 and 65 years of age, inclusive.

3. The subjects were in good physical health and had no clinically significant findings from investigator physical examination, twelve lead ECG, or clinical laboratory testing.

4. Subjects agreed to comply with the study requirements.

5. The subject had an MDD diagnosis diagnosed by SCID-5-CT, and symptoms had been present for at least 4 weeks.

6. Within 5 years prior to the screening time, the subject had at least 1 prior Major Depressive Episode (MDE) (not including the current episode).

7. On day 1 of the screening and open label phase (pre-dose), subjects had a MADRS score of 32 or more and a HAM-D score of 22 or more.

8. The subject is willing to postpone any treatment regimen of antidepressants, anxiolytics, insomnia drugs, psychostimulants, or prescribed opioids until the end of the study.

9. A subject receiving psychological treatment must receive treatment regularly scheduled for at least 60 days before day 1.

10. Female subjects agreed to use the following contraceptive method during participation in the study and within 30 days after the last study medication, except post-menopause (defined as no menstruation within 12 months without other medical reasons and confirmed by follicle stimulating hormone [ FSH ] >40 mIU/mL), surgical sterilization (hysterectomy or bilateral ovariectomy) or no sexual relationship that could lead to pregnancy occurred:

combined oral (containing oestrogen and progestogen) intravaginal or transdermal hormonal contraception in connection with ovulation inhibition

Hormonal contraception with ovulation inhibition only with an oral, injectable or implantable progestogen

Intrauterine device

Intrauterine hormone Release System

Ligation/occlusion of bilateral fallopian tubes

Partners for vasectomy.

11. Male subjects agreed to use an acceptable effective contraceptive method during the study and within 5 days after receiving the last dose of study medication, unless the subject did not develop a sexual relationship that could lead to pregnancy. Effective methods of contraception acceptable for men include vasectomy or the use of condoms with spermicides along with highly effective female contraception (see inclusion criteria 10 for acceptable methods of contraception) if the female partner has fertility.

12. Male subjects were willing to avoid donation of sperm during the study period and 5 days after receiving the final dose of study drug.

13. Subjects agreed to avoid abuse of drugs and alcohol during the study.

Exclusion criteria:

subjects meeting any of the following criteria will be disqualified from the study:

1. the subject has attempted suicide associated with the current onset of MDD.

3. The Body Mass Index (BMI) is less than or equal to 18 or more than or equal to 50kg/m2 is excluded during screening; BMI at screening 40 to 49kg/m2 inclusive, received a more extensive assessment of medical complications (e.g. sleep apnea, COPD)), tolerance to concomitant medications, prior sedatives.

4. The subject has treatment-resistant depression, which is defined as persistent depressive symptoms despite treatment with adequate doses of two different classes of antidepressants for at least 4 weeks within the current major depressive episode (excluding antipsychotics). For this purpose, the massachusetts state general hospital antidepressant therapy response questionnaire was used.

5. The subjects received vagal stimulation, electroconvulsive therapy, or ketamine administered during the current major depressive episode.

6. The subjects took the antidepressant within 60 days prior to day 1.

7. Subjects were either taking benzodiazepines, barbiturates or GABAA modulators (e.g., eszopiclone, zopiclone, zaleplon and zolpidem) on day 28 or using these drugs daily or nearly daily (4 times weekly) for more than one year on day 28.

8. From day 60 prior to day 1, the subject is taking any benzodiazepine or GABA modulator (e.g., diazepam) with a half-life of greater than or equal to 48 hours.

9. The subject takes a non-GABA anti-insomnia drug (e.g., melatonin, diphenhydramine (Benadryl) [ antihistamine drug ], trazodone) on day 14 or a first or second generation (typical/atypical) antipsychotic on day 14.

10. On day 28, subjects take psychostimulants (e.g., methylphenidate, amphetamines) or opioids (opioids) on a regular or on-demand basis.

11. The subject is allergic to compound 1, allopregnanolone (allopregnanolone) or a related compound.

12. During any treatment cycle, subjects had a positive pregnancy test on day 1 prior to screening or initiation of study drug administration.

