Polymorphic forms of the atica plant for use in the treatment of major depressive disorder

Abstract

The present disclosure provides crystalline and amorphous forms of Atikaplant. Also provided by the present disclosure are pharmaceutical compositions comprising the amorphous or crystalline forms, the amorphous or crystalline forms of Atikaplant for use in treating major depressive disorder in human patients with anhedonia, methods of treating major depressive disorder using the amorphous or crystalline forms of Atikaplant, the use of the amorphous or crystalline forms of Atikaplant in the manufacture of medicaments for treating major depressive disorder, and packages or pharmaceutical products comprising (i) the amorphous or crystalline forms of Atikaplant and (ii) instructions for treating major depressive disorder. In some embodiments, the human patient treated as described herein has anhedonia.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 317,475, filed March 7, 2022.

[0002] FIELD OF THEINVENTION The present disclosure relates to polymorphs of Atikaplant and methods of using these polymorphs. [Background technology]

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

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

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

[0006] In some embodiments, the present disclosure provides crystalline form I of Aticaplant.

[0007] In another aspect, the present disclosure provides crystalline form II of Aticaplant.

[0008] In a further aspect, the present disclosure provides crystalline Form III of Aticaplant.

[0009] In yet another aspect, the present disclosure provides an amorphous form of Aticaplant.

[0010] In yet a further aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Aticaplant or an amorphous form of Aticaplant described herein. The crystalline form of Aticaplant can be Form I, Form II, or Form III.

[0011] In another aspect, the present disclosure provides 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 crystalline form of Aticaplant or an amorphous form of Aticaplant as described herein. The crystalline form of Aticaplant can be Form I, Form II, or Form III.

[0012] In a further aspect, the present disclosure provides a crystalline form of Aticaplant described herein for use in treating major depressive disorder in a human patient. The crystalline form of Aticaplant can be Form I, Form II, or Form III.

[0013] In yet another aspect, the present disclosure provides an amorphous form of aticaplant for use in treating major depressive disorder in a human patient.

[0014] In yet a further aspect, the present disclosure provides the use of a crystalline form of aticaplant or an amorphous form of aticaplant described herein in the manufacture of a medicament for the treatment of major depressive disorder in a human patient. The crystalline form of aticaplant can be Form I, Form II, or Form III.

[0015] In another aspect, the disclosure provides a package or pharmaceutical product comprising (i) a crystalline form of Aticaplant, an amorphous form of Aticaplant, or a combination thereof, as described herein, and (ii) instructions for treating major depressive disorder in a human patient. The crystalline form of Aticaplant can be Form I, Form II, or Form III. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is the X-ray powder diffraction (XRPD) pattern (transmission mode) of Atika Plant Form III. [Diagram 2] XRPD patterns of amorphous Atika plant. The top pattern is obtained from 1,4-dioxane, the middle pattern from t-butanol, and the bottom pattern from THF / H2O. [Diagram 3] Modulated differential scanning calorimetry (mDSC) thermogram of amorphous Atika plant. [Figure 4] 1 is a differential scanning calorimetry (DSC) thermogram of Atika Plant Form III. [Diagram 5] FIG. 4 is a DSC thermogram of the sample from FIG. 3 heated from −40 to 131° C. / 10° C. / min. [Figure 6] FIG. 1 is an XRPD pattern of crystalline form I of Atika Plant. [Figure 7] 1 is a DSC thermogram of crystalline form I of Atika Plant. [Figure 8] FIG. 1 is an XRPD pattern of crystalline form II of Atika Plant (1 g scale). [Figure 9] This is an mDSC thermogram of crystalline form II of Atika Plant (1 g scale). [Figure 10] FIG. 1 is a gravimetric vapor sorption (GVS) isotherm plot of crystalline form II (1 g scale) of Atika Plant. [Figure 11] FIG. 1 is a GVS kinetic plot of crystalline form II of Atikaplant (1 g scale). [Figure 12] 1 is an mDSC thermogram of crystalline form III of Atika Plant. [Figure 13] FIG. 1 is a schematic showing a decision tree for the treatment of gums / oils in solubility screening. [Figure 14] 1 shows the clinical trial design for Example 1. [Figure 15] 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 16] 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 17] FIG. 13 is a line graph showing least squares mean change (±SE) in SHAPS (Snaith Hamilton Pleasure Scale) total score from baseline during the treatment period for the eITT analysis set. [Figure 18] 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 19] 1 is a line graph showing MADRS total scores over time for the eITT analysis set: Mean (±SE). [Figure 20-A] FIG. 1 is a line graph showing MADRS total scores over time for the full intent-to-treat (fITT) analysis set: mean (±SE). [Figure 20-B] This is an excerpt from Figure 20-A for weeks 0 to 6 of treatment. [Figure 21] 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 22] 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 23] 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 24] fLine graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the ITT analysis set. [Diagram 25] 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 26] fLine graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the ITT analysis set. [Figure 27] SHAPS total score over time for the eITT analysis set: line graph showing mean (±SE). [Figure 28] SHAPS total score over time for the fITT analysis set: line graph showing mean (±SE). [Figure 29] Changes in MADRS from baseline according to severity of anhedonia are shown. [Figure 30-A] FIG. 1 is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS≧38. [Figure 30-B] FIG. 1 is a line graph showing MADRS change from baseline in patients with low anhedonia, i.e., SHAPS<38. [Diagram 31] FIG. 1 is a bar graph showing a comparison of MADRS in patients with low and high anhedonia. [Diagram 32] 1 is a line graph showing the mean ASEX total score change from baseline. [Diagram 33] 1 is a bar graph showing the mean ASEX item-level change total score change from baseline. [Diagram 34] 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 35] f Plot showing MADRS total score at week 6 by different subgroups for the ITT analysis set: LS mean difference (60%). In this plot, <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] 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).

[0018] The present disclosure provides novel crystalline and amorphous forms of Aticaplant. The crystalline forms, i.e., Forms I, II, and III, are anhydrous and stable in solid form. In some embodiments, crystalline Form I is anhydrous. In other embodiments, crystalline Form II is anhydrous. In further embodiments, crystalline Form III is anhydrous.

[0019] The term "crystal" refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.

[0020] 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.

[0021] The term "amorphous" refers to a solid form of a chemical moiety that exists in a non-crystalline state. Amorphous solids are crystals that do not have a characteristic shape or form. That is, amorphous forms lack long-range structural order. Characterization of amorphous forms can be performed by one of skill in the art, including, but not limited to, XRPD, TGA, infrared spectroscopy, Raman spectroscopy, solid-state NMR, DSC, scanning electron microscopy, dynamic solvent sorption, laser diffraction, dissolution, MET analysis, densitometry, viscometry, high pressure liquid chromatography (HPLC), inverse gas chromatography, or combinations thereof. In some embodiments, an amorphous sample is free of other forms, i.e., the sample is 100% w / w amorphous. A crystalline sample can also contain solids that are crystalline. In certain embodiments, an amorphous form may comprise a solid such that a sample is at least about 99% w / w crystalline, at least about 95% w / w amorphous, at least about 90% w / w crystalline, at least about 85% w / w crystalline, at least about 80% w / w crystalline, etc.

[0022] 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.

[0023] The term "anhydrous" or "anhydrate" as used herein refers to a crystalline or amorphous form described herein that is substantially devoid of water. In some embodiments, the anhydrous form contains less than about 1% w / w water. In other embodiments, the anhydrous form contains 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.

[0024] 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°.

[0025] 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.

[0026] 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.

[0027] The present disclosure also provides crystalline form I of Atikaplant. Atikaplant crystalline form I can be characterized by a number of techniques, including but not limited to, X-ray diffraction and differential scanning calorimetry. In some embodiments, Atikaplant crystalline form I is characterized by X-ray diffraction. Atikaplant crystalline form I is characterized by four or more X-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, or 24.0°. In some embodiments, Atikaplant crystalline form I is characterized by X-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, or 24.0°. In further embodiments, crystalline form I of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.6°, 13.9°, 17.3°, 17.4°, 18.0°, or 24.0° 2θ (±0.2). In other embodiments, crystalline form I of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (±0.2), and one or more additional peaks at 3.8°, 7.7°, 10.1°, 19.7°, 21.8°, 22.4°, 23.1°, and 25.3° 2θ (±0.2). In a further embodiment, crystalline Form I of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (±0.2), and one or more additional peaks 2θ (±0.2) 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 25.3°, 28.2°, 29.5°.In yet other embodiments, crystalline Form I of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (±0.2), and one or more additional peaks at 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 12.5°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 26.6°, 25.3°, 27.0°, 28.2°, 28.9°, 29.5°, and 30.3° 2θ (±0.2). In yet other embodiments, crystalline Form I of Atikaplant is characterized by four or more X-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, or 24.0° 2θ (±0.2), and one or more additional peaks in Table 1.

[0028] [Table 1] In yet a further embodiment, crystalline form I of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 2.

[0029] [Table 2] In another embodiment, crystalline form I of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 3.

[0030] [Table 3] In a further embodiment, crystalline form I of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0031] Atikaplant crystalline form I may also be characterized by differential scanning calorimetry. In some embodiments, Atikaplant crystalline form I has a T of about 92.9° C. onsetIn a further embodiment, the crystalline form I of Atikaplant is characterized by a differential scanning calorimetry thermogram comprising a peak temperature (T m ) In another embodiment, the crystalline form I of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0032] The present disclosure also provides crystalline form II of Atikaplant. Atikaplant crystalline form II can be characterized by a number of techniques, including but not limited to, X-ray diffraction and differential scanning calorimetry. In some embodiments, Atikaplant crystalline form II is characterized by X-ray diffraction. In other embodiments, Atikaplant crystalline form II 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). In a further embodiment, crystalline Form II 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 at 12.9°, 14.6°, 20.8°, 22.7°, and 23.5° 2θ (±0.2). In yet other embodiments, crystalline Form II 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 at 11.9°, 12.9°, 14.6°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5°, and 28.4° 2θ (±0.2). In yet further embodiments, crystalline Form II 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 at 6.2°, 9.3°, 11.9°, 12.9°, 14.6°, 16.7°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5°, 27.6°, 28.4°, and 29.5° 2θ (±0.2). In other embodiments, crystalline Form II 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 4.

