Treatment for depression

Abstract

To provide treatment for depression.SOLUTION: Described herein are methods for treating depression and / or preventing a relapse in depression in a patient, comprising the steps of: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("compound A" or "CMPD A") or a salt thereof; and administering to the patient at least one daily maintenance dose comprising compound A or a salt thereof, wherein the at least one daily maintenance dose is less than the first dose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 025,405, filed May 15, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Major depressive disorder ("MDD") is characterized by a pervasive depressed mood or loss of interest or pleasure in almost all activities (anhedonia) in discrete episodes of at least two weeks duration, with distinct alterations in affect, cognition, and autonomic nervous system function, and remission or reduction in symptom severity between episodes. MDD has been identified as the second leading cause of years lived with disability and designated as a major public health priority. Currently available antidepressants have limitations, including low treatment response rates (e.g., treatment-resistant depression ("TRD")) and a time lag of several weeks before a therapeutic effect is observed. Therefore, there is a significant unmet medical need for novel antidepressant treatments with a more rapid onset of action and improved efficacy. Summary of the Invention [Means for solving the problem]

[0003] 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A"), or a salt thereof, is a potent and selective positive allosteric modulator (PAM) of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. The present application discloses methods for treating depression in a patient and for treating and / or preventing the recurrence of depression, comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A"), or a salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof.

[0004] In some embodiments, Compound A or a salt thereof is Compound A.

[0005] In some embodiments, the first dose comprises Compound A. In some embodiments, the first dose comprises a salt of Compound A. In some embodiments, the first dose comprises a pharmaceutically acceptable salt of Compound A.

[0006] In some embodiments, at least one daily maintenance dose comprises Compound A. In some embodiments, at least one daily maintenance dose comprises a salt of Compound A. In some embodiments, at least one daily maintenance dose comprises a pharmaceutically acceptable salt of Compound A.

[0007] In one aspect, the disclosure relates to a method of treating depression in a patient, comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (“Compound A” or “CMPD A”) or a salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof, wherein the maintenance dose is less than the first dose.

[0008] In some embodiments, the depression is disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder dysthymia, premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, depressive disorder not otherwise specified, moderate depression, severe depression, and / or a specific factor of a depressive disorder. In some embodiments, the depression is major depressive disorder. In some embodiments, the depression is treatment-resistant depression.

[0009] In some embodiments, the method further treats a cognitive impairment associated with depression. In some embodiments, the method further treats a cognitive impairment associated with depression as measured by a Brief Assessment of Cognition. In some embodiments, the method further treats a cognitive impairment associated with depression-related declines in processing speed, executive function, attention, or verbal learning and memory. In some embodiments, the method further treats a cognitive impairment associated with depression with declines in processing speed. In some embodiments, the method further treats a cognitive impairment associated with depression with declines in executive function. In some embodiments, the method further treats a cognitive impairment associated with depression with declines in attention. In some embodiments, the method further treats a cognitive impairment associated with depression with declines in verbal learning. In some embodiments, the method further treats a cognitive impairment associated with depression with declines in memory.

[0010] In some embodiments, the patient has already received at least one previous treatment for depression. In some embodiments, the patient has not responded to at least one previous treatment for depression. In some embodiments, the patient is a responder to at least one previous treatment for depression.

[0011] In some embodiments, at least one previous treatment for depression comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, at least one previous treatment comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.

[0012] In some embodiments, at least one daily maintenance dose is administered about 12 hours or more after the first dose.

[0013] In some embodiments, the first dose comprises about 5 mg to about 9 mg of Compound A.

[0014] In some embodiments, the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A once a day.

[0015] In some embodiments, the first dose provides a mean C of at least about 6 ng / mL in the patient. max In some embodiments, the first dose is effective to achieve a mean C of 100 ng / mL or less in the patient. max In some embodiments, the first dose is effective to achieve a mean C of about 100 ng / mL or less in the patient. max In some embodiments, the first dose is effective to achieve a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max It is effective in achieving this.

[0016] In some embodiments, at least one daily maintenance dose is administered to a patient with a mean Cmax of about 130 ng / mL or less at steady state. max It is effective in achieving this.

[0017] In some embodiments, the first dose provides a mean C of 6 ng / mL to about 100 ng / mL in the patient. max In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of 42 ng / mL in the patient. max In some embodiments, at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state. max It is effective in achieving this.

[0018] In some embodiments, the mean AUC τ In some embodiments, the mean AUC at steady state in the patient is about 2600 ng·h / mL or less. τ In some embodiments, the mean AUC at steady state in a patient is between about 700 ng·h / mL and about 2600 ng·h / mL. τ is about 75% to about 130% of 1487 ng·h / mL. ∞ is approximately 75% to 130% of 2328 ng·h / mL.

[0019] In some embodiments, the first dose is administered orally. In some embodiments, at least one daily maintenance dose is administered orally.

[0020] In some embodiments, the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the maintenance dose comprises about 3 mg of Compound A once daily.

[0022] In some embodiments, the first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max and at least one daily maintenance dose is effective to achieve a mean C of about 130 ng / mL or less at steady state in the patient. max , and a mean AUC of approximately 2600 ng·h / mL or less at steady state in patients τ It is effective in achieving this.

[0023] In some embodiments, the first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in patients ∞ and at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ It is effective in achieving this.

[0024] In another aspect, the disclosure relates to a method for treating and / or preventing recurrence of depression in a patient, comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (“Compound A” or “CMPD A”) or a salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof, wherein the maintenance dose is less than the first dose.

[0025] In some embodiments, the depression is major depressive disorder. In some embodiments, the depression is treatment-resistant depression. In some embodiments, the method treats and / or prevents cognitive impairment. In some embodiments, the method treats and / or prevents cognitive impairment associated with depression as measured by a brief assessment of cognition. In some embodiments, the method treats and / or prevents cognitive impairment involving declines in processing speed, executive function, attention, or verbal learning and memory. In some embodiments, the method treats and / or prevents cognitive impairment associated with depression. In some embodiments, the method treats and / or prevents cognitive impairment including declines in processing speed, executive function, attention, or verbal learning and memory associated with depression.

[0026] In some embodiments, the patient has already received at least one previous treatment for depression. In some embodiments, the patient has not responded to at least one previous treatment for depression. In some embodiments, the patient is a responder to at least one previous treatment for depression.

[0027] In some embodiments, at least one previous treatment for depression comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, at least one previous treatment comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.

[0028] In some embodiments, at least one daily maintenance dose is administered about 12 hours or more after the first dose.

[0029] In some embodiments, the first dose comprises about 5 mg to 9 mg of Compound A.

[0030] In some embodiments, the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A once a day.

[0031] In some embodiments, the first dose provides a mean C of about 6 ng / mL or greater in the patient. max In some embodiments, the first dose is effective to achieve a mean C of 100 ng / mL or less in the patient. max It is effective in achieving this.

[0032] In some embodiments, at least one daily maintenance dose is administered to a patient with a mean Cmax of about 130 ng / mL or less at steady state. max It is effective in achieving this.

[0033] In some embodiments, the first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of 42 ng / mL in the patient. max In some embodiments, the patient's mean C max is approximately 75% to approximately 130% of 78 ng / mL.

[0034] In some embodiments, the mean AUC τ In some embodiments, the mean AUC at steady state in the patient is about 2600 ng·h / mL or less. τ In some embodiments, the mean AUC at steady state in a patient is between about 700 ng·h / mL and about 2600 ng·h / mL. τis about 75% to about 130% of 1487 ng·h / mL. ∞ is approximately 75% to 130% of 2328 ng·h / mL.

[0035] In some embodiments, the first dose is administered orally. In some embodiments, at least one daily maintenance dose is administered orally.

[0036] In some embodiments, the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 6 mg of Compound A.

[0037] In some embodiments, the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once daily.

[0038] In some embodiments, the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof, and at least one daily maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, the first dose comprises about 6 mg of Compound A, and at least one daily maintenance dose comprises about 3 mg of Compound A, once daily.

[0039] In some embodiments, the first dose provides a mean C of about 40 ng / mL to about 100 ng / mL in the patient. max and at least one daily maintenance dose is effective in achieving a mean C of 130 ng / mL or less at steady state in patients max , and a mean AUC of 2600 ng·h / mL or less at steady state in patients τ In some embodiments, the first dose is effective to achieve a mean C of about 40 ng / mL to about 100 ng / mL in the patient. max and at least one daily maintenance dose is effective to achieve a mean C of about 130 ng / mL or less at steady state in the patient.max , mean AUC of approximately 2600 ng·h / mL or less at steady state in patients τ It is effective in achieving this.

[0040] In some embodiments, the first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of 42 ng / mL. max At least one daily maintenance dose is effective to achieve in a patient a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in patients ∞ and at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ In some embodiments, the first dose is effective to achieve a mean C of about 75% to about 130% of 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in patients ∞and at least one daily maintenance dose is effective to achieve a mean C of about 75% to about 130% of 78 ng / mL at the patient's steady state after at least one daily maintenance dose. max , and a mean AUC of approximately 75% to approximately 130% of 1487 ng·h / mL at steady state in patients τ It is effective in achieving this.

[0041] It will be understood that references herein to methods of treatment and / or prevention (e.g., methods of treating and / or preventing the recurrence of depression) using 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a salt thereof, or a pharmaceutical composition comprising same, should also be interpreted as references to the following: Compound A or a salt thereof, or a pharmaceutical composition comprising same, for use in a method for treating and / or preventing, for example, the recurrence of depression; and / or For example, use of Compound A or a salt thereof, or a pharmaceutical composition containing same, in the manufacture of a medicament for treating and / or preventing the recurrence of depression. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method for treating depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof; administering to said patient at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: (Item 2) Item 10. The method of item 1, wherein the depression is major depressive disorder. (Item 3) 3. The method of item 1 or 2, wherein the depression is treatment-resistant depression. (Item 4) 4. The method of any one of items 1 to 3, wherein treating depression comprises treating a cognitive impairment associated with said depression. (Item 5) 5. The method of any one of items 1 to 4, wherein the patient has already received at least one previous treatment for depression. (Item 6) 6. The method of item 5, wherein the patient has not responded to at least one previous treatment for depression. (Item 7) 7. The method of item 5 or 6, wherein the patient is a responder to at least one previous treatment for depression. (Item 8) 8. The method of any one of items 5 to 7, wherein the at least one prior treatment for depression comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2-diastereomeric hydroxyketamine or a salt thereof; 6-diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. (Item 9) 9. The method of any one of items 5 to 8, wherein the at least one prior treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. (Item 10) 10. The method of any one of items 1 to 9, wherein the at least one daily maintenance dose is administered about 12 hours or more after the first dose. (Item 11) 11. The method of any one of items 1 to 10, wherein the first dose comprises about 5 mg to about 9 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 12) 12. The method of any one of items 1 to 11, wherein the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. (Item 13) The first dose provides a mean C of at least about 6 ng / mL in the patient. max 13. The method according to any one of items 1 to 12, which is effective to achieve (Item 14) The first dose has a mean C of about 100 ng / mL or less in the patient. max 14. The method according to any one of items 1 to 13, which is effective to achieve (Item 15) The at least one daily maintenance dose provides the patient with a mean Cmax of about 130 ng / mL or less at steady state. max 15. The method according to any one of items 1 to 14, which is effective to achieve (Item 16) The first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max 16. The method according to any one of items 1 to 15, which is effective to achieve (Item 17) the first dose results in a mean C of about 75% to about 130% of 42 ng / mL in the patient max 17. The method according to any one of items 1 to 16, which is effective to achieve (Item 18) The at least one daily maintenance dose is administered to the patient at a mean C of about 75% to about 130% of 78 ng / mL at steady state. max 18. The method according to any one of items 1 to 17, which is effective to achieve (Item 19) The patient's mean AUC at steady state τ 19. The method of any one of items 1 to 18, wherein the IL-10 is about 2600 ng·h / mL or less. (Item 20) The patient's mean AUC at steady state τ20. The method according to any one of items 1 to 19, wherein the IL-10 is about 700 ng·h / mL to about 2600 ng·h / mL. (Item 21) The patient's mean AUC at steady state τ 21. The method according to any one of items 1 to 20, wherein the IL-10 is about 75% to about 130% of 1487 ng·h / mL. (Item 22) The mean AUC of the patient ∞ 22. The method according to any one of items 1 to 21, wherein the IL-10 is about 75% to about 130% of 2328 ng·h / mL. (Item 23) 23. The method of any one of items 1 to 22, wherein the first dose is administered orally. (Item 24) 24. The method of any one of items 1 to 23, wherein the at least one daily maintenance dose is administered orally. (Item 25) 25. The method of any one of items 1 to 24, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 26) 26. The method of any one of items 1 to 25, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. (Item 27) The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max is effective in achieving and wherein the at least one daily maintenance dose is administered to the patient at steady state after the at least one daily maintenance dose, and the patient has a mean C of about 130 ng / mL or less at steady state after the at least one daily maintenance dose. max and a mean AUC of about 2600 ng·h / mL or less at steady state in said patient. τ 27. The method according to any one of items 1 to 26, which is effective to achieve (Item 28) the first dose results in a mean C of about 75% to about 130% of about 42 ng / mL in the patient max is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 28. The method according to any one of items 1 to 27, which is effective to achieve (Item 29) the first dose results in a mean C of about 75% to about 130% of 42 ng / mL in the patient max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 29. The method according to any one of items 1 to 28, which is effective to achieve (Item 30) 1. A method for preventing recurrence of depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof; administering to said patient at least one daily maintenance dose comprising Compound A or a salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: (Item 31) 31. The method of item 30, wherein the depression is major depressive disorder. (Item 32) 32. The method of item 30 or 31, wherein the depression is treatment-resistant depression. (Item 33) 33. The method of any one of items 30 to 32, further comprising treating and / or preventing depression-related cognitive impairment in said patient. (Item 34) 34. The method of any one of items 30 to 33, wherein the patient has already received at least one previous treatment for depression. (Item 35) 35. The method of claim 34, wherein the patient has not responded to at least one previous treatment for depression. (Item 36) 36. The method of item 34 or 35, wherein the patient is a responder to at least one previous treatment for depression. (Item 37) The at least one prior treatment for depression was ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. (Item 38) 38. The method of any one of items 34 to 37, wherein the at least one prior treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. (Item 39) 39. The method of any one of items 30 to 38, wherein the at least one daily maintenance dose is administered about 12 hours or more after the first dose. (Item 40) 40. The method of any one of items 30 to 39, wherein the first dose comprises about 5 mg to about 9 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 41) 41. The method of any one of items 30 to 40, wherein the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. (Item 42) The first dose has a mean C of about 6 ng / mL or greater in the patient. max 42. The method according to any one of items 30 to 41, which is effective to achieve (Item 43) The first dose has a mean C of about 100 ng / mL or less in the patient. max 43. The method according to any one of items 30 to 42, which is effective to achieve (Item 44) The at least one daily maintenance dose provides the patient with a mean Cmax of about 130 ng / mL or less at steady state. max 44. The method according to any one of items 30 to 43, which is effective to achieve (Item 45) The first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max 45. The method according to any one of items 30 to 44, which is effective to achieve (Item 46) the first dose results in a mean C of about 75% to about 130% of 42 ng / mL in the patient max 46. ​​The method according to any one of items 30 to 45, which is effective to achieve (Item 47) The patient's mean steady-state C max 47. The method according to any one of items 30 to 46, wherein the IL-10 concentration is about 75% to about 130% of 78 ng / mL. (Item 48) The patient's mean AUC at steady state τ 48. The method according to any one of items 30 to 47, wherein the IL-10 is about 2600 ng·h / mL or less. (Item 49) The patient's mean AUC at steady state τ49. The method according to any one of items 30 to 48, wherein the IL-10 is about 700 ng·h / mL to about 2600 ng·h / mL. (Item 50) The patient's mean AUC at steady state τ is about 75% to about 130% of 1487 ng·h / mL. (Item 51) The mean AUC of the patient ∞ is about 75% to about 130% of 2328 ng·h / mL. (Item 52) 52. The method of any one of items 30 to 51, wherein the first dose is administered orally. (Item 53) 53. The method of any one of items 30 to 52, wherein the at least one daily maintenance dose is administered orally. (Item 54) 54. The method of any one of items 30 to 53, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 55) 55. The method of any one of items 30 to 54, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. (Item 56) The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max is effective in achieving The at least one daily maintenance dose provides the patient with a mean Cmax of about 130 ng / mL or less at steady state. max and a mean AUC of about 2600 ng·h / mL or less at steady state in said patient. τ 56. The method according to any one of items 30 to 55, which is effective to achieve (Item 57) the first dose results in a mean C of about 75% to about 130% of about 42 ng / mL in the patient max is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 57. The method according to any one of items 30 to 56, which is effective to achieve (Item 58) the first dose results in a mean C of about 75% to about 130% of 42 ng / mL in the patient max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 58. The method according to any one of items 30 to 57, which is effective to achieve (Item 59) 59. The method of any one of items 1 to 58, wherein the first dose comprises Compound A. (Item 60) 60. The method of any one of items 1 to 59, wherein the at least one daily maintenance dose comprises Compound A. (Item 61) 61. The method of any one of items 1 to 60, wherein the patient is 18 to 55 years old. (Item 62) 62. The method of any one of items 1 to 61, wherein the patient is 20 to 49 years old. (Item 63) 30. The method of any one of items 1 to 29, wherein treating depression comprises improving symptoms of depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). (Item 64) 64. The method of any one of items 1 to 29 and 63, wherein treating depression comprises reducing MDD severity as measured by Clinical Global Impression-Severity Scale (CGI-S). (Item 65) 65. The method of any one of items 1 to 29, 63 and 64, wherein treating depression comprises treating MDD as measured by Clinical Global Impression-Severity scale (CGI-S). (Item 66) 66. The method of any one of items 1 to 29 and 63 to 65, wherein treating depression comprises improving quality of life as measured by the 5 Level EuroQol-5 Dimension. (Item 67) 67. The method of any one of items 1 to 29 and 63 to 66, wherein the patient is receiving stable pharmacological treatment for depression. (Item 68) 68. The method of any one of items 1 to 29 and 63 to 67, wherein the patient is receiving stable pharmacological treatment for depression, defined as a ≦50% change in dose during the 6 weeks prior to randomization. (Item 69) 69. The method of any one of items 63 to 68, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof, and the at least one daily maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 70) 70. The method of any one of items 63 to 69, wherein the first dose comprises about 6 mg of Compound A and the at least one daily maintenance dose comprises about 3 mg of Compound A. (Item 71) 69. The method of any one of items 63 to 68, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 72) 69. The method of any one of items 63 to 68, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. (Item 73) 1. A pharmaceutical composition for use in the treatment of depression, comprising: a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof; and at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, wherein said at least one daily maintenance dose is less than said first dose; A pharmaceutical composition comprising: (Item 74) 1. A pharmaceutical composition for use in the treatment of depression, comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, administered in a first dose and at least one daily maintenance dose, wherein the at least one daily maintenance dose is less than the first dose. (Item 75) 1. Use of a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, and at least one daily maintenance dose comprising Compound A or a salt thereof, for treating depression, wherein the at least one daily maintenance dose is less than the first dose. (Item 76) A pharmaceutical composition for use in preventing recurrence of depression, comprising: a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof; and at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, wherein said at least one daily maintenance dose is less than said first dose; A pharmaceutical composition comprising: (Item 77) 1. A pharmaceutical composition for use in preventing the recurrence of depression, comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, administered in a first dose and at least one daily maintenance dose, wherein the at least one daily maintenance dose is less than the first dose. (Item 78) 1. Use of a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof, and at least one daily maintenance dose comprising Compound A or a salt thereof, for preventing recurrence of depression, wherein the at least one daily maintenance dose is less than the first dose. [Brief explanation of the drawings]

[0042] [Figure 1A] FIG. 1A is a study schematic of Part 1, single ascending dose (“SRD”) cohorts 1-6.

[0043] [Figure 1B] Figure 1B is a study schematic of Part 2 SRD / multiple ascending dose ("MRD") cohorts 1-5.