13. Subjects breastfeeding at screening or on day 1 (prior to study medication administration) did not agree that breastfeeding of children was temporarily discontinued from day 1 on study medication until day 7 after the last dose of study medication during each treatment period.

14. The subject has detectable hepatitis b surface antigen, anti-Hepatitis C Virus (HCV) and positive HCV viral load (load) or Human Immunodeficiency Virus (HIV) antibodies at the time of screening.

15. Subjects had clinically significant abnormal twelve lead ECGs at screening or baseline visit. Note that: the average QT interval calculated using the frigericia method (QTcF), was >450 milliseconds in men and >470 milliseconds in women, which was the basis for exclusion from this study.

16. The subject had active psychosis, as assessed by the investigator.

17. The subject had a history of epilepsy.

18. The subject has a history of bipolar depression, schizophrenia, and/or schizophrenic affective disorder.

19. The subject had a history of mild, moderate or severe substance use disorders (including benzodiazepines) diagnosed using DSM-5 criteria during the 12 months prior to screening.

20. The subject was exposed to another study drug or device within 30 days prior to screening.

21. The subjects had previously participated in a clinical trial of compound 1 or brexanolone.

22. Subjects used any known strong inhibitor of cytochrome P450(CYP)3a4 within 28 days or within 5 half-lives (whichever is longer) prior to the first dose of study drug, or were scheduled to use these inhibitors during any treatment period, or were scheduled to consume grapefruit juice, grapefruit, or Seville orange juice (Seville) or products containing these within 14 days prior to the first dose of study drug during any treatment period, or were scheduled to consume these products during any treatment period.

23. The following potent CYP3A inducer was used 28 days prior to the first dose of study drug during any compound 1 treatment period: rifampin (rifampin), carbamazepine (carbamazepine), enzalutamide (enzalutamide), mitotane (mitotane), phenytoin (phenytoin) and hypericum (St John's Wort)

24. The subjects were positive for drug and/or alcohol screening at screening or day 1 prior to dosing in the open label period.

25. The subjects planned to undergo selective surgery or procedure of general anesthesia at any time from screening to the study period. Procedures requiring conscious sedation and ambulatory procedures under local anesthesia may be scheduled according to the following guidelines:

surgical procedures requiring conscious sedation (e.g., colonoscopy) were not later than 7 days before the start of the first dose for each treatment period and not earlier than 7 days after the last dose for each treatment period from the start of screening throughout the study.

Selective outpatient surgery under local anesthesia at any time during the study

26. During the year preceding the screening, the subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell carcinoma and melanoma in situ).

27. The subject has undergone gastric bypass surgery, either with gastric cuffs (gastric sleeve) or gastric bands or any related surgery that interferes with gastrointestinal transit.

28. Subjects participated in, or were expected to perform, night shift work regularly during any 14 day treatment period (night shift work was allowed to occur occasionally during follow-up).

Dosage and mode of administration

Compound 1 can be a hard gelatin capsule containing a white to off-white powder. In addition to compound 1 drug substance, compound 1 capsules also contained croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide is a component of SMCC and may also be a separate excipient in the formulation. Compound 1 capsules were administered orally at a dose of 30mg or 20 mg.

Reference therapy, dose and mode of administration:

in the DB phase, placebo is provided in the form of hard gelatin capsules for oral administration with food at night.

Duration of treatment:

all subjects received daily doses of compound 1 from day 1 to day 14 in the OL phase. In the DB phase, subjects who showed HAM-D response to compound 1 in the OL phase received a daily dose of compound 1 or placebo at random for 40 weeks (for a total of six 14-day treatment periods in the 52-week study) over a 14-day treatment period (separated by a 6-week follow-up period).

Table 4.

^aSubjects at the US study site were asked to authorize entry of their unique subject identifiers into a registry to identify subjects who might meet exclusion criteria for participation in another clinical study.

^bIf available, the ICD-10 code is collected.

^cIn screening female subjects who are not surgically sterilized, a serum FSH test will be performed to confirm whether female subjects with ≧ 12 months of spontaneous amenorrhea meet the criteria defined by the post-menopausal protocol.

