Crystalline Atika Plant in its pure form

Abstract

The present disclosure provides compositions containing pure aticaplant, solvates of aticaplant, and methods of treating major depressive disorder with aticaplant.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 317,483, filed March 7, 2022.

[0002] FIELD OF THEINVENTION The present disclosure relates to chemically and / or enantiomerically pure atikaplant, such as pure crystalline form III of atikaplant, compositions containing same, and methods of using same. [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 the mesolimbic dopamine surge 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 the negative emotional states associated with the stress response.

[0004] Atikaplant is an effective treatment for patients diagnosed with depression. However, the synthetic route to Atikaplant is plagued with challenges, including safety concerns, low yields, and low purity, especially on a large scale. Summary of the Invention

[0005] What is needed are new compounds and treatments for patients with depression, and optionally, anhedonia.

[0006] In some aspects, the disclosure provides a tetrahydrofuran solvate of aticaplant.

[0007] [ka]

[0008] In another aspect, the present disclosure provides a process for preparing a tetrahydrofuran solvate of Atikaplant.

[0009] In a further aspect, the present disclosure provides a tetrahydrofuran solvate of aticaplant prepared according to the processes described herein.

[0010] In yet another aspect, the present disclosure provides a composition comprising a crystalline form of aticaplant and less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0011] [ka]

[0012] In a further aspect, the present disclosure provides a process for preparing crystalline aticaplant.

[0013] [ka]

[0014] In another aspect, the present disclosure provides a crystalline form of aticaplant prepared according to the processes described herein.

[0015] In a further aspect, the present disclosure provides a method of treating major depressive disorder in a human patient using a composition or crystalline form of aticaplant described herein. In certain embodiments, the patient has previously had an inadequate response to other antidepressant therapies.

[0016] In yet another aspect, the present disclosure provides a composition or crystalline form of Aticaplant according to claim 43 for use in treating major depressive disorder in a human patient, optionally with anhedonia. In certain embodiments, the patient has had a previous inadequate response to other antidepressant therapies.

[0017] In yet a further aspect, the present disclosure provides the use of a composition or crystalline form of Aticaplant described herein for treating major depressive disorder in a human patient with anhedonia. In certain embodiments, the patient has previously had an inadequate response to other antidepressant therapies. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 is the X-ray powder diffraction (XRPD) pattern (transmission mode) of polymorphic form III of Atika Plant. [Diagram 2] 1 is a differential scanning calorimetry (DSC) thermogram of polymorphic form III of Atika Plant. [Diagram 3] 13 is an mDSC thermogram of polymorphic form III of Atika plant. [Figure 4] Clinical trial design for Example 5. [Diagram 5] 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. [Figure 6]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 7] 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. [Figure 8] 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 9] 1 is a line graph showing MADRS total scores over time for the eITT analysis set: Mean (±SE). [Figure 10A] FIG. 1 is a line graph showing MADRS total scores over time for the full intent-to-treat (fITT) analysis set: mean (±SE). [Figure 10B] This is an excerpt from Figure 10-A for weeks 0 to 6 of treatment. [Figure 11] 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 12] 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 13] 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 14] fLine graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the ITT analysis set. [Figure 15]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 16] fLine graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the ITT analysis set. [Figure 17] SHAPS total score over time for the eITT analysis set: line graph showing mean (±SE). [Figure 18] SHAPS total score over time for the fITT analysis set: line graph showing mean (±SE). [Figure 19] Changes in MADRS from baseline according to severity of anhedonia are shown. [Figure 20A] FIG. 1 is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS≧38. [Figure 20B] FIG. 1 is a line graph showing MADRS change from baseline in patients with low anhedonia, i.e., SHAPS<38. [Figure 21] FIG. 1 is a bar graph showing a comparison of MADRS in patients with low and high anhedonia. [Figure 22] 1 is a line graph showing the mean ASEX total score change from baseline. [Figure 23] 1 is a bar graph showing the mean ASEX item-level change total score change from baseline. [Figure 24] 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. [Diagram 25]f Plot showing MADRS total score:LS mean difference (60%) at week 6 by different subgroups for the ITT analysis set, where <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] 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).

[0020] The present disclosure provides compositions comprising chemically and / or enantiomerically pure crystalline form III of aticaplant, which is anhydrous and stable in solid form.

[0021] The term "crystal" refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.

[0022] The term "polymorph" refers to a crystalline form of a molecule that has one particular crystal structure. A crystalline compound may have one crystalline form or may have two or more crystalline forms, i.e., polymorphs. As will be understood by those skilled in the art, polymorphs of a compound may be distinguished from one another by comparative physicochemical properties, such as solubility, dissolution rate, stability, bioavailability, among others. Polymorphs may also have different spectra selected from, but not limited to, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid-state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot stage microscopy, or dynamic solvent sorption.

[0023] The term "crystalline" refers to a solid state form of a chemical moiety in which atoms, molecules, or ions are assembled into a highly ordered structure that extends in all directions. Thus, "crystalline" includes all crystalline forms of Compound I, including its salts. Characterization of crystalline forms can be performed by one of skill in the art, including, but not limited to, XRPD or DSC. Typically, the XRPD pattern includes a sharp intensity peak. This is in contrast to the XRPD pattern of an amorphous form, which often includes a broad peak without an identifiable peak. A crystalline form may be fully crystalline or partially crystalline. In some embodiments, a crystalline sample may be 100% crystalline w / w. A crystalline sample may also contain a solid that is amorphous. In certain embodiments, a crystalline form may contain a solid such that the sample is at least about 99% crystalline w / w, at least about 95% amorphous w / w, at least about 90% crystalline w / w, at least about 85% crystalline w / w, at least about 80% crystalline w / w, etc.

[0024] The term "anhydrous" or "anhydrate" as used herein refers to the crystals described herein that are substantially devoid of water. In some embodiments, the anhydrous forms contain less than about 1% w / w water. In other embodiments, the anhydrous forms contain less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w / w water.

[0025] As provided herein, all temperature values ​​may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, and / or laboratory conditions. Unless otherwise specified, the temperatures described may vary. In some embodiments, the temperatures described herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.

[0026] Similarly, the 2θ values ​​obtained from the XRPD pattern may vary. Such variations may depend on the instrument type, instrument parameters, laboratory techniques, samples (including particle size, impurities, etc.), and / or laboratory conditions. Unless otherwise specified, the XRPD pattern and / or 2θ peak values ​​may vary. In certain embodiments, the 2θ peak values ​​vary (higher or lower) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other embodiments, one or more of the 2θ peak values ​​are about 0.05°, about 0.1°, about 0.15°, or about 0.2° higher. In further embodiments, one or more of the 2θ peak values ​​are about 0.05°, about 0.1°, about 0.15°, or about 0.2° lower.

[0027] As used herein, the term "corresponding to" may be used in reference to a particular spectrum. Thus, "corresponding" includes a spectrum that is identical or substantially similar to another spectrum. One skilled in the art would be able to compare such spectra and determine whether one spectrum corresponds to another spectrum. Thus, the term "corresponding" is used herein to compare XRPD patterns, DSC thermograms, among others. In some embodiments, one XRPD pattern corresponds to another XRPD pattern if their 2θ values ​​are within the error range described above. In other embodiments, one XRPD pattern corresponds to another XRPD pattern if the peaks have the same 2θ peak values, but one or more peaks have different heights (intensities). In further embodiments, one XRPD pattern corresponds to another XRPD pattern if the peaks have the same 2θ peak values, but one or more peaks have different peak areas. In still other embodiments, one XRPD pattern corresponds to another XRPD pattern if the peaks have the same 2θ peak values, but one or more peaks are obscured. Such obscured peaks may be due to impurities, excipients, and the like. Such unclear peaks typically do not prevent characterization of the crystalline form.

[0028] As used herein, "chemical purity" refers to the relative proportion of attic plant in a sample compared to one or more compounds that are not attic plant. The content or degree of chemical purity is determined in % with reference to theoretical composition, and thus, as used herein, "chemically pure" means that the compound is substantially free of impurities. In some embodiments, pure or chemically pure attic plant has a purity of at least about 99.7 to about 100% as measured by HPLC area %. In further embodiments, pure or chemically pure attic plant has a purity of about 99.7 to about 100% as measured by HPLC area %. In other embodiments, pure or chemically pure attic plant has a purity of about 99.7, about 99.8, about 99.9, about 99.95, or about 100% as measured by HPLC area %.

[0029] The term "optical purity" refers to the optical rotation of a pure sample of atticaprant with unknown stereochemistry versus the optical rotation of a sample of pure atticaprant, expressed as a percentage. "Enantiomerically pure" means that a compound, such as atticaprant, has an optical purity of at least about 99.5% as measured by HPLC area %. Preferably, enantiomerically pure atticaprant contains at least about 99.5% S-atticaprant as measured by HPLC area %. In other embodiments, enantiomerically pure atticaprant has an optical purity of about 99.5-99.9% or about 99.95-99.9% as measured by HPLC area %. In further embodiments, enantiomerically pure atticaprant has an optical purity of at least about 99.9% or at least about 99.95% as measured by HPLC area %.

[0030] Pure atikaplant or compositions containing pure atikaplant can be prepared using a novel intermediate, which is a tetrahydrofuran solvate of atikaplant.

[0031] [ka] In some embodiments, the tetrahydrofuran solvate is a tetrahydrofuran solvate of S-aticaplant.

[0032] [ka]

[0033] Also described is a composition comprising tetrahydrofuran solvate. Advantageously, the composition comprising tetrahydrofuran solvate of Atikaplant contains less impurities than the composition comprising other intermediates leading to the production of Atikaplant. In particular, the composition comprising tetrahydrofuran solvate of Atikaplant contains about 0.10% by weight or less of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition.

[0034] [ka] In some embodiments, compositions containing a tetrahydrofuran solvate of Atikaplant contain about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001 wt. % or less of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the composition containing the tetrahydrofuran solvate of Atikaplant contains about 0.001 to about 0.1, about 0.001 to about 0.05, about 0.001 to about 0.01, about 0.001 to about 0.005, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 0.1, about 0.01 to about 0.05, or about 0.05 to about 0.1% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0035] The composition containing the tetrahydrofuran solvate of Atikaplant may contain at least about 99.5% by weight of the tetrahydrofuran solvate of Atikaplant, based on the weight of the composition. In some embodiments, the composition containing the tetrahydrofuran solvate of Atikaplant contains at least about 99.5, about 99.6, about 99.7, about 99.8, about 99.9, about 99.95, or about 99.99% by weight of the tetrahydrofuran solvate of Atikaplant, based on the weight of the composition.