[0033] [Table 4] In a further embodiment, crystalline form II of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 5.

[0034] [Table 5] In yet another embodiment, crystalline Form II of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 6.

[0035] [Table 6] In yet a further embodiment, crystalline form II of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0036] Atikaplant crystalline Form II may also be characterized by differential scanning calorimetry. In some embodiments, Atikaplant crystalline Form II is characterized by a differential scanning calorimetry thermogram that includes one or both endotherms at about 74.7° C. and about 96.2° C. In other aspects, Atikaplant crystalline Form II has a peak temperature (T m 9. In a further embodiment, the crystalline form II of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0037] The present disclosure further provides crystalline form III of Atikaplant. Atikaplant 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, Atikaplant crystalline form III is characterized by X-ray diffraction. In other embodiments, Atikaplant crystalline form III 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). In further embodiments, Atikaplant crystalline form III 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 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 7.

[0038] [Table 7] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 8.

[0039] [Table 8] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 9.

[0040] [Table 9] In a further embodiment, crystalline Form III of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0041] 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, the crystalline form III of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0042] The present disclosure also provides an amorphous form of Atikaplant. In certain embodiments, the amorphous form has a glass transition temperature (Tg) of about 45.5° C. Tg 3. In yet another embodiment, the amorphous form of Atikaplant is characterized by a differential scanning calorimetry thermogram comprising a T of about 43.8° C. In another embodiment, the amorphous form of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG. onset In a further embodiment, the amorphous form of Atikaplant is characterized by a mDSC thermogram corresponding to FIG.

[0043] 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 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.

[0044] The methods described herein are effective in managing depression and anhedonia in patients using crystalline form I of acetophenone, crystalline form II of acetophenone, crystalline form III of acetophenone, or amorphous acetophenone. 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.

[0045] 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.

[0046] 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.

[0047] In some embodiments, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant crystalline Form I, Atikaplant crystalline Form II, Atikaplant crystalline Form III, or amorphous Atikaplant. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant crystalline Form I, Atikaplant crystalline Form II, Atikaplant crystalline Form III, or amorphous Atikaplant. 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 Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant. 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 following treatment with Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant.

[0048] The reduction in anhedonia after starting treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile can be measured by comparing the patient's anhedonia measured before treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile, 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 crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile.Therefore, a standard method for measuring anhedonia can be used, such as an anhedonia scale, e.g., SHAPS.

[0049] Desirably, the baseline anhedonia measurement is obtained within about one week of initiating treatment with Atikaplant crystalline Form I, Atikaplant crystalline Form II, Atikaplant crystalline Form III, or amorphous Atikaplant. 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 initiating treatment with Atikaplant crystalline Form I, Atikaplant crystalline Form II, Atikaplant crystalline Form III, or amorphous Atikaplant. 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 Atikaplant crystalline Form I, Atikaplant crystalline Form II, Atikaplant crystalline Form III, or amorphous Atikaplant.

[0050] The change in anhedonia in a patient depends on several factors, including, but not limited to, the severity of anhedonia, the patient's sensitivity to crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile, and other drugs being administered. In some embodiments, anhedonia in a patient is reduced about 3 weeks after treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile. In other embodiments, anhedonia in a patient is reduced about 3 weeks after treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile. In further embodiments, the patient's anhedonia is reduced after about 3 weeks to about 6 weeks, and in certain embodiments by the 6th week, of treatment with Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant. 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 with Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 11.

[0056] [Table 10]

[0057] In some embodiments, the following criteria are also met to be diagnosed with MDD:

[0058] [Table 11]

[0059] Major depressive disorder may be classified as mild, moderate, or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In further embodiments, MDD is severe. As used herein, "mild MDD" applies to patients who have few, if any, symptoms beyond those required to make a diagnosis, the intensity of symptoms is distressing but manageable, and the symptoms result in mild impairment in social or occupational functioning. Mild MDD may be a single episode (ICD-10F32.0) or recurrent episodes (ICD-10F33.0). "Moderate MDD" applies to patients who have a number of symptoms, intensity of symptoms, and / or functional impairment that is between those designated as "mild" and those designated as "severe." Moderate MDD may be a single episode (ICD-10F32.1) or recurrent episodes (ICD-10F33.1). "Severe MDD" refers to patients in whom the number of symptoms significantly exceeds that required to make a diagnosis, the intensity of symptoms is severely distressing, the symptoms significantly interfere with social and occupational functioning, and emergency symptom management is required. In some embodiments, severe MDD can be single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition in Table 12.

[0060] [Table 12]

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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"). Total scores range from 0 to 60. The SMDDS uses a 7-day recall period and a verbal rating scale. Higher scores indicate more severe depressive symptomatology.

[0065] 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 a clinical setting 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, greatly improved, or very greatly improved; for worsening of depression, subjects select slightly worse, greatly worse, or very greatly worse. See Table 13.

[0066] [Table 13]

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] In certain embodiments, the patient has been treated with other antidepressant therapy prior to receiving crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant. In some embodiments, the patient has been treated with other antidepressant therapy, including SSRIs, SNRIs, or combinations thereof. In other embodiments, the patient has stopped treatment with other antidepressant therapy prior to starting treatment with crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant.

[0076] 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 treatment by administering crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile in combination with one or more antidepressants to a patient in need thereof, wherein crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile and antidepressants are administered simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means.

[0077] In some aspects, crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant 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., to which the patient's depression was not treated. In other embodiments, crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant is administered adjunctively with antidepressant(s) not previously administered to the patient, i.e., new antidepressants. In yet other embodiments, crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant is administered in a regimen with antidepressant(s) previously administered to the patient.

[0078] When crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant, and 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, and more typically, different.The antidepressant may be administered as prescribed by the attending physician and / or by its label, and crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant is administered as described herein.Typically, the patient is receiving a combination treatment with both an antidepressant and crystalline form I of Atikaplant, crystalline form II of Atikaplant, crystalline form III of Atikaplant, or amorphous Atikaplant, both of which are administered according to the prescribed dosage regimen. Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant and the other antidepressant(s) may be administered simultaneously in divided or single forms at the same or different times during the course of therapy, according to a simultaneous or alternating regimen.

[0079] Aticaplant crystalline form I, Aticaplant crystalline form II, Aticaplant crystalline form III, or amorphous Aticaplant, and antidepressant(s) can be administered via the same or different administration route.Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.In some embodiments, Aticaplant crystalline form I, Aticaplant crystalline form II, Aticaplant crystalline form III, or amorphous Aticaplant is administered orally.

[0080] Treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile or amorphous acetonitrile 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 crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile or amorphous acetonitrile.In certain aspects, patients do not experience weight gain during treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile or amorphous acetonitrile. As used herein, the term "weight gain" refers to an increase in the patient's weight compared to the patient's weight before taking Acanthus crystalline form I, Acanthus crystalline form II, Acanthus crystalline form III, or amorphous ...

[0081] This is in contrast to many other antidepressants for which weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[0082] In a further aspect, the patient does not experience a decrease in sexual function during treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. Thus, the sexual function of a patient while taking Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant can be compared to the sexual function of the patient before administration of Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant. Sexual function can be assessed by using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). The ASEX is used to investigate whether Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant 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.

[0083] 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.

[0084] 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:

[0085] [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:

[0086] [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, which has the following structure: (R)-Aticaplant or (R)-3-Fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide:

[0087] [ka]

[0088] In other embodiments, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant contains less than about 10% by weight of the (R)-enantiomer of aticaplant, based on the weight of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. In further embodiments, Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant 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 Atikaplant, based on the weight of Atikaplant crystalline form I, Atikaplant crystalline form II, Atikaplant crystalline form III, or amorphous Atikaplant. In yet other embodiments, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant contains about 0.001 to about 10% by weight of the (R)-enantiomer of aticaplant, based on the weight of aticaplant, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. In still further embodiments, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant 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 of the (R)-enantiomer of aticaplant, based on the weight of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant.

[0089] The methods described herein include administering to a patient an effective amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous 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 desired 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, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant.

[0090] The amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant to be administered according to the methods described herein may be determined by one skilled in the art and is given based on crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant free base unless otherwise stated. That is, these amounts refer to the amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant administered, excluding, for example, solvent (such as a solvate) or counterion (such as a pharma- ceutically acceptable salt). In some embodiments, the effective amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant is less than about 60 mg. In other embodiments, the effective amount of aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 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, the effective amount of aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant is about 1 to about 50 mg, about 5 to about 50 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, about 40 to about 50 mg, about 1 to about 45 mg, about 2 to about 45 mg, about 5 to about 45 mg, about 10 to about 45 mg, about 20 to about 45 mg, about 30 to about 45 mg, about 30 to about 40 mg, about 30 to about 35 mg, about 1 to about 40 mg, about 5 to about 40 mg, about 10 to about 40 mg, about 20 to about 40 mg, about 30 to about 40 mg, about 1 to about 35 mg, about 2 to about 35 mg, 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 aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant is about 5 to about 15 mg. In yet a further embodiment, the effective amount of aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant is about 10 mg.

