Compositions containing Atica plant

Abstract

The present disclosure relates to compositions, including oral compositions in tablet form, comprising Aticaplant, and methods of use thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 317,471, filed March 7, 2022.

[0002] FIELD OF THEINVENTION The present disclosure relates to compositions, including oral compositions, that contain Aticaplant and methods of use thereof. [Background technology]

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

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

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

[0006] In some aspects, the present disclosure provides a pharmaceutical composition comprising about 2 mg to about 20 mg of acutiloplant and a filler, wherein the composition comprises about 0.1% to about 90% by weight of acutiloplant.

[0007] In another aspect, the present disclosure provides an oral tablet comprising about 5 mg of acicaplant, the oral tablet comprising about 100 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 30 mg of microcrystalline cellulose, about 30 mg of lactose monohydrate, about 2.5 mg of croscarmellose sodium, and about 0.5 mg of colloidal anhydrous silica, and the extragranular phase comprising about 28.5 mg of silicified microcrystalline cellulose, about 2.5 mg of croscarmellose sodium, about 0.5 mg of colloidal anhydrous silica, and about 0.5 mg of magnesium stearate.

[0008] In a further aspect, the present disclosure provides an oral tablet comprising about 10 mg of acicaplant, the oral tablet comprising about 200 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium, and about 1 mg of colloidal anhydrous silica, and the extragranular phase comprising about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of colloidal anhydrous silica, and about 1 mg of magnesium stearate.

[0009] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising about 2 mg to 20 mg of Aticaplant, the composition having a pharmacokinetic (PK) profile (normalized to a 10 mg dose) comprising one or more of the following parameters following administration of the composition to a human following at least a 10 hour fast: (a) a mean C of about 20 to 45 ng / mL. max;(b) Approximately 250~450h * Mean AUC in ng / mL infinity ;(c) Approximately 250~450h * Mean AUC in ng / mL last and (d) a median t between about 1 and 4 hours. max .

[0010] In yet another aspect, the disclosure provides a method for treating major depressive disorder (MDD) in a human patient, comprising administering to the patient a pharmaceutical composition comprising about 2 mg to 20 mg of aticaplant, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with aticaplant, and wherein administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile (dose normalized to 10 mg) comprising one or more of the following PK parameters following administration of the composition to a human following at least a 10 hour fast: (a) a mean C of about 30 to 40 ng / mL max ;(b) Approximately 300~430h * Mean AUC in ng / mL infinity ;(c) Approximately 280~430h * Mean AUC between ng / mL last and (d) a median t between about 1 and 4 hours. max .

[0011] In another aspect, the disclosure provides a solid pharmaceutical composition comprising about 2 mg to 20 mg of Aticaplant, the solid pharmaceutical composition having a dissolution profile comprising a Q value of about 60% to 90% at 45 minutes under the following dissolution operating conditions: Apparatus: Paddle (USP Type 2, Ph.Eur., JP) Dissolution medium: 0.01 M hydrochloric acid; Volume: 900 mL; Temperature: 37 + / - 0.5 °C; Rotation speed: 50 rpm; and Analysis end: UHPLC with UV detection at 247 nm.