[0036] The tetrahydrofuran solvate of Atikaplant or a composition containing it may also contain less than 0.05% by weight of one or more of organic impurities, inorganic impurities, or residual solvents, based on the total weight of the composition. Examples of organic impurities include, but are not limited to, starting materials, by-products, intermediates, decomposition products, reagents, ligands, catalysts, or combinations thereof. Examples of inorganic impurities include, but are not limited to, reagents, ligands, catalysts, heavy metals, inorganic salts, or other materials such as filter aids, charcoal, sulfated ash, among others. In some embodiments, the residual solvent is one or more of tetrahydrofuran, ethanol, and water. In further embodiments, the residual solvent is tetrahydrofuran. In further embodiments, the residual solvent is one or more of acetic acid, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethyl acetate, 1-pentanol, ethyl ether, 1-propanol, ethyl formate, 2-propanol, formic acid, propyl acetate, or triethylamine.

[0037] The term "intermediate" as used herein refers to a material that is produced during the process of the synthesis of Atikaplant or crystalline Atikaplant tetrahydrofuran solvate described herein and that undergoes further chemical transformation.

[0038] As used herein, the term "ligand" refers to an agent that has a strong affinity for metal ions.

[0039] As used herein, the term "solvent" refers to an inorganic or organic liquid used as a vehicle for the preparation of a solution or suspension in the methods described herein.

[0040] As used herein, the term "starting material" refers to a material used in the synthesis of an aticaplant or crystalline aticaplant tetrahydrofuran solvate prepared as described herein, and which is incorporated as an element into the structure of an intermediate and / or aticaplant or crystalline aticaplant tetrahydrofuran solvate prepared as described herein.

[0041] In some embodiments, the composition containing a tetrahydrofuran solvate contains no more than about 0.10% by weight of the tetrahydrofuran solvate of R-aticaplant, based on the weight of the composition.

[0042] [ka] In some embodiments, the composition containing a tetrahydrofuran solvate of Atikaplant contains about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001% by weight or less of a tetrahydrofuran solvate of R-Atikaplant, based on the weight of the composition. In other embodiments, the composition containing a tetrahydrofuran solvate of atikaplant contains about 0.001 to about 0.1, about 0.001 to about 0.05, about 0.001 to about 0.01, about 0.001 to about 0.005, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 0.1, about 0.01 to about 0.05, or about 0.05 to about 0.1% by weight of R-tetrahydrofuran solvate of atikaplant, based on the weight of the composition.

[0043] In other embodiments, the composition containing the tetrahydrofuran solvate contains no more than about 0.10% by weight of R-aticaplant, based on the weight of the composition.

[0044] [ka] In some embodiments, a composition containing a tetrahydrofuran solvate of atikaplant contains about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001% by weight or less of R-atikaplant, based on the weight of the composition. In other embodiments, a composition containing a tetrahydrofuran solvate of aticaplant contains about 0.001 to about 0.1, about 0.001 to about 0.05, about 0.001 to about 0.01, about 0.001 to about 0.005, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 0.1, about 0.01 to about 0.05, or about 0.05 to about 0.1% by weight of R-aticaplant, based on the weight of the composition.

[0045] The tetrahydrofuran solvate of aticaplant may be prepared by crystallizing aticaplant using a mixture of tetrahydrofuran, alcohol, and water. In some embodiments, the alcohol is ethanol or methanol. In other embodiments, the alcohol is ethanol. In further embodiments, the alcohol is methanol. Thus, in some embodiments, the process for preparing the tetrahydrofuran solvate of aticaplant comprises crystallizing (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate in a tetrahydrofuran solvent.

[0046] [ka] 3-Fluoro-4-(4-formylphenoxy)benzamide and

[0047] [ka] The method includes reacting in the presence of a solvent. In some embodiments, the solvent is ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran, or a mixture thereof. In other embodiments, the solvent is tetrahydrofuran. In further embodiments, the solvent is ethyl acetate. In yet other embodiments, the solvent is 2-methyl-tetrahydrofuran. The process for preparing the tetrahydrofuran solvate of Atikaplant can be quenched using a base. Examples of suitable bases include, but are not limited to, alkali hydroxides, such as sodium hydroxide. The process for preparing the tetrahydrofuran solvate of Atikaplant can also be carried out in the presence of a reducing agent. Examples of suitable reducing agents include sodium triacetoxyborohydride. In some embodiments, the reducing agent is sodium triacetoxyborohydride.

[0048] In the method that does not utilize tetrahydrofuran as a solvent, i.e., when the solvent is ethyl acetate or 2-methyl-tetrahydrofuran, the solvent is removed after the completion of the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide. Those skilled in the art will be able to easily apply suitable techniques for removing the solvent. For example, evaporation, distillation, among others, can be used.

[0049] After the solvent is removed, the obtained material, for example, solid, is combined with tetrahydrofuran.In some embodiments, tetrahydrofuran is added to the material obtained from the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide.The amount of tetrahydrofuran utilized can depend on the scale of reaction and can be determined by those skilled in the art.

[0050] In addition to tetrahydrofuran, alcohol and water are added to the material resulting from the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide. In some embodiments, the alcohol is ethanol or methanol. In other embodiments, the alcohol is ethanol. In a further embodiment, the alcohol is methanol. The amount of ethanol and water utilized may depend, among other things, on the scale of the reaction and may be determined by one of skill in the art. In some embodiments, tetrahydrofuran is added to the solid material, followed by ethanol, followed by water to form a tetrahydrofuran / ethanol / water solution. In other embodiments, tetrahydrofuran is added to the solid material, followed by water, followed by ethanol to form a tetrahydrofuran / ethanol / water solution. In a further embodiment, ethanol is added to the solid material, followed by tetrahydrofuran, followed by water to form a tetrahydrofuran / ethanol / water solution. In yet another embodiment, ethanol is added to the solid material, followed by water, followed by tetrahydrofuran to form a tetrahydrofuran / ethanol / water solution. In still further embodiments, water is added to the solid material, followed by ethanol, followed by tetrahydrofuran to form a tetrahydrofuran / ethanol / water solution. In other embodiments, water is added to the solid material, followed by tetrahydrofuran, followed by ethanol to form a tetrahydrofuran / ethanol / water solution.

[0051] The volume ratio of tetrahydrofuran to ethanol to water is about 1:1:1 to about 1:5:10. In some embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:1, about 1:1:2, about 1:1:3, about 1:1:4, about 1:1:5, about 1:1:6, about 1:1:7, about 1:1:8, about 1:1:9, about 1:1:10, about 1:2:2, about 1:2:3, about 1:2:4, about 1:2:5, about 1:2:6, about 1:2:7, about 1:2:8, about 1:2:9, about 1:2:10, about 1:3:1, about 1:3:2, about 1:3:3, about 1:3:4, about 1:3:5, about 1:3:6, about 1:3:7, about 1:3:8, about 1:3:9, about 1:3 ...1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, about 1:3:1, 1:3:4, about 1:3:5, about 1:3:6, about 1:3:7, about 1:3:8, about 1:3:9, about 1:3:10, about 1:4:1:, about 1:4:2, about 1:4:3, about 1:4:4, about 1:4:5, about 1:4:6, about 1:4:7, about 1:4:8, about 1:4:9, about 1:4:10, about 1:5:1, about 1:5:2, about 1:5:3, about 1:5:4, about 1:5:5, about 1:5:6, 1:5:7, about 1:5:8, about 1:5:9, or about 1:5:10. In other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:2, based on the total volume of the solution. In further embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1.6:3.2. In yet other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 3:3:1. In even further embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:4. In other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 4:5:10. In further embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 7:5:10. In yet other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 3:5:10.

[0052] The tetrahydrofuran solvate of Atikaplant is then crystallized from a solution of tetrahydrofuran, ethanol, and water. A person skilled in the art would be able to utilize suitable techniques for crystallizing the tetrahydrofuran solvate of Atikaplant. Examples of techniques include, but are not limited to, evaporation, cooling, concentration, and seeding, or combinations thereof. In some embodiments, the solution of tetrahydrofuran, ethanol, and water is concentrated. In further embodiments, the solution of tetrahydrofuran, ethanol, and water is evaporated. In other embodiments, the solution of tetrahydrofuran, ethanol, and water is cooled, for example, to a low temperature. In further embodiments, the solution of tetrahydrofuran, ethanol, and water is heated to an elevated temperature, for example, the reflux temperature of the solution of tetrahydrofuran, ethanol, and water, and then cooled to a low temperature. The low temperature can be determined by one skilled in the art. In certain aspects, the low temperature is less than about room temperature, for example, about 23°C. In further aspects, the low temperature is less than about 20, about 15, about 10, or about 5°C.

[0053] Alternatively or in addition to the above crystallization techniques, tetrahydrofuran seed crystals of Atikaplant can be added to a solution of tetrahydrofuran, ethanol, and water. As used herein, the term "seed crystals" refers to a solid sample of tetrahydrofuran solvate of Atikaplant that exists in crystalline form. In some embodiments, the seeds comprise S-tetrahydrofuran solvate of Atikaplant. The seed crystals can be in the form of various shapes, including but not limited to needles, blocks, or combinations thereof.

[0054] In contrast to other intermediates utilized to prepare Atikaplant, the tetrahydrofuran solvate of Atikaplant desirably contains no impurities or low levels of one or more impurities. In some embodiments, Atikaplant tetrahydrofuran solvent or compositions containing it contain low levels of 3-fluoro-4-(4-formylphenoxy)benzamide.