[0044] [Figure 2] FIG. 2 shows the linear (top) and semi-logarithmic (bottom) mean plasma concentration-time profiles of Compound A following a single oral dose of Compound A.

[0045] [Figure 3]FIG. 3 shows the linear (top) and semi-log (bottom) mean concentration-time plots of Compound A on day 18 after 13 days of oral administration of Compound A once daily ("QD").

[0046] [Figure 4] FIG. 4 shows a schematic of the final population pharmacokinetic (“PK”) model.

[0047] [Figure 5] Figure 5 shows a summary of the simulated scenario for the planned Phase 2 clinical study. The solid line represents the predicted median concentration. The dashed lines represent the 5%-95% prediction interval.

[0048] [Figure 6] FIG. 6 shows a study schematic of a randomized, double-blind, placebo-controlled, three-period crossover study followed by one open-label comparison period to evaluate the central nervous system ("CNS") pharmacodynamic ("PD") activity of Compound A in healthy subjects using transcranial magnetic stimulation ("TMS").

[0049] [Figure 7] 7 shows a plot of the change in peak-to-peak amplitude of motor evoked potentials ("MEPs") relative to baseline versus time. MEP peak-to-peak amplitudes were obtained using single-pulse TMS for placebo, 0.5 mg Compound A, and 6.0 mg Compound A.

[0050] [Figure 8] FIG. 8 is a schematic representation of the planned Phase 1b randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of adjunct Compound A in adult subjects with major depressive disorder. DETAILED DESCRIPTION OF THE INVENTION

[0051] Exemplary embodiment 1: Non-limiting embodiments of the present disclosure include: 1. A method for treating depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a salt thereof; administering to said patient a maintenance dose comprising Compound A or a salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: 2. The method of embodiment 1, wherein said depression is major depressive disorder. 3. The method of embodiment 1 or 2, wherein said depression is treatment-resistant depression. 4. The method of any one of embodiments 1 to 3, further treating cognitive impairment associated with depression. 5. The method of any one of embodiments 1 to 4, wherein the patient has already received at least one previous treatment for depression. 6. The method of embodiment 5, wherein said patient has failed to respond to at least one previous treatment for depression. 7. The method of embodiment 5 or embodiment 6, wherein the patient is a responder to at least one prior treatment for depression. 8. The method of any one of embodiments 5 to 7, wherein the previous treatment for depression comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 9. The method of any one of embodiments 5 to 8, wherein the at least one previous treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 10. The method of any one of embodiments 1 to 9, wherein the maintenance dose is administered about 12 hours or more after the first dose. 11. The method of any one of embodiments 1 to 10, wherein the first dose comprises about 5 mg to about 9 mg of Compound A. 12. The method of any one of embodiments 1 to 11, wherein the maintenance dose comprises about 0.5 mg to about 4 mg of Compound A once daily. 13. The first dose achieves a mean C of at least about 6 ng / mL in the patient. max 13. The method of any one of embodiments 1 to 12, wherein the method is effective to achieve: 14. The first dose has a mean C of about 100 ng / mL or less in the patient. max 14. The method of any one of embodiments 1 to 13, wherein the method is effective to achieve: 15. The maintenance dose provides a mean C of about 130 ng / mL or less at steady state in the patient. max 15. The method of any one of embodiments 1 to 14, wherein the method is effective to achieve: 16. The first dose provides a mean C of 6 ng / mL to about 100 ng / mL in the patient. max 16. The method of any one of embodiments 1 to 15, wherein the method is effective to achieve: 17. The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max 17. The method of any one of embodiments 1 to 16, wherein the method is effective to achieve: 18. The at least one maintenance dose has a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient. max 18. The method of any one of embodiments 1 to 17, wherein the method is effective to achieve: 19. Mean AUC at steady state in the patient τ 19. The method of any one of embodiments 1 to 18, wherein the IL-10 is about 2600 ng·h / mL or less. 20. Mean AUC at steady state in the patient τ20. The method of any one of embodiments 1 to 19, wherein the IL-10 is from about 700 ng·h / mL to about 2600 ng·h / mL. 21. The mean AUC at steady state in the patient τ 21. The method of any one of embodiments 1 to 20, wherein the IL-10 is about 75% to about 130% of 1487 ng·h / mL. 22. Mean AUC of the patient ∞ 22. The method of any one of embodiments 1 to 21, wherein the IL-10 ... 23. The method of any one of embodiments 1 to 22, wherein the first dose is administered orally. 24. The method of any one of embodiments 1 to 23, wherein the at least one maintenance dose is administered orally. 25. The method of any one of embodiments 1 to 24, wherein the first dose comprises about 6 mg of compound A. 26. The method of any one of embodiments 1 to 25, wherein the maintenance dose comprises about 3 mg of Compound A once daily. 27. The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max is effective in achieving The at least one maintenance dose is administered to a subject in need thereof, wherein the subject has a mean Cmax of 130 ng / mL or less at steady state after the at least one maintenance dose. max , and a mean AUC of 2600 ng·h / mL or less at steady state in said patient τ 27. The method of any one of embodiments 1 to 26, wherein the method is effective to achieve: 28. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max is effective in achieving the at least one maintenance dose is administered to a subject in need of a steroid drug, the subject receiving the at least one maintenance dose having a mean C of about 75% to about 130% of 78 ng / mL at steady state in the subject after the at least one maintenance dose; max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ28. The method of any one of embodiments 1 to 27, wherein the method is effective to achieve: 29. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving the at least one maintenance dose is administered to a subject in need of a steroid drug, the subject receiving the at least one maintenance dose having a mean C of about 75% to about 130% of 78 ng / mL at steady state in the subject after the at least one maintenance dose; max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 29. The method of any one of embodiments 1 to 28, wherein the method is effective to achieve: 30. A method for preventing recurrence of depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a salt thereof; administering to said patient a maintenance dose comprising Compound A or a salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: 31. The method of embodiment 30, wherein the depression is major depressive disorder. 32. The method of embodiment 30 or embodiment 31, wherein the depression is treatment-resistant depression. 33. The method of any one of embodiments 30 to 32, further treating and / or preventing cognitive impairment associated with depression. 34. The method of any one of embodiments 30 to 33, wherein the patient has already received at least one previous treatment for depression. 35. The method of embodiment 34, wherein the patient has failed to respond to at least one previous treatment for depression. 36. The method of embodiment 34 or embodiment 35, wherein the patient is a responder to at least one previous treatment for depression. 37. The method of any one of embodiments 34 to 36, wherein the at least one previous treatment for depression comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 38. The method of any one of embodiments 34 to 37, wherein the previous treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 39. The method of any one of embodiments 30 to 38, wherein the maintenance dose is administered about 12 hours or more after the first dose. 40. The method of any one of embodiments 30 to 39, wherein the first dose comprises about 5 mg to 9 mg of Compound A. 41. The method of any one of embodiments 30 to 40, wherein the maintenance dose comprises about 0.5 mg to about 4 mg of Compound A once daily. 42. The first dose has a mean C of about 6 ng / mL or greater in the patient. max 42. The method of any one of embodiments 30 to 41, wherein the method is effective to achieve: 43. The first dose results in a mean C of 100 ng / mL or less in the patient. max 43. The method of any one of embodiments 30 to 42, wherein the method is effective to achieve: 44. The maintenance dose provides a mean C of about 130 ng / mL or less at steady state in the patient. max 44. The method of any one of embodiments 30 to 43, wherein the method is effective to achieve: 45. The first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max 45. The method of any one of embodiments 30 to 44, wherein the method is effective to achieve: 46. ​​The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max 46. ​​The method of any one of embodiments 30 to 45, wherein the method is effective to achieve: 47. The patient's mean C at steady state max 47. The method of any one of embodiments 30 to 46, wherein the IL-10 is about 75% to about 130% of 78 ng / mL. 48. Mean AUC at steady state in the patient τ 48. The method of any one of embodiments 30 to 47, wherein the IL-10 is about 2600 ng·h / mL or less. 49. Mean AUC at steady state in the patient τ The method of any one of embodiments 30 to 48, wherein the IL-10 is from about 700 ng·h / mL to about 2600 ng·h / mL. 50. The mean AUC at steady state in the patient τ 50. The method of any one of embodiments 30 to 49, wherein the IL-10 is about 75% to about 130% of 1487 ng·h / mL. 51. Mean AUC of the patient ∞ The method of any one of embodiments 30 to 50, wherein the IL-10 is about 75% to about 130% of 2328 ng·h / mL. 52. The method of any one of embodiments 30 to 51, wherein the first dose is administered orally. 53. The method of any one of embodiments 30 to 52, wherein said at least one daily maintenance dose is administered orally. 54. The method of any one of embodiments 30 to 53, wherein the first dose comprises about 6 mg of compound A. 55. The method of any one of embodiments 30 to 54, wherein the maintenance dose comprises about 3 mg of Compound A once daily. 56. The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. maxis effective in achieving The at least one maintenance dose is administered to the patient at steady state to achieve a mean C of 130 ng / mL or less. max , and a mean AUC of 2600 ng·h / mL or less at steady state in said patient τ 56. The method of any one of embodiments 30 to 55, wherein the method is effective to achieve: 57. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max is effective in achieving the at least one maintenance dose is administered to a subject in need of a steroid drug, the subject receiving the at least one maintenance dose having a mean C of about 75% to about 130% of 78 ng / mL at steady state in the subject after the at least one maintenance dose; max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 57. The method of any one of embodiments 30 to 56, wherein the method is effective to achieve: 58. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving the at least one maintenance dose is administered to a subject in need of a steroid drug, the subject receiving the at least one maintenance dose having a mean C of about 75% to about 130% of 78 ng / mL at steady state in the subject after the at least one maintenance dose; max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 58. The method of any one of embodiments 30 to 57, wherein the method is effective to achieve: Exemplary embodiment 2:

[0052] Non-limiting embodiments / items of the present disclosure include: 1. A method for treating depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof; administering to said patient at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: 2. The method of item 1, wherein the depression is major depressive disorder. 3. The method of item 1 or 2, wherein the depression is treatment-resistant depression. 4. The method of any one of items 1 to 3, wherein treating depression comprises treating a cognitive impairment associated with said depression. 5. The method of any one of items 1 to 4, wherein the patient has already received at least one previous treatment for depression. 6. The method of item 5, wherein the patient has not responded to at least one previous treatment for depression. 7. The method of item 5 or 6, wherein the patient is a responder to at least one previous treatment for depression. 8. The method of any one of items 5 to 7, wherein the at least one previous treatment for depression comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2-diastereomeric hydroxyketamine or a salt thereof; 6-diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 9. The method of any one of items 5 to 8, wherein the at least one previous treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 10. The method of any one of items 1 to 9, wherein the at least one daily maintenance dose is administered about 12 hours or more after the first dose. 11. The method of any one of items 1 to 10, wherein the first dose comprises about 5 mg to about 9 mg of Compound A or a pharmaceutically acceptable salt thereof. 12. The method of any one of items 1 to 11, wherein the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. 13. The first dose achieves a mean C of at least about 6 ng / mL in the patient. max 13. The method according to any one of items 1 to 12, which is effective to achieve 14. The first dose has a mean C of about 100 ng / mL or less in the patient. max 14. The method according to any one of items 1 to 13, which is effective to achieve 15. The at least one daily maintenance dose provides the patient with a mean C of about 130 ng / mL or less at steady state. max 15. The method according to any one of items 1 to 14, which is effective to achieve 16. The first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max 16. The method according to any one of items 1 to 15, which is effective to achieve 17. The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max 17. The method according to any one of items 1 to 16, which is effective to achieve 18. The at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient. max 18. The method according to any one of items 1 to 17, which is effective to achieve 19. Mean AUC at steady state in the patient τ 19. The method of any one of items 1 to 18, wherein the IL-10 is about 2600 ng·h / mL or less. 20. Mean AUC at steady state in the patient τ 20. The method according to any one of items 1 to 19, wherein the IL-10 is about 700 ng·h / mL to about 2600 ng·h / mL. 21. The mean AUC at steady state in the patient τ 21. The method according to any one of items 1 to 20, wherein the IL-10 is about 75% to about 130% of 1487 ng·h / mL. 22. Mean AUC of the patient ∞ 22. The method according to any one of items 1 to 21, wherein the IL-10 is about 75% to about 130% of 2328 ng·h / mL. 23. The method of any one of items 1 to 22, wherein the first dose is administered orally. 24. The method of any one of items 1 to 23, wherein the at least one daily maintenance dose is administered orally. 25. The method of any one of items 1 to 24, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. 26. The method of any one of items 1 to 25, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. 27. The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max is effective in achieving and wherein the at least one daily maintenance dose is administered to the patient at steady state after the at least one daily maintenance dose, and the patient has a mean C of about 130 ng / mL or less at steady state after the at least one daily maintenance dose. max and a mean AUC of about 2600 ng·h / mL or less at steady state in said patient. τ 27. The method according to any one of items 1 to 26, which is effective to achieve 28. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 28. The method according to any one of items 1 to 27, which is effective to achieve 29. The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 29. The method according to any one of items 1 to 28, which is effective to achieve 30. A method for preventing recurrence of depression in a patient, comprising: administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof; administering to said patient at least one daily maintenance dose comprising Compound A or a salt thereof, said at least one daily maintenance dose being less than said first dose; A method comprising: 31. The method according to item 30, wherein the depression is major depressive disorder. 32. The method of item 30 or 31, wherein the depression is treatment-resistant depression. 33. The method according to any one of items 30 to 32, further comprising treating and / or preventing cognitive impairment associated with depression in said patient. 34. The method according to any one of items 30 to 33, wherein the patient has already received at least one previous treatment for depression. 35. The method of item 34, wherein the patient has not responded to at least one previous treatment for depression. 36. The method of item 34 or 35, wherein the patient is a responder to at least one previous treatment for depression. 37. The method of any one of items 34 to 36, wherein the at least one previous treatment for depression comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2-diastereomeric hydroxyketamine or a salt thereof; 6-diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 38. The method of any one of items 34 to 37, wherein the at least one previous treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. 39. The method of any one of items 30 to 38, wherein the at least one daily maintenance dose is administered about 12 hours or more after the first dose. 40. The method of any one of items 30 to 39, wherein the first dose comprises about 5 mg to about 9 mg of Compound A or a pharmaceutically acceptable salt thereof. 41. The method of any one of items 30 to 40, wherein the at least one daily maintenance dose comprises about 0.5 mg to about 4 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. 42. The first dose has a mean C of about 6 ng / mL or greater in the patient. max 42. The method according to any one of items 30 to 41, which is effective to achieve 43. The first dose has a mean C of about 100 ng / mL or less in the patient. max 43. The method according to any one of items 30 to 42, which is effective to achieve 44. The at least one daily maintenance dose provides the patient with a mean C of about 130 ng / mL or less at steady state. max 44. The method according to any one of items 30 to 43, which is effective to achieve 45. The first dose provides a mean C of about 6 ng / mL to about 100 ng / mL in the patient. max 45. The method according to any one of items 30 to 44, which is effective to achieve 46. ​​The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max 46. ​​The method according to any one of items 30 to 45, which is effective to achieve 47. The patient's mean C at steady state max 47. The method according to any one of items 30 to 46, wherein the IL-10 concentration is about 75% to about 130% of 78 ng / mL. 48. Mean AUC at steady state in the patient τ 48. The method according to any one of items 30 to 47, wherein the IL-10 is about 2600 ng·h / mL or less. 49. Mean AUC at steady state in the patient τ 49. The method according to any one of items 30 to 48, wherein the IL-10 is about 700 ng·h / mL to about 2600 ng·h / mL. 50. The mean AUC at steady state in the patient τ is about 75% to about 130% of 1487 ng·h / mL. 51. Mean AUC of the patient ∞ is about 75% to about 130% of 2328 ng·h / mL. 52. The method of any one of items 30 to 51, wherein the first dose is administered orally. 53. The method of any one of items 30 to 52, wherein the at least one daily maintenance dose is administered orally. 54. The method of any one of items 30 to 53, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. 55. The method of any one of items 30 to 54, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. 56. The first dose provides a mean C of about 40 to about 100 ng / mL in the patient. max is effective in achieving The at least one daily maintenance dose provides the patient with a mean Cmax of about 130 ng / mL or less at steady state. max and a mean AUC of about 2600 ng·h / mL or less at steady state in said patient. τ 56. The method according to any one of items 30 to 55, which is effective to achieve 57. The first dose achieves a mean C of about 75% to about 130% of about 42 ng / mL in the patient. max is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 57. The method according to any one of items 30 to 56, which is effective to achieve 58. The first dose achieves a mean C of about 75% to about 130% of 42 ng / mL in the patient. max and a mean AUC of approximately 75% to approximately 130% of 2328 ng·h / mL in the patients. ∞ is effective in achieving and wherein the at least one daily maintenance dose provides a mean C of about 75% to about 130% of 78 ng / mL at steady state in the patient after the at least one daily maintenance dose. max , and a mean AUC of about 75% to about 130% of 1487 ng·h / mL at steady state in said patient. τ 58. The method according to any one of items 30 to 57, which is effective to achieve 59. The method of any one of items 1 to 58, wherein the first dose comprises compound A. 60. The method according to any one of items 1 to 59, wherein the at least one daily maintenance dose comprises Compound A. 61. The method of any one of items 1 to 60, wherein the patient is between 18 and 55 years old. 62. The method of any one of items 1 to 61, wherein the patient is between 20 and 49 years old. 63. The method of any one of items 1 to 29, wherein treating depression comprises improving symptoms of depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). 64. The method of any one of items 1 to 29 and 63, wherein treating depression comprises reducing MDD severity as measured by the Clinical Global Impression-Severity Scale (CGI-S). 65. The method of any one of items 1 to 29, 63 and 64, wherein treating depression comprises treating MDD as measured by the Clinical Global Impression-Severity Scale (CGI-S). 66. The method of any one of items 1 to 29 and 63 to 65, wherein treating depression comprises improving quality of life as measured by the 5 Level EuroQol-5 Dimension. 67. The method of any one of items 1 to 29 and 63 to 66, wherein the patient is receiving stable pharmacological treatment for depression. 68. The method of any one of items 1 to 29 and 63 to 67, wherein the patient is receiving stable pharmacological treatment for depression, defined as a ≦50% change in dose during the 6 weeks prior to randomization. 69. The method of any one of items 63 to 68, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof, and the at least one daily maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof. 70. The method of any one of items 63 to 69, wherein the first dose comprises about 6 mg of Compound A and the at least one daily maintenance dose comprises about 3 mg of Compound A. 71. The method of any one of items 63 to 68, wherein the first dose comprises about 6 mg of Compound A or a pharmaceutically acceptable salt thereof. 72. The method according to any one of items 63 to 68, wherein the maintenance dose comprises about 3 mg of Compound A or a pharmaceutically acceptable salt thereof once a day. 73. A pharmaceutical composition for use in the treatment of depression, comprising: a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof; and at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, wherein said at least one daily maintenance dose is less than said first dose; A pharmaceutical composition comprising: 74. A pharmaceutical composition for use in the treatment of depression, comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, administered in a first dose and at least one daily maintenance dose, wherein the at least one daily maintenance dose is less than the first dose. 75. Use of a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, and at least one daily maintenance dose comprising Compound A, or a salt thereof, for treating depression, wherein the at least one daily maintenance dose is less than the first dose. 76. A pharmaceutical composition for use in preventing the recurrence of depression, comprising: a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof; and at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof, wherein said at least one daily maintenance dose is less than said first dose; A pharmaceutical composition comprising: 77. A pharmaceutical composition for use in preventing the recurrence of depression, comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A"), or a pharmaceutically acceptable salt thereof, administered in a first dose and at least one daily maintenance dose, wherein the at least one daily maintenance dose is less than the first dose. 78. Use of a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A") or a pharmaceutically acceptable salt thereof, and at least one daily maintenance dose comprising Compound A or a salt thereof, for preventing recurrence of depression, wherein the at least one daily maintenance dose is less than the first dose. Definition:

[0053] Unless otherwise defined herein, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. The following references provide those of ordinary skill in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (ed. Walker, 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991); The American Psychiatric Association's fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); FDA Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA (2013). As used herein, the following terms have the meanings set forth below unless otherwise specified. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the disclosure.

