Compositions and methods for the treatment of depression

Abstract

The present disclosure provides a method for treating major depressive disorder in a human patient, the patient being identified as positive for a biomarker signature. The method comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof to a patient in need of treatment for major depressive disorder. In some embodiments, the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In other embodiments, the other antidepressant therapy includes a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 298,047, filed January 10, 2022, which is incorporated by reference herein in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods for treating depression using Aticaplant, where a patient has anhedonia and / or is identified as biomarker signature positive. [Background technology]

[0003] Kappa opioid receptors (KOR) and their natural ligand dynorphin are localized in brain regions that provide reward and stress and may play important roles in mood, stress, and addictive disorders. Chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, activating KOR and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surges and contribute to negative emotional states. The behavioral pharmacology of KOR antagonism has been tested in models of anhedonia, depression, and anxiety and found to have meaningful effects that may translate to therapeutic benefit in humans. KOR antagonists may be effective in treating patients with mood disorders, possibly by modulating negative emotional states associated with stress responses.

[0004] Anhedonia is one of the core symptoms of depression. At least anhedonia symptom remission is present in approximately 90% of patients suffering from major depressive disorder (MDD). Only approximately 50% of patients with MDD show a significant response (>50% improvement to first-line antidepressant therapy), leaving many patients with substantial persistent disability. Treatment strategies such as antidepressant switching and the use of adjuvant drug therapy can improve response, but nearly 40% of patients remain symptomatic and fail to achieve complete remission.

[0005] What is needed are improved treatments for patients with depression and anhedonia. Summary of the Invention

[0006] In some aspects, the present disclosure relates to a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is identified as having (a) anhedonia or (b) a biomarker signature positive, and the patient is identified as having a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In certain embodiments, the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaplant or a pharmaceutically acceptable salt thereof. In certain embodiments, the other antidepressant therapy included one or more antidepressants. In certain embodiments, the one or more antidepressants included selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) therapy, or a combination thereof.

[0007] In a further aspect, the disclosure relates to a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and wherein the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0008] In further aspects, the patient has anhedonia, for example, the patient has high anhedonia as measured by a total score of ≧32 on the Snaith-Hamilton Pleasure Scale (SHAPS).

[0009] In certain aspects, the disclosed methods further include adjunctive treatment with an effective amount of one or more antidepressants, such as a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0010] In still further embodiments, the patient is identified as biomarker signature positive. In certain embodiments, the patient is identified as biomarker signature positive when the biological sample obtained from the patient is identified as having at least one of (a) a CRP level higher than the reference CRP level, and (b) (i) a TNF-α level higher than the reference TNF-α level, and (ii) a sIL6R level higher than the reference sIL6R level. In certain embodiments, the patient is identified as biomarker signature positive when the biological sample obtained from the patient is identified as having a dynorphin level higher than the reference dynorphin level. In certain embodiments, the patient is identified as biomarker signature positive when the biological sample obtained from the patient is identified as having (a) a CRP level higher than the reference CRP level, and at least one of (i) a TNF-α level higher than the reference TNF-α level, and (ii) a sIL6R level higher than the reference sIL6R level, or (b) a dynorphin level higher than the reference dynorphin level. In certain embodiments, a patient is identified as being biomarker signature positive when a biological sample obtained from the patient is identified as having (a) a level of CRP higher than a reference CRP level, and at least one of (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level, and (b) a level of dynorphin higher than a reference dynorphin level. In certain embodiments, a patient is identified as being biomarker signature positive when a biological sample obtained from the patient is identified as having a level of dynorphin higher than a first reference dynorphin level, or (i) a level of CRP higher than a reference CRP level, and at least one of a level of TNF-α higher than a reference TNF-α level and a level of sIL6R higher than a reference sIL6R level, and (ii) a level of dynorphin higher than a second reference dynorphin level, where both (i) and (ii) are present. [Brief description of the drawings]

[0011] [Figure 1]1 shows the clinical trial design for Example 1. [Diagram 2] FIG. 1 is a line graph showing least squares mean change (±SE) in MADRS (Montgomerysis-Ausberg Depression Rating Scale) total score from baseline during the treatment period for the enriched intent-to-treat (eITT) analysis set. [Diagram 3] 13 is a plot showing MADRS total score change at 6 weeks of treatment for the enriched and complete populations: MMRM Results-Estimated LS Mean and comparison to placebo. [Figure 4] FIG. 13 is a line graph showing least squares mean change (±SE) in SHAPS (Snaith Hamilton Pleasure Scale) total score from baseline for the eITT analysis set. [Diagram 5] FIG. 13 is a plot showing SHAPS total score change at week 6 of treatment for the enriched and complete populations: MMRM (Mixed-effects Model for Repeated Measures) results--estimated LS means and comparison to placebo. [Figure 6] 1 is a line graph showing MADRS total scores over time for the eITT analysis set: Mean (±SE). [Figure 7A] FIG. 1 is a line graph showing MADRS total scores over time for the full intent-to-treat (fITT) analysis set: mean (±SE). [Figure 7B] Excerpt from Figure 7A for weeks 0 to 6 of treatment. [Figure 8] FIG. 13 is a line graph showing the percentage of subjects with MADRS total score:remission of depressive symptoms (total score≦10) during treatment for the eITT analysis set. [Figure 9] fLine graph showing MADRS total score: percentage of subjects with remission of depression symptoms (total score < 10) during treatment for the ITT analysis set. [Figure 10]FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the eITT analysis set. [Figure 11] fLine graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the ITT analysis set. [Figure 12] FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the eITT analysis set. [Figure 13] fLine graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the ITT analysis set. [Figure 14] SHAPS total score over time for the eITT analysis set: line graph showing mean (±SE). [Figure 15] SHAPS total score over time for the fITT analysis set: line graph showing mean (±SE). [Figure 16] Changes in MADRS from baseline according to severity of anhedonia are shown. [Figure 17A] FIG. 1 is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS≧38. [Figure 17B] FIG. 1 is a line graph showing MADRS change from baseline in patients with low anhedonia, i.e., SHAPS<38. [Figure 18] FIG. 1 is a bar graph showing a comparison of MADRS in patients with low and high anhedonia. [Figure 19] 1 is a line graph showing the mean ASEX total score change from baseline. [Figure 20] 1 is a bar graph showing the mean ASEX item-level change total score change from baseline. [Figure 21]The study scheme of Example 2. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Additionally, approximately 34 elderly participants will be randomized. [Figure 22] The study scheme of Example 3. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Additionally, approximately 68 elderly participants will be randomized. [Figure 23] 1 is a bar graph showing the SHAPS Item:LS Mean Change from Baseline at Week 6 by Baseline SHAPS Total Score for the fITT Analysis Set. In this figure, from top to bottom, the bars alternate between placebo or Atticaplant. For example, the first bar refers to Atticaplant, the second bar refers to placebo, the third bar refers to Atticaplant, etc. [Figure 24] f Plot showing MADRS total score at week 6 by different subgroups for the ITT analysis set: LS mean difference (60%). In this plot, <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe. [Diagram 25] A two-panel boxplot of the effect of biomarker signature on patient response to treatment is shown. Three MM biomarker signature positive patients (21% with MDD) responded with a 6.3 MADRS point difference at final DB compared to placebo, a 4.7 point improvement compared to their biomarker signature negative counterparts. [Figure 26A]Plots summarizing the results of patient subtyping using a biomarker signature consisting of dynorphin levels alone. Figure 26A is a graph of treatment effect and signature dominance in the biomarker signature positive group. Figure 26B shows the signature effect at a δ level of 19.9 pg / mL (SigPos=DYN>19.9, 64% of the cohort). Figure 26C shows the signature effect at a δ level of 30 pg / mL (SigPos=DYN>29.5, 48% of the cohort). Figure 26D shows that the signature effect is more variable at higher levels of dynorphin (SigPos=DYN>48.7, 30% of the cohort). [Figure 26B] Plots summarizing the results of patient subtyping using a biomarker signature consisting of dynorphin levels alone. Figure 26A is a graph of treatment effect and signature dominance in the biomarker signature positive group. Figure 26B shows the signature effect at a δ level of 19.9 pg / mL (SigPos=DYN>19.9, 64% of the cohort). Figure 26C shows the signature effect at a δ level of 30 pg / mL (SigPos=DYN>29.5, 48% of the cohort). Figure 26D shows that the signature effect is more variable at higher levels of dynorphin (SigPos=DYN>48.7, 30% of the cohort). [Figure 26C] Plots summarizing the results of patient subtyping using a biomarker signature consisting of dynorphin levels alone. Figure 26A is a graph of treatment effect and signature dominance in the biomarker signature positive group. Figure 26B shows the signature effect at a δ level of 19.9 pg / mL (SigPos=DYN>19.9, 64% of the cohort). Figure 26C shows the signature effect at a δ level of 30 pg / mL (SigPos=DYN>29.5, 48% of the cohort). Figure 26D shows that the signature effect is more variable at higher levels of dynorphin (SigPos=DYN>48.7, 30% of the cohort). [Figure 26D]Plots summarizing the results of patient subtyping using a biomarker signature consisting of dynorphin levels alone. Figure 26A is a graph of treatment effect and signature dominance in the biomarker signature positive group. Figure 26B shows the signature effect at a δ level of 19.9 pg / mL (SigPos=DYN>19.9, 64% of the cohort). Figure 26C shows the signature effect at a δ level of 30 pg / mL (SigPos=DYN>29.5, 48% of the cohort). Figure 26D shows that the signature effect is more variable at higher levels of dynorphin (SigPos=DYN>48.7, 30% of the cohort). [Figure 27A] Plots summarizing the results of patient subtyping using biomarker signatures using a combination of high dynorphin and 3MM subtypes. Figure 27A is a graph of treatment effect and signature dominance in the biosignature positive group. One caveat is that the signature dominance defined by SigPos and SigNeg is not stable at higher cutoffs. Figure 27B shows that for biomarker signature negative patients (SigPos=3MM or DYN>19.9, 73% of the cohort), the interaction effect is much more pronounced due to a worse mean atcactus response than placebo. Figures 27C and 27D show that the effect of the biomarker signature is more stable at higher dynorphin cutpoints. Figure 27C shows SigPos=3MM or DYN>29.5, 61% of the cohort. Figure 27D shows SigPos=3MM or DYN>48.7, 48% of the cohort. [Figure 27B]Plots summarizing the results of patient subtyping using biomarker signatures using a combination of high dynorphin and 3MM subtypes. Figure 27A is a graph of treatment effect and signature dominance in the biosignature positive group. One caveat is that the signature dominance defined by SigPos and SigNeg is not stable at higher cutoffs. Figure 27B shows that for biomarker signature negative patients (SigPos=3MM or DYN>19.9, 73% of the cohort), the interaction effect is much more pronounced due to a worse mean atcactus response than placebo. Figures 27C and 27D show that the effect of the biomarker signature is more stable at higher dynorphin cutpoints. Figure 27C shows SigPos=3MM or DYN>29.5, 61% of the cohort. Figure 27D shows SigPos=3MM or DYN>48.7, 48% of the cohort. [Figure 27C] Plots summarizing the results of patient subtyping using biomarker signatures using a combination of high dynorphin and 3MM subtypes. Figure 27A is a graph of treatment effect and signature dominance in the biosignature positive group. One caveat is that the signature dominance defined by SigPos and SigNeg is not stable at higher cutoffs. Figure 27B shows that for biomarker signature negative patients (SigPos=3MM or DYN>19.9, 73% of the cohort), the interaction effect is much more pronounced due to a worse mean atcactus response than placebo. Figures 27C and 27D show that the effect of the biomarker signature is more stable at higher dynorphin cutpoints. Figure 27C shows SigPos=3MM or DYN>29.5, 61% of the cohort. Figure 27D shows SigPos=3MM or DYN>48.7, 48% of the cohort. [Figure 27D]Plots summarizing the results of patient subtyping using biomarker signatures using a combination of high dynorphin and 3MM subtypes. Figure 27A is a graph of treatment effect and signature dominance in the biosignature positive group. One caveat is that the signature dominance defined by SigPos and SigNeg is not stable at higher cutoffs. Figure 27B shows that for biomarker signature negative patients (SigPos=3MM or DYN>19.9, 73% of the cohort), the interaction effect is much more pronounced due to a worse mean atcactus response than placebo. Figures 27C and 27D show that the effect of the biomarker signature is more stable at higher dynorphin cutpoints. Figure 27C shows SigPos=3MM or DYN>29.5, 61% of the cohort. Figure 27D shows SigPos=3MM or DYN>48.7, 48% of the cohort. [Figure 28A] Figure 28B is a plot showing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. Figure 28B shows a large treatment effect in biomarker signature positive patients and the dominance of the large signature across a wide range of dynorphin levels (SigPos = (CRP>3&(IL6R>25|TNFα>4))&DYN>11.5). [Figure 28B] Figure 28B is a plot showing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. Figure 28B shows a large treatment effect in biomarker signature positive patients and the dominance of the large signature across a wide range of dynorphin levels (SigPos = (CRP>3&(IL6R>25|TNFα>4))&DYN>11.5). [Figure 29A]FIG. 29 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1 pg / mL or (DYN>δ2 pg / mL and CRP>3 mg / L and (TNFα>4 pg / mL or siL6R>25 ng / mL). FIG. 29 is a graph of the mean difference in response (MADRS) in EP for dynorphin levels in pg / mL. FIG. 29B SigPos=DYN>24.0 or (3MM and DYN>8), 63% of the cohort shown. FIG. 29C SigPos=DYN>50 or (3MM and DYN>8), 38% of the cohort shown. [Figure 29B] FIG. 29 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1 pg / mL or (DYN>δ2 pg / mL and CRP>3 mg / L and (TNFα>4 pg / mL or siL6R>25 ng / mL). FIG. 29 is a graph of the mean difference in response (MADRS) in EP for dynorphin levels in pg / mL. FIG. 29B SigPos=DYN>24.0 or (3MM and DYN>8), 63% of the cohort shown. FIG. 29C SigPos=DYN>50 or (3MM and DYN>8), 38% of the cohort shown. [Figure 29C] FIG. 29 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1 pg / mL or (DYN>δ2 pg / mL and CRP>3 mg / L and (TNFα>4 pg / mL or siL6R>25 ng / mL). FIG. 29 is a graph of the mean difference in response (MADRS) in EP for dynorphin levels in pg / mL. FIG. 29B SigPos=DYN>24.0 or (3MM and DYN>8), 63% of the cohort shown. FIG. 29C SigPos=DYN>50 or (3MM and DYN>8), 38% of the cohort shown. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0012] Any individual feature mentioned herein, e.g., a specific embodiment or a specific preferred feature, may be taken alone or in combination with any other feature (including specific embodiments or preferred features) mentioned herein. Thus, a preferred feature may be taken in conjunction with or independently of other preferred features (and also as a specific embodiment).