[0055] [ka] The term "low level" is used to describe the amount of 3-fluoro-4-(4-formylphenoxy)benzamide in a sample of the tetrahydrofuran solvate of Atikaplant. In some embodiments, the tetrahydrofuran solvate of Atikaplant or a composition containing it comprises about 0.10% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition. In other embodiments, the tetrahydrofuran solvate of Atikaplant or compositions containing it contain about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001 wt.% or less of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the tetrahydrofuran solvate of Atikaplant or the composition containing Atikaplant tetrahydrofuran contains about 0.001 to about 0.1, about 0.001 to about 0.05, about 0.001 to about 0.01, about 0.001 to about 0.005, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 0.1, about 0.01 to about 0.05, or about 0.05 to about 0.1% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0056] Tetrahydrofuran solvate of Atikaplant can be used to prepare crystalline forms of Atikaplant. In some embodiments, tetrahydrofuran solvate of Atikaplant can be used to prepare chemically and / or enantiomerically pure S-Atikaplant. In further embodiments, tetrahydrofuran solvate can be used to prepare chemically and / or enantiomerically pure crystalline form III of Atikaplant. In other embodiments, tetrahydrofuran solvate of Atikaplant can be used to prepare chemically and / or enantiomerically pure crystalline form III of S-Atikaplant.

[0057] The chemically and / or enantiomerically pure forms of Atikaplant prepared as described herein, or compositions containing Atikaplant, contain less impurities than Atikaplant forms in the art. In some embodiments, the chemically and / or enantiomerically pure forms of Atikaplant described herein, or compositions containing Atikaplant, contain less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0058] [ka] In other embodiments, the chemically and / or enantiomerically pure forms of Atikaplant described herein, or compositions containing same, contain less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0059] [ka] In some embodiments, the chemically and / or enantiomerically pure aticaplant prepared as described herein, or a composition containing same, contains about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001 wt. % or less of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition. In other embodiments, the composition containing a tetrahydrofuran solvate of aticaplant contains from about 0.001 to about 0.05, from about 0.001 to about 0.01, from about 0.001 to about 0.005, from about 0.005 to about 0.05, from about 0.005 to about 0.01, or from about 0.01 to about 0.05 weight percent of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0060] The chemically and / or enantiomerically pure aticaplant or the composition containing it also contains about 0.10% or less by weight of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the chemically and / or enantiomerically pure aticaplant or the composition containing it contains about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001% or less by weight of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the chemically and / or enantiomerically pure aticaplant, or a composition containing it, contains about 0.001 to about 0.1, about 0.001 to about 0.05, about 0.001 to about 0.01, about 0.001 to about 0.005, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 0.1, about 0.01 to about 0.05, or about 0.05 to about 0.1 weight percent of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0061] The crystalline form of atticaprantrum, or a composition containing it, may further contain up to about 0.10% by weight of R-atticaprantrum, based on the weight of the composition.

[0062] [ka] In some embodiments, compositions containing a crystalline form of aticaplant contain about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, or about 0.001% by weight or less of R-aticaplant, based on the weight of the composition. In other embodiments, compositions containing a crystalline form of aticaplant contain from about 0.001 to about 0.1, from about 0.001 to about 0.05, from about 0.001 to about 0.01, from about 0.001 to about 0.005, from about 0.005 to about 0.1, from about 0.005 to about 0.05, from about 0.005 to about 0.01, from about 0.01 to about 0.1, from about 0.01 to about 0.05, or from about 0.05 to about 0.1% by weight of R-aticaplant, based on the weight of the composition.

[0063] A composition containing atticaceae prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure atticaceae, based on the weight of the composition. In some embodiments, a composition containing atticaceae, prepared as described herein, may contain at least about 99.5, about 99.6, about 99.7, about 99.8, about 99.9, about 99.95, or about 99.99% by weight of chemically and / or enantiomerically pure atticaceae, based on the weight of the composition. In other embodiments, a composition contains about 97 to about 100% by weight of pure atticaceae, based on the weight of the composition. In further embodiments, a composition containing atticaceae, prepared as described herein, may contain at least about 99.5% by weight of chemically and / or enantiomerically pure S-atticaceae, based on the weight of the composition. In yet other embodiments, a composition containing atticaprantrum prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure crystalline form III of atticaprantrum based on the weight of the composition. In yet further embodiments, a composition containing atticaprantrum prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure crystalline form III of S-atticaprantrum based on the weight of the composition.

[0064] The crystalline acicaplant prepared as described herein, or a composition containing it, may also contain less than 0.05% by weight of one or more of organic impurities, inorganic impurities, or residual solvents, based on the total weight of the composition. Examples of organic impurities include, but are not limited to, starting materials, by-products, intermediates, decomposition products, reagents, ligands, catalysts, or combinations thereof. Examples of inorganic impurities include, but are not limited to, reagents, ligands, catalysts, heavy metals, inorganic salts, or other materials such as filter aids, charcoal, among others.

[0065] Generally, crystalline aticaplant prepared using the methods described herein, or compositions containing it, contain about 0.15% by weight of aticaplant, based on the weight of the composition and the administration to a patient of one or more impurities described herein of 2 g / day or less. Alternatively, crystalline aticaplant prepared using the methods described herein, or compositions containing it, contain about 0.05% by weight of aticaplant, based on the weight of the composition and the administration to a patient of one or more impurities described herein of more than 2 g / day or less. See the thresholds set forth in the ICH Harmonised Guideline, "Impurities: Guide for Residual Solvents Q3C(R8)", April 22, 2021, pages 1-44, and "Guidance for Industry-Q3A Impurities in New Drug Substances", Revision 2, USDepartment of Health and Human Services, June 2008, pages 1-14, which are incorporated herein by reference.

[0066] In some embodiments, the residual solvent is one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethanol, and water. In further embodiments, the residual solvent is tetrahydrofuran. In other embodiments, the residual solvent is ethanol. In still further embodiments, the residual solvent is water. In still other embodiments, the residual solvent is 2-methyl-tetrahydrofuran. In further embodiments, the residual solvent is one or more of acetic acid, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethyl acetate, 1-pentanol, ethyl ether, 1-propanol, ethyl formate, 2-propanol, formic acid, propyl acetate, or triethylamine. In other embodiments, the tetrahydrofuran solvate of Atikaplant, or a composition containing it, contains less than about 57 ppm ethanol. In a further embodiment, the tetrahydrofuran solvate of Atikaplant, or a composition containing it, contains less than about 200 ppm of 2-methyl-tetrahydrofuran.

[0067] The crystalline atikaplant described herein can be prepared in a process that includes crystallizing a tetrahydrofuran solvate of atikaplant from 2-methyltetrahydrofuran and n-heptane. In some embodiments, the process provides crystalline S-atikaplant. In other embodiments, the process provides crystalline form III of atikaplant. In further embodiments, the process provides crystalline form III of S-atikaplant. Without wishing to be bound by theory, the inventors have found that the use of n-heptane protects atikaplant from decomposition, thereby resulting in higher chemical purity and increased yield.

[0068] Crystallization techniques utilized to prepare chemically and / or enantiomerically pure Atikaplant utilize temperatures below about 48° C. In some embodiments, the crystallization temperature is below about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, about 5, about 0, about −5, about −10, about −15, about −20, about −25, about −30, about −35, or about −40° C. In other embodiments, the crystallization temperature is about -40 to about 40, about -40 to about 30, about -40 to about 20, about -40 to about 10, about -40 to about 0, about -40 to about -10, about -40 to about -20, about -40 to about -30, about -30 to about 40, about -30 to about 30, about -30 to about 20, about -30 to about 10, about -30 to about 0, about -30 to about -10, about -30 to about -20, about -20 to about 40, about -20 to about 30, about -20 to about 20, about -20 to about 10, about -20 to about 0, about -20 to about -10, about -10 to about 40, about -10 to about 30, about -10 to about 20, about -10 to about 10, about -10 to about 0, about 0 to about 40, about 0 to about 30, about 0 to about 20, about 0 to about 10, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 40, about 20 to about 30, or about 30 to about 40 ° C. Without wishing to be bound by theory, the inventors have found that lower temperatures allow for higher chemical purity of the Atika plant product.

[0069] The ratio of 2-methyltetrahydrofuran to n-heptane is about 1:1 to about 1:7. In some embodiments, the molar ratio of 2-methyltetrahydrofuran to n-heptane is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, or about 1:7. In other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is from about 1:1 to about 1:6, from about 1:1 to about 1:5, from about 1:1 to about 1:4, from about 1:1 to about 1:3, from about 1:1 to about 1:2, from about 1:2 to about 1:7, from about 1:2 to about 1:6, from about 1:2 to about 1:5, from about 1:2 to about 1:4, from about 1:2 to about 1:3, from about 1.3 to about 1:7, from about 1:3 to about 1:6, from about 1:3 to about 1:5, from about 1:3 to about 1:4, from about 1:4 to about 1:7, from about 1:4 to about 1:6, from about 1:4 to about 1:5, from about 1:5 to about 1:7, from about 1:5 to about 1:6, or from about 1:6 to about 1:7. In a further embodiment, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:3. In yet another embodiment, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:4. In yet a further embodiment, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:5. In another embodiment, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:6. In a further embodiment, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:7.

[0070] In some aspects, the crystalline aticaplant, for example the chemically and / or enantiomerically pure crystalline aticaplant, is aticaplant crystalline form III. Aticaplant crystalline form III can be characterized by a number of techniques, including but not limited to X-ray diffraction and differential scanning calorimetry. In some embodiments, aticaplant crystalline form III is characterized by X-ray diffraction. In other embodiments, aticaplant crystalline form III is characterized by four or more X-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°. In further embodiments, crystalline form III of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°, and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°. In yet other embodiments, crystalline form III of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°, and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°. In still further embodiments, crystalline Form III of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° 2θ (±0.2), and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°. In other embodiments, crystalline Form III of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 3.1°, 19.0°, 24.0°, 24.3°, or 26.2 2θ (±0.2), and one or more additional peaks in Table 1.

[0071] [Table 1] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 2.

[0072] [Table 2] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 3.

[0073] [Table 3] In a further embodiment, crystalline Form III of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0074] Atikaplant crystalline Form III may also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram shows a peak temperature (T m In another embodiment, crystalline form III of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0075] reference standard The present disclosure also provides a reference standard containing an aticaplant prepared as described herein. The term "reference standard" refers to an aticaplant selected by the FDA that an applicant seeking ANDA approval must use in conducting in vivo bioequivalence studies required for ANDA approval. See, for example, "Referencing Approve Drug Products in ANDA Submission-Guidance for Industry," USDepartment of Health and Human Services, pages 1-16, October 2020, incorporated by reference. In some embodiments, the reference standard contains a composition described herein. In further embodiments, the reference standard contains a crystalline form of aticaplant described herein. Desirably, the reference standard comprises crystalline aticaplant having about 99.7% chemical purity and / or enantiomeric purity as measured by HPLC.