^dA comprehensive physical examination will be performed including an assessment of the body system (e.g., head, eyes, ears, nose and throat; heart; lungs; abdomen and limbs).

^eClinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.

^fUreology (according to the laboratory manual) and alcohol breath test of selected drugs of abuse.

^gThe study site personnel will perform training on the subjects for the software applications and equipment usage necessary for the study.

^hVital signs include oral temperature (deg.C), respiratory rate, heart rate, and blood pressure (supine and standing). After the subjects had rested for 5 minutes, heart rate and blood pressure were again collected in the supine position at all the planned time points for the standing position. Clinical researchers can decide whether to repeat vital signs as appropriate.

ⁱTriplicate ECGs will be collected.

^jHAM-D will complete as early as possible during the access. The evaluation time box for the HAM-D scale refers to the past 7 days (1 week).

^kThe collection of adverse events will begin with informed consent and throughout the course of the subject's participation in the study.

Table 5.

^aSubjects who discontinued treatment early should return to the study site as soon as possible for end of treatment (EOT) visits, preferably the next day of treatment discontinuation. The follow-up should be performed 14 days after the last dose treatment. If at any time after an EOT visit, the subject decides to terminate the study, the subject should return for an Early Termination (ET) visit. EOT and ET visits may be made on the same day if the subject discontinues study medication during the clinical visit and terminates the study on the same day; in this case, all events scheduled for EOT access will be scheduled.

^bCompletion of the open label phaseConsistent with the first day of the double-blind phase (study day 56, visit 7). The study was terminated on this day for subjects who did not exhibit a response to SEAGE-217 during the open label phase (see criteria above).

^cThe study site personnel will perform training on the subjects for the software applications and equipment usage necessary for the study.

^dClinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.

^eUreology (according to the laboratory manual) and alcohol breath test of selected drugs of abuse.

^fVital signs include oral temperature (deg.C), respiratory rate, heart rate, and blood pressure (supine and standing). After the subjects had rested for 5 minutes, heart rate and blood pressure were again collected in the supine position at all the planned time points for the standing position. Clinical researchers can decide whether to repeat vital signs as appropriate.

^gTriplicate ECGs will be collected. When ECG and PK samples were collected on the same day, a twelve lead ECG was performed prior to PK sample collection.

^hThe C-SSRS table is completed "since last access".

ⁱHAM-D should be completed as early as possible during an access. The evaluation timeframe for the HAM-D scale at day 56/1 of the double-blind phase refers to the past 7 days (1 week), and day 1 of the open label phase and other visits refers to "since last visit"

^jPlasma samples will be collected at any time during the clinical visit for PK analysis. The date and time of sample collection and the date and time of administration of the last dose must be recorded. When ECGs and PK sample collection occur on the same day, then a twelve lead ECG is performed prior to PK sample collection.

^kAll PHQ-9 evaluations will be performed by the handset supported software application. Subjects will do PHQ-9 every 7 days; if the PHQ-9 score is ≧ 10, the subject is returned to the study site as soon as possible for HAM-D assessment by a clinician. If HAM-D was ≧ 18 at this visit, the subject should return to the study site for HAM-D re-assessment within 7 to 14 days. The evaluation of these access executions is seen in table 3.

^lThe collection of adverse events will begin with informed consent and throughout the course of the subject's participation in the study.

Table 6.

^aClinical laboratory tests will include hematology, serum chemistry, coagulation and urinalysis

^bVital signs include oral temperature (deg.C), respiratory rate, heart rate, and blood pressure (supine and standing). After the subjects had rested for 5 minutes, heart rate and blood pressure were again collected in the supine position at all the planned time points for the standing position. Clinical researchers can decide whether to repeat vital signs as appropriate.

^cThe C-SSRS table will be completed "since the last access.

^dHAM-D will complete as early as possible during the access. The evaluation time box for the HAM-D scale refers to the past 7 days (1 week).

^eThe collection of adverse events will begin with informed consent and throughout the course of the subject's participation in the study.

Example 4

Cognitive deficits may occur in people suffering from depression and anxiety disorders, such as Major Depressive Disorder (MDD). Cognitive changes (if any) will be assessed in subjects receiving compound 1 using a series of cognitive tests or a Cogstate test.