[0091] Pharmaceutical Compositions As used herein, the term "composition" is intended to encompass any product that contains a particular component in a particular amount, as well as any product that is directly or indirectly obtained from the combination of a particular component in a particular amount. A preferred pharmaceutical composition contains crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile as an active ingredient intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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 Aticaplant Crystalline Form I, Aticaplant Crystalline Form II, Aticaplant Crystalline Form III, or amorphous Aticaplant. Preferably, the penetration agent increases or enhances the absorption and / or bioavailability of Aticaplant Crystalline Form I, Aticaplant Crystalline Form II, Aticaplant Crystalline Form III, or amorphous Aticaplant 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:

[0097] [Table 14]

[0098] 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.

[0099] 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.

[0100] 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., crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile in the carrier.

[0101] Suitable tonicity agents, if used, may include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

[0102] 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.

[0103] Advantageously, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant may be administered once daily, or the total daily dosage may be administered in divided doses two, three or four times daily.

[0104] As described herein, in particular, the patient has had an inadequate response to other antidepressant therapy prior to treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile.Accordingly, in certain embodiments, the present disclosure relates to crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile for use as described herein, and the patient has had an inadequate response to other antidepressant therapy prior to treatment with crystalline form I of acetonitrile, crystalline form II of acetonitrile, crystalline form III of acetonitrile, or amorphous acetonitrile. In further specific embodiments, the present disclosure also relates to the use of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant in the manufacture of a medicament as described herein, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. In further specific embodiments, the present disclosure also relates to the package or pharmaceutical product as described herein, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. Such antidepressant therapy may be selected from, inter alia, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or combinations thereof.

[0105] As described herein, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant 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, or may be administered, one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant for the uses described herein, comprising administering crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant as an adjunct treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant for the uses described herein, comprising administering crystalline form I of aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant for the uses described herein, comprising administering crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant in the manufacture of a medicament described herein, wherein the treatment comprises administering an effective amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant described herein, wherein the treatment comprises administration of an effective amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant described herein, wherein the treatment comprises administration of an effective amount of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous 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 aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant in combination with an effective amount of one or more antidepressants, which may be selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or combinations thereof.

[0106] As already mentioned, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant for the uses described herein. In a particular embodiment, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant is S-aticaplant. In a further embodiment of the present disclosure, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant, particularly 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 yet a further embodiment, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant, particularly S-aticaplant, for the uses described herein, is administered orally. Furthermore, in further specific embodiments, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant, particularly 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 crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant is S-aticaplant. In further embodiments of the uses described herein, about 2 to about 35 mg of crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant is administered, more specifically about 10 mg is administered. In yet a further embodiment of the use, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant is administered orally.In yet a further particular embodiment of the use, crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant, particularly S-aticaplant, is administered once a day.In further specific embodiments, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the crystalline form I of aticaplant, the crystalline form II of aticaplant, the crystalline form III of aticaplant, or the amorphous aticaplant is, in particular, S-aticaplant. In further embodiments of the package or pharmaceutical product as described herein, the instructions for treatment direct the administration of about 2 to about 35 mg of crystalline form I of aticaplant, the crystalline form II of aticaplant, the crystalline form III of aticaplant, or the amorphous aticaplant, more particularly, the administration of about 10 mg. In yet further embodiments of the package or pharmaceutical product as described herein, the instructions for treatment with crystalline form I of aticaplant, the crystalline form II of aticaplant, the crystalline form III of aticaplant, or the amorphous aticaplant, in particular, S-aticaplant, is for oral administration. Moreover, in further specific embodiments of the package or pharmaceutical product described herein, the instructions for treatment of aticaplant crystalline form I, aticaplant crystalline form II, aticaplant crystalline form III, or amorphous aticaplant, particularly S-aticaplant, are for once-daily administration.

[0107] Advantageously, administration of crystalline form I of acetoplankton, crystalline form II of acetoplankton, crystalline form III of acetoplankton, or amorphous acetoplankton does not result in weight gain during treatment, including clinically relevant weight gain.Thus, in further specific embodiments, the present disclosure relates to crystalline form I of acetoplankton, crystalline form II of acetoplankton, crystalline form III of acetoplankton, or amorphous acetoplankton for use as described herein, wherein the patient does not experience weight gain during treatment with crystalline form I of acetoplankton, crystalline form II of acetoplankton, crystalline form III of acetoplankton, or amorphous acetoplankton.In further specific embodiments, the present disclosure relates to the use as defined herein, wherein the patient does not experience weight gain during treatment with crystalline form I of acetoplankton, crystalline form II of acetoplankton, crystalline form III of acetoplankton, or amorphous acetoplankton. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during treatment with Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant. The patient's weight can be assessed, particularly upon the first administration of Aticaplant.

[0108] Also, unexpectedly, it was observed that patients do not experience a decrease in sexual function during treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant, based on evaluation at the time of first administration.Thus, in further specific embodiments, the present disclosure relates to crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant for use as described herein, where the patient does not experience a decrease in sexual function during treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant.In further specific embodiments, the present disclosure relates to the use as described herein, where the patient does not experience a decrease in sexual function during treatment with crystalline form I of aticaplant, crystalline form II of aticaplant, crystalline form III of aticaplant, or amorphous aticaplant. In further specific embodiments, the present disclosure relates to a package or pharmaceutical product as described herein, wherein a patient does not experience a decrease in sexual function during treatment with Aticaplant crystalline Form I, Aticaplant crystalline Form II, Aticaplant crystalline Form III, or amorphous Aticaplant. Such term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to those skilled in the art, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[0109] As previously described, the patient has anhedonia. In certain aspects, the anhedonia is moderate. In other aspects, the anhedonia is severe. The 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 crystalline form I of acephalanth, crystalline form II of acephalanth, crystalline form III of acephalanth, or amorphous acephalanth for use 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 crystalline form I of acephalanth, crystalline form II of acephalanth, crystalline form III of acephalanth, or amorphous acephalanth, 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). 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 Atticaplant crystalline form I, Atticaplant crystalline form II, Atticaplant crystalline form III, or amorphous Atticaplant, more particularly, 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 a patient's anhedonia is reduced by at least 40% as measured by a change from baseline in total score on the Anhedonia Scale after 6 weeks of treatment with Aticaplant Crystalline Form I, Aticaplant Crystalline Form II, Aticaplant Crystalline Form III, or amorphous Aticaplant, more particularly, a patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in total score on the Anhedonia Scale. In further specific embodiments, the Anhedonia Scale is the Snaith-Hamilton Pleasure Scale (SHAPS).

[0110] Embodiment The present invention also provides the following non-limiting embodiments. Embodiment 1 is a crystalline form I of Atikaplant characterized by four or more X-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°, and Atikaplant has the following structure:

[0111] [ka]

[0112] Embodiment 2 is crystalline form I of Atikaplant, characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0113] Embodiment 3 is crystalline form I of Atikaplant according to embodiment 1 or 2, characterized by a differential scanning calorimetry thermogram containing one endotherm at about 92.9°C.

[0114] Embodiment 4 is a crystalline form I of Atikaplant according to any one of embodiments 1 to 3, characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0115] Embodiment 5 is crystalline form I of aticaplant according to any one of embodiments 1 to 4, which is anhydrous.

[0116] In embodiment 6, crystalline Form II 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 Atikaplant has the following structure:

[0117] [ka]

[0118] Embodiment 7 is crystalline form II of Aticaplant according to embodiment 6, characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0119] Embodiment 8 is crystalline form II of Aticaplant according to embodiment 6 or 7, characterized by a differential scanning calorimetry thermogram containing one or both endotherms at about 74.7°C and about 96.2°C.

[0120] Embodiment 9 is a crystalline form II of Atikaplant according to any one of embodiments 6 to 8, characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0121] Embodiment 10 is crystalline form II of aticaplant according to any one of embodiments 6 to 9, which is anhydrous.

[0122] Embodiment 11 is a crystalline form III of Atikaplant 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), Atikaplant having the following structure:

[0123] [ka]

[0124] Embodiment 12 is a crystalline form III of the aticaplant of embodiment 11, characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0125] Embodiment 13 is a method for producing a 121° C. m 13. The crystalline form III of aticaplant according to embodiment 11 or 12, characterized in that

[0126] Embodiment 14 is a crystalline form III of Atikaplant according to any one of embodiments 11 to 13, characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0127] Embodiment 15 is crystalline form III of aticaplant according to any one of embodiments 11 to 14, which is anhydrous.

[0128] In embodiment 16, the atikaplant is an amorphous form of atikaplant having the following structure:

[0129] [ka]

[0130] Embodiment 17 has a T of about 45.5° C. g The amorphous form of embodiment 16, characterized by a differential scanning calorimetry thermogram comprising:

[0131] Embodiment 18 is an amorphous form of Atikaplant of embodiment 16 or 17, characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0132] Embodiment 19 is a pharmaceutical composition comprising a crystalline form of aticaplant according to any one of embodiments 1 to 15 or an amorphous form of aticaplant according to any one of embodiments 16 to 18.

[0133] Embodiment 20 is a method of treating major depressive disorder in a human patient using crystalline aticaplant.

[0134] Embodiment 21 is a method of treating major depressive disorder in a human patient, comprising administering crystalline aticaplant to the human patient, wherein the patient has previously responded inadequately to other antidepressant therapies.

[0135] Embodiment 22 is a method for treating major depressive disorder in a human patient, comprising administering an effective amount of a crystalline form of aticaplant according to any one of embodiments 1-15 or an amorphous form of aticaplant according to any one of embodiments 16-18 to a human patient in need thereof.

[0136] Embodiment 23 is the method of embodiment 22, wherein the treating comprises administering an effective amount of a crystalline form of aticaplant or an amorphous form of aticaplant.