[0012] In a further aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human patient, comprising administering to the patient a pharmaceutical composition, oral tablet, or solid pharmaceutical composition described herein. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is the X-ray powder diffraction (XRPD) pattern (transmission mode) of polymorphic form III of Atika Plant. [Diagram 2] 1 is a differential scanning calorimetry (DSC) thermogram of polymorphic form III of Atika Plant. [Diagram 3] 1 is an mDSC thermogram of polymorphic form III of Atika plant. [Figure 4] 1 shows the clinical trial design for Example 1. [Diagram 5] FIG. 1 is a line graph showing least squares mean change (±SE) in MADRS (Montgomerysis-Ausberg Depression Rating Scale) total score from baseline during the treatment period for the enriched intent-to-treat (eITT) analysis set. [Figure 6] 13 is a plot showing MADRS total score change at 6 weeks of treatment for the enriched and complete populations: MMRM Results-Estimated LS Mean and comparison to placebo. [Figure 7] FIG. 13 is a line graph showing least squares mean change (±SE) in SHAPS (Snaith Hamilton Pleasure Scale) total score from baseline for the eITT analysis set. [Figure 8] FIG. 13 is a plot showing SHAPS total score change at week 6 of treatment for the enriched and complete populations: MMRM (Mixed-effects Model for Repeated Measures) results--estimated LS means and comparison to placebo. [Figure 9] 1 is a line graph showing MADRS total scores over time for the eITT analysis set: Mean (±SE). [Figure 10A] FIG. 1 is a line graph showing MADRS total scores over time for the full intent-to-treat (fITT) analysis set: mean (±SE). [Figure 10B] This is an excerpt from Figure 10-A for weeks 0 to 6 of treatment. [Figure 11] FIG. 13 is a line graph showing the percentage of subjects with MADRS total score:remission of depressive symptoms (total score≦10) during treatment for the eITT analysis set. [Figure 12] fLine graph showing MADRS total score: percentage of subjects with remission of depression symptoms (total score < 10) during treatment for the ITT analysis set. [Figure 13] FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the eITT analysis set. [Figure 14] fLine graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the ITT analysis set. [Figure 15] FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the eITT analysis set. [Figure 16] fLine graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the ITT analysis set. [Figure 17] SHAPS total score over time for the eITT analysis set: line graph showing mean (±SE). [Figure 18] SHAPS total score over time for the fITT analysis set: line graph showing mean (±SE). [Figure 19] Changes in MADRS from baseline according to severity of anhedonia are shown. [Figure 20A] FIG. 1 is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS≧38. [Figure 20B] FIG. 1 is a line graph showing MADRS change from baseline in patients with low anhedonia, i.e., SHAPS<38. [Figure 21]FIG. 1 is a bar graph showing a comparison of MADRS in patients with low and high anhedonia. [Figure 22] 1 is a line graph showing the mean ASEX total score change from baseline. [Figure 23] 1 is a bar graph showing the mean ASEX item-level change total score change from baseline. [Figure 24] 1 is a flow chart of a process for preparing tablets containing Atikaplant. In this figure, a refers to ultrafine, i.e., ground Atikaplant. [Diagram 25] FIG. 1 is a schematic diagram of part 1 of the study. In this diagram, treatment A=2×5 mg capsules; treatment B=1×10 mg tablet concept 1; treatment C=1×5 mg tablet concept 1; treatment D=1×10 mg tablet concept 1, high fat diet. [Figure 26] Schematic diagram of part 2 of the study. In this diagram, a) Day 1 of the treatment period is the first day of the washout period. Treatment E: 2 x 5 mg oral capsules are administered in the morning after at least a 10 hour overnight fast. Treatment F: 1 x 10 mg of formulation concept 2 is administered in the morning after at least a 10 hour overnight fast. Treatment G: 1 x 5 mg of formulation concept 2 is administered in the morning after at least a 10 hour overnight fast. Treatment H: 1 x 10 mg of formulation concept 2 is administered in the morning after at least a 10 hour overnight fast, approximately 30 minutes after the start of a standardized high fat breakfast. [Figure 27] Relative bioavailability results for Atikaplant PK profile versus BA are shown. [Figure 28] Relative bioavailability results for Atikaplant PK profile versus BA are shown. [Figure 29] Atikaplant PK profile, relative bioavailability results for dose proportionality are shown. [Diagram 30] Atikaplant PK profile, relative bioavailability results for dose proportionality are shown. [Diagram 31] Figure 1 shows the Atikaplant PK profile, relative bioavailability results for food effect. [Diagram 32] Figure 1 shows the Atikaplant PK profile, relative bioavailability results for food effect. [Diagram 33] Figure 1 shows the Atikaplant PK profile, relative bioavailability results for food effect. [Diagram 34] Figure 7 is a study scheme of Example 7. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Approximately 34 elderly participants will be randomized. [Diagram 35] The study scheme of Example 8. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Additionally, approximately 68 elderly participants will be randomized. [Diagram 36] 1 is a bar graph showing the SHAPS Item:LS Mean Change from Baseline at Week 6 by Baseline SHAPS Total Score for the fITT Analysis Set. In this figure, from top to bottom, the bars alternate between placebo or Atticaplant. For example, the first bar refers to Atticaplant, the second bar refers to placebo, the third bar refers to Atticaplant, etc. [Figure 37] 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

[0014] 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).