[0054] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. "A," "one or more," and "at least one" are used interchangeably herein.

[0055] As used herein, the term "about" or "approximately" means within an acceptable error range of a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 standard deviations or more than 3 standard deviations, according to the practice in the art. Alternatively, "about" can mean within a range of up to 20%, for example, up to 10%, for example, up to 5%, for example, up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, this term can mean within one order of magnitude of a value, for example, within 5 times, for example, within 2 times.

[0056] As used herein, the term "administration" of an agent to a subject includes any route of introducing or delivering an agent to a subject to perform its intended function. Administration can be by any suitable parenteral route, including, but not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes described herein. Administration includes self-administration and administration by another.

[0057] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of Compound A or its salt (e.g., its pharmaceutically acceptable salt) that is sufficient to achieve the desired effect or desired therapeutic effect.In the context of therapeutic application, the amount of Compound A or its salt (e.g., its pharmaceutically acceptable salt) administered to a subject may depend on the type and severity of depression or symptoms and individual characteristics, such as general health, age, sex, weight and tolerance to drugs.Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors.

[0058] In some embodiments, the amount expressed as "mg of [X]", where [X] is an active agent, refers to the total amount in milligrams of [X] calculated based on the free base of [X]. When [X] is a pharmaceutically acceptable salt, there may be one or more equivalent amounts of pharmaceutically acceptable salt of [X] based on the weight of the free base therein.

[0059] As used herein, the term "modulate" means to alter, either positively or negatively. Exemplary modulations include a change of about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100%.

[0060] As used herein, the term "increase" refers to a positive change of at least about 5%, including, but not limited to, a positive change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0061] As used herein, the term "reduce" refers to a negative change of at least about 5%, including, but not limited to, a negative change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0062] As used herein, a "responder" to a previous treatment for depression refers to a patient who has demonstrated improvement in depressive symptoms from baseline (before administration of the treatment) to a time point during or after treatment. For example, a responder may be selected using clinical judgment or a depression rating scale (e.g., the Montgomery-Asberg Depression Rating Scale ("MADRS"), the Hamilton Depression Rating Scale ("HAM-D")). For example, a "ketamine responder" to a previous treatment for depression refers to a subject who, based on the MADRS or HAM-D or clinical observations by a treating physician, demonstrates greater than about 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement in depressive symptoms from pre-ketamine-like compound baseline to Day 1 during or after one or more administrations of a ketamine-like compound.

[0063] As used herein, the patient "has not responded to at least one previous treatment for depression" refers to the subject who has not responded to at least one previous treatment for depression at all, or who has responded to at least one previous treatment for depression but has subsequently relapsed.For example, the patient "has not responded to at least one previous treatment for depression" refers to the subject who has shown less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% improvement in the symptoms of depression from baseline (before treatment administration) to a certain point during or after treatment.For example, the patient who has not responded to at least one previous treatment for depression is selected using clinical judgment or depression rating scale (e.g., MADRS, HAM-D). For example, a patient who has "failed to respond to at least one prior treatment for depression" refers to a subject who, based on the MADRS or HAM-D or clinical findings by a treating physician, shows, for example, less than about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement in symptoms of depression from pre-ketamine-like compound administration baseline to Day 1 during or after one or more administrations of a ketamine-like compound. The terms "patient" and "subject" are used interchangeably herein.

[0064] Detailed Description In one aspect, the disclosure relates to a method of treating depression in a patient, the method comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A") or a salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof. In some embodiments, the disclosure relates to a method of treating depression in a patient, the method comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A") or a pharmaceutically acceptable salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a pharmaceutically acceptable salt thereof.

[0065] 9-[4-(Cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A") or a salt thereof is a potent and selective positive allosteric modulator ("PAM") of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ("AMPA") receptor. The synthesis and characterization of Compound A or a salt thereof can proceed according to the procedures disclosed in U.S. Pat. No. 8,575,154, the entire contents of which are incorporated herein by reference. [ka]

[0066] Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ("AMPA") receptors are ubiquitously expressed throughout the central nervous system ("CNS") and play a central role in numerous higher-order neurophysiological processes, including attention, learning, memory, and other cognitive functions. Therefore, AMPA receptors are attractive as potential therapeutic targets for the rapid development of antidepressant activity in patients who do not respond to classical antidepressants. 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide ("Compound A" or "CMPD A") or its salts are potent and selective positive allosteric modulators (PAMs) of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

[0067] In some embodiments, a salt of Compound A (e.g., a pharmaceutically acceptable salt of Compound A) or a previous treatment for depression, a pharmaceutically acceptable salt, etc. is used. In some embodiments, a salt of Compound A or a previous treatment for depression, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. is used. In some embodiments, salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. In some embodiments, salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. In some embodiments, salts with inorganic acids include salts with hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. In some embodiments, salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. In some embodiments, salts with basic amino acids include salts with arginine, lysine, ornithine, etc. In some embodiments, salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. In some embodiments, when a compound has an acidic functional group, an inorganic salt, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt, etc.), an ammonium salt, etc., is used. In some embodiments, when a compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, are used.

[0068] How to treat depression In one aspect, the disclosure relates to a method of treating depression in a patient.

[0069] In one aspect, the present disclosure relates to a method of treating major mood dysregulation disorder, major depressive disorder, persistent depressive disorder dysthymia, premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, depressive disorder not otherwise specified, moderate depression, severe depression, and / or specific factors of a depressive disorder in a patient. In some embodiments, the depression is major depressive disorder ("MDD"). In some embodiments, the depression is treatment-resistant depression ("TRD"). In some embodiments, the TRD is MDD associated with failure of at least two prior antidepressant treatments and prior confirmation of adequate dosage and duration. In some embodiments, the method further treats cognitive impairment associated with depression. In some embodiments, the method treats and / or prevents cognitive impairment, including declines in processing speed, executive function, attention, or verbal learning and memory, associated with depression. In some embodiments, the disclosure relates to a method of treating and / or preventing recurrence of depression.

[0070] In some embodiments, the patient has already received at least one previous treatment for depression. In some embodiments, the patient has not responded to at least one previous treatment for depression. In some embodiments, the patient is a responder to at least one previous treatment for depression.

[0071] In some embodiments, depression is diagnosed and / or patient subpopulations are selected by at least one diagnostic and / or prognostic test. In some embodiments, the diagnostic and / or prognostic test includes a genomic test, a combinatorial pharmacogenetic test, a proteome / metabolome test, a systematic biological pathway test, a computer-adaptive diagnostic test, a machine learning test, an EEG test, a magnetic resonance imaging (MRI) test, a positron emission tomography (PET) test, a magnetoencephalography (MEG) test, a TMS test, and / or a dexamethasone suppression test. In some embodiments, genomic testing includes CYP1A2, CYP2C19, CYP2D6, SLC6A4, HTR2A, CYP2B6, CYP2C9, CYP3A4, CYP2E1, CYP1A1, CYP1A1*1A, CYP1A1*2, CYP1A1*3, CYP1A1*4, CYP1A2*1A, CYP1A2*3, CYP2C19*1A, CYP2C19*1B, CYP2C19*2A, CYP2D6*1A, CYP2D6*2, CYP2D6*2N, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*12, CYP In some embodiments, the proteome / metabolome testing includes providing a patient's genotype, including 2D6*17, SLC6A4, UGT1A4, UGT2B15, SLC6A4, HTR2A, HLA-A*3101, HLA-B*1502, IL-1, IL-6, and / or TNF. In some embodiments, the proteome / metabolome testing includes providing a patient's proteome / metabolome type, including BDNF, IL-1, IL-6, and / or TNF. In some embodiments, the MRI testing is performed by fMRI, sMRI, and / or DTI. In some embodiments, the TMS testing is performed by TMS and / or rTMS. In some embodiments, the machine learning testing analyzes data generated from genomic testing, proteome / metabolome testing, systematic biological pathway testing, computer-adaptive diagnostic testing, EEG testing, MRI testing, PET testing, MEG testing, TSM testing, dexamethasone suppression testing, sensing devices, and / or mobile devices.

[0072] In some embodiments, the previous treatment for depression comprises the administration of ketamine or a ketamine-like compound (e.g., a ketamine-like compound). In some embodiments, the previous treatment for depression comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2-diastereomeric hydroxyketamine or a salt thereof; 6-diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the previous treatment for depression comprises the administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the previous treatment for depression includes administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; or a combination thereof.

[0073] In some embodiments, the previous treatment for depression may include benzodiazepines (such as chlordiazepoxide or a salt thereof, diazepam or a salt thereof, clorazepate potassium or a salt thereof, lorazepam or a salt thereof, clonazepam or a salt thereof, alprazolam or a salt thereof, etc.); L-type calcium channel inhibitors (such as pregabalin or a salt thereof); tricyclic or tetracyclic antidepressants (such as imipramine or a salt thereof, amitriptyline or a salt thereof, desipramine or a salt thereof, clomipramine or a salt thereof, etc.); selective serotonin inhibitors (such as benzodiazepines, chlordiazepoxide or a salt thereof, diazepam or a salt thereof, clorazepate potassium or a salt thereof, lorazepam or a salt thereof, clonazepam or a salt thereof, alprazolam or a salt thereof, etc.); Serotonin-noradrenaline reuptake inhibitors (such as fluvoxamine or its salt, fluoxetine or its salt, citalopram or its salt, sertraline or its salt, paroxetine or its salt, or escitalopram or its salt); serotonin-noradrenaline reuptake inhibitors (such as venlafaxine or its salt, duloxetine or its salt, or desvenlafaxine or its salt); noradrenaline reuptake inhibitors (such as reboxetine or its salt); noradrenaline-dopamine reuptake inhibitors (such as bupropion or its salt). ); mirtazapine or its salt; trazodone or its salt; nefazodone or its salt; bupropion or its salt; setiptiline or its salt; 5-HT1A agonists (buspirone or its salt, tandospirone or its salt, osemozotan or its salt, etc.); 5-HT3 antagonists (cyamemazine or its salt, etc.); non-selective cardiac inhibitors (propranolol or its salt, oxprenolol or its salt, etc.); histamine H1 antagonists (hydroxyzine or its salt); antipsychotics (chlorpromazine, etc.) Romatine or its salt, haloperidol or its salt, sulpiride or its salt, clozapine or its salt, trifluperazine or its salt, fluphenazine or its salt, olanzapine or its salt, quetiapine or its salt, risperidone or its salt, aripiprazole or its salt, etc.); CRF antagonists; other anxiolytics (meprobamate or its salt, etc.), psilocybin or its salt; lysergic acid diethylamide or its salt; mescaline or its salt; N,N-dimethyltryptamine or its salt;Brexanolone or its salt; Duranolone or its salt; Lapastinel or its salt; Dextromethorphan or its salt; Dextromethadone or its salt; Pimavanserin or its salt; Celtrexant or its salt; L-4-chlorokynurenine or its salt; 2-[(4R)-5-[2-chloro-3-(trifluoromethyl)benzoyl]-4-methyl-1H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-c]piperidin The method includes administration of [lysin-1-yl]-5-fluoropyrimidine or a salt thereof; 3β-methoxypregnenolone or a salt thereof; aticaplant or a salt thereof; cariprazine or a salt thereof; N-(4-chloropyridin-3-yl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazine-1-carboxamide or a salt thereof; chlorokynurenine or a salt thereof; sirukumab or a salt thereof; or a combination thereof.

[0074] In some embodiments, the patient is receiving stable pharmacological treatment for depression, hi some embodiments, the patient is receiving stable pharmacological treatment for depression, defined as a ≦50% change in dose during the 6 weeks prior to randomization.

[0075] In some embodiments, the patient is between 18 and 65 years old. In some embodiments, the patient is between 18 and 55 years old. In some embodiments, the patient is between 20 and 49 years old.

[0076] In some embodiments, the disclosure relates to a method of treating depression in a patient, comprising administering to the patient a first dose comprising 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (“Compound A” or “CMPD A”) or a salt thereof, and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof, wherein the maintenance dose is less than the first dose.

[0077] In some embodiments, the methods of the present disclosure relate to methods for treating depression in a patient (e.g., a human patient) and treating and / or preventing recurrence of depression while reducing the incidence and / or severity of at least one potential adverse event of Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In some embodiments, the methods of the present disclosure also relate to reducing the incidence and / or severity of at least one potential adverse event of Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) in treating depression and / or preventing recurrence of depression in a patient, comprising administering to the patient a first dose comprising Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) and administering to the patient at least one daily maintenance dose comprising Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein the maintenance dose is less than the first dose. In some embodiments, the at least one potential adverse event is neurotoxicity. In some embodiments, the at least one potential adverse event is selected from convulsions, tonic convulsions, seizures, stroke, catalepsy, partial seizures, epilepsy, myoclonic seizures, hypoactivity, weakness, incoordination, salivation, sedation, nystagmus, muscle twitching, tremor, ataxia, vomiting, yawning, and combinations thereof.

[0078] In some embodiments, treating depression comprises improving symptoms of depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, treating depression comprises reducing MDD severity as measured by the Clinical Global Impression-Severity Scale (CGI-S). In some embodiments, treating depression comprises treating MDD as measured by the Clinical Global Impression-Severity Scale (CGI-S). In some embodiments, treating depression comprises improving quality of life as measured by the 5 Level EuroQol-5 Dimension.

[0079] In some embodiments, Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) is used in combination with or in adjunctive combination with a therapeutically effective amount of one or more other active ingredients. In some embodiments, Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) (e.g., Compound A) is used in combination with or in adjunctive combination with a therapeutically effective amount of one or more other previous treatments for depression. In some embodiments, the administration time of Compound A in combination with or in adjunctive combination with one or more other active ingredients is not limited, and Compound A or a pharmaceutical composition thereof and one or more other active ingredients or pharmaceutical compositions thereof are administered to a subject (e.g., a human patient) at the same time or at different times. First dose

[0080] In some embodiments, the first dose is at least about 1 ng / mL, at least about 2 ng / mL, at least about 3 ng / mL, at least about 4 ng / mL, at least about 5 ng / mL, at least about 6 ng / mL, at least about 7 ng / mL, at least about 8 ng / mL, at least about 9 ng / mL, at least about 10 ng / mL, at least about 11 ng / mL, at least about 12 ng / mL, at least about 13 ng / mL, at least about 14 ng / mL, at least about 15 ng / mL, at least about 16 ng / mL, at least about 17 ng / mL , at least about 18 ng / mL, at least about 19 ng / mL, at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, at least about 30 ng / mL, at least about 31 ng / mL, at least about 32 ng / mL, at least about 33 ng / mL, at least about 34 ng / mL, at least about 35 ng / mL mL, at least about 36 ng / mL, at least about 37 ng / mL, at least about 38 ng / mL, at least about 39 ng / mL, at least about 40 ng / mL, at least about 41 ng / mL, at least about 42 ng / mL, at least about 43 ng / mL, at least about 44 ng / mL, at least about 45 ng / mL, at least about 46 ng / mL, at least about 47 ng / mL, at least about 48 ng / mL, at least about 49 ng / mL, at least about 50 ng / mL, at least about 51 ng / mL, at least about 52 ng / mL, at least about 53 ng / mL, g / mL, at least about 54 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL,a mean C of Compound A in the patient of at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, at least about 160 ng / mL, at least about 165 ng / mL, at least about 170 ng / mL, at least about 175 ng / mL, at least about 180 ng / mL, at least about 185 ng / mL, at least about 190 ng / mL, at least about 195 ng / mL, at least about 200 ng / mL, or any range or value therebetween; max It is effective in achieving this.

[0081] In some embodiments, the first dose is about 200 ng / mL or less, about 195 ng / mL or less, about 190 ng / mL or less, about 185 ng / mL or less, about 180 ng / mL or less, about 175 ng / mL or less, about 170 ng / mL or less, about 165 ng / mL or less, about 160 ng / mL or less, about 155 ng / mL or less, about 150 ng / mL or less, about 145 ng / mL or less, about 140 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 125 ng / mL or less, about 14 ...5 ng / mL or less, about 140 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 125 ng / mL or less, about 145 ng / mL or less, about 140 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 125 ng / mL or less, about 145 ng / mL or less, about 140 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less ng / mL or less, approximately 120ng / mL or less, approximately 115ng / mL or less, approximately 110ng / mL or less, approximately 105ng / mL or less, approximately 100ng / mL or less, approximately 95ng / mL or less, approximately 90ng / mL or less, approximately 85ng / mL or less, approximately 80ng / mL or less, about 75ng / mL or less, about 70ng / mL or less, about 65ng / mL or less, about 60ng / mL or less, about 59ng / mL or less, about 58ng / mL or less, about 57ng / mL or less, about 56ng / mL or less, about 55ng / mL or less, about 54ng / mL or less, about 53ng / mL or less, about 52ng / mL or less, about 51ng / mL or less, about 50ng / mL or less, about 49ng / mL or less, about 48ng / mL or less, about 47ng / mL or less, about 46ng / mL Below, about 45ng / mL or less, about 44ng / mL or less, about 43ng / mL or less, about 42ng / mL or less, about 41ng / mL or less, about 40ng / mL or less, about 39ng / mL or less, about 38ng / mL or less, about 37ng / mL or less, about The mean C of Compound A in patients with 36 ng / mL or less, about 35 ng / mL or less, about 34 ng / mL or less, about 33 ng / mL or less, about 32 ng / mL or less, about 31 ng / mL or less, about 30 ng / mL or less, about 29 ng / mL or less, about 28 ng / mL or less, about 27 ng / mL or less, about 26 ng / mL or less, about 25 ng / mL or less, about 20 ng / mL or less, about 15 ng / mL or less, about 10 ng / mL or less, about 5 ng / mL or less, or any range or value therebetween max It is effective in achieving this.

[0082] In some embodiments, the first dose is about 1 ng / mL to about 200 ng / mL, about 1 ng / mL to about 190 ng / mL, about 1 ng / mL to about 180 ng / mL, about 1 ng / mL to about 170 ng / mL, about 1 ng / mL to about 160 ng / mL, about 1 ng / mL to about 150 ng / mL, about 1 ng / mL to about 140 ng / mL, about 1 ng / mL to about 130 ng / mL, about 1 ng / mL to about 125 ng / mL, about 1 ng / mL to about 120 ng / mL, about 1 ng / mL to about 115 ng / mL, about 1 ng / mL to about 110 ng / mL, The mean C of Compound A in patients of about 1 ng / mL to about 105 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 95 ng / mL, about 1 ng / mL to about 90 ng / mL, about 1 ng / mL to about 85 ng / mL, about 1 ng / mL to about 80 ng / mL, about 1 ng / mL to about 75 ng / mL, about 1 ng / mL to about 70 ng / mL, about 1 ng / mL to about 65 ng / mL, about 1 ng / mL to about 60 ng / mL, about 1 ng / mL to about 55 ng / mL, about 1 ng / mL to about 50 ng / mL, or any range or value therebetween max It is effective in achieving this.

[0083] In some embodiments, the first dose is about 1 ng / mL to about 200 ng / mL, about 2 ng / mL to about 200 ng / mL, about 3 ng / mL to about 200 ng / mL, about 4 ng / mL to about 200 ng / mL, about 5 ng / mL to about 200 ng / mL, about 6 ng / mL to about 200 ng / mL, about 7 ng / mL to about 200 ng / mL, about 8 ng / mL to about 200 ng / mL, about 9 ng / mL to about 200 ng / mL, about 10 ng / mL to about 200 ng / mL, about 15 ng / mL to about 200 ng / mL, about 20 ng / mL to about 200 ng / mL, or about 25 ng / mL to about 200ng / mL, about 30ng / mL to about 200ng / mL, about 35ng / mL to about 200ng / mL, about 40ng / mL to about 200ng / mL, about 45ng / mL to about 200ng / mL, about 50ng / mL to about 200ng / mL, about 55ng / mL to about 200ng / mL, about 60ng / mL to about 200ng / mL, about 65ng / mL to about 200ng / mL, about 70ng / mL to about 200ng / mL, about 75ng / mL to about 200ng / mL, about 80ng / mL to about 200ng / mL, or any range or value therebetween max It is effective in achieving this.