[0076] Treatment method In one aspect of the present invention, a method is provided for treating patients with a more severe type of depression, i.e., major depressive disorder. In some embodiments, the patient also experiences moderate to severe anhedonia. Because MDD alone is difficult to treat, treating patients with anhedonia is even more problematic because their ability to measure pleasure is impaired. Thus, such patients are often undertreated, due to ineffective medication, repeated unnecessary medical appointments, lack of patient compliance, and overall patient frustration, among others. Furthermore, antidepressants are known to have various side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among others. Thus, patients may choose to refrain from or discontinue taking antidepressants to avoid or prevent any side effects.

[0077] The methods described herein are effective in managing depression and anhedonia in patients using the chemically and / or enantiomerically pure aticaplant described herein, such as the crystalline form III of chemically and / or enantiomerically pure aticaplant, or compositions containing same. 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 moderate to severe anhedonia. 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 major depressive episodes 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.

[0078] 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.

[0079] 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.

[0080] 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 a chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing the same. 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 a chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing the same. In still 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 change from baseline in total score on the Anhedonia Scale following treatment with a chemically and / or enantiomerically pure atticaplant described herein, e.g., pure crystalline Form III of atticaplant, or a composition containing same. 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 the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same.

[0081] The reduction in anhedonia after starting treatment with a pure aticaplant described herein, for example, chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, can be measured in comparison with the patient's anhedonia as measured before treatment with a chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, 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 a chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. Thus, a standard method for measuring anhedonia can be used, such as the anhedonia scale, for example, SHAPS.

[0082] Desirably, the baseline anhedonia measurement is obtained up to about one week prior to the start of treatment with a chemically and / or enantiomerically pure aticaplant described herein, such as chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same. In some embodiments, the baseline anhedonia measurement is 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 treatment with a chemically and / or enantiomerically pure aticaplant described herein, such as chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same. In further embodiments, the baseline anhedonia measurement is 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 pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same.

[0083] The change in anhedonia in a patient depends on several factors, including, but not limited to, the severity of anhedonia, the sensitivity of the patient to the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, and other drugs administered. In some embodiments, anhedonia in a patient is reduced after about 3 weeks of treatment with a chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In other embodiments, anhedonia in a patient is reduced after about 3 weeks of treatment with a chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In further embodiments, the patient's anhedonia is reduced after about 3 weeks to about 6 weeks, in certain embodiments by the 6th week, of treatment with a chemically and / or enantiomerically pure aticaplant, e.g., chemically and / or enantiomerically pure aticaplant crystalline Form III, or a composition containing same, as described herein. In certain embodiments, the patient's anhedonia is reduced by at least about 40% as measured by change from baseline in total score on the Anhedonia Scale after about 6 weeks of treatment. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, in some embodiments within about 3 weeks to about 6 weeks, as measured by change from baseline in total score on the Anhedonia Scale and / or by physician / clinical judgment.

[0084] The methods described herein have been found to not only improve patients' depression and anhedonia symptoms, but also result in fewer antidepressant side effects, which has resulted 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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 4.

[0089] [Table 4]

[0090] In some embodiments, the following criteria are also met to be diagnosed with MDD:

[0091] [Table 5]

[0092] 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 whose 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 5.

[0093] [Table 6]

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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 6.

[0099] [Table 7]

[0100] The MGH-ATRQ is a self-assessment scale used to determine treatment resistance in patients with MDD. This questionnaire examines antidepressant treatment 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.

[0101] In certain embodiments, the patient has had an inadequate response to other antidepressant therapies. As used herein, "inadequate response" refers to a patient experiencing less than about 50% reduction in the severity of depressive symptoms since the start of treatment. Typically, an inadequate response is depression 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 since the start of treatment. In other embodiments, an inadequate response refers to a patient experiencing 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% reduction in the severity of depressive symptoms since 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, inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS. In further embodiments, inadequate response is measured by MGH-ATRQ.

[0102] 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.

[0103] As used herein, the term "other antidepressant therapy" refers to antidepressant drugs or non-pharmacological treatments used to treat patients with depression. In some aspects, the other antidepressant therapy is an antidepressant medication. In other aspects, the other antidepressant therapy is a non-pharmacological treatment. In further aspects, the other antidepressant therapy is an antidepressant drug other than Aticaplant.

[0104] Antidepressant medication 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 drug comprises a natural product, such as kava-kava, St. John's wort, or a dietary supplement, such as s-adenosylmethionine. In yet other embodiments, the antidepressant drug comprises 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 drug is a hormone, such as triiodothyronine. In other embodiments, the antidepressant drug 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 drug is an SNRI which is venlafaxine, duloxetine, vortioxeine, or desvenlafaxine.

[0105] Non-pharmacological treatments for use herein may be selected by one of skill in the art. In some embodiments, the non-pharmacological treatment is psychotherapy, transcranial magnetic stimulation, and the like.

[0106] 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.

[0107] 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.

[0108] In certain embodiments, the patient has been treated with other antidepressant therapy before receiving the pure aticaplant described herein, for example, pure aticaplant crystal form III, or a composition containing it.In some embodiments, the patient has been treated with other antidepressant therapy, including SSRI, SNRI, or a combination thereof.In other embodiments, the patient has stopped treatment with other antidepressant therapy before starting treatment with the pure aticaplant described herein, for example, pure aticaplant crystal form III, or a composition containing it.

[0109] 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 the pure acetonitrile described herein, for example, the pure crystalline form III of acetonitrile, or a composition comprising the same, in combination with one or more antidepressants, wherein the pure acetonitrile described herein, for example, the pure crystalline form III of acetonitrile, or a composition comprising the same and the antidepressant(s) are administered simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means.

[0110] In some aspects, the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, is administered adjunctively with other antidepressant(s) currently administered to the patient, including current antidepressant(s) to which the patient had an inadequate response, i.e., antidepressants to which the antidepressant(s) failed to treat the patient's depression. In other embodiments, the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, is administered adjunctively with antidepressant(s) not previously administered to the patient, i.e., new antidepressants. In yet other embodiments, the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, is administered in a regimen with antidepressant(s) previously administered to the patient.

[0111] When the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing it, and the other antidepressant(s) are administered in separate dosage forms, the number of doses administered per day for each active compound may be the same or different, more typically different. The antidepressant may be administered as prescribed by the attending physician and / or by its label, and the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing it, is administered as described herein. Typically, the patient is receiving concurrent treatment with both the antidepressant and the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing it, and both are administered according to their prescribed dosing regimens. The chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same and the antidepressant(s) may be administered simultaneously in divided or single forms, at the same or different times during the course of treatment, according to a simultaneous or alternating regimen.

[0112] The chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing the same, and the antidepressant(s) may be administered via the same or different routes of administration. 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, the chemically and / or enantiomerically pure aticaplant, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing the same as described herein, is administered orally.

[0113] Treatment with the chemically and / or enantiomerically pure acetophenone described herein, for example, the chemically and / or enantiomerically pure crystalline form III of acetophenone, or a composition containing the same 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 the chemically and / or enantiomerically pure acetophenone described herein, for example, the chemically and / or enantiomerically pure crystalline form III of acetophenone, or a composition containing the same. In certain aspects, patients do not experience weight gain during treatment with the chemically and / or enantiomerically pure acetophenone described herein, for example, the chemically and / or enantiomerically pure crystalline form III of acetophenone, or a composition containing the same. As used herein, the term "weight gain" refers to an increase in the patient's weight compared to the patient's weight before taking the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same, or the patient's weight assessed upon the first administration of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same. In certain embodiments, the patient may actually experience a decrease in overall weight compared to the patient's weight before taking the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same. In further embodiments, the patient's weight is stable, i.e., it neither increases nor decreases. In certain embodiments, the patient does not experience clinically relevant weight gain, characterized as a weight gain of ≧7%.

[0114] This is in contrast to many other antidepressants for which weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[0115] In a further aspect, the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same. As used herein, the term "decreased 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 evaluated upon the first administration of aticaplant crystalline form III. Thus, the patient's sexual function during intake of aticaplant crystalline form III can be compared to the patient's sexual function prior to administration of aticaplant crystalline form III. 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 Aticaplant crystalline form III has additional positive or negative effects 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.

[0116] 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.

[0117] 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:

[0118] [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:

[0119] [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.

[0120] [ka]

[0121] Pharmaceutically acceptable salts of acetophenone contemplated by the present invention can be easily selected by those skilled in the art. A "pharmaceutical acceptable salt" is a salt of acetophenone 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.

[0122] 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.

[0123] In other embodiments, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, contains less than about 10% by weight of the (R)-enantiomer of aticaplant, based on the weight of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same. In further embodiments, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, contains less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, about 0.5, about 0.1, about 0.005, or about 0.001% by weight of the (R)-enantiomer of aticaplant, based on the weight of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same. In yet other embodiments, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, contains from about 0.001 to about 10% by weight of the (R)-enantiomer of aticaplant, based on the weight of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same.In still further embodiments, the chemically and / or enantiomerically pure aticaplant described herein, e.g., the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same, contains about 0.001 to about 10% by weight, about 0.001 to about 5% by weight, about 0.001 to about 1% by weight, about 0.001 to about 0.5% by weight, about 0.001 to about 0.1% by weight, about 0.1 to about 5% by weight, about 0.1 to about 1% by weight, about 0.1 to about 5% by weight, or about 0.5 to about 5% by weight, based on the weight of the chemically and / or enantiomerically pure aticaplant described herein, e.g., the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same.

[0124] The methods described herein include administering an effective amount of a chemically and / or enantiomerically pure aticaplant described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant. 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, a chemically and / or enantiomerically pure aticaplant described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, is utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressant(s) are utilized in an effective amount separately or in combination with a chemically and / or enantiomerically pure aticaplant described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same.