[0137] Embodiment 24 is the method of embodiment 22 or 23, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0138] Embodiment 25 is the method of any one of embodiments 21, 23, or 24, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0139] Embodiment 26 is the method of any one of embodiments 20-25, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0140] Embodiment 27 is the method of any one of embodiments 20-26, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0141] Embodiment 28 is the method of any one of embodiments 20 to 27, wherein the crystalline form of aticaplant is a crystalline form of S-aticaplant or the amorphous form of aticaplant is an amorphous form of S-aticaplant.

[0142] Embodiment 29 is the method of any one of embodiments 20 to 28, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is from about 2 to about 35 mg.

[0143] Embodiment 30 is the method of embodiment 29, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is about 10 mg.

[0144] Embodiment 31 is the method of any one of embodiments 20-30, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered orally.

[0145] Embodiment 32 is a method according to any one of embodiments 20 to 31, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered once a day.

[0146] Embodiment 33 is the method of any one of embodiments 20 to 32, wherein the patient has anhedonia.

[0147] Embodiment 34 is the method of any one of embodiments 20 to 33, wherein the patient has moderate anhedonia.

[0148] Embodiment 35 is the method of any one of embodiments 20 to 33, wherein the patient has severe anhedonia.

[0149] Embodiment 36 is the method of any one of embodiments 22-35, wherein the patient does not experience weight gain during treatment with the crystalline form of Aticaplant or the amorphous form of Aticaplant.

[0150] Embodiment 37 is the method of embodiment 36, wherein the patient's body weight is assessed at the time of the first administration of the crystalline form of Aticaplant or the amorphous form of Aticaplant.

[0151] Embodiment 38 is the method of any one of embodiments 20-37, wherein the patient does not experience a decrease in sexual function during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0152] Embodiment 39 is the method of embodiment 38, wherein the patient's sexual function is evaluated upon the first administration of the crystalline form of aticaplant or the amorphous form of aticaplant.

[0153] Embodiment 40 is the method of embodiment 38 or 39, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0154] Embodiment 41 is a method according to any one of embodiments 38-40, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0155] Embodiment 42 is the method of any one of embodiments 33-35, wherein the patient's anhedonia is reduced by at least 40% as measured by change from baseline in total score on the Anhedonia Scale after 6 weeks of treatment with the crystalline form of Atikaplant or the amorphous form of Atikaplant.

[0156] Embodiment 43 is the method of any one of embodiments 33-35 and 42, 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.

[0157] Embodiment 44 is the method of embodiment 42 or 43, wherein the anhedonia scale is the Snaith-Hamilton Pleasure Scale.

[0158] Embodiment 45 is a crystalline form of aticaplant for treating major depressive disorder in a human patient.

[0159] Embodiment 46 is a crystalline form of aticaplant according to any one of embodiments 1 to 15 for treating major depressive disorder in a human patient who has previously had an inadequate response to other antidepressant therapies.

[0160] Embodiment 47 is a crystalline form of aticaplant according to any one of embodiments 1 to 15 for treating major depressive disorder in a human patient.

[0161] Embodiment 48 is a crystalline form of aticaplant of embodiment 47, wherein the treatment comprises administration of an effective amount of a crystalline form of aticaplant or an amorphous form of aticaplant.

[0162] Embodiment 49 is a crystalline form of aticaplant according to embodiment 47 or 48, which has had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0163] Embodiment 50 is a crystalline form of aticaplant according to any one of embodiments 46 or 49, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0164] Embodiment 51 is a crystalline form of aticaplant according to any one of embodiments 45 to 50, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0165] Embodiment 52 is a crystalline form of aticaplant according to any one of embodiments 45 to 51, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0166] Embodiment 53 is a crystalline form of aticaplant according to any one of embodiments 45 to 52, wherein the crystalline form of aticaplant is a crystalline form of S-aticaplant or the amorphous form of aticaplant is an amorphous form of S-aticaplant.

[0167] Embodiment 54 is a crystalline form of aticaplant according to any one of embodiments 45 to 53, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is from about 2 to about 35 mg.

[0168] Embodiment 55 is a crystalline form of aticaplant according to embodiment 54, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is about 10 mg.

[0169] Embodiment 56 is a crystalline form of aticaplant according to any one of embodiments 45 to 55, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered orally.

[0170] Embodiment 57 is a crystalline form of aticaplant of any one of embodiments 45 to 56, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered once a day.

[0171] Embodiment 58 is a crystalline form of aticaplant according to any one of embodiments 45 to 57, wherein the patient has anhedonia.

[0172] Embodiment 59 is a crystalline form of aticaplant according to any one of embodiments 45 to 58, wherein the patient has moderate anhedonia.

[0173] Embodiment 60 is a crystalline form of aticaplant according to any one of embodiments 45 to 58, wherein the patient has severe anhedonia.

[0174] Embodiment 61 is a crystalline form of aticaplant according to any one of embodiments 47 to 60, wherein the patient does not experience weight gain during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0175] Embodiment 62 is a crystalline form of Aticaplant according to embodiment 61, wherein the patient's weight is assessed at the time of the first administration of the crystalline form of Aticaplant or the amorphous form of Aticaplant.

[0176] Embodiment 63 is a crystalline form of aticaplant according to any one of embodiments 45 to 62, wherein the patient does not experience a decrease in sexual function during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0177] Embodiment 64 is a crystalline form of aticaplant according to embodiment 63, wherein the patient's sexual function is evaluated upon first administration of the crystalline form of aticaplant or the amorphous form of aticaplant.

[0178] Embodiment 65 is a crystalline form of aticaplant according to embodiment 63 or 64, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0179] Embodiment 66 is a crystalline form of aticaplant according to any one of embodiments 63 to 65, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0180] Embodiment 67 is a crystalline form of Atikaplant according to any one of embodiments 58-60, 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 Atikaplant crystalline form or amorphous form of Atikaplant.

[0181] Embodiment 68 is a crystalline form of aticaplant according to any one of embodiments 58-60 and 67, 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.

[0182] Embodiment 69 is a crystalline form of aticaplant according to embodiment 67 or 68, wherein the anhedonia scale is the Snaith-Hamilton pleasure scale.

[0183] Embodiment 70 is an amorphous form of aticaplant for treating major depressive disorder in a human patient.

[0184] Embodiment 71 is an amorphous form of aticaplant according to any one of embodiments 16 to 18 for treating major depressive disorder in a human patient who has previously had an inadequate response to other antidepressant therapies.

[0185] Embodiment 72 is an amorphous form of aticaplant according to any one of embodiments 16-18 for treating major depressive disorder in a human patient.

[0186] Embodiment 73 is an amorphous form of aticaplant according to embodiment 72, wherein the treatment comprises administration of an effective amount of a crystalline form of aticaplant or an amorphous form of aticaplant.

[0187] Embodiment 74 is an amorphous form of aticaplant according to embodiment 72 or 73, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0188] Embodiment 75 is an amorphous form of aticaplant according to any one of embodiments 71 or 74, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0189] Embodiment 76 is an amorphous form of aticaplant according to any one of embodiments 70 to 75, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0190] Embodiment 77 is an amorphous form of aticaplant according to any one of embodiments 70 to 76, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0191] Embodiment 78 is an amorphous form of aticaplant according to any one of embodiments 70 to 77, wherein the crystalline form of aticaplant is a crystalline form of S-aticaplant or the amorphous form of aticaplant is an amorphous form of S-aticaplant.

[0192] Embodiment 79 is an amorphous form of aticaplant according to any one of embodiments 70 to 78, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is from about 2 to about 35 mg.

[0193] Embodiment 80 is an amorphous form of aticaplant according to embodiment 79, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is about 10 mg.

[0194] Embodiment 81 is an amorphous form of aticaplant according to any one of embodiments 70 to 80, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered orally.

[0195] Embodiment 82 is an amorphous form of aticaplant according to any one of embodiments 70 to 81, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered once a day.

[0196] Embodiment 83 is an amorphous form of Aticaplant according to any one of embodiments 70 to 82, wherein the patient has anhedonia.

[0197] Embodiment 84 is an amorphous form of aticaplant according to any one of embodiments 70 to 83, wherein the patient has moderate anhedonia.

[0198] Embodiment 85 is an amorphous form of aticaplant according to any one of embodiments 70 to 84, wherein the patient has severe anhedonia.

[0199] Embodiment 86 is an amorphous form of aticaplant according to any one of embodiments 72 to 85, wherein the patient does not experience weight gain during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0200] Embodiment 87 is the amorphous form of Aticaplant of embodiment 86, wherein the patient's weight is assessed upon first administration of the crystalline form of Aticaplant or the amorphous form of Aticaplant.

[0201] Embodiment 88 is an amorphous form of aticaplant according to any one of embodiments 70 to 87, wherein the patient does not experience a decrease in sexual function during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0202] Embodiment 89 is an amorphous form of aticaplant according to embodiment 88, wherein the patient's sexual function is evaluated upon the first administration of a crystalline form of aticaplant or an amorphous form of aticaplant.

[0203] Embodiment 90 is an amorphous form of aticaplant according to embodiment 88 or 89, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0204] Embodiment 91 is an amorphous form of aticaplant according to any one of embodiments 88 to 90, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0205] Embodiment 92 is an amorphous form of Atikaplant according to any one of embodiments 83 to 85, 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 Atikaplant crystalline form or the amorphous form of Atikaplant.

[0206] Embodiment 93 is an amorphous form of Aticaplant according to any one of embodiments 83-85 and 92, 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.

[0207] Embodiment 94 is an amorphous form of the atica plant according to embodiment 92 or 93, wherein the anhedonia scale is the Snaith-Hamilton pleasure scale.

[0208] Embodiment 95 is the use of a crystalline form of aticaplant or an amorphous form of aticaplant in the manufacture of a medicament for treating major depressive disorder in a human patient.