[0013] In one aspect of the invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having either (a) anhedonia or (b) a biomarker signature positive, where the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0014] In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, and (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia, and (b) is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0015] In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia or (b) is biomarker signature positive, where the patient is biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia or (b) is biomarker signature positive when a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0016] Further described herein is aticaplant or a pharma- ceutically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive, when a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. Further described herein is aticaplant or a pharma- tically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- tically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0017] In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being identified as a biomarker signature positive, the patient being identified as a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being identified as a biomarker signature positive, the patient being identified as a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, the patient having an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0018] In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being biomarker signature positive, the patient being biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level. In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being biomarker signature positive, the patient being biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level, the patient having an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0019] In a further aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of: evaluating a biological sample obtained from the patient for the presence of a level of at least one biomarker that is higher or lower than a reference biomarker level; and administering to the patient an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof. In a further aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of: evaluating a biological sample obtained from the patient for the presence of a level of at least one biomarker that is higher or lower than a reference biomarker level; and administering to the patient an effective amount of aticaplant or a pharma-ceutically acceptable salt thereof, wherein the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0020] Further described herein is aticaplant or a pharma- ceutically acceptable salt thereof for use in treating major depressive disorder (MDD) in a human patient, comprising administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. Further described herein is aticaplant or a pharma- tically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising administering an effective amount of aticaplant or a pharma- tically acceptable salt thereof to a patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and wherein the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0021] In any of the embodiments of the above-mentioned method of treatment, the patient had an inadequate response to other antidepressant therapy prior to treatment with Aticaplant or a pharma- ceutically acceptable salt thereof. In certain embodiments, the other antidepressant therapy included one or more antidepressants. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy, or a combination thereof. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI). In certain embodiments, the one or more antidepressants included a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy.

[0022] In certain embodiments, described herein are methods for identifying a patient as a candidate for treatment with Aticaplant or a pharma- ceutically acceptable salt thereof if the patient is biomarker signature positive, where the patient is identified as being biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In certain embodiments, the method further comprises administering to the patient an effective amount of Aticaplant or a pharma-ceutically acceptable salt thereof.

[0023] It will be understood that for each of the methods of treatment described herein, the method of treatment may also be configured as a method of manufacturing a medicament for the treatment of the described indication, or as an aticaplant for use in the treatment of the described indication.

[0024] Because MDD alone is difficult to treat, patients with anhedonia are even more problematic because their ability to measure pleasure is impaired.Therefore, such patients often receive inadequate treatment due to, among other things, ineffective medication, repeated unnecessary medical appointments, lack of patient compliance, and overall patient frustration.In addition, antidepressants are known to have various side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among other things.Therefore, patients may choose to refrain from or discontinue taking antidepressants to avoid or prevent any side effects.

[0025] The methods described herein are effective in managing depression and anhedonia in a subject using Atikaplant. Desirably, the methods allow patients to successfully manage their depression and simultaneously reduce anhedonia. In certain embodiments, patients treated according to the methods described have high anhedonia as measured by a total score of ≧32 on the Snaith-Hamilton Pleasure Scale (SHAPS). The term "anhedonia" as used herein refers to a lack or reduced ability to experience pleasure in daily activities. The term anhedonia includes loss of pleasure in sensory experiences (i.e., touch, taste, smell), as well as social interactions. In some embodiments, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia also describes a deficit in one or more components (e.g., desire, liking, and learning) of reward-related behavior, also known as the pleasure cycle. The pleasure cycle can be divided into three stages: the appetitive stage (governed by desire), the consummatory stage (governed by preferences), and the satisficing stage (governed by learning). The appetitive stage is characterized by an initial expenditure of energy to obtain a reward. The consummatory stage is the enjoyment of the reward, and the satisficing stage is characterized by learning and feedback integration.

[0026] To assess potential effects on anhedonia, an anhedonia scale can be used. For example, the Snaith-Hamilton Analysis of Pleasure Scale (SHAPS) is a validated scale for the measurement of anhedonia. The SHAPS is a subject completion scale in which subjects score whether they experience pleasure when performing a list of activities or experiences. The SHAPS is a self-report 14-item set developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure when performing a list of activities or experiences. Subjects can rate their responses as 1-4, where 1 indicates "definitely agree," 2 indicates "agree," 3 indicates "disagree," and 4 indicates "definitely disagree." The subject's item responses are summed to obtain a total score ranging from 14-56. A higher total SHAPS score indicates a higher level of current anhedonia. Physician / clinical judgment can be used to assess anhedonia separately or in conjunction with the anhedonia scale.

[0027] In some embodiments, the patient has anhedonia. In some embodiments, the patient has moderate anhedonia. In other embodiments, the patient has severe anhedonia. The assessment of moderate or severe anhedonia is typically determined by physician / clinical judgment and / or one or more tests that provide insight into whether the patient has anhedonia. For example, the severity of anhedonia can be determined using the SHAPS method. In some embodiments, patients with moderate or severe anhedonia are considered to have high levels of anhedonia. For example, patients with a SHAPS score of 38 or higher are considered to have moderate to severe anhedonia, which can be considered to have high levels of anhedonia. In some embodiments, high levels of anhedonia reflect a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or more. Patients with mild or anhedonia are considered to have low levels of anhedonia as assessed by physician / clinical judgment and / or one or more tests. For example, patients with a SHAPS score of less than 38 are considered to have low anhedonia. In certain embodiments, patients with mild anhedonia are considered to have a SHAPS score of less than 20 to 38, e.g., 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30 to about 36, about 32 to about 36, about 34 to about 3 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36. Typically, a SHAPS score of less than 20 can be considered to correspond to normal hedonic function and, for purposes of the present disclosure, would be classified in the low category of anhedonia, e.g., a SHAPS score of less than 38.

[0028] In some embodiments, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet further embodiments, in still other embodiments, the patient's anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 to about 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant. In other embodiments, the patient's anhedonia is improved, i.e., reduced by 100%, as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant.

[0029] The reduction in anhedonia after starting treatment with Atika Plant can be measured relative to the patient's anhedonia measured before treatment with Atika Plant, i.e., baseline anhedonia measurement. In this way, the treating clinician can calculate the change in anhedonia from baseline to real-time anhedonia measurement at any time after treatment with Atika Plant. Thus, a standard method for measuring anhedonia can be used, such as an anhedonia scale, e.g., SHAPS.

[0030] Desirably, the baseline anhedonia measurements are obtained within about one week of initiating treatment with Atikaplant. In some embodiments, the baseline anhedonia measurements are obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to initiating treatment with Atikaplant. In further embodiments, the baseline anhedonia measurements are obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiating treatment with Atikaplant.

[0031] The change in the patient's anhedonia depends on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to the Atika plant, and other medications being administered, among others. In some embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In other embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In further embodiments, the patient's anhedonia is reduced about 3 to about 6 weeks after Atika plant treatment, and in certain embodiments by the 6th week. In certain embodiments, the patient's anhedonia is reduced by at least about 40% after about 6 weeks of Atika plant treatment, as measured by the change from baseline in the total score on the Anhedonia Scale. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and in some embodiments, within about 3 to about 6 weeks, as measured by the change from baseline in the total score on the Anhedonia Scale and / or by physician / clinical judgment.

[0032] The methods described herein have been found to not only improve patients' depression and anhedonia symptoms, but also result in fewer antidepressant side effects, thereby resulting in, among other things, reduced absenteeism (i.e., more doctor visits or interactions), improved cognitive function, improved health-related quality of life, increased interest and engagement in daily activities, improved family and interpersonal relationships, ability to function at work, and reduced hospitalizations.

[0033] As used herein, unless otherwise specified, the terms "subject" and "patient" refer to a human being who has been the object of treatment, observation or experiment. Preferably, the patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, "adult" refers to a human who is about 18 years of age or older. In certain aspects, the patient is 65 years of age or older, i.e., elderly.

[0034] As used herein, unless otherwise indicated, the terms "treat", "treatment" and the like are intended to include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder and also include the administration of a compound described herein to prevent the occurrence of symptoms or complications, alleviate one or more symptoms or complications, or eliminate the disease, condition, or disorder.

[0035] As used herein, the term "depression" (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, late life depression, bipolar depression, depression due to an identifiable stressor, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, the major depressive disorder is accompanied by depressive features or anxiety distress. In further embodiments, the depression is treatment-resistant depression. In other embodiments, the depression is major depressive disorder accompanied by suicidal ideation.

[0036] As is known in the art, a patient is considered to have major depressive disorder if they exhibit five or more symptoms during the same two-week period that are a change from previous functioning, and depressed mood and / or loss of interest / pleasure must be present, excluding symptoms clearly attributable to another physical illness. See, e.g., Table A.