[0015] The present disclosure provides compositions comprising pure crystalline form III of aticaplant, which is anhydrous and stable in solid form.

[0016] The term "crystal" refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.

[0017] 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.

[0018] 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.

[0019] The term "anhydrous" or "anhydrate" as used herein refers to the crystals described herein that are substantially devoid of water. In some embodiments, the anhydrous forms contain less than about 1% w / w water. In other embodiments, the anhydrous forms contain less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w / w water.

[0020] 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°.

[0021] 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.

[0022] 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.

[0023] 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:

[0024] [ka] Also known as JNJ-67953964, 67953964-AAA, CERC-501, and LY-2456302. In some embodiments, "aticaplant" refers to the (S)-enantiomer of aticaplant, i.e., the following compound:

[0025] [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:

[0026] [ka]

[0027] In other embodiments, the atica plant contains less than about 10% by weight of the (R)-enantiomer of atica plant, based on the weight of the atica plant. In further embodiments, the atica plant 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 atica plant, based on the weight of the atica plant. In yet other embodiments, the atica plant contains about 0.001 to about 10% by weight of the (R)-enantiomer of atica plant, based on the weight of the atica plant. In still further embodiments, the Atika plant contains about 0.001 to about 10% by weight, about 0.001 to about 5% by weight, about 0.001 to about 1% by weight, about 0.001 to about 0.5% by weight, about 0.001 to about 0.1% by weight, about 0.1 to about 5% by weight, about 0.1 to about 1% by weight, about 0.1 to about 5% by weight, or about 0.5 to about 5% by weight, based on the weight of the Atika plant.

[0028] Pharmaceutically acceptable salts of Atikaplant contemplated by the present invention can also be easily selected by those skilled in the art. A "pharmaceutical acceptable salt" is a salt of Atikaplant that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. See generally GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J.Med.Chem., 2007, 50:6665-72; SM Berge, "Pharmaceutical Salts", J.Pharm.Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharma- ceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0029] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide (e.g., hydrobromide), iodide (e.g., hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1, Examples of suitable salts include 4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0030] In some embodiments, the aticaplant is crystalline form III of aticaplant. Aticaplant crystalline form III can be characterized by a number of techniques, including but not limited to, X-ray diffraction and differential scanning calorimetry. In some embodiments, aticaplant crystalline form III is characterized by X-ray diffraction. In other embodiments, aticaplant crystalline form III is characterized by four or more X-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° 2θ (±0.2). In further embodiments, aticaplant 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 1.

[0031] [Table 1]

[0032] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 2.

[0033] [Table 2]

[0034] In yet another embodiment, crystalline form III of Atikaplant is characterized by the X-ray diffraction pattern peaks in Table 3.

[0035] [Table 3]

[0036] In a further embodiment, crystalline Form III of Atikaplant is characterized by an X-ray powder diffraction pattern corresponding to FIG.

[0037] Atikaplant crystalline Form III may also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram shows a peak temperature (T m In another embodiment, crystalline form III of Atikaplant is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