[0084] In some embodiments, the first dose is about 1 ng / mL to about 200 ng / mL, about 2 ng / mL to about 175 ng / mL, about 3 ng / mL to about 150 ng / mL, about 4 ng / mL to about 125 ng / mL, about 5 ng / mL to about 110 ng / mL, about 6 ng / mL to about 100 ng / mL, about 7 ng / mL to about 95 ng / mL, about 8 ng / mL to about 90 ng / mL, about 9 ng / mL to about 90 ng / mL, about 10 ng / mL to about 85 ng / mL, about 15 ng / mL to about 80 ng / mL, about 20 ng / mL to about 75 ng / mL, about 25 ng / mL to about 70 ng / mL, about 30 ng / mL to about 65 ng / mL, about 35 ng / mL to about 60 ng / mL, about 40 ng / mL to about 55 ng / mL, or about 60 ng / mL to about 75 ng / mL. ng / mL, or about 40ng / mL to about 50ng / mL, or about 40ng / mL to about 55ng / mL, or about 40ng / mL to about 60ng / mL, or about 40ng / mL to about 65ng / mL, or about 40ng / mL to about 70ng / mL, or about 40ng / mL to about 75ng / mL, or about 40ng / mL to about 80ng / mL, or about 40ng / mL to about 90ng / mL, about 40ng / mL to about 95ng / mL, about 40ng / mL to about 100ng / mL, about 40ng / mL to about 110ng / mL, about 40ng / mL to about 120ng / mL, or about 40ng / mL to about 130ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0085] In some embodiments, the first dose is at least about 5% of 42ng / mL, at least about 10% of 42ng / mL, at least about 15% of 42ng / mL, at least about 20% of 42ng / mL, at least about 25% of 42ng / mL, at least about 30% of 42ng / mL, at least about 35% of 42ng / mL, at least about 40% of 42ng / mL, at least about 45% of 42ng / mL, at least about 50% of 42ng / mL, at least about 55% of 42ng / mL, at least about 60% of 42ng / mL, at least about 65% of 42ng / mL, at least about 70% of 42ng / mL, at least about 75% of 42ng / mL, at least about 80% of 42ng / mL, at least about 85% of 42ng / mL, at least about 90% of 42ng / mL, at least about 95% of 42ng / mL, at least about 100% of 42ng / mL, at least about 110% of 42ng / mL, at least about 120% of 42ng / mL, at least about 130% of 42ng / mL, at least about 140% of 42ng / mL, at least about 150% of 42ng / mL, at least about 160% of 42ng / mL, at least about 170% of 42ng / mL, at least about 180% of 42ng / mL, at least about 190% of 42ng / mL, at least about 210% of 42ng / mL, at least about 220% of 42ng / mL, at least about 230% of 42ng / mL, at least about 240% of 4 a mean C of Compound A in patients of about 80%, at least about 85% of 42ng / mL, at least about 90% of 42ng / mL, at least about 95% of 42ng / mL, at least about 100% of 42ng / mL, at least about 105% of 42ng / mL, at least about 110% of 42ng / mL, at least about 115% of 42ng / mL, at least about 120% of 42ng / mL, at least about 125% of 42ng / mL, at least about 130% of 42ng / mL, at least about 135% of 42ng / mL, at least about 140% of 42ng / mL, at least about 145% of 42ng / mL, or at least about 150% of 42ng / mL, or any range or value therebetween max It is effective in achieving this.

[0086] In some embodiments, the first dose is about 150% or less of 42ng / mL, about 145% or less of 42ng / mL, about 140% or less of 42ng / mL, about 135% or less of 42ng / mL, about 130% or less of 42ng / mL, about 125% or less of 42ng / mL, about 120% or less of 42ng / mL, about 115% or less of 42ng / mL, about 110% or less of 42ng / mL, about 105% or less of 42ng / mL, about 100% or less of 42ng / mL, about 95% or less of 42ng / mL, about 90% or less of 42ng / mL, about 85% or less of 42ng / mL. % or less, about 80% or less of 42ng / mL, about 75% or less of 42ng / mL, about 70% or less of 42ng / mL, about 65% or less of 42ng / mL, about 60% or less of 42ng / mL, about 55% or less of 42ng / mL, about 50% or less of 42ng / mL, about 45% or less of 42ng / mL, about 40% or less of 42ng / mL, about 30% or less of 42ng / mL, about 20% or less of 42ng / mL, about 10% or less of 42ng / mL, about 5% or less of 42ng / mL, or less, or any range or value therebetween. max It is effective in achieving this.

[0087] In some embodiments, the first dose is about 40% to about 165% of 42 ng / mL, about 45% to about 160% of 42 ng / mL, about 50% to about 155% of 42 ng / mL, about 55% to about 150% of 42 ng / mL, about 60% to about 145% of 42 ng / mL, about 65% to about 140% of 42 ng / mL, about 70% to about 150% of 42 ng / mL, about 80% to about 165% of 42 ng / mL, about 85% to about 160% of 42 ng / mL, about 90% to about 170% of 42 ng / mL, about 95 ... 35%, about 75% to about 130% of 42ng / mL, about 80% to about 125% of 42ng / mL, about 85% to about 120% of 42ng / mL, about 90% to about 115% of 42ng / mL, about 95% to about 110% of 42ng / mL, about 100% to about 105% of 42ng / mL, about 50% to about 80% of 42ng / mL, about 50% to about 42ng / mL 90%, about 50% to about 100% of 42ng / mL, about 50% to about 110% of 42ng / mL, about 50% to about 120% of 42ng / mL, about 50% to about 125% of 42ng / mL, about 50% to about 130% of 42ng / mL, about 40% to about 100% of 42ng / mL, about 40% to about 105% of 42ng / mL, about 40% to about 105% of 42ng / mL 110%, about 40% to about 115% of 42 ng / mL, about 40% to about 120% of 42 ng / mL, about 40% to about 125% of 42 ng / mL, about 40% to about 130% of 42 ng / mL, about 40% to about 135% of 42 ng / mL, about 40% to about 140% of 42 ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0088] In some embodiments, the first dose is about 35% of 42ng / mL, about 40% of 42ng / mL, about 45% of 42ng / mL, about 50% of 42ng / mL, about 55% of 42ng / mL, about 60% of 42ng / mL, about 65% of 42ng / mL, about 70% of 42ng / mL, about 75% of 42ng / mL, about 80% of 42ng / mL, about 85% of 42ng / mL, about 90% of 42ng / mL, or about 95% of 42ng / mL. , about 100% of 42ng / mL, about 105% of 42ng / mL, about 110% of 42ng / mL, about 115% of 42ng / mL, about 120% of 42ng / mL, about 125% of 42ng / mL, about 130% of 42ng / mL, about 135% of 42ng / mL, about 140% of 42ng / mL, about 145% of 42ng / mL or about 150% of 42ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0089] In some embodiments, the first dose is about 3500 ng·h / mL or less, about 3450 ng·h / mL or less, about 3400 ng·h / mL or less, about 3350 ng·h / mL or less, about 3300 ng·h / mL or less, about 3250 ng·h / mL or less, about 3150 ng·h / mL or less, about 3100 ng·h / mL or less, about 3050 ng·h / mL or less, about 3000 ng·h / mL or less, about 2950 ng·h / mL or less, about 2900 ng·h / mL or less, about 2850 ng·h / mL or less, about 2800 ng·h / mL or less, about 2750 ng·h / mL or less, about 2700 ng·h / mL or less, about 2650 ng·h / mL or less, about 2600 ng·h / mL or less, about 2550 ng·h / mL or less, about 2500 ng·h / mL or less The mean AUC of Compound A in patients with ∞ It is effective in achieving this.

[0090] In some embodiments, the first dose is at least about 300 ng·h / mL, at least about 350 ng·h / mL, at least about 400 ng·h / mL, at least about 450 ng·h / mL, at least about 500 ng·h / mL, at least about 550 ng·h / mL, at least about 600 ng·h / mL, at least about 650 ng·h / mL, at least about 700 ng·h / mL, at least about 750 ng·h / mL, at least about 800 ng·h / mL, at least about 850 ng·h / mL, at least about 900ng·h / mL, at least about 950ng·h / mL, at least about 1000ng·h / mL, at least about 1050ng·h / mL, at least about 1100ng·h / mL, at least about 1150ng·h / mL, at least about 1200ng·h / mL, at least about 1250ng·h / mL, at least about 1300ng·h / mL, at least about 1350ng·h / mL, at least about 1400ng·h / mL, at least about 1450ng·h / mL, at least Also about 1500ng·h / mL, at least about 1550ng·h / mL, at least about 1600ng·h / mL, at least about 1650ng·h / mL, at least about 1700ng·h / mL, at least about 1750ng·h / mL, at least about 1800ng·h / mL, at least about 1850ng·h / mL, at least about 1900ng·h / mL, at least about 1950ng·h / mL, at least about 2000ng·h / mL, at least about 2050ng·h / mL, at least about 2100ng·h / mL, ng·h / mL, at least about 2150 ng·h / mL, at least about 2200 ng·h / mL, at least about 2250 ng·h / mL, at least about 2300 ng·h / mL, at least about 2350 ng·h / mL, at least about 2400 ng·h / mL, at least about 2450 ng·h / mL, at least about 2500 ng·h / mL, at least about 2550 ng·h / mL, at least about 2600 ng·h / mL, or any range or value therebetween. ∞ It is effective in achieving this.

[0091] In some embodiments, the first dose is about 1000 ng·h / mL to about 3500 ng·h / mL, about 1350 ng·h / mL to about 3450 ng·h / mL, about 1400 ng·h / mL to about 3400 ng·h / mL, about 1450 ng·h / mL to about 3350 ng·h / mL, about 1500 ng·h / mL to about 3300 ng·h / mL, about 1550 ng·h / mL to about 3250 ng·h / mL, about 1600 ng·h / mL to about 3200 ng·h / mL, about 1650 ng·h / mL to about 3150 ng·h / mL g·h / mL, about 1700 ng·h / mL to about 3100 ng·h / mL, about 1750 ng·h / mL to about 3050 ng·h / mL, about 1800 ng·h / mL to about 3000 ng·h / mL, about 1850 ng·h / mL to about 2950 ng·h / mL, about 1900 ng·h / mL to about 2900 ng·h / mL, about 1950 ng·h / mL to about 2850 ng·h / mL, about 2000 ng·h / mL to about 2800 ng·h / mL, or any range or value therebetween. ∞ It is effective in achieving this.

[0092] In some embodiments, the first dose is about 40% to about 165% of 2328 ng·h / mL, about 45% to about 160% of 2328 ng·h / mL, about 50% to about 155% of 2328 ng·h / mL, about 55% to about 150% of 2328 ng·h / mL, about 60% to about 145% of 2328 ng·h / mL, about 65% to about 140% of 2328 ng·h / mL, about 70% to about 135% of 2328 ng·h / mL, about 75% to about 130% of 2328 ng·h / mL, about 80% to about 125% of 2328 ng·h / mL, about 85% to about 120% of 2328 ng·h / mL, about 90% to about 115% of 2328 ng·h / mL, Mean AUC in patients of about 95% to about 110% of 2328ng·h / mL, about 100% to about 105% of 2328ng·h / mL, about 40% to about 60% of 2328ng·h / mL, about 40% to about 65% of 2328ng·h / mL, about 40% to about 70% of 2328ng·h / mL, about 40% to about 75% of 2328ng·h / mL, about 40% to about 80% of 2328ng·h / mL, about 40% to about 85% of 2328ng·h / mL, about 40% to about 90% of 2328ng·h / mL, about 40% to about 95% of 2328ng·h / mL, about 40% to about 100% of 2328ng·h / mL, or any range or value therebetween ∞ It is effective in achieving this.

[0093] In some embodiments, the first dose is about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, The compound A may be present in an amount of about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg, or any range or value therebetween.

[0094] In some embodiments, the first dose comprises Compound A in an amount of about 1 mg to about 15 mg, about 1.5 mg to about 12.5 mg, about 2 mg to about 12 mg, about 2.5 mg to about 11.5 mg, about 3 mg to about 11 mg, about 3.5 mg to about 10.5 mg, about 4 mg to about 10 mg, about 4.5 mg to about 9.5 mg, about 5 mg to about 9 mg, about 5.5 mg to about 8.5 mg, or about 6 mg to about 8 mg, or any range or value therebetween.

[0095] The first dose may be administered by any route that introduces or delivers Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) to a subject to perform its intended function. In some embodiments, administration of the first dose may be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes described herein, or any combination of suitable routes. In some embodiments, the first dose is administered orally. In some embodiments, the first dose is administered orally in the form of a tablet or capsule. maintenance dose

[0096] In some embodiments, the maintenance dose is administered at about 6 hours or more after the first dose, at about 8 hours or more after the first dose, at about 10 hours or more after the first dose, at about 12 hours or more after the first dose, at about 14 hours or more after the first dose, at about 16 hours or more after the first dose, at about 18 hours or more after the first dose, at about 20 hours or more after the first dose, at about 22 hours or more after the first dose, at about 24 hours or more after the first dose, at about 30 hours or more after the first dose, at about 36 hours or more after the first dose, at about 42 hours or more after the first dose, at about 48 hours or more after the first dose, at about 54 hours or more after the first dose, at about 58 hours or more after the first dose, at about 59 hours or more after the first dose, at about 60 hours or more after the first dose, at about 61 hours or more after the first dose, at about 62 hours or more after the first dose, at about 63 hours or more after the first dose, at about 64 hours or more after the first dose, at about 65 hours or more after the first dose, at about 66 hours or more after the first dose, at about 67 hours or more after the first dose, at about 68 hours or more after the first dose, at about 69 hours or more after the first dose, at about 70 hours or more after the first dose, at about 71 hours or more after the first dose, at about 72 hours or more after the first dose, at about 75 hours or more after the first dose, at about 76 hours or more after the first dose, at about 78 hours or more after the first dose, at about 79 hours or more after the first dose, at about 80 hours or more after the first dose, at about 81 hours or more after the first dose, at about 82 hours or more after the first dose, at about 83 hours or more after the first dose, at about 84 hours or more after the The dose may be administered about 60 hours or more after the first dose, about 66 hours or more after the first dose, about 72 hours or more after the first dose, about 78 hours or more after the first dose, about 84 hours or more after the first dose, about 90 hours or more after the first dose, about 96 hours or more after the first dose, about 102 hours or more after the first dose, about 108 hours or more after the first dose, about 120 hours or more after the first dose, about 132 hours or more after the first dose, about 144 hours or more after the first dose, about 156 hours or more after the first dose, about 168 hours or more after the first dose, or about 180 hours or more after the first dose, or any value therebetween.

[0097] In some embodiments, the maintenance dose is about 150 ng / mL or less, about 145 ng / mL or less, about 140 ng / mL or less, about 135 ng / mL or less, about 130 ng / mL or less, about 125 ng / mL or less, about 120 ng / mL or less, about 115 ng / mL or less, about 110 ng / mL or less, about 105 ng / mL or less, about 100 ng / mL or less, about 95 ng / mL or less, about 90 ng / mL or less, about 89 ng / mL or less, about 88 ng / mL or less, about 87 ng / mL or less, about 86 ng / mL or less or less, about 85 ng / mL or less, about 84 ng / mL or less, about 83 ng / mL or less, about 82 ng / mL or less, about 81 ng / mL or less, about 80 ng / mL or less, about 79 ng / mL or less, about 78 ng / mL or less, about 77 ng / mL or less, about 76 ng / mL or less, about 75 ng / mL or less, about 74 ng / mL or less, about 73 ng / mL or less, about 72 ng / mL or less, about 71 ng / mL or less, about 70 ng / mL or less, or any range or value therebetween. max It is effective in achieving this.

[0098] In some embodiments, the maintenance dose is at least about 2 ng / mL, at least about 3 ng / mL, at least about 4 ng / mL, at least about 5 ng / mL, at least about 6 ng / mL, at least about 7 ng / mL, at least about 8 ng / mL, at least about 9 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 66 ng / mL, at least about 67 ng / mL, at least about 68 ng / mL, at least about 69 ng / mL, at least about 70 ng / mL, at least about 71 ng / mL, at least about 72 ng / mL, at least about 73 ng / mL, at least about or at least about 74 ng / mL, at least about 75 ng / mL, at least about 76 ng / mL, at least about 77 ng / mL, at least about 78 ng / mL, at least about 89 ng / mL, at least about 80 ng / mL, at least about 81 ng / mL, at least about 82 ng / mL, at least about 83 ng / mL, at least about 84 ng / mL, or at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, or at least about 150 ng / mL, or more, or any range or value therebetween. max It is effective in achieving this.

[0099] In some embodiments, the at least one daily maintenance dose is about 1 ng / mL, about 2 ng / mL, about 3 ng / mL, about 4 ng / mL, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 61 ng / mL, about 62 ng / mL, about 63 ng / mL, about 64 ng / mL, about 65 ng / mL, about 66 ng / mL, about 67 ng / mL, about 68 ng / mL, about 69 ng / mL, about 70 ng / mL, about 71 ng / mL, about 72 ng / mL, about 73 ng / mL,

[0049] The mean C at steady state for Compound A in patients of about 74 ng / mL, about 75 ng / mL, about 76 ng / mL, about 77 ng / mL, about 78 ng / mL, about 79 ng / mL, about 80 ng / mL, about 81 ng / mL, about 82 ng / mL, about 83 ng / mL, about 84 ng / mL, about 85 ng / mL, about 86 ng / mL, about 87 ng / mL, about 88 ng / mL, about 89 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL, about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / mL, or about 150 ng / mL, or greater, or any range or value therebetween. max It is effective in achieving this.

[0100] In some embodiments, the at least one daily maintenance dose is at least about 30% of 78ng / mL, at least about 35% of 78ng / mL, at least about 40% of 78ng / mL, at least about 45% of 78ng / mL, at least about 50% of 78ng / mL, at least about 55% of 78ng / mL, at least about 60% of 78ng / mL, at least about 65% of 78ng / mL, at least about 70% of 78ng / mL, at least about 75% of 78ng / mL, at least about 80% of 78ng / mL, at least about 85% of 78ng / mL, at least about 90% of 78ng / mL, at least about 95% of 78ng / mL, at least about 100% of 78ng / mL, at least about 110% of 78ng / mL, at least about 120% of 78ng / mL, at least about 130% of 78ng / mL, at least about 140% of 78ng / mL, at least about 150% of 78ng / mL, at least about 160% of 78ng / mL, at least about 170% of 78ng / mL, at least about 180% of 78ng / mL, at least about 190% of 78ng / mL, at least about 200% of 78ng / mL, at least about 210% of 78ng / mL, at least about 220% of 78ng / mL, at least about 230% of 78ng / mL, at least about 240% of 78ng / mL, at least about 250% of 78ng / mL, at least about 260% of 78ng / mL, at least about 270% of 78ng / mL, at

[0039] The mean C at steady state of Compound A in the patient is at least about 95% of 78ng / mL, at least about 100% of 78ng / mL, at least about 105% of 78ng / mL, at least about 110% of 78ng / mL, at least about 115% of 78ng / mL, at least about 120% of 78ng / mL, at least about 125% of 78ng / mL, at least about 130% of 78ng / mL, at least about 135% of 78ng / mL, at least about 140% of 78ng / mL, at least about 145% of 78ng / mL, or at least about 150% of 78ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0101] In some embodiments, the at least one daily maintenance dose is about 150% or less of 78ng / mL, about 145% or less of 78ng / mL, about 140% or less of 78ng / mL, about 135% or less of 78ng / mL, about 130% or less of 78ng / mL, about 125% or less of 78ng / mL, about 120% or less of 78ng / mL, about 115% or less of 78ng / mL, about 110% or less of 78ng / mL, about 105% or less of 78ng / mL, about 10 ...