The Cogstate test can be designed to measure a specific cognitive domain and can be grouped together to form custom strings based on the study design and the unique requirements of the population. An example of a Cogstate test is as follows:

behavioral Pattern isolation Object (The Behavioral Pattern isolation Object) testing uses Object photogrammetry to identify memory. Participants are presented with a series of photographs of common items and it must be decided whether each item is used indoors or outdoors. The participant is then presented with a picture of the item and must remember whether the item is the same, similar or different from the picture they have displayed.

The Continuous Paired associative Learning (The Continuous Paired associative Learning) test measures visual memory using a Paired associative Learning paradigm. In this test, the participants had to learn and remember the pictures hidden under different positions on the screen. In the first phase of testing, the instructions of the on-screen pretest ask: "which position these pictures belong to". The center of the screen will display the picture. The participants click on the peripheral position of the picture and must remember their positions. In the second stage of the test, the same picture would be displayed in the center of the screen, but the peripheral locations of each picture are hidden. The participant must click on the peripheral location where the picture previously appeared.

The Detection test (The Detection test) uses a simple reaction time paradigm to measure The processing speed. The on-screen instructions ask: "is the card turned over? ". The card appears face down in the center of the screen. The card is turned over so as to face upward. Once the card is turned over, the player must press yes. Participants were encouraged to perform as quickly and as accurately as possible.

Face Name Associative Memory test (The Face Name Associative Memory Exam) uses photographs of real faces to measure Associative Memory. The participants were presented with a series of facial photographs and names, one name for each face. Participants must remember the face-name pair.

The Go-No-Go Test is a measure of response inhibition using a validated recognition response time paradigm with playing card stimulation. In this test, the playing cards were all clown cards, red or black. The subject is asked whether the card displayed in the center of the screen is black. The subject pressed the "yes" key when the clown was black and remained responsive (i.e., non-responsive) when red.

The Groton Maze Learning Test uses a Maze Learning paradigm to measure executive functions. A 10x10 grid of tiles would be displayed on the screen to the participants. The 28-step path is hidden between these tiles. The blue block indicates start and the block with the red circle indicates completion. The participant must move one step at a time from beginning to end by touching the tile to a position next to its current position. If the correct movement is made, a green pair appears, and if the movement is incorrect, a red cross is displayed. After completion, they will return to the starting position to repeat the test and must try to remember the path they just completed.

The Identification test (The Identification test) measures attention using a selection reaction time paradigm. The on-screen instructions ask: "is card red? ". The card appears face down in the center of the screen. The card is turned over so as to face upward. Once turned, the player must decide whether the card is red. If red, the participant should press "yes", if not red, the participant should press "no". Participants were encouraged to perform as quickly and as accurately as possible.

The International Shopping List Test (The International Shopping List Test) measures language learning using a vocabulary learning paradigm. The participant reads the shopping list and must remember and recall as many items as possible from the list.

The One-loop test (The One Back test) measures working memory using an n-loop (n-Back) paradigm. The on-screen instructions ask: "is the last card the same? ". The card appears face up in the center of the screen. The player must decide whether the card is the same as the previous card. If the cards are the same, the player should press "yes", and if the cards are different, the player should press "no". Participants were encouraged to perform as quickly and as accurately as possible.

The One Card Learning test (The One Card Learning test) uses a graph separation model to measure visual memory. The on-screen instructions ask: "do you see the card before the test? ". The card appears right side up in the center of the screen and the players must decide whether they have seen the card before this test. Participants were encouraged to perform as quickly and as accurately as possible.

The Set-Shifting test uses a Set-Shifting model to measure executive functions. The on-screen instructions ask: "is this the target card? ". The card appears face up in the center of the screen with the word "number" or "color" on it. If the word is "color," the player must guess whether the target card is black or red. If the word is "numeric," the player must guess whether the current number displayed on the card is correct. At the beginning of the test, the participant simply guesses whether the current card is the target card. If they believe the card is the target card, the player should press "yes". If they believe the card is not the target card, they must press "no". When the participant guesses, feedback is provided until the correct answer is made and the next card is displayed. Once the player has completed a series of card manipulations, the rules of the hiding change (e.g., from one color to another [ in-dimension conversion ], or from color to number [ out-of-dimension conversion ]). Instead of informing the participants when these module conversions occur, they must learn new target rules to proceed with the test. Participants were encouraged to perform as quickly and as accurately as possible.