[0209] Embodiment 96 is the use of a crystalline form of aticaplant according to any one of embodiments 1 to 15 or an amorphous form of aticaplant according to any one of embodiments 16 to 18 in the preparation of a medicament for treating major depressive disorder in a human patient, wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0210] Embodiment 97 is the use of a crystalline form of aticaplant according to any one of embodiments 1 to 15 or an amorphous form of aticaplant according to any one of embodiments 16 to 18 in the preparation of a medicament for treating major depressive disorder in a human patient.

[0211] Embodiment 98 is the use according to embodiment 97, wherein the treatment comprises administration of an effective amount of a crystalline form of aticaplant or an amorphous form of aticaplant.

[0212] Embodiment 99 is the use according to embodiment 97 or 98, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0213] Embodiment 100 is the use according to any one of embodiments 96 to 99, wherein the other antidepressant therapy comprises a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0214] Embodiment 101 is the use according to any one of embodiments 95 to 100, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0215] Embodiment 102 is the use according to any one of embodiments 95 to 101, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0216] Embodiment 103 is an amorphous form of aticaplant according to any one of embodiments 95 to 102, wherein the crystalline form of aticaplant is a crystalline form of S-aticaplant or the amorphous form of aticaplant is an amorphous form of S-aticaplant.

[0217] Embodiment 104 is an amorphous form of aticaplant according to any one of embodiments 95 to 103, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is from about 2 to about 35 mg.

[0218] Embodiment 105 is the amorphous form of aticaplant according to embodiment 104, wherein the effective amount of the crystalline form of aticaplant or the amorphous form of aticaplant is about 10 mg.

[0219] Embodiment 106 is the amorphous form of aticaplant of any one of embodiments 95 to 105, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered orally.

[0220] Embodiment 107 is an amorphous form of aticaplant according to any one of embodiments 95 to 106, wherein the crystalline form of aticaplant or the amorphous form of aticaplant is administered once a day.

[0221] Embodiment 108 is an amorphous form of aticaplant according to any one of embodiments 95 to 107, wherein the patient has anhedonia.

[0222] Embodiment 109 is an amorphous form of aticaplant according to any one of embodiments 95 to 83, wherein the patient has moderate anhedonia.

[0223] Embodiment 110 is an amorphous form of Aticaplant according to any one of embodiments 95 to 84, wherein the patient has severe anhedonia.

[0224] Embodiment 111 is an amorphous form of aticaplant according to any one of embodiments 77 to 85, wherein the patient does not experience weight gain during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0225] Embodiment 112 is an amorphous form of Aticaplant according to embodiment 111, wherein the patient's weight is assessed upon first administration of the crystalline form of Aticaplant or the amorphous form of Aticaplant.

[0226] Embodiment 113 is an amorphous form of aticaplant according to any one of embodiments 95 to 112, wherein the patient does not experience a decrease in sexual function during treatment with the crystalline form of aticaplant or the amorphous form of aticaplant.

[0227] Embodiment 114 is an amorphous form of aticaplant according to embodiment 113, wherein the patient's sexual function is evaluated upon first administration of the crystalline form of aticaplant or the amorphous form of aticaplant.

[0228] Embodiment 115 is an amorphous form of acetophenone according to embodiment 113 or 114, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction.

[0229] Embodiment 116 is an amorphous form of Aticaplant according to any one of embodiments 113-114, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0230] Embodiment 117 is an amorphous form of Atikaplant according to any one of embodiments 108 to 110, 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 Atikaplant crystalline form or amorphous form.

[0231] Embodiment 118 is an amorphous form of aticaplant according to any one of embodiments 108-110 and 117, 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.

[0232] Embodiment 119 is an amorphous form of the atica plant according to embodiment 117 or 118, wherein the anhedonia scale is the Snaith-Hamilton pleasure scale.

[0233] Embodiment 120 is a package or pharmaceutical product comprising (i) a crystalline form of aticaplant as described in any one of embodiments 1-15, an amorphous form of aticaplant as described in any one of embodiments 16-18, or a combination thereof, and ii) instructions for treating major depressive disorder in a human patient with anhedonia.

[0234] 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.

[0235] [Table 15]

[0236] 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.

[0237] 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.

[0238] Details of the standard Pharmorphix data collection method are as follows. ●Angle range: 2~42°2θ ●Process size: 0.05°2θ ● Collection time: 0.5 seconds / step (total collection time: 6.40 minutes)

[0239] If required, other methods for data collection will be used with details as shown in Table 14.

[0240] [Table 16]

[0241] 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.

[0242] 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.

[0243] The scanning mode for the metal plates used the gonioscan axis, whereas for the Millipore plates 2θ scanning was utilized.

[0244] Details of standard screening data collection methods are as follows: ●Angle range: 2.5~32.0°2θ ●Process size: 0.0130°2θ ●Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0245] The software used for data collection was X'Pert Data Collector and data were analyzed and presented using DiffracPlusEVA.

[0246] B. Nuclear magnetic resonance (NMR) 1 H NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Samples were prepared in DMSO-d6 solvent unless otherwise stated. Standard Bruker loading experiments ( 1 Automated experiments were acquired using the ICON-NMR configuration in Topspin software using H. Off-line analysis was performed using an ACD Spectrus Processor.

[0247] C. 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.

[0248] 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.

[0249] The instrument control software was Advantage for Q Series and Thermal Advantage and data was analyzed using Universal Analysis or TRIOS.

[0250] 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.

[0251] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0252] D. Thermogravimetric analysis (TGA) TA Instruments Q500 TGA data were collected on a TA Instruments Q500TGA equipped with a 16-position autosampler. Typically, 1-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C / min from ambient to 350 °C. A nitrogen purge at 60 mL / min was maintained over the sample.

[0253] The instrument control software was Advantage for Q Series and Thermal Advantage and data was analyzed using Universal Analysis or TRIOS.

[0254] TA Instruments Discovery TGA TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, 1-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C / min from ambient to 350 °C. A nitrogen purge at 25 mL / min was maintained over the sample.

[0255] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0256] E. Polarized Light Microscopy (PLM) Leica LM / DM Polarizing Microscope Samples were analyzed with a Leica LM / DM polarizing microscope equipped with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a glass slip. Samples were viewed with appropriate magnification and partially polarized light coupled with a λ false color filter. Images were captured using Image ProPlus software.

[0257] Nikon LM / DM Polarizing Microscope Samples were studied with a Nikon SMZ1500 polarizing microscope equipped with a digital video camera connected to a DS camera control unit DS-L2 for image capture. Samples were observed with appropriate magnification and partially polarized light coupled with a λ false color filter.

[0258] F. Scanning Electron Microscope (SEM) Data were collected on a Phenom Pro SEM. A small sample was mounted on an aluminum stub using conductive double-sided adhesive tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 sec).

[0259] G. Gravimetric Vapor Sorption (GVS) Sorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software. Sample temperature was maintained at 25° C. by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams at a total flow rate of 200 mL / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0-100% RH) located close to the sample. Sample weight change (mass relaxation) as a function of % RH was constantly monitored by a microbalance (accuracy ±0.005 mg).

[0260] Typically, 5-30 mg of sample was placed into a tared mesh stainless steel basket under ambient conditions. Samples were loaded and removed at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (2 scans per complete cycle). Standard isotherms were performed at 25°C at 10% RH intervals over the 0-90% RH range. Typically, duplicate cycles (4 scans) were performed. Data analysis was performed within Microsoft Excel using the DVS Analysis suite. See Table 15.

[0261] [Table 17]

[0262] Samples were collected after completion of the isotherm and reanalyzed by XRPD.

[0263] H. 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 16.

[0264] [Table 18]

[0265] I. Ion Chromatography (IC) Data was collected on a Metrohm 930 Compact ICFlex with an 858 Professional autosampler and an 800 Dosino dose unit monitor using IC MagicNet software. Accurately weighed samples were prepared as stock solutions in appropriate solvents. Quantification was achieved by comparison with standard solutions of known concentrations of the ion being analyzed. Analyses were performed in duplicate and the average of values ​​is shown unless otherwise stated. See Tables 17A and 17B.

[0266] [Table 19]

[0267] [Table 20]

[0268] J. Single Crystal X-ray Diffraction (SCXRD) Data were collected on a Rigaku Oxford Diffraction Supernova Dual Source, Cu at 0, Atlas CCD diffractometer equipped with an Oxford Cryosystems Cobra refrigerator. Data were collected using Cu Kα or Mo Kα radiation as described in the experimental table. Structures were solved and refined using Bruker AXS SHELXTL suite or OLEX crystallography software. Full details can be found in the CIF. Hydrogen atoms bonded to carbons were geometrically positioned and refined with riding isotropic displacement parameters unless otherwise stated. Hydrogen atoms bonded to heteroatoms were positioned in a differential Fourier synthesis and freely refined with isotropic displacement parameters. Reference diffractograms for the crystal structures were generated as described in Macrae, "Mercury: Visualization and analysis of crystal structures," 2006, J. Appl. Cryst., Vol. 39, pp. 453-457.

[0269] K. Raman spectroscopy Data were collected on a Renishaw inVia Qontor. The instrument control, data analysis and presentation software was WiRE.

[0270] Method: Excitation source, λ ex = 633 nm or 785 nm laser, appropriately attenuated to avoid sample degradation.

[0271] Raman shift range: 100-5000cm-1 ;Exposure time: 0.02-10 seconds;Cumulative: 1-3.

[0272] L. Fourier Transform Infrared (FTIR) Data is from 4000 to 650 cm -1 16 scans from 1999 to 2012 were collected on a Perkin-Elmer Spectrum One equipped with an attenuated total reflectance (ATR) sampling accessory. Data were collected using Spectrum software and processed using an ACD Spectrus Processor.