[0047] The mean C at steady state of Compound A in patients with a C of about 95% or less of 78 ng / mL, about 90% or less of 78 ng / mL, about 85% or less of 78 ng / mL, about 80% or less of 78 ng / mL, about 75% or less of 78 ng / mL, about 70% or less of 78 ng / mL, about 65% or less of 78 ng / mL, about 60% or less of 78 ng / mL, about 55% or less of 78 ng / mL, about 50% or less of 78 ng / mL, about 45% or less of 78 ng / mL, about 40% or less of 78 ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0102] In some embodiments, at least one daily maintenance dose is between about 40% and about 165% of 78ng / mL, between about 45% and about 160% of 78ng / mL, between about 50% and about 155% of 78ng / mL, between about 55% and about 150% of 78ng / mL, between about 60% and about 145% of 78ng / mL, between about 65% and about 140% of 78ng / mL, between about 70% and about 135% of 78ng / mL, between about 75% and about 130% of 78ng / mL, between about 80% and about 125% of 78ng / mL, between about 85% and about 120% of 78ng / mL, between about 90% and about 115% of 78ng / mL, between about 95% and about 110% of 78ng / mL, between about 100% and about 105% of 78ng / mL, %, about 40% to about 60% of 78ng / mL, about 40% to about 65% of 78ng / mL, about 40% to about 70% of 78ng / mL, about 40% to about 75% of 78ng / mL, about 40% to about 80% of 78ng / mL, about 40% to about 85% of 78ng / mL, about 40% to about 90% of 78ng / mL, about 40 % to about 95%, about 40% to about 100% of 78ng / mL, about 40% to about 105% of 78ng / mL, about 40% to about 110% of 78ng / mL, about 40% to about 115% of 78ng / mL, about 40% to about 120% of 78ng / mL, about 40% to about 125% of 78ng / mL, about 40% to about 130% of 78ng / mL, about 40% to about 135% of 78ng / mL, or about 40% to about 140% of 78ng / mL, or any range or value therebetween max It is effective in achieving this.

[0103] In some embodiments, the at least one daily maintenance dose is about 30% of 78ng / mL, about 35% of 78ng / mL, about 40% of 78ng / mL, about 45% of 78ng / mL, about 50% of 78ng / mL, about 55% of 78ng / mL, about 60% of 78ng / mL, about 65% of 78ng / mL, about 70% of 78ng / mL, about 75% of 78ng / mL, about 80% of 78ng / mL, about 85% of 78ng / mL, about 90% of 78ng / mL, about 95% of 78ng / mL, about 96% of 78ng / mL, about 97% of 78ng / mL, about 98% of 78ng / mL, about 99% of 78ng / mL, about 100% of 78ng / mL, about 101% of 78ng / mL, about 102% of 78ng / mL, about 103% of 78ng / mL, about 104% of 78ng / mL, about 105% of 78ng / mL, about 106% of 78ng / mL, about 107% of 78ng / mL, about 108% of 78ng / mL, about 109% of 78ng / mL, about 110% of 78ng / mL, about 111% of 78ng / mL, about 112% of 78ng / mL, about 113% of 78ng / mL, about 114% of 78ng / mL, about 115% of 78ng / mL, about 116% of 78ng / mL, about 117% of 78ng / mL, about 118% of 78ng / mL

[0047] The mean C at steady state for Compound A in patients with a C of about 95% of 78ng / mL, about 100% of 78ng / mL, about 105% of 78ng / mL, about 110% of 78ng / mL, about 115% of 78ng / mL, about 120% of 78ng / mL, about 125% of 78ng / mL, about 130% of 78ng / mL, about 135% of 78ng / mL, about 140% of 78ng / mL, about 145% of 78ng / mL, or about 150% of 78ng / mL, or any range or value therebetween. max It is effective in achieving this.

[0104] In some embodiments, the at least one daily maintenance dose is about 3000 ng·h / mL or less, about 2950 ng·h / mL or less, about 2900 ng·h / mL or less, about 2850 ng·h / mL or less, about 2800 ng·h / mL or less, about 2750 ng·h / mL or less, about 2700 ng·h / mL or less, about 2650 ng·h / mL or less, about 2600 ng·h / mL or less, about 2550 ng·h / mL or less, about 2500 ng·h / mL or less, about 2450 ng·h / mL or less, about 25 ...5 mL or less, approx. 2400 ng h / mL or less, approx. 2350 ng h / mL or less, approx. 2300 ng h / mL or less, approx. 2250 ng h / mL or less, approx. h / mL or less, approx. 2050 ng h / mL or less, approx. 2000 ng h / mL or less, approx. 1950 ng h / mL or less, approx. 1900 ng h / mL or less, approx. h / mL or less, approx. 1700ng h / mL or less, approx. 1650 ng h / mL or less, approx. 1600 ng h / mL or less, approx. 1550 ng h / mL or less, approx. ng h / mL or less, approx. 1350 ng h / mL or less, approx. 1300 ng h / mL or less, approx. 1250 ng h / mL or less, approx. 1200 ng h / mL or less, approx. Mean AUC at steady state of Compound A in patients of 50 ng·h / mL or less, about 1000 ng·h / mL or less, about 950 ng·h / mL or less, about 900 ng·h / mL or less, about 850 ng·h / mL or less, about 800 ng·h / mL or less, about 750 ng·h / mL or less, about 700 ng·h / mL or less, about 650 ng·h / mL or less, about 600 ng·h / mL or less, about 550 ng·h / mL or less, about 500 ng·h / mL or less, or any range or value therebetween τ It is effective in achieving this.

[0105] In some embodiments, the at least one daily maintenance dose is at least about 300 ng·h / mL, at least about 350 ng·h / mL, at least about 400 ng·h / mL, at least about 450 ng·h / mL, at least about 500 ng·h / mL, at least about 550 ng·h / mL, at least about 600 ng·h / mL, at least about 650 ng·h / mL, at least about 700 ng·h / mL, at least about 750 ng·h / mL, at least about 800 ng·h / mL, at least about 8 50ng·h / mL, at least about 900ng·h / mL, at least about 950ng·h / mL, at least about 1000ng·h / mL, at least about 1050ng·h / mL, at least about 1100ng·h / mL, at least about 1150ng·h / mL, at least about 1200ng·h / mL, at least about 1250ng·h / mL, at least about 1300ng·h / mL, at least about 1350ng·h / mL, at least about 1400ng·h / mL, at least about 1450ng·h / mL, at least at least about 1500 ng·h / mL, at least about 1550 ng·h / mL, at least about 1600 ng·h / mL, at least about 1650 ng·h / mL, at least about 1700 ng·h / mL, at least about 1750 ng·h / mL, at least about 1800 ng·h / mL, at least about 1850 ng·h / mL, at least about 1900 ng·h / mL, at least about 1950 ng·h / mL, at least about 2000 ng·h / mL, at least about 2050 ng·h / mL, at least about 2100 ng·h / mL ·h / mL, at least about 2150 ng·h / mL, at least about 2200 ng·h / mL, at least about 2250 ng·h / mL, at least about 2300 ng·h / mL, at least about 2350 ng·h / mL, at least about 2400 ng·h / mL, at least about 2450 ng·h / mL, at least about 2500 ng·h / mL, at least about 2550 ng·h / mL, at least about 2600 ng·h / mL, or any range or value therebetween. τ It is effective in achieving this.

[0106] In some embodiments, the at least one daily maintenance dose is from about 300 ng·h / mL to about 3000 ng·h / mL, from about 350 ng·h / mL to about 2950 ng·h / mL, from about 400 ng·h / mL to about 2900 ng·h / mL, from about 450 ng·h / mL to about 2850 ng·h / mL, from about 500 ng·h / mL to about 2800 ng·h / mL, from about 550 ng·h / mL to about 2750 ng·h / mL, h / mL, approximately 600ng·h / mL to approximately 2700ng·h / mL, approximately 650ng·h / mL to approximately 2650ng·h / mL, approximately 700ng·h / mL to approximately 2600ng·h / mL, approximately 750ng·h / mL ~ approx. 2550ng h / mL, approx. 800 ng h / mL ~ approx. 2500 ng h / mL, approx. 850 ng h / mL ~ approx. 2450 ng h / mL, approx. 900 ng h / mL ~ approx. 2400 ng h / mL, approximately 950ng·h / mL to approximately 2350ng·h / mL, approximately 1000ng·h / mL to approximately 2300ng·h / mL, approximately 1050ng·h / mL to approximately 2250ng·h / mL, approximately 1100ng·h / mL h / mL ~ approx. 2200ng h / mL, approx. 1150 ng h / mL ~ approx. 2150 ng h / mL, approx. 1200 ng h / mL ~ approx. 2100 ng h / mL, approx. 1250 ng h / mL ~ approx. 2050 n g·h / mL, about 1300 ng·h / mL to about 2000 ng·h / mL, about 1350 ng·h / mL to about 1950 ng·h / mL, about 1400 ng·h / mL to about 1900 ng·h / mL, about 1450 ng·h / mL to about 1850 ng·h / mL, about 1500 ng·h / mL to about 1800 ng·h / mL, or any range or value therebetween, τ It is effective in achieving this.

[0107] In some embodiments, the at least one daily maintenance dose is between about 40% and about 165% of 1487 ng·h / mL, between about 45% and about 160% of 1487 ng·h / mL, between about 50% and about 155% of 1487 ng·h / mL, between about 55% and about 150% of 1487 ng·h / mL, between about 60% and about 145% of 1487 ng·h / mL, between about 65% and about 140% of 1487 ng·h / mL, between about 70% and about 135% of 1487 ng·h / mL, between about 75% and about 130% of 1487 ng·h / mL, between about 80% and about 125% of 1487 ng·h / mL, between about 85% and about 120% of 1487 ng·h / mL, between about 90% and about 115% of 1487 ng·h / mL, %, about 95% to about 110% of 1487ng·h / mL, about 100% to about 105% of 1487ng·h / mL, about 40% to about 60% of 1487ng·h / mL, about 40% to about 65% of 1487ng·h / mL, about 40% to about 70% of 1487ng·h / mL, about 40% to about 75% of 1487ng·h / mL, about 40% to about 80% of 1487ng·h / mL, about 40% to about 85% of 1487ng·h / mL, about 40% to about 90% of 1487ng·h / mL, about 40% to about 95% of 1487ng·h / mL, about 40% to about 100% of 1487ng·h / mL, or any range or value therebetween τ It is effective in achieving this.

[0108] In some embodiments, the maintenance dose comprises Compound A in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, or about 15 mg, or any range or value therebetween.

[0109] In some embodiments, the maintenance dose comprises Compound A in an amount of about 0.1 mg to about 6 mg, about 0.2 mg to about 5.5 mg, about 0.3 mg to about 5 mg, about 0.4 mg to about 4.5 mg, about 0.5 mg to about 4 mg, about 0.6 mg to about 3.9 mg, about 0.7 mg to about 3.8 mg, about 0.8 mg to about 3.7 mg, about 0.9 mg to about 3.6 mg, about 1 mg to about 3.5 mg, about 1.1 mg to about 3.4 mg, about 1.2 mg to about 3.3 mg, about 1.3 mg to about 3.2 mg, about 1.4 mg to about 3.1 mg, or about 1.5 mg to about 3.0 mg, or any range or value therebetween.

[0110] In some embodiments, the maintenance dose may be administered once a day. In some embodiments, the maintenance dose may be administered twice a day. In some embodiments, the maintenance dose may be administered three times a day. In some embodiments, the maintenance dose may be administered multiple times a day, for example, twice a day or three times a day. In some embodiments, the maintenance dose may be administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days, or at longer intervals. In some embodiments, the maintenance dose may be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, eight times a week, nine times a week, ten times a week, or more. In some embodiments, the maintenance dose can be administered once every 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 30 hours, 36 hours, 40 hours, 44 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, 72 hours, 78 hours, 84 hours, 96 hours, 102 hours, 108 hours, 120 hours, 132 hours, or 144 hours, or at longer intervals, or any range or value therebetween.

[0111] The maintenance dose may be administered by any route that introduces or delivers Compound A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) to a subject to perform its intended function. In some embodiments, the maintenance dose may be administered by any suitable route, including, but not limited to, oral, intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes described herein, or any combination of suitable routes. In some embodiments, the maintenance dose is administered orally.

[0112] The present disclosure is not limited with respect to the specific embodiments described in this application, which are intended as single illustrations of individual aspects of the present disclosure. Not all of the various embodiments of the present disclosure are described herein. As will be apparent to those skilled in the art, many modifications and variations of the present disclosure can be made without departing from the spirit and scope of the present disclosure. Functionally equivalent methods and apparatuses within the scope of the present disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be included within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full range of equivalents to which such claims are entitled.

[0113] Unless otherwise specified, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Terms, such as those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with their meaning in the context of this application and related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Unless expressly defined below, such terms should be interpreted according to their common meaning.

[0114] As will be understood by those skilled in the art, for all purposes, particularly with respect to providing a written description, all ranges disclosed herein encompass all possible subranges and combinations of subranges. Any recited range can be readily recognized as fully descriptive and permitting the same range to be broken down into at least two equal parts, a third, a quarter, a fifth, a tenth, etc. As a non-limiting example, each range described herein can be readily broken down into a lower third, a middle third, and an upper third, etc. Also, as will be understood by those skilled in the art, all language such as "up to," "at least," "greater than," and "less than" refers to a range that is inclusive of the recited numbers and can be subsequently broken down into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes individual members. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 cells, etc.

[0115] It is to be understood that this disclosure is not limited to particular applications, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0116] Furthermore, where features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0117] It is specifically contemplated that the various features of the present disclosure can be used in any combination unless the context indicates otherwise. Furthermore, the present disclosure also contemplates that in some embodiments, any feature or combination of features described herein can be excluded or omitted. For illustrative purposes, if the specification states that a composite comprises components A, B, and C, it is specifically contemplated that any or combination of A, B, or C, singly or in any combination, can be omitted and discarded.

[0118] Unless otherwise specified, all specific embodiments, features, and terms are intended to include both the recited embodiment, feature, or term and its biological equivalents.

[0119] All patents, patent applications, provisional applications, and publications mentioned or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the explicit teachings of this specification. [Example]

[0120] Example 1. Randomized, double-blind, placebo-controlled safety, tolerability, and pharmacokinetic study of ascending single and multiple doses of Compound A in healthy subjects 1.0. Study Design and Planning This was a randomized, double-blind, placebo-controlled, single ascending dose (SRD) and multiple ascending dose (MRD) Phase 1 clinical study in healthy adult male and female subjects aged 18 to 55 years. The study was designed to evaluate the safety, tolerability, PK, and PD of Compound A. A total of 88 subjects were enrolled in six SRD and five SRD / MRD cohorts (n=8 per cohort). The study consisted of two parts. A schematic diagram of the study design for Part 1 of the study is shown in Figure 1A. A schematic diagram of the study design for Part 2 of the study is shown in Figure 1B.

[0121] In Part 1 of the study (SRD cohorts), a single oral tablet dose of Compound A (0.3, 1, 3, 5, 9, or 18 mg) or matching placebo was administered on Day 1, followed by safety, tolerability, PK, and PD assessments. Each SRD cohort of eight subjects (six active: two placebo) used sentinel dosing, whereby two initial subjects (one active: one placebo) received study drug and the remaining subjects (five active: one placebo) received study drug after at least a 24-hour interval for pre-dose safety and tolerability assessments. Dosing for the remaining six subjects from each cohort was staggered, with only three subjects receiving study drug on a single day and the final three receiving study drug after an additional 24-hour interval. Data from each cohort were reviewed sequentially to ensure adequate safety and tolerability before administering the next dose level. Study drug was administered after an overnight fast of at least 10 hours. Subjects were confined to the research unit for 5 days, from check-in on Day -1 until approximately 96 hours post-dose. Subjects in Cohorts 1-5 (0.3-9 mg) visited the clinic on Days 6 and 7, and subjects in Cohort 6 (18 mg) visited on Days 6, 7, and 8 for additional PK blood sampling. To allow for a preliminary assessment of the effect of food on the PK of Compound A, subjects in SRD Cohort 3 (3 mg) visited the clinic to receive study drug under fed conditions (standard high-fat meal as defined by the Food and Drug Administration ("FDA")) after the safety and tolerability of the higher dose (5 mg) under fasted conditions had been established.

[0122] In the second part of the study (SRD / MRD cohort), a single oral tablet dose of Compound A (0.3, 1, 3, 6, or 9 mg) or matching placebo was administered on Day 1, followed by safety, tolerability, PK, and PD assessments. Study drug (at the same dose level) was then administered once daily (QD) for 13 days from Days 6 through 18. Each cohort of eight subjects (six active: two placebo) received study drug sequentially to ensure adequate safety and tolerability before administering the next dose level. Neither sentinel nor staggered dosing was used for the SRD / MRD cohort. Subjects were confined to the study unit for 21 days, from check-in on Day -1 until 72 hours after the final dose of study drug.

[0123] For all cohorts in Parts 1 and 2, sequential PK blood samples were collected pre-dose and post-dose on Day 1 to measure plasma concentrations of Compound A and its metabolites. For all SRD / MRD cohorts in Part 2, urine samples were collected pre-dose and post-dose on Day 1 and post-dose on Day 18 to measure concentrations of Compound A and its metabolites.

[0124] In both parts of the study, follow-up occurred approximately 14 days after the last dose of study drug to monitor adverse events (AEs) and concomitant medication use. The end of the study (study completion date) was based on the last data collection date (follow-up phone call / visit) for the entire study.

[0125] 2.0.Evaluation 2.0.1. Analyzed Dataset In Part 1 of the study, the PK set included all 36 subjects who received Compound A. In Part 2 of the study, the PK set included all 30 subjects who received Compound A.

[0126] 2.0.2. Part 1 (SRD Cohort): Plasma PK of Compound A Referring now to FIG. 2, mean plasma concentration-time profiles (linear and semi-logarithmic scales) of Compound A were determined after a single oral dose of Compound A.

[0127] Referring to Table 1, after a single oral dose of Compound A (0.3, 1, 3, 5, 9, and 18 mg) to healthy subjects, the mean plasma concentration of Compound A increased rapidly, with a median t max The values ​​ranged from 1.25 to 5.5 hours. Thereafter, the mean concentrations decreased monoexponentially. The shape of the concentration-time profiles was similar across dose levels, and the mean concentrations of Compound A increased in a dose-dependent manner.

[0128] Descriptive statistics of plasma PK parameter estimates of Compound A after a single oral dose of Compound A are shown in Table 1.

[0129] After a single oral dose of Compound A, the mean plasma C max The values ​​increased dose-dependently from 3.63 to 126 ng / mL over the dose range of 0.3 to 18 mg. Similarly, the mean AUC ∞ Values ​​increased dose-dependently from 148 to 8882 ng·h / mL.

[0130] The inter-subject variability (%CV) of exposure parameters for Compound A was low, and C max 10% to 20%, AUC ∞ The mean final t 1 / 2z The values ​​were similar for each dose level, ranging from 33.1 to 47.8 hours. Furthermore, the mean CL / F and V for Compound A z The / F values ​​are 1.79 to 2.29 L / h for CL / F and V z For / F, the range was 95.1–133 L and was similar across all dose levels. 2.0.3. Part 2 (SRD / MRD Cohort): Plasma PK of Compound A

[0131] Referring now to Figure 3, mean plasma concentration-time profiles (linear and semi-logarithmic scales) of Compound A were determined on day 18 after 13 days of oral administration of Compound A QD.

[0132] After oral administration of Compound A QD (0.3, 1, 3, 6, and 9 mg) to healthy subjects, pre-dose Compound A concentrations approached a maximum on day 14 for each dose level, and Compound A exposure appeared to reach a steady state on day 18. The mean Compound A concentrations increased in a dose-dependent manner. The median t max was 2.5 to 4 hours across the dose range.

[0133] Descriptive statistics of plasma PK parameter estimates of Compound A following single and QD oral administration of Compound A are shown in Table 2.