The Social Emotional awareness Test (The Social-Emotional awareness Test) measures Emotional awareness using an odd-man out paradigm. The on-screen instructions ask: "press different one". Four pictures are displayed on the screen. One of these pictures will be different from the others and the participant has to decide which picture is different and press the picture. Participants were encouraged to perform as quickly and as accurately as possible.

The Two-pass test (The Two Back test) uses an n-round norm to measure working memory. The on-screen instructions ask: "is the card the same as was previously displayed by two cards? ". The card appears face up in the center of the screen. The player must decide whether the card is the same as the card displayed before the two cards. If the cards are the same, the player should press "yes", and if the cards are different, the player should press "no". Participants were encouraged to perform as quickly and as accurately as possible.

To assess cognitive decline, deficiency, or improvement in subjects receiving compound 1, cognition can be assessed using a series of tests, such as the cluster shown in table 7.

Table 7 details of computerized cognitive testing in the Cogstate cluster.

Subjects can be evaluated with a series of Cogstate tests before, during, and after administration of compound 1.

References cited in table 7:

davis MT, DelllaGioia N, Matuskey D, et al, preferably even evaluating the pattern and the map of the cognitive gravity function in the master default dis-ordance using the master measures J Afffect dis-ordance 2017; 218, doi:10.1016/j.jad.2017.04.064

Holmes SE, Scheinost D, Finnema SJ, et al, Lower synthetic teeth is associated with a expression preference and network alterations.nat com.2019; 10(1) 1529.doi 10.1038/s41467-019-

Olver JS, ignatidis S, Maruff P, Burrows GD, Norman TR. quetiapine (quetiapine) augmentation in compressed partitions with partial response to anti-depressants, hum psychopharmacol.2008; 653-660 in 23(8), doi 10.1002/hu p.970

G.lvez V, Li A, Huggins C, et al, reproduced indoor key for a treatment-resistant suppression-the way to go? Results from a pilot ran combined controlled trial tri.2018. doi:10.1177/0269881118760660

Hashimoto K, Yoshida T, Ishikawa M, et al, incorporated sera lev els of serine organisms in tissues with depth suppression. acta Neuropsychiater.2015; (November):1-6.doi:10.1017/neu.2015.59

Yoshida T, Ishikawa M, Niitsu T, et al, classified serum level o f raw blue-derived neuropathic factor (BDNF), but not present pr oBDNF, in Patients with major de-pressing recorder. 7(8) e42676. doi 10.1371/juurnal. pane.0042676

Equivalents and ranges

In the claims, articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Unless indicated to the contrary or otherwise evident from the context, a claim or specification including "or" between one or more members of a group is deemed to be satisfied if one or more or all of the group members are present, employed, or otherwise relevant in a given product or process. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise associated with a given product or process. The invention includes embodiments in which more than one, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process.

Furthermore, the present invention encompasses all variations, combinations, and permutations that introduce one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims into another claim. For example, any claim that references another claim may be amended to include one or more limitations found in any other claim that references the same base claim. Where elements are represented in a list, such as in a markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. It will be understood that, in general, certain embodiments of the invention or aspects of the invention consist of, or consist essentially of, such elements and/or functions when the invention or aspects of the invention relate to, e.g., include, particular elements and/or features. For the sake of brevity, these embodiments are not specifically set forth herein. It should also be noted that the terms "comprising" and "comprises" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated range, up to one tenth of the unit of the lower limit of the stated range, unless the context clearly dictates otherwise.

This application is related to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. In the event of a conflict between any cited reference and this specification, the present specification shall control. In addition, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more claims. Since such 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 invention may be excluded from any claim for any reason, whether or not related to the presence of prior art.

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 present embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the following claims. It will be understood by those of ordinary skill in the art that various changes and modifications may be made to the description without departing from the spirit or scope of the invention as defined by the following claims.

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