[0125] The amount of chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, for administration according to the methods described herein may be determined by one skilled in the art and, unless otherwise indicated, is given based on the free base of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III. That is, the amount refers to the amount of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, administered molecules, excluding, e.g., solvents (such as solvates) or counterions (such as pharma- ceutically acceptable aticaplant). In some embodiments, the effective amount of aticaplant crystalline form III is less than about 60 mg. In other embodiments, an effective amount of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same, 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 further embodiments, an effective amount of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same, 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. g, about 20 to about 40 mg, about 30 to about 40 mg, about 1 to about 35 mg, about 2 to about 35 mg, 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 chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of the chemically and / or enantiomerically pure aticaplant, is about 5 to about 15 mg. In yet a further embodiment, the effective amount of the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of the chemically and / or enantiomerically pure aticaplant. The amount of aticaplant for administration by the methods described herein may be determined by one of skill in the art and is given on a free base basis of aticaplant, unless otherwise indicated. 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).

[0126] Pharmaceutical Compositions As used herein, the term "composition" is intended to encompass a product containing a particular component in a particular amount, as well as any product that is obtained directly or indirectly from the combination of a particular component in a particular amount. A preferred pharmaceutical composition contains a chemically and / or enantiomerically pure aticaplant as described herein, e.g., crystalline form III of aticaplant, as an active ingredient intimately mixed with a pharmaceutical carrier or excipient according to conventional pharmaceutical compounding techniques, the carrier may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers or excipients are well known in the art. A description of some of these pharmaceutically acceptable carriers or excipients can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] Optionally, the pharmaceutical composition herein may contain a preservative. As used herein, unless otherwise stated, 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.

[0131] 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 the chemically and / or enantiomerically pure aticaplants described herein, for example, crystalline form III of the chemically and / or enantiomerically pure aticaplants. Preferably, the penetrant increases or enhances the absorption and / or bioavailability of the chemically and / or enantiomerically pure aticaplants described herein, for example, crystalline form III of the chemically and / or enantiomerically pure aticaplants, after administration. Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycol cholate, tauroursodeoxycholic acid, lecithin, etc.; and chitosan (and salts), as well as surfactants such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxinol, sodium deoxycholate, polyarginine, etc. Preferably, the penetrant is selected to meet one or more, more preferably all, of the following general requirements:

[0132] [Table 8]

[0133] 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.

[0134] 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.

[0135] Solubilizers and emulsifiers may be included to promote more uniform dispersion of active ingredients or other excipients that are not generally soluble in liquid carriers. Examples of suitable emulsifiers, if used, include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof. Examples of suitable 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. The solubilizer or emulsifier may be present in an amount sufficient to dissolve or disperse the active ingredient, i.e., the chemically and / or enantiomerically pure acetophenone described herein, e.g., the crystalline form III of the chemically and / or enantiomerically pure acetophenone, in the carrier.

[0136] Suitable tonicity agents, if used, may include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

[0137] 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.

[0138] Advantageously, the chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, or a composition containing same, may be administered once daily, or the total daily dose may be administered in divided doses two, three or four times daily.

[0139] As described herein, in particular, the patient had an inadequate response to other antidepressant therapy prior to treatment with the chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it.Thus, in certain embodiments, the present disclosure relates to a chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, for use as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with the chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In further specific embodiments, the present disclosure also relates to the use of the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, in the manufacture of a medicament as described herein, in which the patient has had an inadequate response to other antidepressant therapy prior to treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In further specific embodiments, the present disclosure also relates to a package or pharmaceutical product as described herein, in which the patient has had an inadequate response to other antidepressant therapy prior to treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. Such antidepressant therapy may be selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or combinations thereof, among others.

[0140] As described herein, the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, may be used as an adjunct treatment, or in other words, in combination with, add-on to, or in combination with one or more antidepressants, for example, a patient may already be administered one or more antidepressants or may also be administered one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, for the uses described herein, including administering the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, as an adjunct treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant for the uses described herein, comprising administration of aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, for the uses described herein, comprising administration of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, in combination with an effective amount of one or more antidepressants.In further specific embodiments, the present disclosure also relates to the use of the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same, in the manufacture of a medicament described herein, wherein the treatment comprises administering an effective amount of the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same, 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 the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same, in the manufacture of a medicament described herein, wherein the treatment comprises administering an effective amount of the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same, in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing the same, wherein the treatment comprises administering an effective amount of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, 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 indicate the administration of an effective amount of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, 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 administration of an effective amount of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, 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 administration of an effective amount of a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, in combination with an effective amount of one or more antidepressants. Such one or more antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0141] As already mentioned, the present disclosure relates to a chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, for the uses described herein. In certain embodiments, the chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, is S-aticaplant. In further embodiments of the present disclosure, the chemically and / or enantiomerically pure aticaplant as described herein, for example, a chemically and / or enantiomerically pure crystalline form III of aticaplant, in particular, S-aticaplant, for the uses described herein, is administered in an amount of about 2 to about 35 mg, more particularly about 10 mg. In still further embodiments, the aticaplant as described herein, in particular, a crystalline form III of S-aticaplant, is administered orally. Furthermore, in further specific embodiments, the present disclosure relates to aticaplant, particularly crystalline form III of S-aticaplant, for the uses described herein, administered once a day. The present disclosure also relates to the use of aticaplant in the manufacture of a medicament as described herein. In a specific embodiment, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, is chemically and / or enantiomerically pure S-aticaplant. In another embodiment, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, is administered in an amount of about 2 to about 35 mg, more specifically about 10 mg, of the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III. In a further embodiment of the uses described herein, the chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure aticaplant crystalline form III, is administered in an amount of about 2 to about 35 mg, more specifically about 10 mg. In yet a further embodiment of the use, the chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, is administered orally.In yet further specific embodiments of the use, the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, in particular, S-aticaplant, is administered once a day. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product described herein, in which the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, in particular, is chemically and / or enantiomerically pure S-aticaplant. In further embodiments of the package or pharmaceutical product described herein, the instructions for treatment direct the administration of about 2 to about 35 mg of the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, more particularly, about 10 mg. In a further embodiment of the package or pharmaceutical product described herein, the instructions for treatment are for oral administration of the chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, particularly S-aticaplant. Furthermore, in a further specific embodiment of the package or pharmaceutical product described herein, the instructions for treatment are for once-daily administration of the chemically and / or enantiomerically pure aticaplant described herein, for example, chemically and / or enantiomerically pure aticaplant crystalline form III, particularly S-aticaplant.

[0142] Advantageously, administration of the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, does not result in weight gain during treatment, including clinically relevant weight gain.Thus, in further specific embodiments, the present disclosure relates to the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, for the uses described herein, whereby the patient does not experience weight gain during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In further specific embodiments, the present disclosure relates to the use described herein, wherein the patient does not experience weight gain during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same. In further specific embodiments, the present disclosure also relates to the package or pharmaceutical product described herein, wherein the patient does not experience weight gain during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing same. The patient's weight can be evaluated, particularly at the first administration of aticaplant.

[0143] Also, unexpectedly, it was observed that patients do not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, based on evaluation at the time of first administration.Thus, in a further specific embodiment, the present disclosure relates to the chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it, for the uses described herein, and patients do not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure aticaplant described herein, such as the chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing it. In further specific embodiments, the present disclosure relates to the use described herein, wherein the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing the same. In further specific embodiments, the present disclosure relates to the package or pharmaceutical product described herein, wherein the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure aticaplant described herein, for example, the crystalline form III of chemically and / or enantiomerically pure aticaplant, or a composition containing the same. As such, the 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).

[0144] As previously described, the patient has anhedonia. In certain embodiments, the anhedonia is moderate. In other embodiments, the anhedonia is severe. Anhedonia can be measured by an anhedonia scale, such as the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the present disclosure relates to a chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, for the uses described herein, wherein the patient's anhedonia is reduced by at least 40% as measured by a change in total score from baseline on the anhedonia scale after 6 weeks of treatment with a chemically and / or enantiomerically pure aticaplant described herein, e.g., chemically and / or enantiomerically pure crystalline form III of aticaplant, or a composition containing same, and more specifically, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change in total score from baseline on the anhedonia scale. In further specific embodiments, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the present disclosure relates to the use described herein, wherein the patient'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 the chemically and / or enantiomerically pure Atticaplant, such as the chemically and / or enantiomerically pure Atticaplant crystalline Form III, or a composition containing same, more specifically, the patient'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).In further specific embodiments, the present 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 a chemically and / or enantiomerically pure Atticaplant, such as chemically and / or enantiomerically pure Atticaplant crystalline Form III, or a composition containing same, more specifically, 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 specific embodiments, the Anhedonia Scale is the Snaith-Hamilton Pleasure Scale (SHAPS).

[0145] Embodiments: The present invention also provides the following non-limiting embodiments. Embodiment 1 is a tetrahydrofuran solvate of Atikaplant.

[0146] [ka]

[0147] Embodiment 2 is a tetrahydrofuran solvate as described in embodiment 1 which is S-aticaplant.

[0148] [ka]

[0149] Embodiment 3 is a composition comprising a tetrahydrofuran solvate of aticaplant according to embodiment 1 or 2.

[0150] Embodiment 4 is the composition of embodiment 2, comprising about 0.10% or less by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0151] [ka]

[0152] Embodiment 5 is the composition of embodiment 3 or 4, comprising at least about 99.5% by weight of the tetrahydrofuran solvate of aticaplant of embodiment 1 or 2, based on the weight of the composition.

[0153] Embodiment 6 is the composition of any one of embodiments 3-5, comprising less than 0.05 wt. % of one or more of organic impurities, inorganic impurities, or residual solvents, based on the total weight of the composition.

[0154] Embodiment 7 is a composition according to any one of embodiments 3-6, comprising about 0.10% by weight or less of a tetrahydrofuran solvate of R-aticaplant, based on the weight of the composition.

[0155] [ka]

[0156] Embodiment 8 is the composition of any one of embodiments 3-7, comprising about 0.10% or less by weight of R-aticaplant, based on the weight of the composition.

[0157] [ka]

[0158] Embodiment 9 is a process for preparing a tetrahydrofuran solvate of atikaplant according to embodiment 1 or 2, comprising crystallizing atikaplant using tetrahydrofuran, ethanol, and water.

[0159] Embodiment 10 is directed to (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate.

[0160] [ka] 3-Fluoro-4-(4-formylphenoxy)benzamide and

[0161] [ka] A process for preparing a tetrahydrofuran solvate of Atikaplant of embodiment 1 or 2, comprising reacting in the presence of tetrahydrofuran.

[0162] Embodiment 11 is directed to (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate.