[0134] As shown in Table 2, after multiple oral doses of Compound A, the mean plasma C max,ss The values ​​increased dose-dependently from 7.86 to 243 ng / mL over the dose range of 0.3 to 9 mg. Similarly, the mean AUC of Compound A on Day 18 τ The values ​​increased dose-dependently from 151 to 4598 ng·h / mL. The inter-subject variability (%CV) of the exposure parameters of Compound A was low, and C max,ss 27%-37% and AUC τ The mean C for Compound A on Day 18 ranged from 23% to 41%. av,ss The values ​​also increased dose-dependently from 6.27 to 192 ng / mL. [Table 1] Abbreviations: %CV, percent coefficient of variation; AUC ∞ , area under the plasma concentration-time curve from time 0 to infinity; AUC last , area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; CL / F, apparent clearance after extravascular administration; C max , maximum observed plasma concentration;t 1 / 2z , terminal elimination half-life; t max , C max The time when V first occurred; z / F, apparent volume of distribution during the terminal elimination phase after extravascular administration. a Median (min-max). [Table 2-1] [Table 2-2] Abbreviations: %CV, percent coefficient of variation; AUC, area under the concentration-time curve; AUC 24 , area under the plasma concentration-time curve from time 0 to 24 hours; AUC ∞ , area under the plasma concentration-time curve from time 0 to infinity; AUC last , area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC τ Area under the plasma concentration-time curve during the dosing interval; CL / F, apparent clearance after extravascular administration; C av,ss , mean plasma concentration at steady state; C max , maximum observed plasma concentration; C max,ss , maximum observed plasma concentration during the dosing interval at steady state; NC, not calculated; PK, pharmacokinetics; QD, once daily; t 1 / 2z , terminal elimination half-life; t max , C max The time when V first occurred; z / F, apparent volume of distribution during the terminal elimination phase after extravascular administration. a Median (min-max). b n=5.

[0135] Example 2: 14-day rat neurotoxicity study 2.1. Materials and Methods 2.1.1. Formulation An appropriate amount of methylcellulose (MC) was weighed and mixed with a small amount of warm water for injection. The mixture was then diluted with water for injection to prepare a 0.5% (w / v) MC solution. The vehicle was used for administration to the control group. To prepare a 40 mg / mL suspension of Compound A, an appropriate amount of test article was weighed and mixed with the vehicle using a planetary centrifugal mixer, and the mixture was then diluted with additional vehicle. The 40 mg / mL suspension was used for serial dilutions with the vehicle to make 20 and 10 mg / mL suspensions. The dosing suspension was stored in a refrigerator (sealed container) under light-resistant conditions (actual value: 3.7°C to 6.1°C, acceptable range: 2°C to 8°C) and used within 8 days of preparation.

[0136] 2.1.2.Animals Sprague-Dawley rats were used because they are a standard rodent strain frequently used in toxicity studies. Additionally, previous repeat-dose toxicity studies with Compound A used Sprague-Dawley rats.

[0137] Males and females in good condition were selected for this study based on an examination performed within 4 days prior to the first dose. Based on their body weight, animals were stratified and randomly assigned to three main study groups, each consisting of 18 males and 18 females, and two satellite groups, each consisting of 9 males and 9 females, for determination of plasma drug and metabolite concentrations. Surplus animals after animal selection were removed from the study the day after animal selection or on the first day of dosing (Day 1).

[0138] 2.1.3.Animal husbandry Animals were individually housed in stainless steel mesh cages. They were assigned to shelf positions in the animal room in order of their animal identification number. The room conditions were: temperature 21.8°C–23.8°C (acceptable range: 19.0°C–25.0°C); relative humidity 49.0%–78.9% (acceptable range: 35.0%–75.0%); fresh air exchange rate 6–20 times per hour; and a 12-hour light / dark cycle (lights on from 7:00 AM to 7:00 PM). When animals were unfed, they were given free access to pelleted laboratory chow (CR-LPF, Oriental Yeast Co., Ltd., gamma-irradiated, lot 170630) and tap water (passed through a 5-μm filter and exposed to UV light), except for approximately 16–23 hours prior to scheduled necropsy. It was confirmed that no contaminants were present in the food or water at levels that could interfere with this study.

[0139] Experimental design The experimental design is summarized in Tables 3A and 3B below.

[0140] 2.1.5. Experiments and Methods The day before dosing began was designated as day -1, and the first day of dosing was designated as day 1. The period from day 1 to day 7 was designated as week 1.

[0141] 2.1.5.1.Toxicity kinetics Plasma concentrations of Compound A were determined in each satellite group on days 2, 7, and 14, as shown in Tables 4A and 4B. Blood samples (approximately 0.25 mL) were collected without anesthesia from the subclavian vein of three animals of each sex in each satellite group at each sampling point using sodium-heparinized syringes. Sampling times were as follows: pre-dose and 1, 2, 4, 8, and 24 hours post-dose. Additionally, plasma concentrations of Compound A were determined in each main study group before scheduled necropsy. Plasma samples (≥0.08 mL) in polypropylene tubes were frozen and stored in a freezer (actual values: -87.0 °C to -83.5 °C) until shipment, along with parallel quality control (QC) samples prepared at Test Site 2. These samples were stored under the same conditions as the study plasma samples at the test facility. Samples, including the parallel QC samples, were packaged on dry ice and transported to Test Site 2. Samples were frozen at -85.8 °C to -75.5 °C until assay. Plasma concentrations of Compound A and its metabolites were determined by liquid chromatography / tandem mass spectrometry (LC / MS / MS), and TK parameters (t max , C max , AUC 24 values) were calculated for the satellite group at test site 2.

[0142] 2.1.5.2. Clinical signs All animals were observed for survival and clinical signs four times on day 1 (pre-dose and approximately 1, 2, and 4 hours post-dose) during the dosing period and three times daily from days 2 through 14 (pre-dose and approximately 1 and 4 hours post-dose) and once on the day of necropsy.

[0143] The behavior of the high-dose main study and TK satellite groups was continuously video-recorded under non-GLP conditions throughout the dosing period (until the morning of necropsy). Video-recorded images were retained on a hard drive and archived as study data. Videos from three 200 mg / kg / day females with test article-related histopathological changes were examined for the presence of convulsions during the dosing period.

[0144] Weight During the administration period, the pre-dose body weight of each animal was measured using an electronic balance (PB3002-S; Mettler-Toledo, UX4200H; Shimadzu) on days 1, 2, 4, 7, 11, and 14. In addition, all animals were weighed on the necropsy days of days 3, 8, and 15, and these final body weight values ​​were also used to calculate the anesthetic dose.

[0145] Autopsy The animals were fasted for approximately 16–23 h and then weighed to calculate the anesthetic dose. Approximately 0.5–2 h after analgesic administration with an intramuscular injection of buprenorphine (0.01 mg / kg), the animals were anesthetized with an intraperitoneal injection of thiopental sodium (Ravonal®, Mitsubishi Tanabe Pharma Corporation). Buprenorphine (Repetan® Injection 0.2 mg, Otsuka Pharmaceutical Factory, Inc.) was diluted 5-fold (0.04 mg / mL) with saline (Japanese Pharmacopoeia, Otsuka Pharmaceutical Factory, Inc.).

[0146] A cannula was inserted from the left ventricle to the aortic root, and blood was flushed with 0.1 mol / L phosphate buffer using a peristaltic pump. After that, the whole body was fixed by perfusion with 4% paraformaldehyde fixative (perfusion fixation). For the TK satellite group, blood was collected on days 3, 8, and 15, and all animals were necropsied.

[0147] Animals were weighed to calculate the anesthetic dose before being euthanized by exsanguination under thiopental sodium anesthesia (Ravonal®, Mitsubishi Tanabe Pharma Corporation). Brains were examined macroscopically at necropsy on days 3, 8, and 15.

[0148] 2.1.5.5. Histopathological examination After perfusion fixation, the brains, excluding the olfactory bulbs, were harvested and fixed by immersion in 10% phosphate-buffered formalin (vol. 1). The olfactory bulbs, along with the skull, were fixed by immersion in 10% phosphate-buffered formalin (vol. 1) and removed after fixation without decalcification. Brains from all control animals, 100 mg / kg / day males and 200 mg / kg / day females on days 3, 8, and 15, and 100 mg / kg / day females on day 15 were coronally trimmed at seven levels according to the STP position paper (Bolon B, Garman RH, Pardo ID, Jensen K, Sills RC, Roulois A, et al., STP position paper: Recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol. 2013;41:1028-48). These trimmed tissues were embedded in paraffin, sectioned, and processed using standard methods to prepare hematoxylin and eosin (HE)-stained sections, which were then evaluated using Fluoro-Jade C (Fluoro-Jade C Ready-to-Dilute Staining Kit, batch number BA01-30-100FJTK261017, Biosensis; thickness: 4–5 μm). The HE-stained specimens were transported to Test Site 1 and examined for histopathology. After examination at Test Site 1, the specimens were returned to the test facility. Fluoro-Jade staining included negative control sections not infiltrated with Fluoro-Jade C and positive control sections (kainic acid neurotoxicity model). Fluoro-Jade-stained specimens were examined using a fluorescent microscope at the test facility. None of the brains from 50 mg / kg / day males (days 3, 8, and 15) or 100 mg / kg / day females (days 3 and 8) were examined histopathologically because no abnormalities were noted in 100 mg / kg / day males or 200 mg / kg / day females on days 3 or 8.

[0149] For animals in the TK satellite group, brains and olfactory bulbs were collected at necropsy and fixed by immersion in 10% phosphate-buffered formalin (vol. 1). The olfactory bulbs were fixed together with the skull in 10% phosphate-buffered formalin (vol. 1), but were not examined microscopically.

[0150] 2.1. Conclusion The purpose of this study was to evaluate the potential neurotoxicity of Compound A in rats orally treated with the compound for 2, 7, or 14 days and euthanized several days after the last dose. TK analysis was also performed.

[0151] TK analysis showed similar C values ​​to those seen in previous rat toxicity studies at doses similar to those used in the current study. max and AUC 24 The values ​​were shown.

[0152] All rats survived until scheduled euthanasia and were free of test article-related abnormalities in clinical signs of the brain, body weight, or macroscopic parameters.

[0153] Test article-related changes were observed in the cerebellum of three females at 200 mg / kg / day on day 15. Purkinje cell necrosis in one female was confirmed by HE staining, and necrotic cells were also positive for Fluoro-Jade staining. Two other females also showed Fluoro-Jade staining of Purkinje cell dendrites that was not confirmed using HE. Fluoro-Jade staining is considered a marker of neurodegeneration, and the labeling of dendrites, axons, and cell bodies in this study suggests Purkinje cell necrosis or degeneration (Schmued LC, Albertson C, Slikker W Jr. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neural degeneration.Brain Res.1997;751:37-46).

[0154] Glutamate is the major excitatory neurotransmitter in the brain, including the cerebellum. Purkinje cells receive two types of excitatory input from outside the cerebellum: one directly from climbing fibers and the other indirectly from parallel fibers. Each Purkinje cell receives excitatory input from tens of thousands of parallel fibers and specialized glial cells called Bergmann glia, which provide excitatory input to Purkinje cells and regulate the level of glutamate at the synapse with the Purkinje cell (Dzubay JA, Jahr CE. The concentration of synaptically released glutamate outside of the climbing fiber-Purkinje cell synaptic cleft.J.Neurosci.1999;19;5265-74).

[0155] AMPA receptors are particularly important for fast synaptic transmission in neurons in the cerebellar cortex, and Purkinje cell degeneration has been reported to occur as a result of excessive glutamate-induced AMPA receptor activation secondary to a number of insults (Mansouri B, Henne WM, Omman SK, Bliss R, Attridge J, Finckbone V, et al., Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje cells. neurons.Eur.J.Pharmacol.2007;557:106-14;Barenberg P, Strahlendorf H, Strahlendorf J. Hypoxia induces an excitotoxic-type of dark cell degeneration in cerebellar Purkinje neurons. Neurosci. Res. 2001;40:245-54; Garthwaite G, Garthwaite J. AMPA neurotoxicity in rat cerebellar and hippocampal slices: histological evidence for three mechanisms. Eur. J. Neurosci. 1991;3:715-28). Because Compound A is an AMPA receptor potentiator, the changes observed in Purkinje neurons in this study may reflect excessive glutamate-induced excitation as a result of AMPA receptor potentiation by Compound A.

[0156] No clinical signs were recorded in any of the animals at the scheduled observation times. However, video recordings of three 200 mg / kg / day females with cerebellar findings were examined, and two of them exhibited tonic convulsions. One animal had a single convulsion on day 3 of dosing. Another female with convulsions had multiple tonic or intermittent convulsions (mainly in the forelimbs) that began immediately after treatment on day 6 and continued for 18 hours after dosing. These two animals had Fluoro-Jade-positive staining of Purkinje cells, which was also confirmed in HE-stained sections in one animal. However, the other female with brain histopathological findings did not exhibit convulsions. Assessment of Compound A exposure at the time of sacrifice (day 15) showed Compound A plasma levels of 935 ng / mL in the animal (with visible lesions on both HE and Fluoro-Jade) and exposures of 182 ng / mL and 138 ng / mL in the remaining two females with visible lesions only on Fluoro-Jade. Plasma Compound A exposures at sacrifice in the remaining three females at 200 mg / kg / day, which did not exhibit seizures or brain histopathology, were 192, 968, and 114 ng / mL. While the tonic seizures may have been related to Purkinje cell necrosis, the absence of seizures in the one animal with Purkinje cell damage argues against this. However, it is noteworthy that the animals with the highest plasma drug levels and the highest frequency of seizures at sacrifice also had the greatest degree of neuropathology.

[0157] In conclusion, tonic convulsions in two rats and necrosis and / or FluoroJade-positive staining of Purkinje cells (dendrites, cell bodies, or axons) in three rats were observed in females administered Compound A at 200 mg / kg / day for 14 days. Therefore, the no-observed-adverse-effect level (NOAEL) was 100 mg / kg / day for both males and females on day 14, and the mean C of Compound A was 100 mg / kg / day for both males and females. max The values ​​were 1290 and 1670 ng / mL, and the mean AUC 24 The values ​​were 17,000 and 17,800 for males and females, respectively. It was concluded that the mean ng·hr / mL. [Table 3A] Control: 0.5 (w / v) MC solution; NA: not available * 1: Scheduled slaughter on day 3 * 2: Scheduled slaughter on day 8 * 3: Scheduled slaughter on day 15 [Table 3B] NA: Not available [Table 4A] NA: Not available [Table 4B] NA: Not available [Table 5]

[0158] Example 3: 13-week NHP GLP Toxicity Study 3.1. Materials and Methods An appropriate volume of reverse osmosis water was added to an appropriately sized container and heated to 70-90°C. An appropriate amount of MC (Shin-Etsu Chemical Co., Ltd., METOLOSE SM-100) was weighed and transferred to the container along with the heated reverse osmosis water (while stirring). This solution was cooled (using an ice bath) until a clear solution was obtained. The solution was stored refrigerated (set at 2-8°C) until use. Unused reference / vehicle was discarded when no longer needed. To prepare a 0.2 w / v% suspension of Compound A, an appropriate amount of test article was weighed. A small amount of vehicle was added to slowly wet the test article. The appropriate volume of vehicle was added to reach the final volume, and the formulation was homogenized using a homogenizer until a uniform suspension was achieved and stirred for 30-59 minutes. The 0.2 w / v% suspension was then diluted with 0.5 w / v% MC in reverse osmosis water to produce 0.12, 0.06, and 0.006 w / v% suspensions. However, on October 1, 2015, instead of diluting the 2 mg / mL formulation to reach the appropriate concentration, a 1.2 mg / mL formulation was prepared by dissolving the appropriate amount of Compound A in the vehicle. This deviation did not affect the study as it was prepared at the appropriate concentration.

[0159] 3.1.1. Test System The test systems for NHP GLP toxicity studies are summarized in Table 6. [Table 6]

[0160] 3.1.2. Breeding Due to the nature of the study, group housing (telemetry data acquisition) was not possible; therefore, animals were housed individually in stainless steel monkey cages equipped with an automatic water supply system. Primary enclosures were as specified in the most recent "Guide to the Care and Use of Experimental Animals" published by the Canadian Council on Animal Care and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Research Council, 2011). The room in which animals were housed during treatment was recorded in the study records. After assignment to dose groups, all cages were clearly labeled with color-coded cage cards indicating, at a minimum, the study number and animal number (including sex and group number). For telemetry data acquisition, one receiver for telemetry signals was installed in each animal's cage. Cages were also equipped with light- and night-vision cameras for continuous behavioral video monitoring.

[0161] 3.1.3.Indoor environment The animal room environment was maintained at a temperature of 21°C ± 3°C (actual range: 17.30°C to 22.64°C); relative humidity of 50% ± 20% (actual range: 26.84% to 93.76%); a 12-hour light / 12-hour dark (lights on at 7:00 AM, lights off at 7:00 PM) light / dark cycle, except during protocol-specified procedures; and set to maintain 10–15 air changes per hour. Temperature and relative humidity were continuously monitored. Cage changes were not performed during telemetry data acquisition. Cage changes were performed approximately once every two weeks before and after telemetry data acquisition. Animal enrichment during this period included a tuned radio and the provision of toys, treats, and / or fresh or frozen fruits and vegetables.

[0162] 3.1.4. Food / Water Standard certified commercial chow (Harlan Teklad Certified Hi-Fiber Primate Diet #7195 C) was provided to animals twice daily, except during designated procedures. As part of the animal enrichment program, treats (Fruity Gems, Supreme Mini-Treat, Prima-Treat, Yogurt Drops, Fruity Crunch, or Fruity Bites) or fresh or frozen fruits / vegetables (pears, bananas, cucumbers, honey melons, cantaloupes, watermelons, or celery) were provided. Provision of treats or fresh fruits / vegetables was approved by the principal investigator prior to provision.

[0163] Adaptation To allow the animals to adapt to the laboratory environment, an acclimation period of 2 to 11 days was allowed between the transfer of animals to the study and surgery. A recovery period of 20 to 35 days was allowed between surgery and Phase 1. According to the study design, the recovery period between surgery and administration was at least 3 weeks. This deviation did not affect the study, as all animals recovered well after surgery and were in good health at the start of administration.

[0164] Animals were acclimated to gavage three times prior to Phase 1.

[0165] 3.1.6. Test System Preparation Thirty-seven animals (18 males and 19 females, including 3 reserve animals per sex) were surgically cannulated with a catheter (LABPC-01 or LABPFC-01, SAI Infusion Technologies) inserted into the femoral vein for blood sampling and veterinary care during seizures, and were implanted with a telemetry transmitter (Data Science International, model: D70-EEE) and instrumented for EMG and EEG monitoring (EMG, C4-O2, and Cz-Oz).

[0166] Animals were fasted overnight before surgery. A mixture of ketamine hydrochloride (9.09 mg / kg intramuscularly (IM)) and acepromazine (0.09 mg / kg IM) was used to sedate the animals, followed by intubation. Lidocaine spray (10% w / w) was administered into the glottis before intubation. Ophthalmic ointment was applied to both eyes to prevent corneal dryness before and after anesthesia. If necessary, animals were anesthetized with isoflurane using a mask before intubation. Anesthesia was maintained with inhaled isoflurane at an oxygen flow rate of approximately 200 mL / kg / min or as needed. The surgical site was shaved and aseptically prepared using chlorhexidine gluconate 4% and isopropyl alcohol 70%.

[0167] The animals were placed on a heating pad set to maintain the animal's body temperature at approximately 37°C. The animals were mechanically ventilated at a rate of 8-20 breaths / min with an inspiratory pressure of 18-25 cmH2O. Hemoglobin oxygen saturation (SpO2) and heart rate were monitored regularly to ensure adequate ventilation of the animals but are not reported. Intravenous fluid therapy was administered throughout the anesthesia period using sterile lactated Ringer's solution at a rate of 10 mL / kg / h or as needed.

[0168] Prophylactic antibiotics (Pencillin G procaine 300,000 IU / mL) were administered IM twice daily, starting at least 30 minutes before surgery, and then twice daily for two days postoperatively, according to appropriate standard operating procedures. Enrofloxacin (Baytril 50 mg / mL) was also administered intramuscularly once daily as a prophylactic antibiotic, starting at least 15 minutes before surgery for five days postoperatively, according to appropriate standard operating procedures. Analgesia was achieved via a transdermal fentanyl patch (approximately 12.5 μg / h for animals weighing less than 5 kg or 25 μg / h for animals weighing 5-10 kg), which was applied to the animals the day before surgery and removed two days after surgery. Local anesthetic (50:50, Marcaine® 0.25% and lidocaine 20 mg / ml) was injected subcutaneously into 6 to 10 sites (maximum 0.1 mL / site, maximum total volume 0.8 mL) distributed throughout the surgical site on the skull, neck, and abdomen during surgery.