[0037] [Table 1]

[0038] In some embodiments, the following criteria are also met to be diagnosed with MDD:

[0039] [Table 2]

[0040] Major depressive disorder may be classified as mild, moderate, or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In further embodiments, MDD is severe. As used herein, "mild MDD" applies to patients who have few, if any, symptoms beyond those required to make a diagnosis, the intensity of symptoms is distressing but manageable, and the symptoms result in mild impairment in social or occupational functioning. Mild MDD may be a single episode (ICD-10F32.0) or recurrent episodes (ICD-10F33.0). "Moderate MDD" applies to patients who have a number of symptoms, intensity of symptoms, and / or functional impairment that is between those designated as "mild" and those designated as "severe." Moderate MDD may be a single episode (ICD-10F32.1) or recurrent episodes (ICD-10F33.1). "Severe MDD" refers to patients in whom the number of symptoms significantly exceeds that required to make a diagnosis, the intensity of symptoms is severely distressing, the symptoms significantly interfere with social and occupational functioning, and emergency symptom management is required. In some embodiments, severe MDD can be single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition in Table B.

[0041] [Table 3]

[0042] Several scales are known in the art that can be used to diagnose or monitor patients with MDD. Examples of these scales include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) scale, the Symptoms of Major Depressive Disorder Scale (SMDDS), the Self-Assessment of Treatment Experience (SATE) scale, and the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), or MGH-ATRQ.

[0043] In some embodiments, the MADRS is utilized to diagnose and / or monitor patients. The MADRS is a 10-item rating scale used in antidepressant drug trials. It is administered by clinicians and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms. The MADRS scale is validated, reliable, and accepted by regulatory health agencies as the primary scale for determining efficacy in major depression. In some embodiments, the MADRS is administered using the Structured Interview Guide for MADRS (SIGMA). The scale consists of 10 items, each scored from 0 (absent or normal item) to 6 (severe or continued presence of symptoms), with a maximum total score of 60. Higher scores indicate a more severe condition. The MADRS assesses apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, fatigue, apathy (attention level), pessimistic thoughts, and thoughts of suicide.

[0044] In another embodiment, the CGI-S is utilized to diagnose and / or monitor depression in patients. The CGI-S is a scale that assesses the severity of a subject's illness at the time of evaluation, compared to the clinician's past experience with subjects with the same diagnosis and improvement with treatment. The CGI-S provides an overall clinician-determined summary scale of the severity of a subject's illness, taking into account all available information, including the subject's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the subject's ability to function. The CGI-S assesses the severity of psychopathology on a scale of 0 to 7. Taking into account the entire clinical experience, subjects are assessed for the severity of their psychiatric illness at the time of evaluation according to the following: 0 = not rated, 1 = normal (not ill at all), 2 = borderline psychotic, 3 = mildly ill, 4 = moderately ill, 5 = significantly ill, 6 = severely ill, 7 = most severely ill patient.

[0045] In a further embodiment, the SMDDS is utilized to diagnose and / or monitor depression in a patient. The SMDDS is a subjective assessment of the patient. The SMDDS is a 16-item PRO scale. Each item is rated by the subject according to a 5-point Likert scale. The subject answers each question using a rating scale between 0 ("never" or "never") and 4 ("extremely" or "always"). The total score ranges from 0 to 60. The SMDDS uses a 7-day recall period and a verbal rating scale. Higher scores indicate more severe depressive symptomatology.

[0046] In yet another embodiment, the SATE is utilized to diagnose and / or monitor depression in patients. The SATE is a 1-3 time questionnaire administered to subjects away from clinical settings such as at home, i.e. when they are unable to complete other assessments. The SATE is useful for assessing improvement or worsening of a subject's depressive symptoms over a short period of time. To assess overall depression, subjects select one of the following options: improved, unchanged, or worsened; for improvement of depression, subjects select one of the following options: slightly improved, much improved, very much improved; for worsening of depression, subjects select slightly worse, much worse, very much worse. See Table C.

[0047] [Table 4]

[0048] The MGH-ATRQ is a self-assessment scale used to determine treatment resistance in patients with MDD. This questionnaire examines antidepressant therapy history, using specific anchor points to define the appropriateness of both the dose and duration of each antidepressant trial, as well as the degree of symptom improvement. The MGH-ATRQ allows for the determination of treatment resistance in depression and is known to those skilled in the art.

[0049] In certain embodiments, the patient has had an inadequate response to other antidepressant therapies (i.e., antidepressant medications or treatments used to treat depression other than Aticaplant). As used herein, "inadequate response" refers to a patient experiencing less than about 50% reduction in the severity of depressive symptoms from the start of treatment. Typically, an inadequate response is one in which depression is in a current / active episode. In some embodiments, an inadequate response refers to a patient experiencing less than about 26 to about 50% reduction in the severity of depressive symptoms from the start of treatment. In other embodiments, an inadequate response refers to a patient experiencing a reduction in severity of depressive symptoms of about 26 to about 49, about 26 to about 45, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45% from the start of treatment. Patient response may be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by the MGH-ATRQ, MADRS, or SHAPs. In further embodiments, an inadequate response is measured by the MGH-ATRQ.

[0050] To the extent that a patient is said to have a partial response to treatment, this refers to some mild to moderate improvement in symptoms since the beginning of treatment, but some of the initial symptoms are still present and bothersome to the patient, and the persistence of these symptoms still affects behavior and functioning: for example, the patient's motivation, productivity, and interest in his or her usual activities may still be impaired.

[0051] Antidepressant therapy refers to any medicine that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclics, tetracyclics, non-cyclic compounds, triazolopyridines, selective serotonin reuptake inhibitors (SSRIs), serotonin receptor antagonists, serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline and specific serotonin agonists, noradrenaline reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, etc. Examples of tricyclic antidepressants include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc. Examples of tetracyclics include maprotiline, etc. Examples of acyclic drugs include nomifensine. Examples of triazolopyridines include trazodone. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine. Examples of serotonin receptor antagonists include nefazadone. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, and levomilnacipran. Examples of noradrenergic and specific serotonin agonists include mirtazapine. Examples of noradrenaline reuptake inhibitors include reboxetine and edivoxetine. Exemplary antipsychotic drugs include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like.Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonepiprazole, aripiprazole, nemonapride, SR-31742, CX-516, SC-111, NE-100, divalproate (mood stabilizer), and the like. In further embodiments, the antidepressant therapy includes natural products such as kava-kava, St. John's wort, or dietary supplements such as s-adenosylmethionine. In yet other embodiments, the antidepressant therapy includes a neuropeptide such as thyrotropin releasing hormone, or a compound that targets a neuropeptide receptor, such as a neurokinin receptor antagonist. In yet further embodiments, the antidepressant therapy is a hormone such as triiodothyronine. In other embodiments, the antidepressant therapy is an SSRI, SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI, which is escitalopram, sertraline, paroxetine, fluoxetine, or citalopram. In other embodiments, the antidepressant is an SNRI, which is venlafaxine, duloxetine, vortioxeine, or desvenlafaxine. There are also non-pharmacological treatments, such as psychotherapy and transcranial magnetic stimulation, which are also available and are adjunctive therapeutic options.

[0052] Therapeutically effective amounts / dosage levels for other antidepressant therapies can be readily determined by one of ordinary skill in the art. For example, therapeutic dosages and regimens for pharmaceuticals approved for marketing are generally available and are listed, for example, in package labels, standard dosing guidelines, standard dosing references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / / www.pdrel.com), or other sources.

[0053] In some embodiments, the other antidepressant therapy may include one antidepressant drug. In other embodiments, the other antidepressant therapy includes two or more antidepressants. In further embodiments, the other antidepressant therapy includes two antidepressants. In yet other embodiments, the other antidepressant therapy includes three antidepressants. The attending physician may select the appropriate antidepressant therapy for use as described herein.

[0054] In certain embodiments, the patient has been treated with other antidepressant therapy prior to receiving Atikaplant. In some embodiments, the patient has been treated with other antidepressant therapy, including an SSRI, an SNRI, or a combination thereof. In other embodiments, the patient has stopped other antidepressant therapy prior to initiating treatment with Atikaplant.

[0055] The methods described herein also include adjunctive treatment with a therapeutically effective amount of one or more antidepressants. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" refer to the treatment of a patient in need thereof by administering Aticaplant in combination with one or more antidepressants, where Aticaplant and the antidepressants are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.

[0056] In some aspects, Atikaplant is administered adjunctively with other antidepressants currently administered to the patient, including current antidepressants to which the patient has had an inadequate response. In other embodiments, Atikaplant is administered adjunctively with antidepressants not previously administered to the patient. In yet other embodiments, Atikaplant is administered in a regimen with an antidepressant previously administered to the patient.

[0057] When acicaplant and other antidepressants are administered in separate dosage forms, the number of doses administered per day for each active compound may be the same or different, and more typically, different.Antidepressants may be administered as prescribed by the attending physician and / or by its label, and acicaplant is administered as described herein.Typically, patients are under concurrent treatment with both antidepressants and acicaplant, both of which are administered according to their prescribed dosing regimen.Aticaplant and antidepressants may be administered simultaneously in divided or single forms, at the same or different times during the course of therapy, according to simultaneous or alternating regimens.

[0058] Aticaplant and antidepressant can be administered via the same or different administration routes.Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.In some embodiments, Aticaplant is administered orally.

[0059] Treatment with Atikaplant as described herein has several advantages over treatments in the art. In some embodiments, patients do not experience many of the side effects associated with other antidepressants (i.e., antidepressants other than Atikaplant). In certain aspects, patients do not experience weight gain during treatment with Atikaplant. As used herein, the term "weight gain" refers to an increase in a patient's weight compared to the subject's weight prior to taking Atikaplant or the patient's weight assessed at the time of the first administration of Atikaplant. In certain embodiments, patients can actually see a decrease in overall weight compared to the patient's weight prior to receiving Atikaplant. In further embodiments, the patient's weight is stable, i.e., it neither increases nor decreases. In certain embodiments, patients do not experience clinically relevant weight gain, characterized as a weight gain of ≧7%.

[0060] This is in contrast to many other antidepressants for which weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[0061] In certain embodiments, administration of acanthopanthracene results in a maximum plasma concentration (C) of acanthopanthracene of about 20 to about 45 ng / mL. max In a further embodiment, administration of acicaplant achieves a maximum plasma concentration (C) of about 25 to about 35 ng / mL of acicaplant. max In yet further embodiments, administration of acicaplant achieves a maximum plasma concentration (C) of about 30 to about 35 ng / mL of acicaplant. max ) to be achieved.

[0062] In a further aspect, the patient does not experience a decrease in sexual function during treatment with Atikaplant. As used herein, the term "decrease in sexual function" refers to a decrease or reduction in one or more components of human sexual activity (i.e., sexual function). In some embodiments, sexual function includes one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. In other embodiments, sexual function includes sexual drive. In further embodiments, sexual function includes vaginal lubrication satisfaction. In further embodiments, sexual function includes orgasmic achievement. In yet other embodiments, sexual function includes orgasmic satisfaction. Desirably, the patient's sexual function is assessed upon the first administration of Atikaplant. Thus, the subject's sexual function during Atikaplant intake can be compared to the subject's sexual function prior to Atikaplant administration. Sexual function can be assessed by using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). The ASEX is used to investigate whether Atikaplant has an additional positive or negative effect on sexual function. The ASEX is a five-item rating scale administered to patients that quantifies sexual drive, sexual arousal, vaginal lubrication or erection, ability to achieve orgasm, and satisfaction. Scores range from 5 to 30, and two different versions of the scale (male and female) are available.

[0063] Other scales can be utilized to determine the effectiveness of the methods used herein to treat patients. Examples include the Cognitive and Physical Function Questionnaire (CPFQ), the Karolinska Sleepiness Scale (KSS), and the Temporal Pleasure Experience Scale (TEPS). The CPFQ is a brief self-report scale that provides additional information about the impact of adjunctive treatments on aspects of cognition and executive function, including attention, memory, and mental acuity. Subjects with MDD often report having difficulty functioning in this area. The KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from "extremely alert" (1) to "very sleepy, great efforts to stay awake, fighting sleep" (9). The TEPS includes 18 items, with two subscales designed to distinguish between anticipatory and consummatory pleasure.

[0064] As used herein, unless otherwise stated, the term "aticaplant" refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, i.e., the following compound:

[0065] [ka] Also known as JNJ-67953964, CERC-501, and LY-2456302. In some embodiments, "aticaplant" refers to the (S)-enantiomer of aticaplant, i.e., the following compound:

[0066] [ka] Also known as (S)-Aticaplant or (S)-3-Fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide. In other embodiments, Aticaplant used in the methods described herein is substantially free of the (R)-enantiomer having the following structure: (R)-Aticaplant or (R)-3-Fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide.