[0038] Pharmaceutical Compositions The present disclosure also contemplates a pharmaceutical composition comprising Atikaplant and one or more pharma- ceutical acceptable excipients. 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 obtained directly or indirectly from the combination of a particular component in a particular amount. A preferred pharmaceutical composition contains Atikaplant crystalline form III 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 pharma-ceutical acceptable carriers are well known in the art. A description of some of these pharma-ceutical acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0039] The amount of acantha plant present in the composition is about 2 mg to about 60 mg. In some embodiments, the composition contains about 2 mg to about 20 mg of acantha plant. In some embodiments, the composition contains about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of acantha plant. In other embodiments, the composition contains 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 of acantha plant. In yet other embodiments, the effective amount of acantha plant is about 5 to about 15 mg. In further embodiments, the amount of acantha plant is about 5 or 10 mg. In other embodiments, the amount of acantha plant is about 5 mg. In even further embodiments, the amount of acantha plant is about 10 mg. The composition contains about 0.1% to about 90% by weight of acantha plant. In some embodiments, the composition contains about 0.1, about 0.5, about 1, 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90% by weight of acantha plant, based on the weight of the composition.In other embodiments, the composition may have a concentration of from about 0.1 to about 80, from about 0.1 to about 70, from about 0.1 to about 60, from about 0.1 to about 50, from about 0.1 to about 40, from about 0.1 to about 30, from about 0.1 to about 20, from about 0.1 to about 10, from about 0.1 to about 5, from about 0.1 to about 1, from about 0.1 to about 0.5, from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 The composition contains about 40, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 90, about 70 to about 80, or about 80 to about 90% by weight of the Atica plant. In a further embodiment, the composition contains about 5% by weight of the Atica plant. In yet another embodiment, the composition contains about 6% by weight of the Atica plant. In yet another embodiment, the composition contains about 7% by weight of the Atica plant. In another embodiment, the composition contains about 8% by weight of the Atica plant. In a further embodiment, the composition contains about 9% by weight of the Atica plant. In yet another embodiment, the composition contains about 10% by weight of the Atica plant. The amount of aticaplant for administration according to the methods described herein may be determined by one of skill in the art and, unless otherwise indicated, is given on a free base basis of aticaplant, i.e., the amount refers to the amount of aticaplant molecule administered, excluding, for example, solvent (such as in the form of a solvate) or counterion (such as in the form of a pharma- ceutically acceptable salt).

[0040] In some embodiments, the pharmaceutical composition has a particular pharmacokinetic (PK) profile at a particular dose. In some embodiments, the pharmaceutical composition has a PK profile that is dose-proportional. In other embodiments, the pharmaceutical composition has a dose-proportional parameter, e.g., C max In further embodiments, the pharmaceutical composition has a PK profile or PK parameters that are dose proportional for about 1 mg to 60 mg of acetoplankton, about 2 mg to 60 mg of acetoplankton, about 2 mg to 40 mg of acetoplankton, about 2 mg to 20 mg of acetoplankton, about 2 mg to 15 mg of acetoplankton, about 2 mg to 10 mg of acetoplankton, and about 5 mg to 10 mg of acetoplankton.

[0041] Some embodiments include a pharmaceutical composition comprising aticaplant that is bioequivalent to any one of the pharmaceutical compositions described herein. In some embodiments, the pharmaceutical composition comprises about 2 mg to about 60 mg, about 2 mg to about 20 mg, about 5 mg to about 10 mg, or about 5 mg or about 10 mg of aticaplant, and the composition has a mean Cmax of about 30-35 ng / mL, a mean AUCinfinity of about 300-320 ng / mL, and a median t of about 1.5 hours when administered to a human following at least a 10 hour fast. max The aticaplant is bioequivalent to a pharmaceutical composition comprising aticaplant that results in a PK profile (dose normalized to 10 mg) comprising one or more of the following: Bioequivalence can be demonstrated by any method known to those skilled in the art, for example, as described in Example 9 herein or as described in Chow, Bioavailability and Bioequivalence in Drug Development, Wiley interdisciplinary reviews, Computational statistics, 6, 4 (2014): 304-312. doi: 10.1002 / wics.1310.

[0042] In some embodiments, the pharmaceutical composition comprises about 2 mg to about 20 mg of acetonitrile, about 5 mg of acetonitrile, or about 10 mg of acetonitrile, and when the pharmaceutical composition is compared to a reference composition, the 90% confidence interval of the geometric mean ratio of one or more PK parameters of the pharmaceutical composition and the reference composition is within the 80% and 125% bioequivalence limits. In some embodiments, the reference composition has a mean Cmax of about 30-35 ng / mL, a mean AUCinfinity of about 300-320 ng / mL, and a median t of about 1.5 hours when administered to humans following at least a 10 hour fast. max In some other embodiments, the reference composition has a PK profile of any one of Treatment A, Treatment B, Treatment C, or Treatment D as set forth in Table 69.