[0169] Transmitter and subcutaneous lead implantation was performed as follows: Sterile transmitter (Data A cephalad catheter (Science International, Model: D70-EEE) was inserted between the aponeurosis of the internal abdominal oblique muscle and the transverses abdominis muscle (the position was recorded in the raw data). An incision was made at the nape of the neck. EEG leads were threaded from the abdominal cavity (where the transmitter was placed) to the cervical incision. To monitor two standard bipolar leads (C4-O2 and Cz-Oz), EEG leads were placed directly on the skull. A linear groove was made in the cortical bone of the skull to secure the metal portion of the electrode. The EEG leads were secured to the skull with surgical adhesive (Vetbond) near the implantation site at the level of the distal portion of the silicone insulator, and the metal portion of the lead was secured with acrylic. A loop was prepared using the distal segment of the electrode and secured to the neck musculature with nonabsorbable sutures. EMG electrodes were placed parallel to the longitudinal axis of the neck muscles, with a distance of at least 20 mm between the two electrodes.

[0170] A small incision was made in the left groin and the femoral vein was isolated. A small venous incision was made in the vein and a medical-grade catheter was inserted. The catheter tip was fed through the vein until it was positioned in the inferior vena cava approximately at the level of the kidney. The catheter was secured in place with appropriate suture material and exposed at the nape of the neck via a subcutaneous tunnel from the groin to the dorsal cervical region.

[0171] All surgical sites were rinsed with warm sterile saline and closed with absorbable sutures in the anatomical plane. Cefazolin was administered locally to the surgical site on the head (approximately 0.4 mL, concentration 80 mg / mL). The animals were dressed in clean jackets.

[0172] Catheter patency was maintained by continuous infusion of 0.9% Sodium Chloride Injection, USP (saline) at a rate of 4.0 mL / hour. Catheter patency checks were performed at least daily. Approximately 0.5 mL of fluid was withdrawn from the catheter, and the catheter was flushed with approximately 4 mL of 0.9% Sodium Chloride Injection, USP (saline). Accountability testing for infusion administration was not required because the infusion system was used only for blood sampling and bolus administration of diazepam during seizures.

[0173] Experimental design After appropriate acclimation to the dosing procedure, the reference article (0.5% methylcellulose (MC) in reverse osmosis water) was administered once by oral gavage during Phase 1 of the study. The purpose of Phase 1 was to confirm EEG morphology in all animals before and after the dosing procedure. Traces generated during Phase 1 were used to interpret the data in Phase 2. Starting one day later, the reference article or Compound A was administered once daily by oral gavage for 90 days during Phase 2, as shown in Table 7.

[0174] 3.1.8. Experiments and Methods 3.1.8.1. Mortality rate Mortality checks were recorded simultaneously with cage-side observations (see below) during all phases of the study.

[0175] Clinical observations Clinical signs (illness, behavioral changes, etc.) were recorded twice daily in surviving animals during all phases of the study and monitored continuously for at least 16 hours after the 1st, 3rd, 7th, 14th, and 28th doses in Phase 2 using a digital camera (to minimize animal stress) or direct observation when necessary or during dose administration. Further clinical observations were made if deemed necessary.

[0176] A detailed clinical examination was performed on each animal prior to treatment group assignment and weekly thereafter up to 1 day before treatment initiation and up to the day of necropsy (pre-necropsy).

[0177] Medical Treatment Animals were examined by veterinary staff when indicated by clinical signs or other changes. All veterinary examinations and recommended treatments were recorded in the study record and kept in the study file. Initiation of medical treatments recommended by veterinarians was initiated only after authorization (except for pre-approved treatments) by the study principal investigator (in consultation with the sponsor, if possible). Whenever possible, the sponsor was consulted before administration of systemic medications (i.e., other than topical or emergency diazepam administration). Administration of these medical treatments did not affect the study because they were administered to Group 1 animals (controls), were administered topically, or were not considered to have any interaction with the test article.

[0178] Weight All animals were weighed prior to treatment group assignment, at least weekly before dosing began, and twice weekly thereafter. On the day of necropsy, overnight fasted body weights were recorded for the calculation of relative organ weights.

[0179] Appetite Beginning at least 1 week before treatment initiation and continuing throughout the study, qualitative appetite assessments were performed and recorded once daily (except on food deprivation days) as part of cage-side clinical observations. Appetite was assessed based on the number of cookies remaining in the cage after each daily feeding period.

[0180] 3.1.8.6.Clinical pathology Clinical pathology evaluations (hematology, clinical chemistry, coagulation, and urinalysis parameters) were performed on all animals twice prior to Phase 1 and during weeks 4 and 13 of dosing in Phase 2. Blood samples were collected from the femoral vein via femoral vein catheter or venipuncture, and urine was collected overnight (approximately 14.5–17 h) at room temperature. Food was removed overnight before blood collection (required for clinical chemistry evaluation), and food and water were removed overnight before urine collection. Various additional clinical pathology parameters not mandated by the study design were automatically measured and recorded by the instrument but are not reported. Repeat clinical pathology collections (for hematology and / or coagulation) were performed as needed, with or without food and / or water deprivation.

[0181] 3.1.8.7. Ophthalmology Direct, indirect (fundusoscopy), and biomicroscopic (slit-lamp) examinations were performed on all animals once prior to Phase 1 and once toward the end of the dosing period (week 13 of dosing) in Phase 2. All examinations were performed by a board-certified veterinary ophthalmologist. Animals were anesthetized with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, and mydriatic solution (tropicamide 1%) was applied to both eyes according to standard operating procedures.

[0182] Electrocardiogram Electrocardiograms (ECGs; limb leads I, II, and III and augmented leads aVR, aVL, and aVF) were obtained from all surviving animals once before Phase 1 and once toward the end of the dosing period (week 13 of dosing) in Phase 2. ECGs were recorded 3-5 hours after dosing for each animal.

[0183] Qualitative and quantitative evaluation of ECG recordings was performed to determine the presence of gross changes indicative of cardiac electrical dysfunction, as well as the potential presence of abnormalities including heart rate (lead II), sinus and atrioventricular rhythm, or conduction. Measurements of heart rate, PR interval, QRS duration, QT and QTc (QTcB) intervals were tabulated and incorporated into the study report. Electrocardiograms were evaluated by a board-certified veterinary cardiologist.

[0184] 3.1.8.9. Telemetric EEG and EMG Monitoring EEG and EMG were obtained from the animals using subcutaneously inserted telemetry transmitter leads with bipolar leads (EMG, C4-O2 and Cz-Oz).

[0185] To ensure animal suitability, EEG and EMG of each animal were recorded at least once, approximately 24 hours prior to Phase 1 during pre-procedure. These recordings were examined for abnormalities and kept in the study file but are not included in the study report. Video monitoring was recorded simultaneously but is not reported.

[0186] EEG and EMG monitoring was recorded continuously (except during study-specified procedures or other procedures such as data backup) from at least 72 hours before the first dose in Phase 1 until at least 24 hours after the 28th dose in Phase 2. EEG and EMG monitoring was also recorded continuously (except during study-specified procedures or other procedures such as data backup) for a period of at least 36 hours (from at least 12 hours before dosing until at least 24 hours after dosing), once during week 8 of dosing, and once toward the end of the dosing period (week 13 of dosing) in Phase 2.

[0187] NeuroScore software (Data Science International) was used to analyze EEGs from at least 24 hours before the first dose in Phase 1 to at least 24 hours after the 28th dose in Phase 2, and for at least a 36-hour period (at least 12 hours before dosing to at least 24 hours after dosing), once at week 8 of dosing, and once toward the end of the Phase 2 dosing period (week 13 of dosing). EEGs were evaluated by a neurologist when abnormal clinical signs (e.g., tremors, ataxia, vomiting, muscle twitching, yawning, and / or convulsions) were observed in the EEG sequences identified by the seizure detection module of the NeuroScore software. Electromyography (EMG) was used to aid in the interpretation of the EEG data.

[0188] EEGs were reviewed by a neurologist at 1–1.5, 2.5–5.5, and 7–7.5 hours after doses 1, 3, 7, 14, and 28 in Phase 2. If abnormal behavior / convulsions were observed by the experimenter in an individual animal, EEG review was also performed for approximately the same time period as the abnormal behavior was observed.

[0189] The duration of each seizure was recorded and reported. Prodromal EEG and clinical signs were identified and discussed in relation to seizure onset. The onset of burst waves, onset of generalized seizures, and end of spike trains (or end of generalized seizures) were also recorded and reported. EMG was used to complement EEG interpretation. A signed contribution report was provided by a veterinary neurologist and included in the study report.

[0190] For all animals in Groups 1, 2, and 3, absolute power in the frequency bands delta [0.5-4 Hz], theta [4-8 Hz], alpha [8-12 Hz], sigma [12-16 Hz], beta 1 [16-20 Hz], beta 2 [20-30 Hz], gamma 1 [30-55 Hz], gamma 2 [55-1000 Hz], and total power [0.5-1000 Hz] was calculated in 30-minute bins using NeuroScore software for two periods: approximately 24 hours before the first dose (reference product) in Phase 1, and 24 hours after the second and 27th doses of the reference product in Phase 2 (Group 1) or the second and 27th doses of the test product (Groups 2 and 3). For each frequency band, results were reported as the percent change from a time-matched 30-minute baseline period for each animal.

[0191] Additionally, percent changes from time-matched baseline in the frequency bands listed above were calculated after the 2nd and 27th doses of the reference product in Phase 2 (Group 1) or the 2nd and 27th doses of the test product (Groups 2 and 3) using the following bins: Set A: 2-8 hours, 8-14 hours, 14-20 hours, 20-24 hours after administration Set B: 2-hour bottles from 0 to 24 hours after administration.

[0192] These two sets of data were used for statistical analysis (see Data Analysis). Individual results, group means, and standard deviations for Sets A and B were not reported, but statistical reports were provided to the principal investigator for inclusion in the final report. Frequency bands were calculated for Cz-Oz or C4-O2 derivations.

[0193] 3.1.8.10. Behavioral Video Monitoring Animals were continuously monitored (simultaneously with telemetry-monitored EEG) using a video camera (except during designated study procedures or other procedures such as data backup) from at least 72 hours before the first dose in Phase 1 until at least 24 hours after the 28th dose in Phase 2, and for at least a 36-hour period (from at least 12 hours before dosing until at least 24 hours after dosing), once at week 8 of dosing, and once toward the end of the Phase 2 dosing period (week 13 of dosing). Additionally, behavioral assessments of all animals were performed by technicians in real time for 16 hours after the administration of the first, third, seventh, fourteenth, and twenty-eighth doses in Phase 2. Video monitoring was used to complement EEG interpretation.

[0194] 3.1.8.11. Procedures for when a seizure occurs If convulsions were observed to occur after treatment, either spontaneously or after administration of an anticonvulsant, every attempt was made to obtain blood samples for TK analysis from the animals immediately (within 5 minutes) after resolution of the seizures. If several episodes of convulsions occurred within a short period of time, blood samples could not be collected or were not collected within 5 minutes after resolution of the seizures.

[0195] Convulsions that occurred during the treatment period and did not resolve within 3 minutes of onset were controlled by administration of diazepam (1.0 mg / kg, IV).

[0196] The convulsions observed in two females administered Compound A at 10.0 mg / kg were sufficient to treat with diazepam, and administration of phenytoin or propofol was not necessary.

[0197] 3.1.8.12.Toxicity kinetics Blood samples (target 0.5 mL each, Na-heparin tubes) were collected from all animals at the following time points: Phase 1: 4 hours after administration. Phase 2: Plasma concentrations of Compound A and its metabolites were determined for all dose groups after the first, 29th, and 90th doses. Blood samples were collected from each animal in all groups pre-dose (for the 29th and 90th doses only) and 1, 2, 4, 8, and 24 hours post-dose. Blood samples were collected into Na-heparin tubes via an implanted catheter or by venipuncture from the jugular, cephalic, or femoral vein. Tubes were kept on wet ice until centrifugation. Blood samples were centrifuged at 5400 × g for 5 minutes under refrigerated conditions (set at 4 °C) to obtain plasma. Plasma was divided into duplicate samples (at least 100 μL each), kept on dry ice, and stored in a freezer set at -20 °C until shipment. A backup sample (set 2 of 2) was stored separately from set 1 of 2.

[0198] Non-compartmental toxicokinetic analysis of the plasma concentration data of Compound A and its metabolites was performed by a subcontractor using validated WinNonlin software. For all animals except control animals, the TK parameter (t max , C max , t 1 / 2 , MRT 24 , MRT inf , AUC 24 and AUC inf ) was calculated.

[0199] An attempt was made to collect blood samples (target 0.5 mL) from animals exhibiting convulsions within 5 minutes after resolution of the seizure. If the animal was convulsing and an implanted catheter was used to inject diazepam before blood collection, blood samples were collected from the femoral vein by venipuncture.

[0200] Cerebrospinal fluid collection Prior to necropsy, CSF (target volume: 2 mL) was collected from anesthetized animals by puncturing the cerebello-medullary cistern of the foramen magnum using a needle and infusion or aspiration. Animals were anesthetized with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, followed by maintenance with isoflurane via inhalation. A fixed volume of rat plasma was added to each CSF sample at a ratio of 1 part rat plasma for every 9 parts CSF. For example, if 2 mL of CSF was retained, 0.222 mL of rat plasma was added. The volume was adjusted to maintain a plasma-to-CSF ratio of 1:9.

[0201] Rat blood was collected from rats of any strain into tubes containing K2 EDTA or sodium heparin as an anticoagulant. The tubes were kept on wet ice until centrifugation, which was performed under refrigeration (set at +4°C and 1500g RCF) for a target time of 10 minutes to obtain plasma. Plasma was kept on dry ice until stored in a freezer (set at -70°C) until use. Rat plasma was thawed and kept on wet ice on the day of use, or collected on the same day as CSF collection and kept on wet ice.

[0202] After the addition of rat plasma, the samples were thoroughly mixed (using a vortex) and transferred to two separate tubes. CSF samples were labeled with, at a minimum, the animal number, species, dose group, collection date, date, nominal collection time, sample type (i.e., CSF), storage conditions, and study number. Samples were flash-frozen using liquid nitrogen and placed on dry ice until storage in a freezer set at -70°C. Backup samples (Set 2 of 2) were stored separately from Set 1 of 2, except for December 22–24, 2015, and December 29, 2015–January 4, 2016, when both sets of samples were stored in the same freezer. Because the freezer temperature during these periods remained within acceptable limits, this deviation did not affect the study.

[0203] 3.1.8.14. Visual Inspection Animals surviving to scheduled termination were euthanized after an overnight period without food and subjected to macroscopic examination. Animals were sedated with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, then euthanized by an intravenous overdose of sodium pentobarbital, followed by exsanguination.

[0204] For all animals, necropsies consisted of an external gross examination, including identification of all clinically documented lesions, as well as a detailed internal examination. Necropsies, performed during normal working hours, were performed under the supervision of a veterinary pathologist.

[0205] Similar proportions of animals from each group and sex were euthanized on any one day, as needed. When possible, the necropsy sequence for each study group began with the controls (Group 1).

[0206] To avoid autolytic changes, all animals that died prematurely or at scheduled termination underwent a gross carcass examination as soon as possible.

[0207] The implanted transmitter was retrieved by visual inspection.

[0208] 3.1.9. Brain Tissue for Compound A and Metabolite Concentration Analysis Two samples of fresh brain tissue per animal were weighed: one from the frontal cortex and two from the striatum (minimum 100 mg, ideally 150 mg per sample). A fixed amount of rat plasma was added to each brain sample at a 1:4 ratio. For example, if 150 mg of fresh brain tissue was retained, 600 μL of rat plasma was added. If different amounts of tissue were collected, the volume of rat plasma was adjusted to maintain a 1:4 ratio.

[0209] Rat blood was collected from rats of any strain in advance in tubes containing Na-heparin as an anticoagulant. The tubes were kept on ice until centrifugation, and centrifuged for a target time of 10 minutes under refrigeration (set at +4°C and 1500g RCF) to obtain plasma. Rat plasma was stored frozen (in a freezer set at -70°C) until thawed, and then kept on wet ice on the day of use.

[0210] After the addition of rat plasma, the samples were homogenized. Two frontal cortex samples from each animal were combined after homogenization and divided into two equal aliquots. Two striatum samples from each animal were combined after homogenization and divided into two equal aliquots. Samples were kept on wet ice while awaiting storage in a -70°C freezer until shipment. The analytical method used for brain tissue was not GLP-compliant. The concentrations of Compound A and its metabolites in brain tissue samples were determined using an LC-MS / MS method and Analyst software.

[0211] 3.2. Discussion and Conclusions Oral administration of Compound A to male and female cynomolgus monkeys once daily for 13 weeks at dose levels of 10.0 mg / kg / day or less was not associated with any effects on mortality, body weight, clinical pathology, electrocardiography, ophthalmology, organ weights, or gross or microscopic parameters.

[0212] There were no adverse clinical signs or abnormal EEG changes in males or females at 0.3 or 3.0 mg / kg / day of Compound A. In males, hypoactivity, tremors, and circling were observed at 10 mg / kg / day; however, these were mild, transient, and not associated with abnormal EEG activity and were not considered adverse. In females, myoclonic seizures, hypoactivity, weakness, and incoordination were observed at 6.0 mg / kg / day, and salivation, excessive licking, hypoactivity, weakness, lying on the cage floor, nystagmus, incoordination, muscle twitching, and myoclonic seizures were observed at 10.0 mg / kg / day. In females, these clinical signs were observed with a higher incidence and / or severity at 6.0 and 10.0 mg / kg / day compared to control animals and were considered adverse. An episode suggestive of self-limited convulsions in a female monkey was observed by technical staff on the second day of administration at 6.0 mg / kg / day. However, analysis of the EEG and EMG obtained during the observation period showed that typical seizures or postictal changes did not occur after clinical signs, suggesting that the episode may have been catalepsy or a partial seizure rather than a generalized seizure. In humans, catalepsy has been reported after administration of drugs such as ketamine (Heitz CR, Bence JR. Ketamine-induced catalepsy during adult sedation in the Emergency Department. J. Emerg. Med. 2013 Feb;44(2):e243-5). Furthermore, partial seizures in humans may not be identified by EEG if focal ictal discharges are distal or deep, or if the neuronal aggregates for synchronous depolarizing activity are too small to be detected on EEG (Smith, 2005). Technical staff also reported a convulsion in the same animal after administration of Compound A at 6.0 mg / kg / day on day 79, but no EEG tracings or video were available to characterize the episode.

[0213] Self-limited generalized seizures confirmed by EEG were observed in two female monkeys treated with 10.0 mg / kg / day Compound A (animal 5502 on day 2 and animal 5504 on days 3, 7, and 8, respectively, with one and ten generalized seizure episodes). Tremor was present across all dose groups, but incidence and / or severity was highest in females treated with 10.0 or 6.0 mg / kg / day, including two female monkeys that did not exhibit seizures. Therefore, the increased incidence and / or severity of tremor and seizures at 6.0 / 10.0 mg / kg / day likely reflects an excessive pharmacological effect of Compound A at higher dose levels, although the incidence of tremor and seizures were separable. In animals that exhibited seizures, tremor was observed at least 2 hours before seizure onset. Therefore, an increased incidence of tremor may be useful for monitoring early signs of potential toxicity associated with Compound A treatment in humans, although the presence of tremor is not always associated with convulsions.

[0214] Overall, Compound A was associated with increases in total EEG power. The effects appeared to be greater in males, but females still showed increased power, primarily after the second dose. In many cases, the magnitude of the stimulation effect did not show a dose-dependent pattern, suggesting that a dose as low as 0.3 mg / kg / day had activity comparable to that of 3 mg / kg / day. In some cases, increases in power bands were followed by compensatory decreases, as might be expected after activation. The most consistent qEEG effects were increases in low frequencies (i.e., delta, theta) and decreases in high frequencies (i.e., gamma 1), as well as an overall increase in total power in males after the 27th dose.