[0067] [ka]

[0068] In other embodiments, the Atika plant contains less than about 10% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In further embodiments, the Atika plant contains less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.005% by weight, or less than about 0.001% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In yet other embodiments, the Atika plant contains about 0.001 to about 10% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In still further embodiments, the Atika plant contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5 weight percent of the (R)-enantiomer of Atika plant, based on the weight of the Atika plant sample.

[0069] Pharmaceutically acceptable salts of Atikaplant contemplated by the present invention can also be easily selected by those skilled in the art. A "pharmaceutical acceptable salt" is a salt of Atikaplant that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. See generally GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J.Med.Chem., 2007, 50:6665-72; SM Berge, "Pharmaceutical Salts", J.Pharm.Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharma- ceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0070] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide (e.g., hydrobromide), iodide (e.g., hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1, Examples of suitable salts include 4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0071] The methods described herein include administering to a subject an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof. The term "effective amount" as used herein means an amount of an active compound or pharmaceutical agent that induces a biological or medicinal response in a human tissue system that is sought by a researcher, physician, or other clinician, including the alleviation of one or more of the symptoms of the disease or disorder being treated. In some embodiments, aticaplant is utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressants are utilized in effective amounts, separately or in combination with aticaplant.

[0072] The amount of aticaplant for administration by the methods described herein may be determined by one of skill in the art and is provided on a free base basis of aticaplant unless otherwise stated. That is, the amount refers to the amount of aticaplant molecule administered, excluding, for example, solvent (such as in the form of a solvate) or counterion (such as in the form of a pharma- ceutically acceptable salt). In some embodiments, the effective amount of aticaplant is less than about 60 mg. In other embodiments, the effective amount of aticaplant is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In a further embodiment, the effective amount of Atikaplant is about 1 to about 50 mg, about 5 to about 50 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, about 40 to about 50 mg, about 1 to about 45 mg, about 2 to about 45 mg, about 5 to about 45 mg, about 10 to about 45 mg, about 20 to about 45 mg, about 30 to about 45 mg, about 30 to about 40 mg, about 30 to about 35 mg, about 1 to about 40 mg, about 5 to about 40 mg, about 10 to about 40 mg, about 20 to about 40 mg, about 30 to about 40 mg, about 1 to about 35 mg, about 2 to about 35 mg. g, about 5 to about 35 mg, about 10 to about 35 mg, about 20 to about 35 mg, about 25 to about 35 mg, about 30 to about 35 mg, about 1 to about 30, about 2 to about 30 mg, about 5 to about 30 mg, about 10 to about 30 mg, about 20 to about 30 mg, about 25 to about 30 mg, about 1 to about 20 mg, about 2 to about 20 mg, about 5 to about 20 mg, about 10 to about 20 mg, about 15 to about 20 mg, about 1 to about 15 mg, about 2 to about 15 mg, about 5 to about 15 mg, about 10 to about 15 mg, about 1 to about 10 mg, about 2 to about 10 mg, or about 5 to about 10 mg. In yet another embodiment, the effective amount of the Atica plant is about 5 to about 15 mg. In yet a further embodiment, the effective amount of the Atica plant is about 10 mg. In yet a further embodiment, the effective amount of aticaplant is about 5 mg.

[0073] As used herein, the term "composition" is intended to encompass any product that contains a particular ingredient in a particular amount, as well as any product that is directly or indirectly obtained from the combination of a particular ingredient in a particular amount. A preferred pharmaceutical composition contains Aticaplant as an active ingredient, thoroughly mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier can take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutical acceptable carriers are well known in the art. A description of some of these pharmaceutical acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0074] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al., all published by Marcel Dekker, Inc.

[0075] In certain embodiments, pharmaceutical compositions for use herein further comprise one or more buffering agents, preservatives, osmotic agents, wetting agents, surfactants, solubilizing agents, viscosity enhancing agents, coloring agents, antioxidants, emulsifying agents, isotonicity agents, suspending agents, and / or thickening agents.

[0076] In some embodiments, the pharmaceutical composition comprises one or more buffers and / or buffer systems (i.e., conjugate acid-base pairs). As used herein, the term "buffer" refers to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts the pH of an aqueous formulation when added to the formulation. Those skilled in the art will recognize that a buffer can adjust the pH of an aqueous formulation in any direction (towards a more acidic, more basic, or more neutral pH). Preferably, the buffer is pharma- ceutically acceptable. Suitable examples of buffers that may be used in the aqueous formulations described herein include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, and the like.

[0077] Optionally, the pharmaceutical composition herein may contain a preservative. As used herein, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" refer to any substance added to a pharmaceutical composition to protect the pharmaceutical composition against microbial degradation or microbial growth. In this regard, microbial growth typically plays an essential role. That is, the preservative serves the main purpose of avoiding microbial contamination. It may also be desirable to avoid any microbial effect on the active ingredient and excipients, respectively, i.e. to avoid microbial degradation. Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0078] As used herein, the terms "penetration agent", "penetration enhancer" and "penetrant" refer to any substance that increases or enhances the absorption and / or bioavailability of acetophenone. Preferably, the penetrant increases or enhances the absorption and / or bioavailability of acetophenone after administration. Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycolcholate, tauroursodeoxycholic acid, lecithin, and the like; and chitosan (and salts), as well as surfactants such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxinol, sodium deoxycholate, polyarginine, and the like. Preferably, the penetrant is selected to meet one or more, and more preferably all, of the following general requirements:

[0079] [Table 5]

[0080] Pharmaceutical compositions for use herein may further contain one or more additional excipients, such as wetting agents, surfactant components, solubilizers, thickeners, colorants, antioxidant components, and the like.

[0081] Examples of suitable antioxidant components, when used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbate salts, such as sodium, calcium, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid or its sodium or calcium salts; tocopherol; gallates, such as propyl, octyl, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long-term stability to the liquid composition.

[0082] Solubilizers and emulsifiers can be included to promote more uniform dispersion of active ingredients or other excipients that are not generally soluble in liquid carriers.Suitable examples of emulsifiers, if used, include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof.Suitable examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.Solubilizers or emulsifiers can generally be present in an amount sufficient to dissolve or disperse the active ingredient, i.e., acica plant, in the carrier.

[0083] Suitable tonicity agents, if used, may include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

[0084] Suspending or thickening agents may also be added to the pharmaceutical composition. Suitable examples include, but are not limited to, hydroxypropylmethylcellulose, carmellose sodium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinylpyrrolidone, xanthan gum, etc.

[0085] Advantageously, Aticaplant may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0086] As described herein, in particular, the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Thus, in certain embodiments, the present disclosure relates to aticaplant or a pharma- ceutically acceptable salt thereof for use as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In further particular embodiments, the present disclosure also relates to the use of aticaplant or a pharma-ceutically acceptable salt thereof in the manufacture of a medicament as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In further particular embodiments, the present disclosure also relates to a package or pharmaceutical product as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Such antidepressant therapy may in particular be selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or a combination thereof.

[0087] As described herein, aticaplant may be used as an adjunctive treatment, or in other words, in conjunction with, add-on to, or in combination with one or more antidepressants, for example, a patient may already be administered one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof as an adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof as adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment instruct the administration of an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof as adjunctive treatment with an effective amount of one or more antidepressants.In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant or a pharma- ceutical acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant or a pharma-ceutical acceptable salt thereof in combination with an effective amount of one or more antidepressants. The one or more antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0088] As already mentioned, the present disclosure relates to aticaplant or a pharma- ceutically acceptable salt thereof for the uses described herein. In certain embodiments, aticaplant is S-aticaplant or a pharma- ceutically acceptable salt thereof. In further embodiments of the present disclosure, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein is administered in an amount of about 2 to about 35 mg, more particularly about 10 mg, more particularly about 5 mg. In still further embodiments, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein is administered orally. In yet further particular embodiments, the present disclosure relates to aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein, administered once a day. The present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament as described herein. In certain embodiments, aticaplant is S-aticaplant or a pharma- ceutically acceptable salt thereof. In further embodiments of the uses described herein, about 2 to about 35 mg of aticaplant, more particularly about 10 mg, more particularly about 5 mg, is administered. In yet further embodiments of the uses, aticaplant is administered orally. In yet further specific embodiments of the uses, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof, is administered once a day. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product described herein, wherein aticaplant is, in particular, S-aticaplant, or a pharma- ceutically acceptable salt thereof. In further embodiments of the packages or pharmaceutical products described herein, the instructions for treatment direct the administration of about 2 to about 35 mg of aticaplant, more particularly about 10 mg, more particularly about 5 mg. In further embodiments of the packages or pharmaceutical products described herein, the instructions for treatment of direct aticaplant, in particular S-aticaplant, or a pharma- ceutically acceptable salt thereof, are for oral administration. Moreover, in further specific embodiments of the package or pharmaceutical product described herein, the instructions for treatment of direct aticaplant, particularly S-aticaplant, or a pharma- ceutical acceptable salt thereof, are for once-daily administration.

[0089] Advantageously, administration of Atikaplant does not result in weight gain during treatment, including clinically relevant weight gain. Thus, in further specific embodiments, the present disclosure relates to Atikaplant or a pharma- ceutically acceptable salt thereof for the use described herein, wherein the patient does not experience weight gain during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the use defined herein, wherein the patient does not experience weight gain during treatment with Atikaplant. In further specific embodiments, the present disclosure further relates to the package or pharmaceutical product described herein, wherein the patient does not experience weight gain during treatment with Atikaplant. The patient's weight can be assessed, in particular, at the first administration of Atikaplant.

[0090] Also, unexpectedly, it was observed that patients do not experience a decline in sexual function during treatment with Atikaplant based on the evaluation at the first administration. Thus, in further specific embodiments, the present disclosure relates to Atikaplant or its pharma- ceutically acceptable salts for the use described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the use described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the package or pharmaceutical product described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. Such term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to those skilled in the art, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[0091] As previously described, the patient has moderate or severe anhedonia. Anhedonia can be measured by an anhedonia scale, for example, the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the present disclosure relates to acicaplant or a pharma- ceutically acceptable salt thereof for use as described herein, wherein the subject's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on the anhedonia scale after 6 weeks of treatment with acicaplant, and more particularly, the subject's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the anhedonia scale. In further specific embodiments, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the disclosure relates to a use as described herein, wherein after 6 weeks of treatment with Atika plant, the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in the total score on the Anhedonia Scale. In further particular embodiments, the Anhedonia Scale is the Snaith-Hamilton Pleasure Scale (SHAPS). In further particular embodiments, the disclosure relates to a package or pharmaceutical product as described herein, wherein the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale after 6 weeks of treatment with Atika plant, more particularly, the subject's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in the total score on the Anhedonia Scale. In a further particular embodiment, the anhedonia scale is the Snaith-Hamilton Anhedonia Scale (SHAPS).

[0092] In certain embodiments, the patient is identified as biomarker signature positive.

[0093] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("3MM") with a positive status defined by CRP>3mg / L and (TNFα>4pgmL or siL6R>25ngmL. In the disclosed methods using the 3MM biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level, and (b) (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level. In certain embodiments, patients identified as biomarker signature positive exhibit an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive exhibit an improvement of about 6.3 MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as positive for the biomarker signature are administered Atikaplant or a pharmaceutically acceptable salt thereof and show an improvement in MADRS points compared to a comparison population of patients not positive for the biomarker signature. In certain embodiments, patients identified as positive for the biomarker signature are administered Atikaplant or a pharmaceutically acceptable salt thereof and show an improvement of about 4.7 MADRS points compared to a comparison population of patients not positive for the biomarker signature.