[0043] In some embodiments, the PK profile is based on administration of a composition containing about 2 mg to about 60 mg of acicular plant to a human after at least 10 hours of fasting. In some other embodiments, the PK profile is based on administration of a composition containing about 2 mg to about 60 mg of acicular plant to a human about 30 minutes after the start of a high-fat meal after at least 10 hours of fasting. As another example, the PK profile is based on administration of a composition containing about 2 mg to about 20 mg of acicular plant to a human after at least 10 hours of fasting. In some embodiments, the PK profile is based on administration of a composition containing about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of acicular plant to a human. In further embodiments, the PK profile is from about 2 to about 19, from about 2 to about 18, from about 2 to about 16, from about 2 to about 14, from about 2 to about 12, from about 2 to about 10, from about 2 to about 8, from about 2 to about 6, from about 2 to about 4, from about 4 to about 20, from about 4 to about 18, from about 4 to about 16, from about 4 to about 14, from about 4 to about 12, from about 4 to about 10, from about 4 to about 8, from about 4 to about 6, from about 6 to about 20, from about 6 to about 18, from about 6 to about 16, from about 6 to about 14, from about 6 to about 12, from about 6 to about 10, from about 6 to about 8, from about 8 to about These results are based on administration of about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20 mg of acica plant to a human.

[0044] In certain aspects, the PK profile is determined after at least a 10 hour fast. In some embodiments, the fast is at least about 1, about 2, about 4, about 5, about 10, about 12, about 15, about 18, about 20, about 22, 24, about 28, or about 32 hours.

[0045] For example, the PK profile may have a C in the range of about 1 to about 100, about 5 to about 70, about 5 to about 65, about 5 to about 60, about 5 to about 55, about 5 to about 50, about 5 to about 45, about 10 to about 70, about 10 to about 65, about 10 to about 60, about 10 to about 55, about 10 to about 50, about 10 to about 45, about 13 to about 60, about 13 to about 55, about 13 to about 50, about 20 to about 70, about 20 to about 65, or about 20 to about 63 ng / mL. max (dose normalized to 10 mg). In some embodiments, the PK profile may include a C in the range of about 20 to about 45, about 22 to about 45, about 23 to about 45, or about 24 to about 44 ng / mL when administered after at least a 10 hour fast. max (dose normalized to 10 mg). In some embodiments, the PK profile comprises a C in the range of about 25 to about 50, about 27 to about 38, about 25 to about 40, or about 28 to about 38 ng / mL when administered about 30 minutes after the start of a high fat meal following at least a 10 hour fast. max (dose normalized to 10 mg).

[0046] In some embodiments, the PK profile is from about 50 to about 800, about 100 to about 500, about 100 to about 480, about 100 to about 450, about 100 to about 400, about 110 to about 500, about 110 to about 480, about 110 to about 450, about 110 to about 400, about 150 to about 700, about 200 to about 700, about 200 to about 650, about 250 to about 450, about 280 to about 420, about 290 to about 410, or about 210 to about 650 h. * AUC in ng / mL range infinity (dose normalized to 10 mg). In some embodiments, the PK profile comprises a PK profile of about 200 to about 400, about 210 to about 400, about 210 to about 398, about 220 to about 400, or about 220 to about 398 h when administered after at least a 10 hour fast. * AUC in ng / mL range infinity (dose normalized to 10 mg). In some embodiments, the PK profile is from about 300 to about 600, from about 300 to 550, or from about 320 to about 530 h when administered about 30 minutes after the start of a high fat meal following at least a 10 hour fast. * AUC in ng / mL range infinity(dose normalized to 10 mg).

[0047] In some embodiments, the PK profile is from about 50 to about 800, about 100 to about 500, about 100 to about 480, about 100 to about 450, about 100 to about 400, about 110 to about 500, about 110 to about 480, about 110 to about 450, about 110 to about 400, about 150 to about 700, about 200 to about 700, about 200 to about 650, about 250 to about 450, about 280 to about 420, about 290 to about 410, or about 210 to about 650 h. * AUC in ng / mL range last (dose normalized to 10 mg). In some embodiments, the PK profile comprises an AUC last (dose normalized to 10 mg).