[0215] Pharmacokinetic analysis revealed higher Compound A exposure in both females that exhibited generalized seizures compared to other animals. After administration of 6.0 and 10.0 mg / kg / day, the highest concentrations of Compound A in plasma, CSF, and brain were observed in the two females that exhibited convulsions. The convulsive episodes occurred at t maxFurthermore, TK analysis of plasma collected from these two animals immediately after the onset of what appeared to be a seizure episode showed that plasma levels of Compound A were highest at these time points, with C max suggesting a relationship between cerebrospinal fluid (CEF) and seizure episodes.

[0216] The average t for compound A across all TK sampling days max The values ​​ranged from 2.0 to 15.0 hours. max and AUC 24 The mean C values ​​increased dose-dependently after the 1st, 29th, and 90th doses in males, except for Compound A at 3.0 to 10.0 mg / kg / day. max and AUC 24 Values ​​were increased or tended to increase. There were no clear gender differences in exposure, except at the highest dose (10.0 / 6.0 mg / kg / day), where females received higher exposure than males.

[0217] Based on the above, adverse clinical signs (salivation, excessive licking, hypoactivity, weakness, tremors, muscle twitching, myoclonic seizures, incoordination, nystagmus, and lying on the cage floor) and abnormal EEG changes suggestive of catalepsy or seizures were observed in females at >3.0 mg / kg / day. Therefore, the no observed adverse effect level (NOAEL) was concluded to be 10.0 mg / kg / day for males and 3.0 mg / kg / day for females. [Table 7-1] [Table 7-2] M: male, F: female a The same animals were utilized in Phases 1 and 2 because no EEG, behavioral, or other abnormalities occurred in any of the animals during Phase 1. b Reference product = 0.5 w / v%MC in reverse osmosis water. cDose volume was 5 mL / kg for all animals. d Due to clinical findings of convulsions in two females at 10.0 mg / kg / day, the dose of Compound A was reduced to 10.0-6.0 mg / kg / day for all females starting at the indicated dose number. e Animal 5504 had a washout period that included doses 2-4 and doses 8-12. f Animal 5502 had a washout period that included doses 2-4.

[0218] Example 4: Population PK modeling and simulation of Compound A to support dose selection for planned clinical studies 4.1. Method Data Processing Data processing and graph visualization were performed using Matlab® (version R2019a; MathWorks, Inc., Natick, MA, USA). Outliers were not removed from the available data, but one missing data point was excluded from the analysis, and concentration-time points below the LOQ were excluded. The data (points) were processed using the M3 Beal method implemented in Monolix (2019-R1 suite; Lixoft SAS, Antony, France).

[0219] 4.1.2. Model building and evaluation A population PK model describing the PK of Compound A after oral administration in eligible subjects enrolled in the Compound A study (Example 1) was developed using nonlinear mixed-effects modeling implemented in Monolix. The Stochastic Approximation of Expectation Maximization (SAEM) algorithm, a probabilistic algorithm for calculating maximum likelihood estimators, was selected as the model estimation method due to its ability to accurately estimate population parameters.

[0220] Model construction and selection was based on the following criteria / procedures: ·Evaluation of individual and population parameter estimates and their precision (precision was quantified using the percentage relative standard error (%RSE)); ·Graphical inspection of diagnostic plots and goodness-of-fit plots; ·Analysis of correlation matrix and condition number of estimates; · Reduction of both residual and inter-individual variability; and · Decrease in log likelihood (-2LL), Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) for all nested models.

[0221] Base models were constructed using these criteria by comparing different structural models (e.g., one-compartment, two-compartment, three-compartment) with different absorption (e.g., zero-order, first-order) and elimination (e.g., linear, nonlinear) processes. Base model development was performed by adding the interindividual variability (IIV) of one structural parameter at a time and applying set criteria to select the best model. IIV was generally modeled as an exponential term as follows: log(Par)=log(TV Par )+ETA Par (1) or equivalently: Par=TV Par * exp(ETA Par )(2)

[0222] In equations (1) and (2), ETA was assumed to be normally distributed. Several error models were also tested, including additive error, proportional error, and combined (additive + proportional) error. The combined additive and proportional error terms in functional form are: Y=Y+(a+bY) * eps(3)

[0223] In equation (3), eps was assumed to be normally distributed. Correlations between random effects were also included to account for potential collinearity between individual parameters.

[0224] Next, a covariate model was constructed to further reduce unexplained interindividual variability. The covariate model was developed using forward and backward elimination methods. In the forward step, covariates were tested one by one. Those that significantly (p-value < 0.05) reduced -2LL (Δ-2LL < -3.84) were retained, and the one that produced the most significant reduction was finally incorporated into the base model. This step was repeated until no covariate was found to significantly reduce -2LL. In the backward elimination step, covariates were eliminated one by one, and the change in -2LL was recorded. If the elimination of a covariate significantly increased -2LL (Δ-2LL > 10.83) (p-value < 0.001), the covariate was eliminated from the model. Otherwise, the covariate was retained. This step was repeated until the elimination of a covariate was found not to significantly increase -2LL, and the corresponding model was considered the final model.

[0225] All investigated continuous covariates were centered / normalized to their baseline values ​​and added to the base model using a power function as follows: log(Par)=log(TV Par )+THETA * log(Cov / Cov Ref )+ETA Par (4) or equivalently: Par=TV Par *(Cov / Cov Ref )^THETA*exp(ETA Par )(5)

[0226] All investigated categorical covariates were scaled to a reference value (set equal to 0) and added to the base model as follows:

number

[0227] The final model was evaluated using visual predictive check, a simulation-based method for visually assessing the agreement between model-based simulations and observed data. Bootstrap analyses were also performed to determine the precision of parameter estimates, estimate confidence intervals for identified parameters, and assess the stability of the model.

[0228] 4.1.3.Model-based Simulation The developed POPPK model was used to assess Compound A steady-state exposure (C) in 1000 healthy subjects receiving different dosing regimens. max,ss The median and variability of AUC,ss (and AUC,ss) were simulated to inform the design of the planned phase 2 clinical study. In performing this scenario analysis, the predicted AUC,ss of Compound A was constrained to always remain below 10x the NOAEL exposure cap (17,400 ng·h / mL) derived from a 14-day neurotoxicity study in rats to ensure the safety of the recommended dose for the upcoming phase 2 trial. The R-based Monolix PK simulator, SimulX, was used to simulate the final models for various dose regimens. SimulX was implemented in R (version 3.5.3; Vienna, Austria) via the RStudio console (version 1.2.133).

[0229] 4.2.Results Final Model Figure 4 shows the schematic structure of the final POPPK model. The parameter estimates of the final model, the precision of the parameter estimates reported as percent relative standard error (RSE%), the parameter estimates of the final model, and their confidence intervals (CI) obtained from the bootstrap analysis are listed in Table 8. All values ​​of the population parameters were estimated with good precision (RSE<37%). The IIV was <70% for TLag, V1 / F, and CL, and <10% for K. AThe additive and proportional residual variability was approximately 35% SD and 38% CV, respectively.

[0230] 4.2.2. Model-Based Simulation to Inform Compound A Study Design Because the final POPPK model adequately described the PK of orally administered Compound A in the SRD / MRD cohort of healthy subjects, this model was used to guide the design of planned Compound A clinical trials. A scenario analysis was performed to simulate various dose regimens and recommend a dose that would maximize Compound A exposure (AUC,ss) while maintaining exposure below 10-fold the NOAEL exposure cap (17,400 ng·h / mL) derived from a 14-day neurotoxicity study in rats. The following scenarios were investigated: 1. Daily administration of 2.5 mg of Compound A for 8 days; 2. A loading dose of 6 mg, followed by 2.5 mg of Compound A daily for 7 days; and 3. A loading dose of 6 mg followed by 3 mg of Compound A daily for 7 days.

[0231] Figure 5 summarizes the results of the simulated dose regimens considered for the planned Compound A clinical study.

[0232] Table 9 reports the exposure margins for exposures in rats at 1 / 10 of the NOAEL from neurotoxicity studies. Simulation results show that for all proposed scenarios in the Compound A study, the median exposure margin remains well below the NOAEL cap.

[0233] Table 10 shows the C achieved after repeated administration. max,ss The use of a loading dose allows for fine tuning the achievement of steady-state conditions within a pre-specified timeline. [Table 8] TLag_ pop:T Lag The population value of K A_ pop:K A Population value of CL / F; CL / F_pop: Population value of CL / F; V / F_pop: Population value of V / F; DOSE on K A : Effect of dose as a covariate on KA; WT on K A :K A WT on V / F: Effect of weight as a covariate on V1 / F; WT on CL / F: Effect of weight as a covariate on CL / F; T Lag_ IIV: Inter-individual variability of TLag; K A_ IIV:K A V / F_IIV: Inter-individual variability of V / F; CL / F_HV: Inter-individual variability of CL / F; V / F-CL / F corr: Correlation between V / F and CL / F [Table 9] [Table 10]

[0234] 4.3. Summary and Conclusions Using data from the Compound A clinical study (Example 1), a POPPK model was developed to recommend optimal dosing regimens for planned Compound A clinical studies using model-based simulations. A total of 2,377 observed individual Compound A plasma concentration-time points from 66 eligible subjects were used for model development. A total of 44 Compound A plasma concentration-time points (1.85% of all data) were found to be below the limit of quantitation (LOQ) of 0.1 ng / mL. All available data were used for model construction and evaluation.

[0235] A one-compartment model with a delayed first-order absorption process and linear elimination was identified to best describe the PK of Compound A after single (0.3-18 mg) and multiple (0.3-9 mg QD) oral dose administration in healthy subjects. Interindividual variability (IIV) was calculated using the absorption rate constant (K A ), delay time (T Lag ), was included as an exponential term for the apparent volume of distribution in the central compartment (V / F) and the apparent clearance after extravascular administration (CL / F). max and C trough To better capture K across all dose regimens, a power function was used to A , CL / F and V / F are weighted as covariates, and a power function is used to calculate K A Dose was included as a covariate for . Significant errors were modeled as a combination of additive and proportional errors. Model qualification was performed using visual predictive checks and bootstrapping.

[0236] The developed PopPK model adequately describes the PK of Compound A, and the model was used to select the optimal dose regimen for the planned Compound A clinical study. Based on model simulations, subjects enrolled in the Compound A study will receive a 6 mg loading dose of Compound A on Day 1, followed by a 3 mg daily maintenance dose. The proposed daily maintenance dose after the loading dose has a predicted area under the time-concentration curve at steady state (AUC,ss) that is, on average, at least 10-fold lower than the observed NOAEL exposure cap obtained from rat neurotoxicity studies.

[0237] Example 5: A randomized, double-blind, placebo-controlled, three-period crossover study followed by one open-label comparison period to evaluate the CNS PD activity of Compound A in healthy subjects using TMS 5.1. Overall study design and planning This randomized, double-blind, placebo-controlled, three-period crossover study, followed by one open-label comparison period, was designed to evaluate the CNS PD activity of Compound A in healthy subjects using transcranial magnetic stimulation (TMS), as shown in Table 11. Twenty-four healthy male and female subjects aged 18 to 55 years were enrolled. [Table 11] a The all-human analysis included 24 subjects, excluding the MEP 6.0 g dose change (only 23 of 24 subjects were included). * Black and White mixed race subjects were counted once as Black.

[0238] The study included three treatments (placebo, 0.5 mg Compound A, and 6 mg Compound A) over three periods, each 1 day long, followed by a 2-day comparison (IV ketamine 0.5 mg / kg) period, alternating with three washout periods of at least 10 days (but not more than 15 days). There were five clinic visits, including a screening where a complete medical, neurological, and psychiatric examination was conducted. On Day 1 of each of the first three treatment periods, TMS testing was conducted before and after subjects received placebo or Compound A. On Day 1 of the fourth treatment period, TMS testing was conducted before and after subjects received the NMDA antagonist ketamine (this was open-label).

[0239] Prior to the start of each treatment period, the investigator reviewed the subject's safety assessments, including vital signs and ECG.

[0240] Referring now to Figure 6, on the first day of each treatment period (Day 1), each subject underwent a TMS session to assess baseline TMS-evoked MEP amplitude and threshold, followed by administration of Compound A or placebo (Treatment Periods 1-3) or ketamine (Treatment Period 4). For the first three treatment periods, TMS and MEP / EEG assessment sets were conducted pre-dose and starting 30 and 150 minutes (2.5 hours) post-dose, along with blood sample collection for PK analysis. The 2.5 hour time point was C max The 30-minute time point was selected to obtain a lower exposure level in each subject. In treatment period 4, each subject underwent a TMS session to assess baseline TMS-evoked MEP amplitude and threshold, as well as blood sampling for pre-dose pharmacokinetic analysis, followed by IV ketamine (0.5 mg / kg over 40 minutes). TMS assessment was performed 150 minutes (2.5 hours) after ketamine initiation (when the acute dissociative effects of ketamine had subsided), and blood samples were collected for pharmacokinetic analysis at selected time points. To obtain ketamine modulation of TMS responses at a time when ketamine's antidepressant effects are already present in the MDD population, subjects underwent a follow-up TMS session starting 24 hours later (day 2 of treatment period 4).

[0241] On the day of treatment, subjects remained at the clinic until approximately 2 hours after the TMS procedure for safety observations. During the ketamine study, subjects remained at the site overnight after the injection until a 24-hour follow-up TMS assessment was completed. Prior to discharge, neurological and mental status examinations were performed.

[0242] TMS-induced EEG and MEP signals were selected as PD endpoints to assess the effects of Compound A based on preclinical data showing that Compound A increases MEP amplitude in rats. The purpose of this study was to evaluate the PD effects of Compound A after a single dose treatment as measured by the response to TMS.

[0243] Details of the investigational drugs and sequences are shown in Table 12. [Table 12]

[0244] Subjects reported to the clinical site on Day 1 of all treatment periods and discharged after completing all study-related procedures on each of Treatment Periods 1-3. At the investigator's discretion, subjects may be required to remain at the clinical site longer. On Day 1 of Treatment Period 4, during the ketamine testing period, subjects remained at the site overnight after infusion until a 24-hour follow-up TMS assessment was completed. Prior to discharge, neurological and mental status examinations were performed.

[0245] Subjects fasted from all food and beverages, except water, for at least 8 hours prior to screening and study drug administration during all four treatment periods. Subjects received a single oral dose of study drug (Compound A or placebo tablets in Treatment Periods 1-3), ketamine (Treatment Period 4), and TMS procedures. They were offered meals with approximately 240 mL of water after the second TMS assessment on the day of administration. Water was restricted 1 hour before and 1 hour after study drug administration. A standard meal was offered to subjects present during mealtimes on scheduled study visits as outlined in the study procedure schedule. The caloric content and composition of the meals were the same for all subjects in each treatment period. During Treatment Period 4, after the 24-hour post-dose procedures were completed, subsequent meals and snacks were not restricted in caloric content, composition, or timing.

[0246] Safety was assessed by complete physical examination, vital signs, 12-lead ECG, AE monitoring, and clinical laboratory tests (hematology, chemistry, and urinalysis).

[0247] PD assessment was performed to determine the threshold and amplitude of MEPs driven by single-pulse TMS, TMS stimulation paradigms, EEG signals, and CHDR Neurocart (body sway, smooth pursuit eye movements, saccadic eye movements, adaptive pursuit, Stroop test, Bond and Lader visual analog scale (VAS) and Bowdle VAS).

[0248] Plasma concentrations of Compound A and ketamine were determined for all evaluable subjects.

[0249] In this study, TMS-induced MEPs were the key procedure.

[0250] Post-TMS dose assessments were performed as close to the exact nominal time point / scheduled time as possible.

[0251] All other procedures were performed as close in time as possible (either before or after the nominal time of the critical procedure).

[0252] If co-scheduled, ECG and vital signs were obtained before PK blood sampling.

[0253] Priorities may be changed during the study with the joint consent of the investigator and sponsor.

[0254] Any unscheduled procedures requiring urgent evaluation of safety concerns took priority over all routinely scheduled procedures.

[0255] 5.2. Discussion and Overall Conclusions 5.2.1. Discussion This study was designed to evaluate whether Compound A increases CNS excitability in healthy subjects compared to placebo. This study provides a preliminary assessment of whether Compound A modulates responses evoked by paired TMS pulses to obtain intracortical modulation and whether ketamine increases CNS excitability as assessed by TMS-evoked MEPs.

[0256] Peak-to-peak amplitude of MEPs was obtained with single-pulse TMS (stimulus intensity 120% of baseline rMT). At 2.5 hours post-dose, 6 mg of Compound A demonstrated a statistically significant difference from baseline when compared with placebo. The change from baseline in rMT obtained with single-pulse TMS was not statistically significant. The change from baseline in LICI 300 ms was statistically significant for 0.5 mg of Compound A at 2.5 hours post-dose. SICI measurements and other secondary endpoints were not statistically significant. Compound A was generally well tolerated at single doses of 0.5 mg and 6 mg of Compound A as oral tablets, and 20 subjects received a single dose of ketamine 0.5 mg / kg administered as an IV infusion. No deaths or SAEs were reported, and no subjects treated with placebo or Compound A discontinued due to AEs or experienced AESIs (convulsions and seizures). One ketamine-treated subject discontinued study drug due to an AE.

[0257] 5.2.2. Conclusion 6 mg of Compound A demonstrated statistically significant PD effects as measured by single-pulse peak-to-peak amplitude TMS measurements at 2.5 hours post-dose. Additionally, 0.5 mg of Compound A demonstrated statistically significant PD effects as measured by rMT, LICI 300 ms only, at 2.5 hours post-dose.

[0258] Example 6: A randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of adjunct Compound A in adult subjects with major depressive disorder A Phase 1b randomized, double-blind, placebo-controlled trial will be conducted in approximately 10 subjects (minimum 6 active and 2 placebo completers) at up to three study sites in the United States.

[0259] Subjects included male and female subjects aged 18-65 years (inclusive) with a primary diagnosis of MDD, defined as currently receiving stable pharmacological treatment for depression and a ≤50% change in dose during the 6 weeks prior to randomization. Any other psychopharmacological treatment, if present, must also be stable.

[0260] Subjects will be housed in an inpatient research center for two weeks to monitor the safety and tolerability of Compound A. After providing informed consent, subjects will be screened for eligibility within 28 days prior to Day 1 (first day of dosing). Eligible subjects will be admitted to the research center on Day -1 (the day prior to dosing) and safety assessments will be performed.

[0261] On day 1, subjects are randomized to receive either Compound A or placebo for two weeks. The dose is formulated as a tablet for oral administration, and subjects are instructed to take the study drug with water. Subjects in the Compound A group receive a single loading dose of 6 mg on day 1, followed by 3 mg daily from day 2 to day 14. Subjects in the placebo group receive matching placebo tablets on the same schedule as Compound A. The test treatment is administered orally every morning from day 1 to day 14 (the test treatment can be administered with or without food).

[0262] The expected duration of study participation for each subject is approximately 53 days, including up to 28 days of screening, 15 days of hospitalization, and 10 days of follow-up. A schematic diagram of the study design is provided in Figure 8.

[0263] The primary objective of this study is to evaluate the safety and tolerability of Compound A when administered to subjects with major depressive disorder (MDD) taking antidepressants. Safety endpoints investigated include treatment-emergent adverse events (TEAEs), electrocardiogram (ECG), vital signs, clinical laboratory values, and Columbia-Suicide Severity Rating Scale (C-SSRS) outcomes.

[0264] Exploratory endpoints include: (1) assessing the PK of Compound A in subjects with MDD taking antidepressants; (2) examining the efficacy of Compound A on depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS); (3) exploring the overall effect of Compound A on MDD severity as measured by the Clinical Global Impression-Severity Scale (CGI-S); and (4) exploring the overall effect of Compound A on MDD improvement as measured by the Clinical Global Impression-Improvement Scale (CGI-I).

[0265] All safety and exploratory endpoints will be summarized narratively by treatment group. [Table 13] HDPE = High Density Polyethylene [Table 14-1] [Table 14-2] [Table 14-3]

Claims

[Claim 1] The invention described in the specification.

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