[0094] In certain embodiments, the biomarker signature is a dynorphin ("DYN") biomarker signature with a positive status identified by DYN>δpg / mL. In the disclosed methods using the dynorphin biomarker signature, a patient is identified as biomarker positive if a biological sample obtained from the patient is identified as having a level of dynorphin higher than a reference dynorphin level. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients not biomarker signature positive who are administered aticaplant or a pharma- ceutically acceptable salt thereof. In certain embodiments, a patient identified as biomarker signature positive does not show an improvement in MADRS points at dynorphin levels above about 48 pg / mL.

[0095] In certain embodiments, the biomarker signature is a 3MM positive or DYN positive signature. In the disclosed methods using the 3MM or DYN biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having at least one of (a) a level of CRP higher than a reference CRP level, and (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level, or (b) a level of dynorphin higher than a reference dynorphin level. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients treated with placebo. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients administered aticaprant or a pharma- ceutically acceptable salt thereof and not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not show MADRS point improvement at dynorphin levels greater than about 48 pg / mL.

[0096] In certain embodiments, the biomarker signature is a 3MM positive and DYN positive signature. In the disclosed methods using the 3MM or DYN biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having (a) a level of CRP higher than a reference CRP level, and at least one of (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level, and (b) a level of dynorphin higher than a reference dynorphin level. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not show MADRS point improvement at dynorphin levels greater than about 48 pg / mL.

[0097] In any of the disclosed embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 116.2 pg / mL. In certain embodiments, the reference dynorphin level is between about 6 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 11.4 pg / mL and about 116.2 pg / mL. In certain embodiments, the reference dynorphin level is between about 11 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 24 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 19.9 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is between about 20 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 19.9 pg / mL. In certain embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is about 11.4 pg / mL. In certain embodiments, the reference dynorphin level is about 11 pg / mL. In certain embodiments, the reference dynorphin level is about 19.9 pg / mL. In certain embodiments, the reference dynorphin level is about 20 pg / mL. In certain embodiments, the reference dynorphin level is about 24 pg / mL. In certain embodiments, the reference dynorphin level is about 30 pg / mL. In certain embodiments, the reference dynorphin level is about 50 pg / mL. In certain embodiments, the reference dynorphin level is less than about 48.7 pg / mL. In certain embodiments, the reference dynorphin level is less than about 50 pg / mL.

[0098] In certain embodiments, the biomarker signature is a 4MM positive signature. In the disclosed methods using the 4MM biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a dynorphin level higher than a first reference dynorphin level, or (i) a CRP level higher than a reference CRP level, and at least one of a TNF-α level higher than a reference TNF-α level and a sIL6R level higher than a reference sIL6R level, and (ii) a dynorphin level higher than a second reference dynorphin level, and both (i) and (ii). In certain embodiments, patients identified as biomarker signature positive show an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show an improvement in MADRS points compared to a comparison population of patients not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not show MADRS point improvement at dynorphin levels greater than about 48 pg / mL.

[0099] In any of the disclosed embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 116.2 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 11.4 pg / mL and about 116.2 pg / mL. In certain embodiments, the first reference dynorphin level is between about 11 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 24 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 19.9 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is between about 20 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 19.9 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is about 11.4 pg / mL. In certain embodiments, the first reference dynorphin level is about 11 pg / mL. In certain embodiments, the first reference dynorphin level is about 19.9 pg / mL. In certain embodiments, the first reference dynorphin level is about 20 pg / mL. In certain embodiments, the first reference dynorphin level is about 24 pg / mL. In certain embodiments, the first reference dynorphin level is about 30 pg / mL. In certain embodiments, the first reference dynorphin level is about 50 pg / mL. In certain embodiments, the first reference dynorphin level is less than about 48.7 pg / mL. In certain embodiments, the first reference dynorphin level is less than about 50 pg / mL.

[0100] In any of the disclosed embodiments, the second reference dynorphin level is about 8 pg / mL.

[0101] In certain embodiments, the first reference dynorphin level is about 50 pg / mL and the second reference dynorphin level is about 8 pg / mL. In further embodiments, the first reference dynorphin level is about 24 pg / mL and the second reference dynorphin level is about 8 pg / mL.

[0102] In any one of the disclosed embodiments, a biomarker correlate of any of the biomarkers may be used, for example, a biomarker correlate of CRP, TNF-α, sIL6R, or dynorphin. As used herein, a "biomarker correlate" of a biomarker is another marker whose level or activity correlates with the level or activity of the biomarker. For example, if a biomarker is X and the level of Y correlates with the level of X, then Y is a biomarker correlate of X.

[0103] As used herein, "CRP" refers to C-reactive protein. In certain embodiments, CRP has the UniProtKB / Swiss-Prot number P02741.

[0104] As used herein, "TNF-α" refers to tumor necrosis factor alpha. In certain embodiments, TNF-α has the UniProtKB / Swiss-Prot number P01375.

[0105] As used herein, "IL6R" refers to the interleukin 6 receptor. In certain embodiments, IL6R has the UniProtKB / Swiss-Prot number P08887. As used herein, "sIL6R" refers to the soluble form of IL6R.

[0106] As used herein, "DYN" refers to dynorphin. In certain embodiments, CYN has the UniProtKB / Swiss-Prot number P01213.

[0107] In any of the disclosed embodiments, the reference CRP level is about 3 mg / L.

[0108] In any of the disclosed embodiments, the reference TNF-α level is about 4 pg / mL.

[0109] In any of the disclosed embodiments, the reference sIL6R level is about 25 ng / mL.

[0110] In any of the disclosed embodiments, reference CRP, TNF-α, sIL6R and / or dynorphin reference levels may be calculated according to the methods disclosed in the Examples.

[0111] The following examples are provided to aid in the understanding of the present invention and are not intended, and should not be construed, as in any way limiting the invention described in the claims appended hereto.

[0112] [Table 6-1]

[0113] [Table 6-2] Example 1

[0114] This was a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who had an inadequate response to SSRI / SNRI treatment. Atticaplant was evaluated as an adjunctive therapy. Eligible subjects therefore maintained SSRI / SNRI treatment without modification throughout the study. At least 50% of recruited subjects had to be anhedonic (measured by a SHAPS total score ≥ 20).

[0115] A.Purpose The primary objective was to evaluate the efficacy of aticaplant compared with placebo when administered as adjunctive treatment in subjects with MDD partially responsive to SSRI / SNRI treatment, in reducing depressive symptoms as assessed by change from baseline in the MADRS in non-responders during the placebo run-in period.

[0116] Secondary objectives are to: To evaluate the efficacy of Aticaplant compared to placebo when administered as an adjunctive treatment in subjects with MDD who are partially responsive to SSRI / SNRI treatment, in reducing symptoms of depression as assessed by change from baseline in MADRS in both responders and non-responders during the placebo run-in period. ii. To investigate the overall safety and tolerability of adjunctive Aticaplant treatment in subjects with MDD when used in combination with an SSRI or SNRI. iii.To investigate the effects of Aticaplant versus placebo on depression-related anhedonia as assessed by SHAPS. iv. To investigate the effect of Aticaplant on symptoms of depression using the Clinical Global Impression-Severity (CGI-S), patient reported symptoms scale for Major Depressive Disorder (SMDDS) and Self-Evaluation of Treatment Experience (SATE). v. To investigate the effects of Aticaplant on symptoms of anxiety using the HAM-A and on core symptoms of anxiety using the HAM-A6 subscale. vi. To evaluate the plasma PK of Atikaplant in subjects with MDD and investigate its relationship with efficacy and safety parameters.

[0117] Secondary exploration objectives are: To investigate the effects of Aticaplant on aspects of cognition and executive function using the CPFQ. ii. To explore mood-related biomarkers (including but not limited to growth factors, HPA axis markers, immune system activation, metabolic markers) and genetic / epigenetic variations that may be associated with clinical response, non-response, or safety and tolerability parameters of the Atticaplant.

[0118] B. Study Design For each subject, the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. See Figure 1.

[0119] Subjects with MDD who had initiated treatment with an approved SSRI / SNRI and had an inadequate or partial response to this treatment were screened. Assessments included the MINI, Antidepressant Treatment History Questionnaire (TRQ), and MADRS.

[0120] The treatment phase consisted of three periods: a concealed placebo run-in period, after which subjects were randomly assigned to 10 mg of aticaplant (two 5 mg capsules) or placebo, lasting 6 weeks. Each capsule contained aticaplant (5 mg), microcrystalline cellulose (94.95 mg) and magnesium stearate (0.05 mg) in a hard gelatin capsule. Subjects who completed the treatment period entered a withdrawal period and were treated with placebo for the remainder of the treatment phase. The total duration of each subject was approximately 16 weeks. There were 11 scheduled visits, including screening. The overall flow is shown in Figure 1.

[0121] Subjects were screened within 3-2 days prior to Day 1 to confirm eligibility according to the inclusion and exclusion criteria. Depressive symptoms were assessed using a structured interview guide for the MADRS.

[0122] Double-blind treatment phase The duration of the double-blind treatment phase was 11 weeks divided into three periods. Subjects received medication after completion of the Day 1 visit. The first dose was administered at home on Day 2. All medications were taken in the fasting state. At Visits 3, 4, and 5, subjects were re-randomized to blinded subjects for the placebo run-in period. During the double-blind phase, subjects visited the center for outpatient visits every 1-2 weeks. See Table 1.

[0123] [Table 7]

[0124] Run-in Period: Subjects who successfully completed the baseline examination visit at the clinical site / unit were treated with placebo for the entire duration of the run-in period.

[0125] Treatment Period: At the end of the run-in period, both placebo-initiated responders and placebo-initiated non-responders were randomized to receive either placebo or 10 mg Aticaplant in a 1:1 ratio for 6 weeks. Subjects remained blinded to the exact timing of randomization, response criteria, and medication assignment for each subject.

[0126] Weaning Period: Subjects who completed the double-blind treatment period before the end of week 11 entered a weaning period and were treated with placebo for the remainder of the treatment phase.

[0127] C. Dosage and Administration Atikaplant was provided as a 5 mg capsule. Placebo was provided as a matching capsule. All subjects received 2 capsules QD. Capsules were taken daily under fasting conditions (fasting at least 4 hours prior to dosing) with some water from day 2 through day 78. Drug was taken before breakfast. If a subject forgot to take a drug before breakfast, this was done before the next meal, at the latest the evening meal of the same day. If a subject remembered later than the evening meal, the dose for that day was omitted and the subject took the dose before breakfast the following day.

[0128] If Visit 11 was scheduled for 3 days later, subjects continued taking medication until Visit 11.

[0129] Capsules were swallowed whole without chewing, splitting, dissolving, or crushing. After taking the medication, subjects did not eat or drink anything for at least 30 minutes.

[0130] The first dose was taken in the fasting state on day 2 of the double-blind phase. 10mg Atika Plant: 2 capsules of 5mg Atika Plant Placebo: 2 placebo capsules.

[0131] The dose was adjusted to 5 mg QD as necessary based on the results of a blinded review of safety data. When a dose reduction was decided upon, this was only applicable to new subjects, and the drug doses were as follows: 5mg Atika Plant: 1 capsule of 5mg Atika Plant Placebo: 1 placebo capsule.

[0132] As used herein, the enhanced ITT analysis set (eITT) is defined as all enrolled lead-in placebo non-responders who are randomized to the treatment period, receive at least one dose of study drug during the treatment period, and have at least one post-baseline MADRS assessment during the treatment period. Similarly, the full ITT analysis set (fITT) is defined as all enrolled subjects who are randomized to the treatment period, receive at least one dose of study drug during the treatment period, and have at least one post-treatment baseline MADRS assessment during the treatment period.