[0163] [ka] 3-Fluoro-4-(4-formylphenoxy)benzamide and

[0164] [ka] A process for preparing the tetrahydrofuran solvate of Atikaplant of embodiment 1 or 2, comprising reacting in the presence of a base, a reducing agent, and a solvent.

[0165] Embodiment 12 is the process of embodiment 11, wherein the base is sodium hydroxide.

[0166] Embodiment 13 is the process of embodiment 11 or 12, wherein the reducing agent is sodium triacetoxyborohydride.

[0167] Embodiment 14 is the process of any one of embodiments 11 to 13, wherein the solvent is ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran, or a mixture thereof.

[0168] Embodiment 15 is the process of any one of embodiments 11 to 14, further comprising removing the solvent and adding tetrahydrofuran.

[0169] Embodiment 16 is the process of embodiment 15, further comprising adding ethanol and water to form a tetrahydrofuran / ethanol / water solution.

[0170] Embodiment 17 is the process of embodiment 15 or 16, further comprising adding aticaplant seed crystals.

[0171] Embodiment 18 is the process of embodiment 16 or 17, wherein the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:2, based on the total volume of the solution.

[0172] Embodiment 19 is the process of any one of embodiments 9 to 18, wherein the composition comprising the tetrahydrofuran solvate of Atikaplant comprises about 0.10 wt.% or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0173] [ka]

[0174] Embodiment 20 is a tetrahydrofuran solvate of aticaplant prepared according to the process described in any one of embodiments 9-19.

[0175] Embodiment 21 is a composition comprising a crystalline form of aticaplant and less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0176] [ka]

[0177] Embodiment 22 is the composition of embodiment 21, wherein the crystalline form of Aticaplant is characterized by four or more X-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° 2θ (±0.2).

[0178] Embodiment 23 is the composition of embodiment 21 or 22, comprising about 0.10% or less by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0179] [ka]

[0180] Embodiment 24 is a composition according to any one of embodiments 21-23, comprising at least about 99.5% by weight of the crystalline form of Aticaplant, based on the weight of the composition.

[0181] Embodiment 25 is the composition of any one of embodiments 21-24, comprising about 0.10% or less by weight of R-aticaplant, based on the weight of the composition.

[0182] Embodiment 26 is a composition according to any one of embodiments 21 to 25, wherein the crystalline form of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG. 1.

[0183] Embodiment 27 relates to a crystalline form of Atikaplant having a differential scanning calorimetry peak temperature (T m 27. The composition according to any one of embodiments 21 to 26, characterized in that

[0184] Embodiment 28 is a composition according to any one of embodiments 21 to 27, wherein the crystalline form of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG. 4.

[0185] Embodiment 29 is a composition according to any one of embodiments 21 to 28, wherein the crystalline form of Aticaplant is anhydrous.

[0186] Embodiment 30 is a process for preparing crystalline aticaplant, comprising:

[0187] [ka] A process comprising crystallizing the tetrahydrofuran solvate of Atikaplant according to embodiment 1, 2, or 20 from 2-methyltetrahydrofuran and n-heptane.

[0188] Embodiment 31 is the process of embodiment 30, wherein the crystalline atticaplant is S-atticaplant.

[0189] [ka]

[0190] Embodiment 32 is the process of embodiment 30 or 31, carried out at a temperature of less than about 48° C.

[0191] Embodiment 33 is the process of any one of embodiments 30 to 32, wherein the ratio of 2-methyltetrahydrofuran to n-heptane is from about 1:1 to about 1:4.

[0192] Embodiment 34 is the process of any one of embodiments 30 to 33, wherein the crystalline form of aticaplant is present in a composition comprising less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0193] [ka]

[0194] Embodiment 35 is the process of any one of embodiments 30-34, wherein the crystalline form of the aticaplant is characterized by four or more X-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° 2θ (±0.2).

[0195] Embodiment 36 is the process of any one of embodiments 30 to 35, wherein the crystalline form of aticaplant is present in a composition comprising about 0.10 wt.% or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0196] [ka]

[0197] Embodiment 37 is the process of any one of embodiments 30-36, comprising at least about 99.5% by weight of the crystalline form of Aticaplant, based on the weight of the composition.

[0198] Embodiment 38 is the process of any one of embodiments 30 to 37, comprising about 0.10% by weight or less of R-aticaplant, based on the weight of the composition.

[0199] Embodiment 39 is the process of any one of embodiments 30 to 38, wherein the crystalline form of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG. 1.

[0200] Embodiment 40 relates to a crystalline form of Atikaplant having a differential scanning calorimetry peak temperature (T m 40. The process according to any one of embodiments 30 to 39, characterized in that

[0201] Embodiment 41 is the process of any one of embodiments 30 to 40, wherein the crystalline form of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0202] Embodiment 42 is the process of any one of embodiments 30-41, wherein the crystalline form of aticaplant is anhydrous.

[0203] Embodiment 43 is a crystalline form of aticaplant prepared according to any one of embodiments 30 to 42.

[0204] Embodiment 44 is a reference standard comprising a composition according to any one of embodiments 21 to 29 or a crystalline form of aticaplant according to embodiment 43.

[0205] Embodiment 45 is a reference standard comprising an Atika plant having a purity of about 99.7%.

[0206] Embodiment 46 is a composition of any one of embodiments 21-29, further comprising a pharma- ceutically acceptable excipient.

[0207] Embodiment 47 is a method of treating major depressive disorder in a human patient using a composition according to any one of embodiments 1-29 or 43, or a crystalline form of aticaplant according to embodiment 43.

[0208] Embodiment 48 is a method of treating major depressive disorder in a human patient, optionally with anhedonia, comprising administering to the human patient a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43, wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0209] Embodiment 49 is a method for treating major depressive disorder in a human patient, comprising administering to a human patient in need thereof an effective amount of a composition according to any one of embodiments 1-29 or 43, or a crystalline form of aticaplant according to embodiment 43.

[0210] Embodiment 50 is the method of embodiment 49, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with the composition or crystalline form of Aticaplant.

[0211] Embodiment 51 is the method of any one of embodiments 48-49, wherein the other antidepressant therapy comprises a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0212] Embodiment 52 is the method of any one of embodiments 47-50, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0213] Embodiment 53 is the method of any one of embodiments 47-52, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0214] Embodiment 54 is the method of any one of embodiments 47-53, wherein the effective amount of the crystalline form of Aticaplant is from about 2 to about 35 mg.

[0215] Embodiment 55 is the method of embodiment 54, wherein the effective amount of the crystalline form of aticaplant is about 10 mg.

[0216] Embodiment 56 is a method according to any one of embodiments 47-55, wherein the composition or crystalline form of Aticaplant is administered orally.

[0217] Embodiment 57 is a method according to any one of embodiments 47 to 56, wherein the composition or crystalline form of aticaplant is administered once a day.

[0218] Embodiment 58 is the method of any one of embodiments 47 to 57, wherein the patient has anhedonia.

[0219] Embodiment 59 is the method of any one of embodiments 47-58, wherein the patient has moderate anhedonia.

[0220] Embodiment 60 is the method of any one of embodiments 47-58, wherein the patient has severe anhedonia.

[0221] Embodiment 61 is the method of any one of embodiments 47-60, wherein the patient does not experience weight gain during treatment with the composition or crystalline form of Aticaplant.

[0222] Embodiment 62 is the method of embodiment 61, wherein the patient's body weight is assessed at the time of the first administration of the composition or crystalline form of Aticaplant.

[0223] Embodiment 63 is the method of any one of embodiments 47-62, wherein the patient does not experience a decrease in sexual function during treatment with a crystalline form of aticaplant.

[0224] Embodiment 64 is the method of embodiment 63, wherein the patient's sexual function is assessed upon the first administration of the composition or crystalline form of Aticaplant.

[0225] Embodiment 65 is the method of embodiment 63 or 64, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0226] Embodiment 66 is a method according to any one of embodiments 63 to 65, wherein sexual function is assessed by the Arizona Sexual Experience Scale (ASEX).

[0227] Embodiment 67 is a method according to any one of embodiments 59 to 61, wherein the patient'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 the composition or crystalline form of Aticaplant.

[0228] Embodiment 68 is the method of any one of embodiments 59-61 and 67, wherein the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by change from baseline in total score on the Anhedonia Scale.

[0229] Embodiment 69 is the method of embodiment 67 or 68, wherein the anhedonia scale is the Snaith-Hamilton Pleasure Scale.

[0230] Embodiment 70 is a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43 for use in the treatment of major depressive disorder in a human patient, optionally with anhedonia.

[0231] Embodiment 71 is a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43 for use in the treatment of major depressive disorder in a human patient who has previously had an inadequate response to other antidepressant therapies.

[0232] Embodiment 72 is a composition according to any one of embodiments 1-29 or 43 or a crystalline form of aticaplant according to embodiment 43 for use in treating major depressive disorder in a human patient.

[0233] Embodiment 73 is a composition or crystalline form of Aticaplant according to embodiment 72, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with the composition or crystalline form of Aticaplant.

[0234] Embodiment 74 is a composition or crystalline form of aticaplant according to any one of embodiments 71 or 72, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0235] Embodiment 75 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 74, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0236] Embodiment 76 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 75, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0237] Embodiment 77 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 76, wherein the effective amount of the crystalline form of aticaplant is from about 2 to about 35 mg.

[0238] Embodiment 78 is a composition or crystalline form of aticaplant according to embodiment 77, wherein the effective amount of the crystalline form of aticaplant is about 10 mg.

[0239] Embodiment 79 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 78, wherein the composition or crystalline form of aticaplant is administered orally.

[0240] Embodiment 80 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 79, wherein the composition or crystalline form of aticaplant is administered once a day.

[0241] Embodiment 81 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 80, wherein the patient has anhedonia.

[0242] Embodiment 82 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 81, wherein the patient has moderate anhedonia.

[0243] Embodiment 83 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 81, wherein the patient has severe anhedonia.

[0244] Embodiment 84 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 83, wherein the patient does not experience weight gain during treatment with the composition or crystalline form of aticaplant.

[0245] Embodiment 85 is a composition or crystalline form of aticaplant according to embodiment 84, wherein the patient's weight is assessed at the time of the first administration of the composition or crystalline form of aticaplant.

[0246] Embodiment 86 is a composition or crystalline form of aticaplant according to any one of embodiments 70 to 85, wherein the patient does not experience a decrease in sexual function during treatment with the crystalline form of aticaplant.