[0273] Example 2 - Technology A. Crystallization technology To investigate the crystal morphology, maturation experiments (or slurry maturation) were carried out in various solvents or solvent mixtures and subjected to heating-cooling cycles.

[0274] Aging chamber procedure The suspension for maturation was placed in a platform shaker incubator (Heidolph Titramax / Incubator 1000) and subjected to a series of heating-cooling cycles from ambient temperature to approximately 50° C. This was accomplished by switching the heat on and off every 4 hours. Shaking was maintained throughout.

[0275] polar bear instructions The suspension was stirred in a polar bear (Cambridge Reactor Design) at 50° C. The mixture was then cooled to 25° C. and stirred for a further 4 hours. After this time the sample was heated to 50° C. The cycle was then repeated.

[0276] Cooling crystallization Crystallization was obtained by lowering the temperature of the clear solution.

[0277] Evaporation Control Crystallization was induced by controlled evaporation of a transparent particulate-free solution. At approximately constant temperature, solvent was removed from the system, thereby increasing the solute concentration. Crystal nucleation and growth were obtained when a certain maximum supersaturation was reached.

[0278] Precipitation / crystallization by addition of antisolvent Antisolvent crystallization (or immersion precipitation crystallization) has been used to precipitate substances from solution. Crystallization involves adding a miscible antisolvent to a solute solution, decreasing the original solubility of the solute and increasing supersaturation, thereby causing precipitation.

[0279] Crystallization by solvent deposition or solvent layer diffusion Solvent diffusion crystallization was used to slowly precipitate substances from solution. The material was dissolved in a suitable solvent in a vial, and a miscible anti-solvent was added very slowly and allowed to settle on the solvent layer. The vial was then closed.

[0280] The antisolvent chosen was miscible with the solvent in any proportion in which the solute was relatively insoluble, and a density gradient was required for the antisolvent to gradually diffuse into the solvent layer, decreasing the overall solubility and ultimately resulting in the crystallization of the material.

[0281] B. Thermal technology Solvates / desolvations of hydrates (when dry) Various environmental conditions (eg, temperature and pressure) were used to desolvate Atikaplant from the solid-state hydrated or solvated phases.

[0282] C. Crushing Technology Milling has been used herein both alone and with polymer assisted milling (POLAG). An alternative to liquid assisted milling, POLAG is a mechanochemical process that uses polymers in conjunction with milling to promote and / or accelerate the mechanochemical reaction.

[0283] Planetary Mill Procedure: Atikaplant and related polymers were placed in a sample vial and two stainless steel grinding beads (3 mm diameter) were added. The mixture was milled for 2 hours at 500 rpm using a planetary Fritsch Mill (Pulverisette 6) equipped with an Automaxion adapter. After milling, all samples were first analyzed by XRPD.

[0284] Example 3 - Preparation and characterization of amorphous Atikaplant Both freeze-drying and fast evaporation techniques were utilized to produce amorphous aticaplant.

[0285] A.Lyophilization Atikaplant Form III (20 mg) was weighed into three HPLC vials. Each vial was treated with 10 vol (250 μL) of the relevant solvent at 25° C. and shaken. The sample in t-BuOH was placed at 90° C. for a few seconds, resulting in a solution. The solution was filtered using a 0.45 μm PTFE membrane Acrodisc filter and then flash frozen in an acetone / dry ice bath for 5 minutes. The sample was then lyophilized overnight. The resulting solid was characterized by XRPD.

[0286] Form III was shown to be soluble in 70% THF / H2O at room temperature (biphasic) and soluble in t-BuOH at 90° C. The results are shown in Table 18.

[0287] [Table 21]

[0288] XRPD analysis showed that the freeze-drying method was successful in producing amorphous material from t-BuOH and 70% THF / H2O. See Figure 2. For the sample from THF / water. 1 H NMR indicated the presence of residual THF (peaks too small to integrate) and the glass transition temperature was found to be 56.8° C. See mDSC of the amorphous Atika plant (FIG. 3).

[0289] After static storage of amorphous Atikaplant at 40°C / 75% RH for 1 week, Form II was obtained.

[0290] B. Blowdown Evaporation (BDE) Procedure BDE was investigated as a technique to generate amorphous Atikaplant using THF and acetone as solvents. Atikaplant Form III (30 mg) was dissolved in 5 vol (150 μL) of acetone at room temperature and shaken to obtain a clear solution. The solvent was removed by BDE with N2 at 60°C for 40 minutes at a flow rate of 30 L / min. This material was subsequently used for polymorph screening at 5°C and 50°C.

[0291] Fresh amorphous aticaplants were prepared for one week of static storage at 40°C / 75%RH. Both solvents produced amorphous aticaplants. g was determined by mDSC to be 45.5° C. See Table 19 for characterization of amorphous Atika plant.

[0292] [Table 22]

[0293] Example 4 - Polymorph Screening A. Solubility Assessment Atikaplant Form III (20 mg) was dispensed into amber HPLC vials equipped with a magnetic stir bar. Each vial was treated with the relevant solvent (5 vol) at room temperature and stirred at 300 rpm for 10 minutes. If a suspension was still observed, Atikaplant Form III (20 mg) was dispensed into amber HPLC vials (×49) equipped with a magnetic stir bar. Each vial was treated with the relevant solvent (5 vol) at room temperature and stirred at 300 rpm for 10 minutes. If a suspension was still observed, increasing volumes of solvent were added until the material was completely dissolved or until a maximum of 80 vol had been used (Table 20). All samples were heated to 50° C. and held for 1 hour. The samples were then cooled to 5° C. at a rate of 0.1° C. / min and left to stir overnight. The suspension remaining at this point was subjected to aging at room temperature / 50° C. for 2 weeks.

[0294] After 24 hours the remaining solution was evaporated to dryness, the suspension was isolated by filtration under positive pressure and all solids were analysed by XRPD. The gums or oils were further processed using the schematic in Figure 13.

[0295] The results of the solubility evaluation are shown in Table 20. Atikaplant Form III was obtained from water, DMSO (after aging the formed rubber for 8 days at 25 / 50°C), diethyl ether (crystals), DCM (crystals), heptane, 3-methyl-1-butanol, water / methanol (20%), nitromethane, chloroform (crystals) and cyclohexane.

[0296] [Table 23]

[0297] B. Low-temperature polymorph screening Low temperature polymorph screening was performed at 5° C. using amorphous Atika plant. Amorphous Atika plant (30 mg) produced by BDE in the section "Blowdown Evaporation (BDE) Procedure" above was used. Each vial was treated with a given volume of the solvent listed in Table 21 to produce a slurry at 5° C. and stirred at 500 rpm for 10 minutes. A small aliquot was taken of the clear solution at 10 minutes that had converted to a slurry and analyzed by XRPD. The sample that remained as a clear solution was set aside and cooled to room temperature overnight and then treated with an anti-solvent. The results of the low temperature polymorph screening can be found in Table 21.

[0298] [Table 24]

[0299] Most samples formed clear solutions within 10 minutes and remained in solution after 24 hours. Samples that formed cloudy solutions after 10 minutes formed suspensions within 1 hour. Form III was obtained from 1-propanol, 2-propanol, acetone, MEK, NBP, DMF, DMI, DMPU, 10% water / methanol, 5% water / EtOH, 20% water / methanol, 10% water / IPA, 10% water / ACN, pyridine, 1-methylpyrrolidine, and DMAc.

[0300] Samples that remained in solution after 14 days were left to equilibrate at room temperature and treated with water as an anti-solvent to induce precipitation. See Table 21. Samples were treated with anti-solvent / solvent ratios starting at 1:1 and increasing to 2:1, 3:1 or 5:1 until precipitation occurred. After 3 hours, any solids / suspensions were isolated by filtration onto a Millipore well plate and analyzed by XRPD.

[0301] Of the anti-solvent treated samples, Form III was obtained using 1-propanol and 2-propanol, acetone, MEK, NBP, DMF, DMI, DMPU, 10% water / methanol, 10% water / ACN, pyridine, 1-methylpyrrolidine, and DMAc.

[0302] C. High Temperature Polymorph Screening A high temperature polymorph screening was performed at 50° C. using the amorphous Atika plant. The procedure was as described in the low temperature screening, except that the samples were first shaken at 50° C. for 10 minutes. Initial observations were recorded and recorded again at 1 hour and 24 hours. If the clear solution transformed into a slurry at 10 minutes, an aliquot was taken and analyzed by XRPD. After 7 days, the suspension was reanalyzed by XRPD. Any samples that remained as clear solutions after 24 hours were cooled to room temperature overnight and then treated with an antisolvent. The results of the high temperature polymorph screening can be found in Table 22.

[0303] [Table 25-1]

[0304] [Table 25-2]

[0305] Samples that remained as solutions after 7 days at 50° C. were cooled to room temperature and treated with n-heptane. Samples were first treated with a 1:1 anti-solvent / solvent ratio and observed again after 10 minutes of stirring (300 rpm / 10 min). Further volumes of anti-solvent were added until a precipitate formed. If a thin white suspension was obtained or if recovery after filtration was estimated to be low, additional anti-solvent was also added. Further observations were made after 3 and 16 hours and aliquots of the suspension were taken and analyzed by XRPD. Crystallization of the gum formed was followed by further treatment as detailed in Table 22. The results of anti-solvent addition can also be seen in Table 22. Form III was obtained from anti-solvent addition of heptane to a number of solvent systems.

[0306] D. Temperature Cycling Polymorph Screening A temperature cycle screen (25 / 50°C) was performed on the amorphous Atika plant. Samples were treated with the solvents in Table 23 (2.5-5 vol depending on solubility). Initial observations were made before placing the samples on a platform shaker incubator programmed with a 4 hour cycle at 25 / 50°C. Observations were made after 1 and 7 days and any solids were analyzed by XRPD. Samples remaining in solution were treated with cold anti-solvent (either n-heptane or water) before being returned to the aging chamber.