[0133] D. Clinical Evaluation (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Major Depressive Disorder Symptom Scale (SMDDS), and Self-Evaluation of Treatment Experience (SATE). (ii) Anhedonia: Snaith-Hamilton Pleasure Scale (SHAPS) (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and HAM-A6 (iv) Effects on cognition: Cognitive and Physical Functioning Questionnaire (CPFQ) (v) Safety assessment Standard safety evaluations were performed, including physical and neurological examinations, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI complaints in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical test panel to test for gastric mucosal status. (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Central sedative effect: Karolinska Sleepiness Scale (ix) Sexual dysfunction: ASEX

[0134] E. Patient Population Of the 184 subjects, 169 were randomized to the treatment period and included in the safety population, while 166 subjects were considered for the full ITT population. Of the 166 subjects in the full ITT population, 121 (73%) were induction placebo non-responders (enhanced ITT population), and the remaining 45 (27%) were induction placebo responders. Of the 121 subjects in the enriched population, 112 (92.6%) were white and 84 (69.4%) were female. The mean age was 41.6 years, ranging from 19 to 64 years. All subjects had anhedonia (defined as a SHAPS total score ≥ 20) at treatment baseline. High anhedonia levels (defined as a SHAPS total score ≥ 38) were observed in 43.8% of subjects. In general, the treatment groups were similar with respect to baseline characteristics. Subject demographics for the eITT and safety analyses are shown in Tables 2 and 3.

[0135] [Table 8]

[0136] [Table 9]

[0137] E. Efficacy Assessment At the end of the run-in period, subjects' response status was assessed according to double-blind response criteria based on the reduction in MADRS relative to the run-in baseline. Both run-in placebo responders and run-in placebo non-responders were randomly assigned in a 1:1 ratio to either Aticaplant or placebo in the treatment period. Randomization was based on run-in response status (non-responders: <30% reduction from baseline in MADRS total score at the end of the run-in period vs. responders: ≥30% reduction from baseline at the end of the run-in period) and the presence / absence of anhedonia (presence defined as a SHAPS total score ≥20).

[0138] Treatment Period: The study consisted of two periods: a screening phase of up to 5 weeks and a double-blind treatment phase of 11 weeks. The double-blind treatment phase of the study consisted of three periods. The first period was a 3-week placebo run-in, after which subjects entered either the treatment period in which they were randomly assigned to Atikaplant or a 6-week placebo extension period. Subjects who successfully completed the treatment period were treated with placebo for a 2-week withdrawal period, the third period. The total duration for each subject was approximately 16 weeks.

[0139] Primary Analysis Set for Efficacy: Efficacy analyses are based on the eITT set, defined as all enrolled lead-in placebo non-responders who were randomized in the treatment period, received at least one dose, and had at least one post-baseline MADRS assessment during the treatment period. The primary analysis set will be used for all efficacy endpoints.

[0140] Secondary Analysis Set for Efficacy: The secondary analysis set is the fITT set, defined as all enrolled subjects who were randomized in the treatment period, received at least one dose, and had at least one post-baseline MADRS assessment during the treatment period. The secondary analysis set will be used for all efficacy endpoints to examine effects in the general population, which may be useful for designing subsequent studies in the development program.

[0141] Analysis Set for Safety: The safety analysis is based on the full safety analysis set, defined as all enrolled subjects who received at least one dose of medication during the treatment period.

[0142] Efficacy endpoints were presented for both eITT and fITT.

[0143] Significance level: Analysis of the primary efficacy endpoint was performed at a significance level of 0.20 (one-sided). Analysis of efficacy endpoints was performed at a significance level of 0.20 (two-sided). No adjustment for multiple comparisons was made.

[0144] F. Results (i) Primary endpoint: Change from baseline in MADRS total score at week 6 of treatment in non-responders during the placebo run-in period

[0145] Enriched ITT analysis population The mean (SD) MADRS total score at treatment baseline was 29.0 (4.61) with a range of 19 to 41. See Figure 2. The mean change from treatment baseline (SD) in MADRS total score at week 6 of treatment was -10.2 (8.44) for Aticaplant and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 4-6 and Figure 6.

[0146] [Table 10]

[0147] [Table 11]

[0148] [Table 12]

[0149] Based on the results of the MMRM model with subjects as random effects; country, treatment, time, and treatment-by-time interactions as factors; and baseline MADRS total score A significant positive efficacy signal was detected at the one-sided 0.20 significance level for Atikaplant vs. placebo. The estimated LS mean difference at week 6 of treatment between Atikaplant and placebo was -2.1, with an upper 80% one-sided Cl limit of -1.09. The corresponding p-value was 0.044. The treatment effect was larger in the fITT population than in the eITT population: -3.1, with an upper 80% one-sided CI limit of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figures 2 and 3.

[0150] Complete ITT Analysis Set The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86) with a range of 0 to 41. See Figures 7A and 7B. The mean change from treatment baseline in MADRS total score at treatment week 6 for fITT was smaller than for eITT: -9.7 (8.02) for Aticaplant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results indicate a statistical advantage over placebo with a persistence of effect with the largest difference seen at week 6. See Table 7.

[0151] [Table 13]

[0152] A significant effect for Atikaplant vs. placebo in the fITT population was also detected. The estimated LS mean difference between Atikaplant and placebo at week 6 of treatment was -3.1, with an 80% one-sided Cl upper limit of -2.21. The corresponding p-value was 0.002. See Tables 8-9 and 3.

[0153] [Table 14]

[0154] [Table 15]

[0155] Impact of COVID-19 on primary efficacy assessment A supplemental analysis was performed on all data collected before March 15, 2020 (the estimated date of COVID-19 lockdown in most countries participating in the trial) using the same MMRM model as described for the primary analysis. Seventeen percent of subjects in the fITT and 19% in the eITT population had at least one MADRS assessment excluded from the model due to COVID-19 impact. Results of the analysis supported the findings of the primary efficacy analysis in both the eITT and fITT populations. The LS mean difference estimate was -3.0 (upper limit of 80% one-sided CI -1.88) for eITT and -3.4 (upper limit of 80% one-sided CI -2.51) for fITT.

[0156] (ii) Secondary Endpoints MADRS remission rate over the treatment period At week 6 of treatment, the percentage of subjects with MADRS remission (MADRS total score ≦10) in the eITT population was 16.9% for Atika plant and 16.9% for placebo. At week 6 of treatment, the remission rate in the fITT population was 31.2% for Atika plant and 22.2% for placebo. No significant treatment differences were detected at week 6 of treatment for both populations (eITT and fITT) using a chi-square test (two-tailed p=0.999 and p=0.203, respectively). See Figures 8 and 9.

[0157] MADRS response rate (at least 30% improvement) over the treatment period The proportion of subjects with a ≥ 30% improvement in MADRS total score at week 6 in the eITT population was 57.6% for Atikaplant and 45.8% for placebo. The response rate at week 6 in the fITT population was 61.8% for Atikaplant and 44.4% for placebo. For both populations, the treatment difference at week 6 was significant at the 20% two-sided significance level (chi-square test: p = 0.197 for eITT and p = 0.029 for fITT).

[0158] MADRS response rate (at least 50% improvement) over the treatment period The proportion of subjects with a ≥ 50% improvement in MADRS total score at week 6 in the eITT population was 35.6% for the Atika plant and 22.0% for the placebo group. The response rate at week 6 in the fITT population was 38.2% for the Atika plant and 23.5% for the placebo group. For both populations, the treatment difference at week 6 was significant at the 20% two-sided significance level (chi-square test: p = 0.104 for eITT and p = 0.046 for fITT). See Table 10 and Figures 10-13.

[0159] [Table 16]

[0160] Change in SHAPS total score from baseline to week 6 of treatment Enriched ITT analysis population In the eITT population, a larger difference was observed between acicaplant and placebo at week 6 of treatment in the subgroup of subjects with high anhedonia levels (baseline SHAPS total score ≥ 38) than in subjects with low anhedonia levels (baseline SHAPS total score ≤ 20 < 38). The effect sizes were 0.38 and 0.11, respectively.

[0161] The mean (SD) SHAPS total score at treatment baseline was 36.6 (5.45) with a range of 20 to 50. The mean change from treatment baseline (SD) in SHAPS total score at week 6 of treatment was -4.6 (6.23) for Aticaplant and -4.2 (5.04) for placebo. The observed effect size was 0.07. See Table 11 and Figures 14 and 23.

[0162] [Table 17]

[0163] The change in SHAPS total score was analyzed using the same MMRM model used for the MADRS total score. The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.7 [-1.81, 0.41]. See Figure 4 and Tables 12 and 13 and Figure 15. The corresponding p-value was 0.419.

[0164] [Table 18]

[0165] [Table 19]

[0166] The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.8 [-1.79, 0.10]. The corresponding p-value was 0.250. See Figures 4 and 5.

[0167] Complete ITT Analysis Set A similar trend was observed in the fITT population, with the difference being larger than that observed in the eITT population. The effect sizes were 0.51 and 0.29, respectively. The mean (SD) baseline SHAPS total score at treatment baseline was 35.6 (5.67), with a range of 14 to 50. The mean change from treatment baseline in SHAPS total score at treatment week 6 for the fITT population was similar to the change in the eITT: -4.7 (5.91) for Atticaplant and -4.2 (4.98) for placebo. The observed effect size was 0.08. See Table 14.

[0168] [Table 20]

[0169] Change in MADRS total score from baseline to week 6 of treatment by baseline anhedonia level Enriched ITT analysis population In the subgroup of subjects with high anhedonia levels (SHAPS total score ≥ 38) at treatment baseline, n = 53, a larger difference between Aticaplant and placebo was observed at week 6 of treatment than in subjects with low anhedonia levels (baseline SHAPS total score ≤ 20 < 38), n = 65: -3.4 with 90% two-sided CI of [-7.5, 0.7] and -0.9 with 90% two-sided CI of [-4.2, 2.5], respectively (Table 15). The observed effect sizes were 0.38 and 0.11, respectively.

[0170] [Table 21]

[0171] Complete ITT Analysis Set A similar trend was observed in the fITT population. The difference was larger in magnitude compared to the eITT population: -4.6 with a 90% 2-sided CI of [-8.4, -0.8] for subjects with high anhedonia levels (n=63) and -2.3 with a 90% 2-sided CI of [-5.0, 0.4] for subjects with low anhedonia levels (n=94). See Table 16. The observed effect sizes were 0.51 and 0.29, respectively.

[0172] [Table 22]

[0173] The data indicate that segmentation into high vs. low anhedonia was beneficial for treating MDD, i.e., the treatment effect for the Atika plant was higher. Furthermore, the placebo response was lower in patients with high anhedonia compared to low anhedonia.

[0174] Change from treatment baseline in CGI-S total score upon treatment

[0175] [Table 23]

[0176] Change from baseline in SMDDS total score at week 6 of treatment

[0177] [Table 24]

[0178] Number of subjects with SATE score at 6 weeks of treatment

[0179] [Table 25]

[0180] Change from baseline in HAM-A6 total score at week 6 of treatment

[0181] [Table 26]

[0182] These data show greater improvements in HAMA6 scores in Atticaplant treated patients versus placebo.

[0183] Change from treatment baseline in structured interview guide for SIGH-A scores at week 6 of treatment

[0184] [Table 27]

[0185] Maximum plasma concentration of Atikaplant (C max ) C max is defined as the maximum plasma concentration of Aticaplant. The eITT population included all enrolled lead-in placebo non-responders who were randomized into the treatment period, received at least one dose of study drug, and had at least one post-baseline MADRS assessment during the treatment period. Here, "N" (number of subjects analyzed) includes the number of subjects evaluable for this endpoint. Here, "n" (number analyzed) includes all subjects evaluable for a particular time point category.

[0186] [Table 28]

[0187] (iii) Safety Endpoints Overall, 40 / 85 (47.1%) subjects in the Atticaplant group and 30 / 84 (35.7%) in the placebo group in the full safety analysis set experienced at least one TEAE during the treatment period. See Table 23.

[0188] [Table 29]

[0189] The most common TEAEs during treatment were headache (experienced by 10 / 85 subjects in the Atika Plant group - 11.8% and 6 / 84 subjects in the placebo group - 7.1%) and diarrhea (experienced by 7 / 85 subjects in the Atika Plant group - 8.2% and 2 / 84 subjects in the placebo group - 2.4%). See Table 24.

[0190] [Table 30]

[0191] A total of two subjects discontinued during the treatment period due to treatment-emergent adverse events: one subject in the Aticaplant 10 group due to diarrhea, nausea, vomiting, and headache, and one subject in the placebo group due to acute gallstone cholecystitis.