[0048] In some embodiments, the PK profile has a t in the range of about 0.5 to about 5, about 1 to about 4.5, about 1 to about 4, about 1 to about 3, about 1 to about 2.5, or about 1 to about 2 hours. max In some embodiments, the PK profile includes a t in the range of about 1 to about 2.5, about 1 to about 2, or about 1 to about 3 hours when administered following at least a 10 hour fast. max In some embodiments, the PK profile includes a t in the range of about 1 to about 4 hours when administered about 30 minutes after the start of a high fat meal after at least a 10 hour fast. max Includes.

[0049] In some embodiments, the PK profile has a t range of between about 5 to about 60, about 5 to about 55, about 5 to about 50, about 5 to about 45, about 5 to about 40, about 9 to about 60, about 9 to about 55, about 9 to about 50, about 9 to about 45, or about 9 to about 40 hours. 1 / 2 Includes.

[0050] In some embodiments, the PK profile has a λ range of about 0.010 to about 0.080, about 0.010 to about 0.075, about 0.010 to about 0.070, about 0.015 to about 0.080, about 0.015 to about 0.075, about 0.015 to about 0.070, about 0.015 to about 0.065, about 0.015 to about 0.060, about 0.015 to about 0.055, or about 0.015 to about 0.050 1 / hr. z Includes.

[0051] In some other embodiments, the PK profile comprises a CL / F in the range of about 10 to about 90, about 10 to about 85, about 10 to about 80, about 10 to about 75, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 15 to about 90, about 15 to about 80, about 15 to about 70, about 15 to about 60, about 15 to about 50, about 20 to about 90, about 20 to about 80, about 20 to about 75, about 20 to about 70, about 20 to about 60, or about 20 to about 50 L / h.

[0052] In some other embodiments, the PK profile comprises a Vd / F in the range of about 400 to about 6000, about 400 to about 5500, about 400 to about 5000, about 400 to about 4000, about 400 to about 3500, about 400 to about 3400, about 450 to about 3500, about 450 to about 3000, about 500 to about 3500, about 500 to about 3000, about 400 to about 2000, about 400 to about 1500, about 400 to about 1200, about 550 to about 3500, about 550 to about 3000, about 600 to about 3500, about 600 to about 3000, about 600 to about 2500, or about 450 to about 1200 L.

[0053] For example, the PK profile, when dose-normalized to 10 mg, had a mean C of approximately 20–45 ng / mL. max In some embodiments, the average C max is about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, or about 55 ng / mL (dose normalized to 10 mg). maxis about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 45, about 35 to about 40, or about 40 to about 45 ng / mL (dose normalized to 10 mg). max is about 30-35 ng / mL, about 31-35 ng / mL, or about 31-34 ng / mL (dose normalized to 10 mg) when administered after at least a 10 hour fast. max is about 35-40, about 36-39, or about 37-38 ng / mL (dose normalized to 10 mg) when administered about 30 minutes after the initiation of a high fat meal after at least a 10 hour fast.

[0054] The PK profile is also approximately 250-450h. * Mean AUC in ng / mL infinity (dose normalized to 10 mg). In some embodiments, the AUC infinity is about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, or about 450 hours. * ng / mL (dose normalized to 10 mg). In another embodiment, the mean AUC infinityis about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about 400, about 300 to about 390, about 300 to about 380, about 300 to about 370, about 300 to about 360, About 300 to about 350, about 300 to about 340, about 300 to about 330, about 300 to about 320, about 300 to about 310, about 325 to about 450, about 325 to about 425, about 325 to about 400, about 325 to about 375, about 325 to about 350, about 350 to about 450, about 350 to about 425, about 350 to about 400, about 350 to about 375, about 375 to about 450, about 375 to about 425, about 375 to about 400, about 400 to about 450, about 400 to about 425, or about 425 to about 450 hours * ng / mLs (dose normalized to 10 mg). In a further embodiment, the mean AUC infinity Approximately 300-320 h after fasting for at least 10 h. * ng / mL (dose normalized to 10 mg). In a further embodiment, the mean AUC infinity When administered approximately 30 minutes after the start of a high-fat meal after at least a 10-hour fast, * ng / mL (dose normalized to 10 mg).