[0307] As with the previous two screens, most samples formed solutions upon addition of solvent and remained in solution after 7 days. Suspensions were observed in the heptane and 20% water / methanol samples, while gums formed in the water and 10% water / acetone samples. A suspension in heptane showed Form III after 24 hours and remained in Form III after 7 days. The remaining samples formed solutions and were treated with anti-solvent.

[0308] Samples that formed solutions were used in the temperature cycling screen and treated with either water or heptane as the antisolvent in the reverse antisolvent screen.

[0309] Solutions were treated with either water or n-heptane as anti-solvent at a 5:1 anti-solvent:solvent ratio depending on solvent miscibility. Vials containing the relevant anti-solvent in predetermined amounts were prepared and placed in the refrigerator for approximately 2 hours. Solutions from the maturation screen were kept at room temperature for approximately 4 hours before being added to the anti-solvent sample. Aliquots of solids were taken and analyzed by XRPD. See Table 23.

[0310] [Table 26]

[0311] E. Solvent Deposition (Solvent Layer Diffusion) Screening A stock solution of Form III was prepared, see Table 24.

[0312] [Table 27]

[0313] The solution was then divided into an appropriate number of vials to obtain 30 mg per HPLC vial. The samples in DMSO and t-BuOH were placed in a freezer for approximately 1 hour, then removed and treated with the relevant anti-solvent at a 5:1 anti-solvent / solvent ratio. The anti-solvent was added slowly to the frozen solution. The samples were then allowed to stand at room temperature. The results of the solvent deposition screen can be found in Table 25.

[0314] [Table 28]

[0315] Solutions that did not produce solids after 6 days were removed from the refrigerator, uncovered, and the solvent allowed to evaporate. After being left to evaporate for 6 days, the sample in t-BuOH / cyclohexane also produced a solid, which was shown by XRPD to be Form II. The t-BuOH sample was isolated by vacuum filtration and dried under vacuum for 2 hours. After this, it was covered and left overnight.

[0316] F. Solvent Interface Crystallization Screening Solvent interface screening was performed by utilizing immiscible solvent / anti-solvent combinations. A stock solution of Atikaplant Form III was first made. See Table 26. The solution was then divided into vials to obtain 30 mg per vial. The sample was treated with the relevant anti-solvent at an anti-solvent / solvent ratio of 5:1. The sample was then left at room temperature. The sample that remained as a solution was placed in the refrigerator and the solids that formed were analyzed by XRPD.

[0317] [Table 29]

[0318] The results of the solvent interface crystallization screen are shown in Table 27. In the t-BuOH / water system, a white suspension consisting of a gummy solid formed immediately after addition of the anti-solvent to frozen t-BuOH. Aging of the gum at room temperature / 50° C. produced a white solid which was found to be Form II after analysis by XRPD. Form II was also produced from systems in MEK / water and 2-methyl THF which initially produced a gum which gave Form II after aging.

[0319] [Table 30]

[0320] K. Characterization of Forms I, II, and III Form I Form I was obtained in screening from ethyl acetate and MEK (both by solvent evaporation). It was also obtained by adding heptane anti-solvent to solutions in ethyl acetate and diethyl ether. Samples from the solubility evaluation in ethyl acetate were isolated and analyzed by XRPD, 1 It was characterized by H NMR, and DSC (Figure 7), as well as static storage at elevated temperature and humidity, and the results are shown in Table 30.

[0321] [Table 31]

[0322] DSC shows a broad endotherm at 92.9° C. (57.4 J / g). After static storage, the sample was shown to remain as Form I. These findings indicate that Form I is likely an anhydrous form that remains stable after storage at elevated temperature and humidity.

[0323] Form II As mentioned above, Form II was obtained from static storage of amorphous Atika plant for 1 week at 40°C / 75%RH and was also observed in several screenings from amorphous. Form II is anhydrous, exhibits low hygroscopicity, and remains stable both through GVS analysis and static storage at high temperature and humidity conditions (40°C / 75%RH and 25°C / 97%RH).

[0324] Form III Form III exhibits desirable solid state properties and appears to be the most stable form. Furthermore, it is readily accessible from many solvents (including solutions of methanol, 20% methanol / water, 10% water / IPA, and 5% water / ethanol) and crystallizes at 5° C. Form III was characterized and the results are shown in Table 31.

[0325] [Table 32]

[0326] 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. 12. Cycling the amorphous form for two cycles (cycle 1=cooling 131° C. to −40° C.; cycle 2=heating 10° C. to 131° C. at 10° C. / min) resulted in an annealed glass. See FIG. 5.

[0327] Example 5 - Thermodynamic Stability Relationships A. Competitive Slurry To determine the relative order of stability, competitive slurry experiments were performed with Form I, Form II, and Form III. Slurry experiments were performed in six different solvent systems at 5° C. and 50° C.

[0328] B. Preparation of Saturated Solutions Saturated solutions of Form III were prepared in different solvent systems. See Table 32. Each vial was filled with the relevant solvent (1.5 mL each) and left to equilibrate at the relevant temperature. After this, small amounts of solid were added with a spatula until the solid no longer dissolved. Samples were left stirring at 5° C. and 50° C. for approximately 2 weeks or longer as indicated.

[0329] [Table 33]

[0330] C. Preparation of a Mixture of Forms I and II Form III (180 mg) and Form II (180 mg) were combined and placed in a 4 mL vial. The sample was placed on a Turbula blender for 30 minutes, after which a small sample was taken and analyzed by XRPD to confirm the mixture. 10 mg of this mixture was weighed out and used instead as seeds in the competitive slurry with the mixture of Form I and Form II. To each vial was added a mixture of Form I and II (7 mg). See Table 33.

[0331] [Table 34]

[0332] After 15 hours, some of the samples converted to Form III. After 15 days, most of the samples converted to Form III, and after 56 days, all samples converted to Form III (samples in 20% MeOH / HO and cyclohexane, both at 5° C., took longer to convert), indicating that Form III is the most stable form under these conditions.

[0333] Example 6 - Scale-up of Form I A. Route 1 - Precipitation from ethyl acetate / n-heptane (0.5 g) solution Atikaplant Form III (0.5 g) was weighed into a large vial. The solid was dissolved in ethyl acetate (2.5 mL / 5 vol). The solution was allowed to evaporate overnight (the cap of the vial was loosened). The next morning a solution remained. The sample was placed in a vacuum oven for approximately 1 hour to further concentrate the solution. After this, a white precipitate began to form. The suspension was left at room temperature overnight after which a white solid was obtained. The solid was placed in a vacuum oven at 50° C. to remove the residual ethyl acetate for approximately 2.5 hours before being reanalyzed by XRPD. The initial suspension was found to be Form I. This was converted to Form III after drying in the vacuum oven.

[0334] B. Route 2 - Evaporation of ethyl acetate (0.5 g) solution The sample from Route 1 was redissolved in ethyl acetate (volume reduced to 2 mL). The sample was left uncovered and a white precipitate was observed the next day. The sample was placed in a vacuum oven to dry for 3 days. The solid was determined to be Form III.

[0335] C. Route 3 - Addition of heptane antisolvent to a solution of diethyl ether (0.5 g) Form III (0.5 g) was dissolved in ethyl acetate (2.5 mL / 5 vol) in a large vial. The solution was allowed to evaporate overnight (the vial was uncapped). The next morning a gum had formed and a small amount of white solid had grown within the gum. An aliquot of the solid was taken and analyzed by XRPD. After 24 hours the sample had completely turned solid and very fine needle-like crystals had grown. The solid was found to be a mixture of Form II and Form III.

[0336] D. Route 4 - Addition of 8-heptane antisolvent to a solution of diethyl ether (100 mg) A smaller scale experiment was carried out to re-preparate Form I. Different size vials were utilized at different temperatures. Form III (100 mg) was placed in five vials to which ethyl acetate (500 μL) was added, thereby dissolving the solids. Unless otherwise specified in Table 34, the vial cap was removed and each vial was placed at the relevant conditions. When solids were observed, a small sample was taken and analyzed by XRPD.

[0337] [Table 35]

[0338] Example 7 - Scale-up of Form II (1 g scale) Form III (1 g) was weighed into a 50 mL Duran bottle. The solid was dissolved in DMSO (13.3 mL / 13.3 vol) and the solution was placed in a freezer for approximately 30 minutes. Water was added slowly to the frozen solution (added around the side of the bottle in 10 mL aliquots while rotating to minimize perturbation of the solids) until a total of 50 mL of water had been added. A white suspension formed almost immediately on top of the frozen solvent layer. The suspension was left for 4 days. After this time the sample appeared more homogenous (no longer two layers) with a slight white precipitate on the top of the container and a gummy solid on the bottom. The sample was aged overnight (25 / 50°C - 4 hour cycle). The following morning solids were observed to be stuck around the sides of the container and this was loosened / broken up with a spatula. A small sample was taken and analyzed by XRPD. Amorphous content was still evident by XRPD so the sample was placed back in the aging chamber for another day. After this, improved crystallinity was observed and the sample was isolated by vacuum filtration / drying. The above method was successful in preparing Form II on a large scale. See Table 35.

[0339] [Table 36]

[0340] Form II was successfully scaled up (1 g) from a water / DMSO solvent phase diffusion and was found to be anhydrous and exhibit low hygroscopicity. The sample remained in Form II after GVS analysis. See Figures 10 and 11. There are large aggregates composed of smaller particles (size <10 μm) as well as the presence of plates (length approx. 60 μm) in the aggregates and larger ridged particles (length approx. 120 μm). Form II remained stable after one week of static storage at elevated temperature and humidity conditions.