[0192] Overall, 17 of 169 subjects experienced TEAEs of special interest during the treatment period: 13 of 85 (15.3%) in the Atikaplant group and 4 of 84 (4.8%) in the placebo group. The most common treatment-emergent adverse events during the treatment phase were headache and diarrhea. The most common TEAEs of special interest during the treatment period were diarrhea and pruritus (experienced by 5 / 85 subjects - 5.9% in the Atikaplant group and 0 / 84 subjects in the placebo group). In addition, 1 patient (1.19%) in the placebo group experienced acute cholecystitis compared to 0 patients who received Atikaplant. See Table 25.

[0193] [Table 31]

[0194] Two serious adverse events occurred: one subject in the placebo group experienced acute gallstone cholecystitis during the treatment period, and the other subject experienced suicidal ideation during the run-in period. Both subjects discontinued due to these AEs.

[0195] No deaths were reported.

[0196] (iv) Anhedonia analysis Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 26-28.

[0197] [Table 32]

[0198] The results show that the treatment effect was greater in patients with more anhedonia at baseline. See Figure 16.

[0199] [Table 33]

[0200] [Table 34]

[0201] The results show that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 17A and 17B. In Figure 17A, i.e., in the high anhedonia group, the placebo + oral antidepressant group shows less placebo response compared to the low anhedonia group in Figure 17B. Similarly, the treatment effect of the Aticaplant + oral antidepressant group is higher in the high anhedonia group compared to the low anhedonia group. Overall, the effect size is greater in the high anhedonia group at all single time points (from week 1 onwards). The LSMD in the high anhedonia group is more than twice that of the low anhedonia group at week 6. Furthermore, looking at symptom levels, there is a greater improvement in anhedonia and dysphoria-related items in the subgroups with high vs. low anhedonia. See Figure 18.

[0202] (v) Weight change At the induction baseline, the mean weight of subjects in the placebo group was 76.17 kg compared to 78.66 kg in the Atika Plant group. After 6 weeks in the double-blind treatment phase, the mean weight in the placebo group was 75.75 kg compared to 78.57 kg in the Atika Plant group. This indicates that the weight of both groups remained relatively stable over the 6-week double-blind treatment period. This is unexpected, as other adjunctive treatments for MDD result in mean weight gain. Thase M,et al.J Clin Psych.2015:76(9),1224-1231,Thase,J Clin Psych.2015,76(9):1232-1240;El Khalili,Int J Neuropsychopharmacol.2010,13,917-932, Marcus,J.Clin.Psychopharmacol.2008,28:156-165, Berman,J.Clin.Psychiatry 2007;68:843-853;Berman,American College of Neuropsychopharmacology,2008,Annual Meeting Abstracts (Scottsdale,Ariz,Dec. 7-11, 2008). Nashville, Tenn, ACNP, 2008, Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Boca Raton, Fla., Dec 9-13, 2007). Nashville, TN, ACNP, 2007). See Table 29.

[0203] [Table 35]

[0204] (vi) Completion rate Patients who passed the screening phase entered the run-in phase followed by the double-blind phase. Patients who responded to the placebo during the run-in phase were classified as non-responders. Patients who did not respond to the placebo were classified as non-responders. The double-blind treatment phase then continued for an additional 6 weeks, after which patients entered a withdrawal period.

[0205] Of the 121 subjects in the enrichment population (60 in the Atika Plant and 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate for the full ITT analysis set is 95%. This contrasts with a completion rate of approximately 85% for the adjunctive aripiprazole study (Pae, CNS Drugs, 2011;25,109-127) and 45-62% for adjunctive quetiapine (El Khalili, cited above). A total of four subjects (3.3%) discontinued the study: two subjects in the placebo and two subjects in the Atika Plant treatment group. See Tables 30 and 31.

[0206] [Table 36]

[0207] [Table 37]

[0208] (vii) Sexual function Impaired sexual function is a common side effect of antidepressant therapy and can be very disruptive to patients and their sexual partners. Major depression itself is associated with increased sexual dysfunction, and many pharmacological treatments are known to further worsen sexual function. In a large survey of almost 5000 patients in France, the prevalence of sexual dysfunction was estimated to be 65% in untreated patients with MDD. The prevalence of sexual dysfunction increased to 71% for patients treated with antidepressant therapy.

[0209] Sexual pleasure is an important component of hedonism. The brain reward circuit is controlled by several areas: the nucleus accumbens, the ventral tegmental area and the amygdala. It is hypothesized that treatment with kappa opioid receptors may restore normal homeostatic balance in patients with overactivation. Treatment with Aticaplant may improve symptoms of anhedonia. Other symptoms related to the reward circuit include lack of sexual pleasure, lack of interest and lack of enjoyment.

[0210] Patients had sexual function measured using the ASEX, a standard, familiar rating scale. See Table 32.

[0211] [Table 38]

[0212] The mean change from treatment baseline (SD) in ASEX total score by week 6 was -1.5 (4.02) points for Atika Plant compared to -0.7 (2.98) points for placebo. Lower scores in ASEX indicate improvement. Score reduction at week 6 was greater in the Atika Plant group compared to placebo. This is unexpected, since adjunctive treatment with other drugs is expected to worsen sexual function, i.e., increase ASEX score over time. See Figure 19.

[0213] Patients who received Aticaplant had significant improvements in sexual function. Examination of individual item-level changes was also performed and revealed that the greatest changes were seen in items related to consummatory pleasure: orgasm satisfaction, orgasm attained, and vaginal lubrication / erection. Most of the improvement is seen in items 3, 4, and 5 in Figure 20.

[0214] (viii) Onset of Effect The onset of effect for Atikaplant can be estimated from the study. Figure 7B shows the least squares mean change from baseline. A significant treatment effect in favor of Atikaplant was seen as early as week 3. At this time point, Atikaplant showed a statistically superior effect compared to placebo.

[0215] Example 2: Single-dose Aticaplant as adjunctive antidepressant therapy Study Design: A 6-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia (MDD ANH+) and who had an inadequate response to SSRIs or serotonin and SNRIs in the current depressive episode. See Figure 21.

[0216] For all subjects, the study will consist of three phases: an eligibility screening phase (up to 4 weeks prior to administration of the first dose), a 6-week double-blind treatment phase, and a 1-2 week follow-up. Subjects who complete the double-blind phase may enter an open-label long-term safety study.

[0217] Sample size and randomization: Approximately 544 subjects with MDD with prominent anhedonia (MDD ANH+) and MDD without prominent anhedonia (MDD ANH-) will be randomized in a 1:1 ratio to adjunctive placebo or acicaplant to achieve a minimum of 314 adult subjects meeting predefined criteria for MDD ANH+ eligible for inclusion in the primary analysis. Randomization will be stratified by study center, age group (adult [<65 years], elderly [>=65 years]), baseline anhedonia, and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0218] Dose and Administration All eligible subjects will receive aticaplant or placebo in addition to their baseline SSRI / SNRI. Study drug will be taken daily.

[0219] Inclusion Criteria:

[0220] [Table 39]

[0221] Exclusion criteria:

[0222] [Table 40-1]

[0223] [Table 40-2]

[0224] A. Efficacy Objectives and Endpoints Assessment of primary and secondary (primary and other) endpoints will be performed on the FAS, which includes adult (non-elderly) subjects with MDD ANH+ who have taken at least one dose of study medication.

[0225] Primary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects with MDD ANH+ and an inadequate response to current antidepressants, as assessed by change from baseline in MADRS total score from Day 1 (pre-randomization) to the end of the 6-week double-blind treatment phase (Day 43): - Change from baseline to week 43 in MADRS total score.

[0226] Primary Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as adjunctive therapy to antidepressants on patient-reported assessment of anhedonia outcomes: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0227] Other Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as an adjunctive treatment for: Proportion of responders at Day 43 (≥ 50% reduction in MADRS total score). Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43. - Change in MADRS6 from baseline to day 43. - Change in PHQ-9 total score from baseline to day 43. - Change in SHAPS total score from baseline to day 43. - Change in symptoms of anxiety using GAD-7 from baseline to day 43.

[0228] Exploratory: To evaluate the efficacy of Aticaplant as an adjunctive treatment compared to placebo in adult subjects with MDD ANH+ and all MDD subjects (adults and elderly subjects with MDD ANH+ and MDD ANH-) on: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to week 43 in SDS total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0229] To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH- as an adjunctive treatment for: -Change from baseline over time in MADRS total score. -Change from baseline over time in DARS total score.

[0230] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. ·AE includes AESI. An AE may be any untoward or unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product (investigational or non-investigational medicinal product), whether or not it is causally related to the medicinal product (investigational or non-investigational medicinal product). A TEAE was an AE that occurred during the treatment phase that worsened from baseline. The full safety analysis set included all enrolled subjects who received at least one dose of the investigational product during the treatment period.

[0231] Vital signs ECG, laboratory data ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0232] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0233] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, as indicated, except to treat AEs or breakthrough symptoms, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening through the first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin / agomelatine. Subjects taking benzodiazepines and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to the equivalent of 6 mg / day lorazepam) during the double-blind treatment phase. Dose escalation above the equivalent of 6 mg / day lorazepam or new benzodiazepine medications will not be permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. Any form of new psychotherapy or change in current psychotherapy is prohibited during the screening and double-blind phases. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0234] Example 3: A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety, and tolerability of fixed doses of Aticaplant 5 mg and 10 mg as adjunctive therapy in adult and geriatric subjects with MDD with prominent anhedonia and inadequate response to current antidepressant therapy Study Design: An 8-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia and who have had an inadequate response to SSRIs or SNRIs in the current depressive episode. See Figure 22.

[0235] For all subjects, the study consisted of three phases: Eligibility Screening Phase (up to 4 weeks prior to first dose administration) 8-week double-blind treatment phase · and a 1-2 week follow-up phase.

[0236] Approximately 624 subjects (randomized in a 2:1:1 ratio to placebo, 5 mg acetaminophen, and 10 mg acetaminophen) will be enrolled in the study with the goal of achieving a minimum of 556 adult subjects with MDD with prominent anhedonia and approximately 68 elderly subjects (>= 65 years) with MDD with prominent anhedonia.

[0237] Subjects who complete the double-blind treatment phase may enter an open-label long-term safety study.

[0238] Sample size and randomization: Approximately 624 adult (<65 years) and elderly (>65 years) subjects with MDD with prominent anhedonia will be randomized in a 2:1:1 ratio to adjunctive placebo, 5 mg ataticaplant, or 10 mg ataticaplant to achieve a minimum of 556 adult subjects who meet the predefined criteria for MDD with prominent anhedonia eligible for inclusion in the primary efficacy analysis set. Randomization will be stratified by study center, age group (adult, elderly), and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0239] Dose and Administration: All eligible subjects will receive Aticaplant 5 mg, Aticaplant 10 mg, or placebo in addition to their baseline SSRI / SNRI, which will be continued for the entire study. Study medication will be taken daily.

[0240] Inclusion Criteria:

[0241] [Table 41] Exclusion criteria:

[0242] [Table 42-1]

[0243] [Table 42-2]

[0244] A. Efficacy Objectives and Endpoints Assessment of the primary and secondary (primary and other) endpoints will be performed on the full analysis set (FAS), which includes adult (non-elderly) subjects with MDD with significant anhedonia who have taken at least one dose of study medication.

[0245] Primary: To evaluate the efficacy of two fixed doses of Aticaplant (5 mg and 10 mg) compared with placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects (18-64 years) with MDD with prominent anhedonia and inadequate response to current antidepressants. - Change from baseline to week 43 in MADRS total score.

[0246] Primary Secondary: To evaluate the efficacy of Aticaplant 10 mg compared with placebo as adjunctive therapy to antidepressants on patient-reported assessments of anhedonia outcomes in adult subjects with MDD with prominent anhedonia: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0247] Other secondary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in adult subjects with MDD with prominent anhedonia. Proportion of responders (≥ 50% reduction in MADRS total score) at Day 43 and Day 57. Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43 and Day 57. Changes from baseline to days 43 and 57 in MADRS-6 Change from baseline to Day 43 and Day 57 in the Patient Health Questionnaire, 9-item (PHQ-9) total score.