[0055] In another embodiment, the pharmaceutical composition is administered for about 250 to 450 hours. * Mean AUC in ng / mL last (dose normalized to 10 mg). In some embodiments, the AUC last is about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, or about 450 hours. * In another embodiment, the mean AUC lastis about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about 400, about 300 to about 390, about 300 to about 380, about 300 to about 370, about 300 to about 360, About 300 to about 350, about 300 to about 340, about 300 to about 330, about 300 to about 320, about 300 to about 310, about 325 to about 450, about 325 to about 425, about 325 to about 400, about 325 to about 375, about 325 to about 350, about 350 to about 450, about 350 to about 425, about 350 to about 400, about 350 to about 375, about 375 to about 450, about 375 to about 425, about 375 to about 400, about 400 to about 450, about 400 to about 425, or about 425 to about 450 hours * In a further embodiment, the PK profile is about 280-310 h * Mean AUC in ng / mL last (dose normalized to 10 mg).

[0056] In yet a further aspect, the pharmaceutical composition has a median t max In some embodiments, the PK profile comprises a median t max is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, or about 3.7, or about 3.8, or about 3.9, or about 4 hours. maxis about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 4, about 3 to about 3.5, or about 3.5 to about 4 hours. In a further embodiment, the median t max is about 1.5 hours.

[0057] In some embodiments, the pharmaceutical composition comprises the PK profile of Treatment A, Treatment B, Treatment C, or Treatment D shown in Table 69.

[0058] In some embodiments, the pharmaceutical composition has a mean C of about 30, about 31, about 32, about 33, about 34, or about 35 ng / mL when administered after at least 10 hours of fasting. max In some embodiments, the pharmaceutical composition has a PK profile (dose normalized to 10 mg) comprising a mean C of about 31.2 ng / mL with a standard deviation of about 6.9 ng / mL. max In some embodiments, the pharmaceutical composition comprises about 10 mg of aticaplant and has a mean C of about 34.1 ng / mL with a standard deviation of about 10.0 ng / mL when administered after at least 10 hours of fasting. max In some embodiments, the pharmaceutical composition comprises about 5 mg of aticaplant and has a PK profile comprising a mean Cmax of about 17.0 ng / mL and a standard deviation of about 4.48 ng / mL when administered after at least a 10 hour fast.

[0059] In some embodiments, the pharmaceutical composition has a PK profile (dose normalized to 10 mg) comprising a mean Cmax of about 36, about 37, about 38, about 39, or about 35 ng / mL when administered about 30 minutes after the start of a high fat meal after at least a 10 hour fast. In some embodiments, the pharmaceutical composition comprises about 10 mg of aticaplant and has a PK profile comprising a mean Cmax of about 37.7 ng / mL and a standard deviation of about 9.18 ng / mL when administered about 30 minutes after the start of a high fat meal after at least a 10 hour fast.

[0060] In some embodiments, the pharmaceutical composition has a saturation rate of about 300, about 305, about 310, about 315, or about 320 h when administered after at least a 10-h fast. * The PK profile includes a mean AUCinfinity in ng / mL (dose normalized to 10 mg).

[0061] In some embodiments, the pharmaceutical composition has a saturation rate of about 400, about 420, about 425, about 430, about 440, or about 450 h when administered about 30 minutes after the initiation of a high fat meal following at least a 10 hour fast. * The PK profile includes a mean AUCinfinity in ng / mL (dose normalized to 10 mg).

[0062] In some embodiments, the pharmaceutical composition has a median t of about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 hours when administered after at least 10 hours of fasting. max In some embodiments, the pharmaceutical composition has a PK profile comprising a median t of about 1.5 hours when administered following at least a 10 hour fast. max The PK profile includes

[0063] In some embodiments, the pharmaceutical composition has a median t of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3.0 hours when administered about 30 minutes after the initiation of a high fat meal after at least a 10 hour fast. maxIn some embodiments, the pharmaceutical composition has a PK profile comprising a median t of about 2.75 hours when administered about 30 minutes after the start of a high fat meal after at least a 10 hour fast. max The PK profile includes