[0247] Embodiment 87 is a composition or crystalline form of aticaplant according to embodiment 86, wherein the patient's sexual function is evaluated upon the first administration of the composition or crystalline form of aticaplant.

[0248] Embodiment 88 is a composition or crystalline form of acetophenone according to embodiment 86 or 87, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0249] Embodiment 89 is a composition or crystalline form of aticaplant according to any one of embodiments 86 to 88, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0250] Embodiment 90 is a composition or crystalline form of Atikaplant according to any one of embodiments 81 to 83, wherein the patient'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 the composition or crystalline form of Atikaplant.

[0251] Embodiment 91 is a composition or crystalline form of aticaplant according to any one of embodiments 81-83 and 90, wherein the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by change from baseline in the total score on the Anhedonia Scale.

[0252] Embodiment 92 is a composition or crystalline form of the atica plant according to embodiment 90 or 91, wherein the anhedonia scale is the Snaith-Hamilton pleasure scale.

[0253] Embodiment 93 is the use of a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43 for treating major depressive disorder in a human patient with anhedonia.

[0254] Embodiment 94 is the use of a crystalline form of aticaplant according to any one of embodiments 1 to 29 or 43 or embodiment 43 for treating major depressive disorder in a human patient who has previously had an inadequate response to other antidepressant therapies.

[0255] Embodiment 95 is the use of a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43 for treating major depressive disorder in a human patient.

[0256] Embodiment 96 is the use according to embodiment 95, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with the composition or crystalline form of Aticaplant.

[0257] Embodiment 97 is the use according to any one of embodiments 94 to 95, wherein the other antidepressant therapy comprises a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0258] Embodiment 98 is the use according to any one of embodiments 93 to 97, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0259] Embodiment 99 is the use according to any one of embodiments 93 to 98, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0260] Embodiment 100 is the use according to any one of embodiments 93 to 98, wherein the effective amount of the crystalline form of Aticaplant is from about 2 to about 35 mg.

[0261] Embodiment 101 is the use according to embodiment 100, wherein the effective amount of the crystalline form of aticaplant is about 10 mg.

[0262] Embodiment 102 is the use according to any one of embodiments 93 to 101, wherein the composition or crystalline form of aticaplant is administered orally.

[0263] Embodiment 103 is a method according to any one of embodiments 93 to 102, wherein the composition or crystalline form of aticaplant is administered once a day.

[0264] Embodiment 104 is the use according to any one of embodiments 93 to 103, wherein the patient has anhedonia.

[0265] Embodiment 105 is the use according to any one of embodiments 93 to 104, wherein the patient has moderate anhedonia.

[0266] Embodiment 106 is the use according to any one of embodiments 93 to 105, wherein the patient has severe anhedonia.

[0267] Embodiment 107 is the use according to any one of embodiments 93 to 106, wherein the patient does not experience weight gain during treatment with the composition or crystalline form of aticaplant.

[0268] Embodiment 108 is the use according to embodiment 107, wherein the patient's weight is assessed at the time of the first administration of the composition or crystalline form of Aticaplant.

[0269] Embodiment 109 is the use according to any one of embodiments 93 to 108, wherein the patient does not experience a decrease in sexual function during treatment with a crystalline form of aticaplant.

[0270] Embodiment 110 is the use described in embodiment 109, wherein the patient's sexual function is evaluated upon the first administration of the composition or crystalline form of Aticaplant.

[0271] Embodiment 111 is the use of embodiment 109 or 110, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.

[0272] Embodiment 112 is the use according to any one of embodiments 100 to 111, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0273] Embodiment 113 is the use according to any one of embodiments 104 to 106, wherein the patient'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 the composition or crystalline form of Aticaplant.

[0274] Embodiment 114 is the use according to any one of embodiments 104 to 106 and 113, wherein the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by change from baseline in the total score on the Anhedonia Scale.

[0275] Embodiment 115 is the use according to embodiment 113 or 114, wherein the anhedonia scale is the Snaith-Hamilton Pleasure Scale.

[0276] Embodiment 116 is a package or pharmaceutical product comprising (i) a composition according to any one of embodiments 1 to 29 or 43 or a crystalline form of aticaplant according to embodiment 43, and (ii) instructions for treating major depressive disorder in a human patient with anhedonia.

[0277] 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.

[0278] [Table 9]

[0279] Example 1: Equipment and Method Details AX-Ray Powder Diffraction (XRPD) Bruker AXS D8 Advance XRPD diffractograms were collected on a Bruker D8 diffractometer using CuKα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passes through an 8.0 mm receiving slit with a 2.5° Soller slit followed by a Lynxeye detector. The software for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0280] Samples were tested under ambient conditions as flat plate samples using the as-received powder. Samples were prepared on polished zero background (510) silicon wafers by gently pressing onto a flat surface or filling into a cut cavity. The sample was rotated on its own plane.

[0281] Details of the standard Pharmorphix data collection method are as follows. Angle range: 2~42°2θ Step size: 0.05°2θ Collection time: 0.5 seconds / step (total collection time: 6.40 minutes)

[0282] If required, other methods for data collection will be used with details as shown in Table 7.

[0283] [Table 10]

[0284] PANalytical Empyrean XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using CuKα radiation (45 kV, 40 mA) in transmission geometry. A 0.04 rad Soller slit with a 0.5° slit, a 4 mm mask, and a focusing mirror was used in the incident beam. A PIXcel placed on the diffracted beam 3D The detector was fitted with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector using the X'Pert Operator Interface. Data was analysed and presented using Diffrac Plus EVA or HighScore Plus.

[0285] Samples were prepared and analyzed in transmission mode in metal or Millipore 96-well plates. X-ray transparent film was used between metal sheets on metal well plates, and the as-received powder (approximately 1-2 mg) was used. Millipore plates were used to isolate and analyze solids from suspension by adding a small amount of suspension directly to the plate, followed by filtration under light vacuum.

[0286] The scanning mode for the metal plates used the gonioscan axis, whereas for the Millipore plates 2θ scanning was utilized.

[0287] Details of standard screening data collection methods are as follows: Angle range: 2.5~32.0°2θ Step size: 0.0130°2θ Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0288] The software used for data collection was X'Pert Data Collector and data were analyzed and presented using DiffracPlusEVA.

[0289] B. Differential Scanning Calorimetry (DSC) TA Instruments Q2000 DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample in a pinhole aluminum pan was heated from 25 °C to 275 °C at 10 °C / min. A dry nitrogen purge at 50 mL / min was maintained over the sample.

[0290] Modulated temperature DSC was performed using a base heating rate of 2° C. / min and temperature modulation parameters of ±0.636° C. (amplitude) every 60 seconds.

[0291] The instrument control software was Advantage for Q Series and Thermal Advantage and data was analyzed using Universal Analysis or TRIOS.

[0292] TA Instruments Discovery DSC DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample in a pinhole aluminum pan was heated from 25 °C to 275 °C at 10 °C / min. A dry nitrogen purge at 50 mL / min was maintained over the sample.

[0293] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0294] C. Determination of Chemical Purity by HPLC Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector using OpenLAB software. Complete method details are shown in Table 8.

[0295] [Table 11]

[0296] Example 2 - Analytical Procedures A. Identification and Quantitative Determination of Atika Plant and Purity by HPLC Method See Table 10.

[0297] [Table 12]

[0298] B. Determination of residual solvents by gas chromatography (GC). See Table 11 for operating conditions and Table 12 for validation summary.

[0299] [Table 13]

[0300] [Table 14]

[0301] Example 3 - Preparation of Atikaplant THF solvate

[0302] [ka]

[0303] Aqueous sodium hydroxide was added to compound 1 in 2-methyltetrahydrofuran. After phase separation, compound 2 in 2-MeTHF, i.e., the free base of compound 1, was solvent exchanged into tetrahydrofuran (THF). Reductive amination of compound 3 with compound 2 was carried out by adding sodium triacetoxyborohydride and THF. Upon completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 was concentrated and ethanol and water were added. The product was crystallized using THF, ethanol, and water to yield compound 4 as a solid.

[0304] To a stirring room temperature reaction vessel were added water (7.3 L / kg), 2-methyltetrahydrofuran (6.6 L / kg), and (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate (1.15 mol / mol), followed by NaOH (2.3 mol / mol 50% aqueous solution) over a minimum of 20 minutes at 22° C. The reactor was rinsed with water (1.0 L / kg) and the mixture was stirred at 22° C. for a minimum of 30 minutes, then it was allowed to settle for a minimum of 30 minutes. The layers were separated and the lower aqueous layer was discarded. The organic layer was concentrated under vacuum at up to 45° C. to a minimum volume. THF was charged in portions and distilled back to a minimum volume to complete the solvent exchange. The temperature was then adjusted to 20° C. and THF (5.0 L / kg) was added, followed by 3-fluoro-4-(4-formylphenoxy)benzamide (1.00 mol) and additional THF (10.0 L / kg). The temperature was adjusted to 32° C. and the mixture was stirred for a minimum of 1 hour. The temperature was then adjusted to 15° C. and then NaBH(OAc)3 (1.50 mol / mol) was added portionwise at 15° C. The mixture was further stirred at 15° C. for a minimum of 1 hour. Water (5.0 L / kg) was then added at 15° C., followed by NaOH (3.05 mol / mol 50% aqueous solution) at 15° C. and the resulting mixture was further stirred for a minimum of 2 hours. The reaction vessel was rinsed with water (0.5 L / kg) and the mixture was allowed to settle for a minimum of 30 minutes. The aqueous layers were separated and the lower aqueous layer was discarded. NaCl (6.2 L / kg 20% ​​aqueous solution) was then added to the organic layer at 15° C. and stirred for a minimum of 30 minutes, then the mixture was allowed to settle for a minimum of 30 minutes, the layers were separated, and the lower aqueous layer was discarded. The organic layer was concentrated under vacuum to 8.0 L / kg at a maximum of 45° C. The temperature was adjusted to 25° C., then EtOH (2% MeOH) (8.0 L / kg) and water (8.0 L / kg) were added at 25° C. Additional water (2.0 L / kg) was added at 25° C. over a minimum of 2.5 hours. Crude Atica plant seeds (0.03 kg / kg) were added at 25° C., and the mixture was stirred at 25° C. for a minimum of 2 hours. Additional water (6.0 L / kg) was added at 25° C. over a minimum of 7.5 hours. The mixture was then cooled to 2.5° C. over a minimum of 7 hours and stirred at 2.5° C. for a minimum of 6 hours. The product was isolated, washed with THF / EtOH / water 1:1:2 (volume ratio) and dried at 25°C.