[0248] Exploratory: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD with prominent anhedonia as an adjunctive treatment: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to Day 43 in Sheehan Disability Scale (SDS) total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0249] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. AE includes AESI Vital signs ECG Test values ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0250] Other objectives (exploratory): To identify diagnostic biomarkers and investigate changes in MDD-related biomarkers in relation to clinical response to depression and anhedonia during monotherapy with Aticaplant. To identify genetic and other factors that may affect the pharmacokinetics (PK), safety, or tolerability of Atikaplant.

[0251] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0252] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, as indicated, except to treat AEs or breakthrough symptoms, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening through the first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedative antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin. Subjects taking benzodiazepine and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to the equivalent of lorazepam 6 mg / day) during the double-blind treatment phase. Dose escalation above the equivalent of lorazepam 6 mg / day, or new benzodiazepine medications, are not permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. During the screening and double-blind phases of the study, any form of new psychotherapy or change in current psychotherapy is prohibited. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0253] Example 4: Biomarker Assays Venous blood samples were obtained from patients and healthy control subjects from a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who showed an inadequate response to SSRI / SNRI treatment as described in Example 1. Serum or plasma was prepared from the venous blood samples. Human CRP and IL-6-R measurements were performed in serum using an MSD Sector 6000 with kits #K151STD and K151ALC (MesoScale Discovery, Rockville, MD). Human TNFα was quantified in serum using a Simoa HD-1 analyzer with kit #143 (Quanterix, Lexington, MA). Human dynorphin was assayed in plasma using a SpectraMax M plate reader (Molecular devices, San Jose, CA) with kit #CSB-E09128h (Cusabio, Wuhan, China). All measurements were performed according to the kit manufacturer's recommendations.

[0254] As used in the following biomarker assay analyses, treatment (TRT) refers to treatment with SSRI / SNRI+atticaplant and placebo (PBO) refers to treatment with SSRI / SNRI+placebo.

[0255] The following biomarker signatures were used:

[0256] Treatment outcome: change in clinical scales at the end of the dual period. Negative values ​​indicate improvement in depression levels relative to baseline levels. The more negative the change, the greater the improvement.

[0257] Sig Pos : Patients who meet criteria defined by a biomarker signature and / or clinical scale.

[0258] 3MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or siL6R>25ng / mL).

[0259] 4MM: Inflammatory biomarker signature with positive status defined by 3MM with high dynorphin (δ1) or intermediate dynorphin (δ2) subtype, specifically DYN>δ1 pg / mL or (DYN>δ2 pg / mL and CRP>3 mg / L and (TNFα>4 pg / mL or siL6R>25 ng / mL). In certain embodiments, the 4MM DYN cutoff is as follows: Dyn>50 OR (3MM and Dyn>8); Dyn>24 OR (3MM and Dyn>8), or Dyn>11.4 and 3MM.

[0260] TE Sig Pos Treatment effect in signature positive group:Sig Pos In groups (mean MADRS change in placebo - mean MADRS change in treatment).

[0261] TE Sig Neg :Treatment effect in signature-negative group.

[0262] Sig Adv: Signature dominance (interaction) difference in TE between signature groups: Sig Adv = TE Sig Pos -TE Sig Neg .

[0263] The effect of biomarker signatures on patients' response to treatment is summarized in graphical form using two panel box plots in FIG. 25. The left panel of FIG. 25 shows treatment outcomes relative to baseline in the biomarker signature positive group, defined herein as subjects whose biomarker profile fits the three-marker model (3MM) (21% of MDD). The right panel of FIG. 25 shows treatment outcomes in the biomarker signature negative group using Tukey box plots, in addition to individual patient outcomes marked by circle points. Red represents placebo and cyan represents Aticaplant. The rectangular box spanning the diamond and error bars represent the mean and 95% confidence interval (CI) of treatment outcomes by treatment group and biomarker signature status. In the signature positive group, the treatment outcome (difference in mean treatment outcomes between treatment groups) was 6.29 MADRS points (one-sided p=0.07, effect size=0.75). Meanwhile, in the signature-negative group, the treatment effect was 1.59 MADRS points. In other words, subjects who are biomarker signature positive improve an additional 4.7 points (6.29 to 4.7) over placebo when treated with Aticaplant compared to subjects who are biomarker signature negative. This signature advantage of 4.7 MADRS points represents the interaction between biomarker signature status and treatment effect. Treatment effect, signature advantage, and corresponding p-values ​​are assessed using a linear regression model for treatment outcome with independent variables for treatment, biomarker signature status, and their interactions. All p-values ​​are one-sided. Significance is defined as a nominal one-sided p-value <0.05.

[0264] Figures 26A-26D show the results of patient subtyping using a biomarker signature consisting of dynorphin levels only, i.e., DYN>δpg / mL. Biomarker signature effects are shown across a range of values ​​for δ from 6.2pg / mL to 116.2pg / mL. At each value tested, the treatment effect and signature dominance in the biomarker signature positive group are calculated and graphed in Figure 26A. The percentages shown along the top of the graphs indicate the proportion of subjects that are biomarker signature positive at the particular threshold. Both treatment effect (SigPos: PBO-TRT) and signature dominance (SigPos.DIFF-SigNeg.DIFF) increase with increasing δ, peaking around δ=19.9pg / mL. Figures 26B and 26C show the signature effect at δ levels of 19.9 and 30pg / mL, respectively. However, at high levels of dynorphin (FIG. 26D), the signature effect was more variable.

[0265] Figures 27A-27D summarize the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes, specifically DYN>δpg / mL or CRP>3mg / L and (TNFα>4pg / mL or siL6R>25ng / mL). Similar to Figures 26A-26D, the effect of the biomarker signature is evaluated at a range of dynorphin cut points (δ). Similar to the signature with dynorphin alone, the treatment effect increases with increasing δ, but the interaction effect is considerably more pronounced due to the mean Atticaplant response being worse than placebo for biomarker signature negative patients (Figure 26B). More importantly, the effect of the biomarker signature is more stable at higher dynorphin cut points (Figures 27C and 27D), making this biomarker signature a more reliable identifier of patients most likely to benefit from treatment with Atticaplant as an adjunctive treatment compared to SOC alone. Targeting both the DYN high and 3MM subtypes results in a 3-8 point signature advantage in over 60% of patients.

[0266] Figures 28A and 28B show the effect of the biomarker signature to capture subjects who are both 3MM positive and have high dynorphin: DYN>δpg / mL and CRP>3mg / L and (TNFα>4pg / mL or siL6R>25ng / mL). A very large treatment effect was observed in biomarker signature positive patients and a large signature advantage over a wide range of dynorphin levels (Figure 28B, corresponding to δ=11.5). This significant improvement by Atika plant in patients with both high dynorphin and high inflammation suggests that the two identified subtypes reflect different pathologies that are both responsive to Atika plant.

[0267] Figures 29A-29C summarize the results of patient subtyping using biomarker signatures using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1pg / mL or (DYN>δ2pg / mL and CRP>3mg / L and (TNFα>4pg / mL or siL6R>25ng / mL). The effect of the biomarker signatures is evaluated over a range of dynorphin cut points (δ) for δ1, while the δ2 ​​cut point in combination with 3MM is kept constant. These signatures show a treatment effect of 4.5 MADRS points or more, resulting in a signature advantage of >5 points in 38-63% of patients. Figure 29B corresponds to SigPos=DYN>24.0 or (3MM and DYN>8), 63% of the cohort. Figure 29C shows SigPos=DYN>50 or (3MM and DYN>8), corresponding to 38% of the cohort. As shown in Figures 29A-29C, 4 MM biomarker signature positive patients (63% of MDD) responded with a 4.6 MADRS point difference at final DB compared to placebo, a 6 point improvement compared to their biomarker signature negative counterparts.

Claims

1. 1. A pharmaceutical composition for use in a method for treating major depressive disorder (MDD) in a human patient, the pharmaceutical composition comprising aticaplant, the method comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to the patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

2. 10. The pharmaceutical composition of claim 1, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaplant or a pharmaceutically acceptable salt thereof.

3. 3. The method of claim 2, wherein the other antidepressant therapy comprises one or more antidepressants.

4. 4. The pharmaceutical composition of claim 3, wherein the one or more antidepressants comprise a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy, or a combination thereof.

5. The pharmaceutical composition of claim 1, wherein the patient has anhedonia.

6. 6. The pharmaceutical composition of claim 5, wherein the patient has a total score of ≥ 32 on the Snaith-Hamilton Patient Pleasure Scale (SHAPS).

7. 10. The pharmaceutical composition of claim 1, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

8. 8. The pharmaceutical composition of claim 7, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

9. 2. The pharmaceutical composition of claim 1, wherein the aticaplant is S-aticaplant or a pharmaceutically acceptable salt thereof.

10. 2. The method of claim 1, wherein the effective amount of aticaplant is from about 2 to about 35 mg.

11. 11. The pharmaceutical composition of claim 10, wherein the effective amount of aticaplant is about 10 mg.

12. 11. The pharmaceutical composition of claim 10, wherein the effective amount of aticaplant is about 5 mg.

13. 10. The pharmaceutical composition of claim 1, wherein the aticaplant is administered orally.

14. 10. The pharmaceutical composition of claim 1, wherein the aticaplant is administered once daily.

15. the biological sample obtained from the patient a. a level of CRP higher than a reference CRP level, and b. i. a level of TNF-α that is higher than a reference TNF-α level, and ii. at least one of a level of sIL6R higher than a reference sIL6R level,

16. 2. The pharmaceutical composition of claim 1, wherein the patient is identified as biomarker positive if the biological sample obtained from the patient is identified as having a level of dynorphin that is higher than a reference dynorphin level.

17. the biological sample obtained from the patient a. a level of CRP higher than a reference CRP level, and i. a level of TNF-α that is higher than a reference TNF-α level, and ii. at least one of a level of sIL6R that is higher than a reference sIL6R level; or b) The pharmaceutical composition of claim 1, wherein the patient is identified as biomarker signature positive if identified as having a level of dynorphin higher than a reference dynorphin level.

18. the biological sample obtained from the patient a. a level of CRP higher than a reference CRP level, and i. a level of TNF-α that is higher than a reference TNF-α level, and ii. at least one of a level of sIL6R that is higher than a reference sIL6R level; and b. a level of dynorphin that is higher than a reference dynorphin level, the patient is identified as being biomarker signature positive.

19. The pharmaceutical composition according to any one of claims 15 and 17 to 18, wherein the reference CRP level is about 3 mg / L.

20. The pharmaceutical composition of any one of claims 15 and 17 to 18, wherein the reference TNF-α level is about 4 pg / mL.

21. The pharmaceutical composition of any one of claims 15 and 17-18, wherein the reference sIL6R level is about 25 ng / mL.

22. The pharmaceutical composition of any one of claims 16 to 18, wherein the reference dynorphin level is about 20 pg / mL.

23. The pharmaceutical composition of any one of claims 16 to 18, wherein the reference dynorphin level is about 30 pg / mL.

24. The pharmaceutical composition of any one of claims 16 to 18, wherein the reference dynorphin level is about 11.4 pg / mL.

25. the biological sample obtained from the patient a. a level of dynorphin that is greater than a first reference dynorphin level, or b. The pharmaceutical composition of claim 1, wherein the patient is identified as having both (i) a level of CRP higher than a reference CRP level, and at least one of a level of TNF-α higher than a reference TNF-α level and a level of sIL6R higher than a reference sIL6R level, and (ii) a level of dynorphin higher than a second reference dynorphin level, wherein the patient is identified as having a positive biomarker signature.

26. 26. The pharmaceutical composition of claim 25, wherein the first reference dynorphin level is about 50 pg / mL and the second reference dynorphin level is about 8 pg / mL.

27. 26. The pharmaceutical composition of claim 25, wherein the first reference dynorphin level is about 24 pg / mL and the second reference dynorphin level is about 8 pg / mL.

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