[0341] The isolated solid 1 H NMR indicated the presence of residual DMSO (0.08 mol equiv.). TGA showed a small mass loss at ambient temperature -108 °C (0.95% / -0.05 mol equiv. DMSO)) and an additional mass loss from 108 to 255 °C due to the onset of decomposition. XRPD is shown in Figure 8. DSC analysis showed an endotherm at 74.7 °C (4.7 J / g) overlapping with a second sharper endotherm at 96.2 °C (onset, 51.3 J / g). See Figure 9. GVS analysis showed that Form II is slightly hygroscopic. A mass uptake of 0.26% is observed from 40 to 90% RH in the first cycle with a mass loss of 0.57%. Similar mass water uptake (0.25%) is observed in the second sorption cycle and all water is lost again in the second desorption cycle with slight hysteresis observed. See Figures 10 and 11. XRPD analysis after GVS indicates that the sample remains in Form II. HPLC analysis indicates a purity of 99.7%. Microscopic analysis by SEM / PLM indicates the presence of irregular particles. Particle size ranges from <10 μm to about 200 μm. There are larger aggregates composed of smaller particles (<10 μm in size), plates (length about 60 μm) present in the aggregates, and larger ridged particles (length about 120 μm). Static storage at elevated temperature and humidity conditions (40° C. / 75% RH and 25° C. / 97% RH) indicates that the sample remains in Form II. See Table 36.

[0342] [Table 37]

[0343] Example 8 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).

[0344] A.Purpose The primary objective was to evaluate the efficacy of aticaplant compared with placebo when administered as adjunctive treatment in subjects with MDD partially responsive to SSRI / SNRI treatment, in reducing depressive symptoms as assessed by change from baseline in the MADRS in non-responders during the placebo run-in period.

[0345] Secondary objectives are to: i. 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 depressive symptoms as assessed by change from baseline in MADRS in both responders and non-responders during the placebo run-in period. ii. To investigate the overall safety and tolerability of adjunctive Aticaplant treatment in subjects with MDD when used in combination with an SSRI or SNRI. iii. To investigate the effects of Aticaplant versus placebo on depression-related anhedonia as assessed by SHAPS. iv. To investigate the effect of Aticaplant on symptoms of depression using the Clinical Global Impression-Severity (CGI-S), patient reported symptoms scale for Major Depressive Disorder (SMDDS) and the Self-Evaluation of Treatment Experience (SATE). v. To investigate the effect of Aticaplant on symptoms of anxiety using HAM-A and on core symptoms of anxiety using HAM-A6 subscale. vi. To evaluate the plasma PK of Atikaplant in subjects with MDD and investigate its relationship to efficacy and safety parameters.

[0346] Secondary exploration objectives are to: i. 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.

[0347] 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 14.

[0348] Subjects with MDD who had initiated treatment with an approved SSRI / SNRI and had an inadequate or partial response to this treatment were screened. Assessments included the MINI, Antidepressant Treatment History Questionnaire (TRQ), and MADRS.

[0349] The treatment phase consisted of three periods. After a concealed placebo run-in period, 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 diagram is shown in Figure 14.

[0350] 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.

[0351] 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 37.

[0352] [Table 38]

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] If Visit 11 was scheduled for 3 days later, subjects continued taking medication until Visit 11.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] D. Clinical Evaluation

[0363] (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

[0364] 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.

[0365] (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Central sedative effect: Karolinska Sleepiness Scale (ix) Sexual dysfunction: ASEX

[0366] 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 38 and 39.

[0367] [Table 39-1]

[0368] [Table 39-2]

[0369] [Table 40-1]

[0370] [Table 40-2]

[0371] 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).

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] Efficacy endpoints were presented for both eITT and fITT.

[0377] 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.

[0378] 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

[0379] Enriched ITT analysis population The mean (SD) MADRS total score at treatment baseline was 29.0 (4.61) with a range of 19-41. See Figure 15. 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 40-42 and Figure 18.

[0380] [Table 41]

[0381] [Table 42]

[0382] [Table 43]

[0383] Based on the results of the MMRM model with subjects as random effects; country, treatment, time, and treatment-by-time interactions as factors; and baseline MADRS total score 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 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 of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figures 15 and 16.

[0384] 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 20-A and 20-B. The mean change from treatment baseline in MADRS total score at treatment week 6 for fITT was smaller than for eITT: -9.7 (8.02) for Aticaplant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results indicate a statistical advantage over placebo with a persistence of effect with the largest difference seen at week 6. See Table 43.

[0385] [Table 44]

[0386] 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 44-45 and Figure 16.

[0387] [Table 45]

[0388] [Table 46]

[0389] 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.

[0390] (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 21 and 22.

[0391] 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).

[0392] 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 46 and Figures 23-26.

[0393] [Table 47]

[0394] 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.

[0395] 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 treatment week 6 was -4.6 (6.23) for Aticaplant and -4.2 (5.04) for placebo. The observed effect size was 0.07. See Table 47 and Figures 27 and 34.

[0396] [Table 48]

[0397] 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 value between Aticaplant and placebo at week 6 of treatment was -0.7 [-1.81, 0.41]. See Figure 17 and Tables 48 and 49 and Figure 28. The corresponding p-value was 0.419.

[0398] [Table 49]

[0399] [Table 50]

[0400] 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 17 and 18.

[0401] 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 50.

[0402] [Table 51]

[0403] 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 51). The observed effect sizes were 0.38 and 0.11, respectively.

[0404] [Table 52]

[0405] 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 52. The observed effect sizes were 0.51 and 0.29, respectively.

[0406] [Table 53]

[0407] 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.

[0408] Change from treatment baseline in CGI-S total score upon treatment

[0409] [Table 54]

[0410] Change from baseline in SMDDS total score at week 6 of treatment

[0411] [Table 55]

[0412] Number of subjects with SATE score at 6 weeks of treatment

[0413] [Table 56] Change from baseline in HAM-A6 total score at week 6 of treatment

[0414] [Table 57]

[0415] These data show greater improvements in HAMA6 scores in Atticaplant treated patients versus placebo.

[0416] Change from treatment baseline in structured interview guide for SIGH-A scores at week 6 of treatment

[0417] [Table 58]

[0418] 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.

[0419] [Table 59]

[0420] (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 59.

[0421] [Table 60]

[0422] 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 60.

[0423] [Table 61]

[0424] 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.

[0425] 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 61.

[0426] [Table 62]

[0427] 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.

[0428] No deaths were reported.

[0429] (iv) Anhedonia analysis Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 62-64.

[0430] [Table 63]

[0431] The results show that the treatment effect was greater in patients with more anhedonia at baseline. See Figure 29.

[0432] [Table 64]

[0433] [Table 65]

[0434] The results show that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 30-A and 30-B. In Figure 30-A, i.e., the high anhedonia group, the placebo + oral antidepressant group, show less placebo response compared to the anhedonia group in Figure 30-B. Similarly, the treatment effect of the Aticaplant + oral antidepressant group is higher in the high anhedonia group compared to the anhedonia group. Overall, the effect size is greater in the high anhedonia group at all single time points (from week 1 onwards). The LSMD in the high anhedonia group is more than twice that of the low anhedonia group at week 6. Furthermore, looking at symptom levels, there is a greater improvement in anhedonia and dysphoria-related items in the subgroups with high anhedonia vs. low anhedonia. See Figure 31.

[0435] (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 65.

[0436] [Table 66]

[0437] (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.

[0438] 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 66 and 67.

[0439] [Table 67]

[0440] [Table 68]

[0441] (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.

[0442] 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.

[0443] Patients had sexual function measured using the ASEX, a standard, familiar rating scale. See Table 68.

[0444] [Table 69]

[0445] The mean change from treatment baseline (SD) in ASEX total score by week 6 was -1.5 (4.02) points for Atika Plant compared to -0.7 (2.98) points for placebo. Lower scores in ASEX indicate improvement. Score reduction at week 6 was greater in the Atika Plant group compared to placebo. This is unexpected, since adjunctive treatment with other drugs is expected to worsen sexual function, i.e., increase ASEX score over time. See Figure 32.

[0446] 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: orgasmic satisfaction, orgasm attained, and vaginal lubrication / erection. Most of the improvement is seen in items 3, 4, and 5 in Figure 33.

[0447] (viii) Onset of Effect The onset of effect for Atikaplant can be estimated from the study. Figure 20-B 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 pharmaceutical composition for treating major depressive disorder in a human patient, the patient having previously shown an inadequate response to other antidepressant treatments, the pharmaceutical composition comprising crystalline aticaplant, the crystalline aticaplant being selected from the group consisting of aticaplant crystalline Form I, aticaplant crystalline Form II, and aticaplant crystalline Form III.

2. 2. The pharmaceutical composition of claim 1, wherein the crystalline aticaplant is crystalline Form I of aticaplant characterized by four or more X-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (±0.2).

3. 2. The pharmaceutical composition of claim 1, wherein the crystalline aticaplant is crystalline Form II of aticaplant 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).

4. 2. The pharmaceutical composition of claim 1, wherein the crystalline aticaplant is crystalline Form III of aticaplant 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).

5. 10. The pharmaceutical composition of claim 1, wherein the crystalline aticaplant is anhydrous.

6. The pharmaceutical composition described in claim 1, wherein the crystalline aticaplant is S-aticaplant.

7. 10. The pharmaceutical composition of claim 1, wherein the effective amount of the crystalline form of aticaplant is about 2 mg to about 35 mg, about 5 mg to about 10 mg, about 5 mg, or about 10 mg.

8. The pharmaceutical composition of claim 1, wherein the effective amount of the crystalline form of Aticaplant is 10 mg.

9. 10. The pharmaceutical composition of claim 1, wherein the crystalline form of aticaplant is orally administered once daily.

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

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