[0305] Example 4 - Preparation of pure Aticaplant

[0306] [ka]

[0307] To a stirred solution of 2-methyltetrahydrofuran and n-heptane in a reaction vessel was added crude Atikaplant (1.0 mol) using the ratio of 2-methyl-tetrahydrofuran to n-heptane listed in Table 13.

[0308] [Table 15]

[0309] Stirring was continued, the temperature was adjusted to 42°C, and the mixture was stirred for a minimum of 10 minutes until complete dissolution. The solution was filtered through a polishing filter into a crystallization reactor to remove any insoluble material that may be present, and the polishing filter was rinsed. The solution was stirred at 40°C for a minimum of 10 minutes, then cooled over a minimum of 1 hour as shown in Table 13, and then stirred at the same temperature for a minimum of 10 minutes. n-Heptane was added over a minimum of 30 minutes. The mixture was stirred for a minimum of 10 minutes, then seeded with Atikaplant (0.02 mol / mol) and stirred for a minimum of 8 hours. Additional n-heptane was added over a minimum of 12 hours, the mixture was stirred for a minimum of 2 hours, then cooled to 10°C over a minimum of 3 hours, and stirred at 10°C for a minimum of 4 hours. The product was then isolated, and the resulting wet cake was washed with 2-methyltetrahydrofuran / n-heptane (25 / 75 w / w%) and dried at 50°C. Characterization of the product showed MS m / z 419 / 2 and elemental analysis as shown in Table 14.

[0310] [Table 16]

[0311] HPLC of samples from Examples 3 and 4 was performed as shown in Table 15.

[0312] [Table 17]

[0313] The results in Table 16 show that the claimed method provides highly chemically pure samples of the Atika plant.

[0314] [Table 18]

[0315] Compound 5 was characterized and the results are shown in Table 17.

[0316] [Table 19]

[0317] Atikaplant Form III was found to be crystalline by XRPD. 1 H NMR showed the material to be consistent with the proposed structure with residual ethyl acetate present. Ion chromatography showed no cations / anions present and HPLC showed 99.8% purity. DSC (heating 20° C. to 131° C. at 10° C. / min) showed a peak temperature at 121° C. See FIG. 3.

[0318] The R-Atika plant, impurities, residual solvents, residuals, and water levels were measured, see Table 18.

[0319] [Table 20]

[0320] [Table 21]

[0321] Impurities in the drug substance were identified. Apart from the toxic batches above the reporting threshold of 0.05%, there were five impurities (Impurity 1, RRT 1.12, RRT 1.20, RRT 1.41, and RRT 0.92). Impurity 1 was the only impurity observed above the discrimination threshold of 0.10% manufactured according to SM1.1.

[0322] The structure of Impurity 1 is in Table 19 and was determined by high resolution mass spectrometry (HRMS) and NMR.

[0323] [Table 22]

[0324] In summary, inorganic impurities, i.e., residue on ignition / sulfated ash levels are consistently below 0.3%. Additionally, residual solvent levels are consistently below the ICH Q3C limits and water levels are consistently below the specification limit of NMT 1.0%.

[0325] Example 5 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).

[0326] 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 symptoms of depression as assessed by change from baseline in the MADRS in non-responders during the placebo run-in period.

[0327] 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 depression symptoms using the Clinical Global Impression-Severity (CGI-S), patient reported Major Depressive Disorder Symptoms Scale (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 to efficacy and safety parameters.

[0328] Secondary exploration objectives are to: 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.

[0329] 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 4.

[0330] 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, the Antidepressant Treatment History Questionnaire (TRQ), and the MADRS.

[0331] 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 4.

[0332] 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.

[0333] 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 clinic visit on Day 1. 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 to 2 weeks. See Table 20.

[0334] [Table 23]

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] If Visit 11 was scheduled for 3 days later, subjects continued taking medication until Visit 11.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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

[0345] 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.

[0346] (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Central sedative effect: Karolinska Sleepiness Scale (ix) Sexual dysfunction: ASEX

[0347] E. Patient Population Of the 184 subjects, 169 were randomized into 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 21 and 22.

[0348] [Table 24-1]

[0349] [Table 24-2]

[0350] [Table 25-1]

[0351] [Table 25-2]

[0352] 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).

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] Efficacy endpoints were presented for both eITT and fITT.

[0358] 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.

[0359] 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

[0360] 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 5. 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 23-25 ​​and Figure 8.

[0361] [Table 26]

[0362] [Table 27]

[0363] [Table 28]

[0364] Based on the results of the MMRM model with subject as a random effect; country, treatment, time, and treatment-by-time interactions as factors; and baseline MADRS total score as a continuous covariate. A significant positive efficacy signal was detected for Atikaplant versus placebo at the one-sided 0.20 significance level. The estimated LS mean difference between Atikaplant and placebo at week 6 of treatment was -2.1, with an upper 80% one-sided CI 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.

[0365] 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 10A and 10B. The mean change from treatment baseline in MADRS total score at treatment week 6 for fITT was smaller than eITT: -9.7 (8.02) for Aticaplant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results show a statistical advantage over placebo with a persistence of effect with the largest difference seen at week 6. See Table 26.

[0366] [Table 29]

[0367] 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 upper 80% one-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 27-28 and Figure 6.

[0368] [Table 30]

[0369] [Table 31]

[0370] 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.

[0371] (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 11 and 12.

[0372] 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).

[0373] 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 placebo. The response rate at week 6 in the fITT population was 38.2% for the Atika plant and 23.5% for placebo. For both populations, the treatment difference at week 6 was significant at the 20% two-sided significance level (chi-square test: p = 0.104 for eITT and p = 0.046 for fITT). See Table 29 and Figures 13-16.

[0374] [Table 32]

[0375] 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.

[0376] 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 30 and Figures 17 and 25.

[0377] [Table 33]

[0378] 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 7 and Tables 31 and 32 and Figure 18. The corresponding p-value was 0.419.

[0379] [Table 34]

[0380] [Table 35]

[0381] 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 7 and 8.

[0382] 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 33.

[0383] [Table 36]

[0384] 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 34). The observed effect sizes were 0.38 and 0.11, respectively.

[0385] [Table 37]

[0386] 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 35. The observed effect sizes were 0.51 and 0.29, respectively.

[0387] [Table 38]

[0388] 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.

[0389] Change from treatment baseline in CGI-S total score upon treatment

[0390] [Table 39]

[0391] Change from baseline in SMDDS total score at week 6 of treatment

[0392] [Table 40]

[0393] Number of subjects with SATE score at 6 weeks of treatment

[0394] [Table 41]

[0395] Change from baseline in HAM-A6 total score at week 6 of treatment

[0396] [Table 42]

[0397] These data show greater improvements in HAMA6 scores in Atticaplant treated patients versus placebo.

[0398] Change from treatment baseline in structured interview guide for SIGH-A scores at week 6 of treatment

[0399] [Table 43]

[0400] 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.

[0401] [Table 44] (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 42.

[0402] [Table 45]

[0403] 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 43.

[0404] [Table 46]

[0405] 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.

[0406] 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 44.

[0407] [Table 47]

[0408] 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.

[0409] No deaths were reported.

[0410] (iv) Anhedonia analysis Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 45-47.

[0411] [Table 48]

[0412] The results show that the treatment effect was greater in patients with more anhedonia at baseline. See Figure 19.

[0413] [Table 49]

[0414] [Table 50]

[0415] The results show that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 20-A and 20-B. In Figure 20-A, i.e., in the high anhedonia group, the placebo + oral antidepressant group shows less placebo response compared to the low anhedonia group in Figures 7-8. 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 at all single time points (week 1 onwards) in the high anhedonia group. 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 subgroup with high vs. low anhedonia. See Figure 21.

[0416] (v) Weight change At the baseline, the mean weight of subjects in the placebo group was 76.17 kg compared to 78.66 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 weights 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 48.

[0417] [Table 51]

[0418] (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.

[0419] 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 49 and 50.

[0420] [Table 52]

[0421] [Table 53]

[0422] (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.

[0423] 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.

[0424] Patients had sexual function measured using the ASEX, a standard, familiar rating scale. See Table 51.

[0425] [Table 54]

[0426] 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. The 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 22.

[0427] 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 attainment, and vaginal lubrication / erection. Most of the improvement is seen in items 3, 4, and 5 in Figure 23.

[0428] (viii) Onset of Effect The onset of effect for Atikaplant can be estimated from the study. Figure 10B 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.

Claims

1. A composition comprising a crystalline form of aticaplant and less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition; 【Transformation 6】 1. A composition, wherein the crystalline form of Aticaplant is characterized by four or more X-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° 2θ (±0.2).

2. The composition described in claim 1, wherein the crystalline form of the aticaplant is characterized by an X-ray powder diffraction pattern corresponding to Figure 1.

3. The composition of claim 1, wherein the crystalline form of Atikaplant is characterized by a differential scanning calorimetry peak temperature (T m ) of about 121°C.

4. The composition described in claim 1, wherein the crystalline form of the Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to Figure 4.

5. The composition described in claim 1, wherein the crystalline form of the aticaplant is an anhydrous form.

6. 10. The composition of claim 1, comprising about 0.10% by weight or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition. 【Transformation 7】

7. 10. The composition of claim 1, comprising at least about 99.5% by weight of the crystalline form of aticaplant, based on the weight of the composition.

8. Atikaplant tetrahydrofuran solvate. 【Chemistry 1】

9. The tetrahydrofuran solvate of claim 8, which is S-aticaplant. 【Chemistry 2】

10. A composition comprising the tetrahydrofuran solvate of aticaplant according to claim 8.

11. 11. The composition of claim 10, comprising about 0.10% by weight or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition. 【Transformation 3】

12. 11. The composition of claim 10, comprising at least about 99.5% by weight of the tetrahydrofuran solvate of aticaplant, based on the weight of the composition.

13. 11. The composition of claim 10, comprising about 0.10% by weight or less of R-aticaplant, based on the weight of the composition. 【Transformation 5】

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