[0064] As described above, the composition contains pharma- ceutically acceptable excipients, one of which may be a filler. In some embodiments, the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose, or a combination thereof. In other embodiments, the filler is microcrystalline cellulose. In further embodiments, the filler is lactose monohydrate. In yet other embodiments, the filler is silicified microcrystalline cellulose. The composition comprises about 10% by weight to about 99.9% by weight of the filler, based on the weight of the composition. In some embodiments, the composition contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 99.9% by weight of the filler based on the weight of the composition. In other embodiments, the composition may comprise, based on the weight of the composition, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 99.9, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 99.9, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 99.9, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 99.9, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 99.9, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 99.9, about 70 to about 90, about 70 to about 80, about 80 to about 99.9, about 80 to about 90, or about 90 to about 99.9 weight percent of the filler, based on the weight of the composition. In further embodiments, the composition comprises about 90 weight percent of the filler, based on the weight of the composition. In other embodiments, the composition comprises about 88.5 weight percent of the filler, based on the weight of the composition.

[0065] The ratio of Atikaplant to filler is about 0.005 to about 9 by weight. In some embodiments, the ratio of Atikaplant to filler is about 0.008 to about 0.8 by weight. In other embodiments, the ratio of Atikaplant to filler is about 0.005 to about 8, about 0.005 to about 7, about 0.005 to about 6, about 0.005 to about 5, about 0.005 to about 4, about 0.005 to about 3, about 0.005 to about 2, about 0.005 to about 1, about 0.005 to about 0.5, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 9, about 0.005 to about 1.0, about 0.005 to about 1.5 ...0, about 0.005 to about 1.0 .01 to about 8, about 0.01 to about 7, about 0.01 to about 6, about 0.01 to about 5, about 0.01 to about 4, about 0.01 to about 3, about 0.01 to about 2, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 1 to about 9, about 1 to about 8, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 9 , about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 4, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 9, about 7 to about 8, or about 8 to about 9. In a further embodiment, the ratio of Atikaplant to filler by weight is about 0.056.

[0066] The composition may further comprise one or more of a filler, a disintegrant, a glidant, a lubricant, a solvent, a colorant, a binder, a buffer, a preservative, an osmotic agent, a wetting agent, a surfactant, a solubilizer, a thickener, a colorant, an antioxidant, an emulsifier, a tonicity agent, a suspending agent, and / or a viscosity enhancing agent.

[0067] In some embodiments, the composition further comprises one or more disintegrants. Examples of disintegrants useful in the composition include, for example, those in which the disintegrant is croscarmellose sodium. The composition comprises about 0.5% to about 50% by weight of the disintegrant based on the weight of the composition. In further embodiments, the composition contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% by weight of the disintegrant based on the weight of the composition. In other embodiments, the composition may comprise, based on the weight of the composition, about 0.5 to about 40% by weight, about 0.5 to about 30% by weight, about 0.5 to about 20% by weight, about 0.5 to about 10% by weight, about 0.5 to about 5% by weight, about 0.5 to about 4% by weight, about 0.5 to about 3% by weight, about 0.5 to about 2% by weight, about 0.5 to about 1% by weight, about 5 to about 50% by weight, about 5 to about 40% by weight, The composition comprises about 5 to about 30% by weight, about 5 to about 20% by weight, about 5 to about 10% by weight, about 10 to about 50% by weight, about 10 to about 40% by weight, about 10 to about 30% by weight, about 10 to about 20% by weight, about 20 to about 50% by weight, about 20 to about 40% by weight, about 20 to about 30% by weight, about 30 to about 50% by weight, about 30 to about 40% by weight, or about 40 to about 50% by weight of the disintegrant. In further embodiments, the composition comprises about 5% by weight of the disintegrant based on the weight of the composition. The ratio of the acicaplant to the disintegrant is about 0.1 to 10 by weight. In some embodiments, the ratio of the acicaplant to the disintegrant is about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 by weight.In other embodiments, the ratio of Atikaplant to disintegrant is about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, about 9 to about 10. In a further embodiment, the ratio of atticaprant to disintegrant is about 5 by weight. In another embodiment, the ratio of atticaprant to disintegrant is about 1 by weight.

[0068] In other embodiments, the composition further comprises one or more glidants. Examples of glidants useful in the composition include, for example, colloidal anhydrous silica. The composition comprises about 0.1% to about 10% by weight of the glidant based on the weight of the composition. In further embodiments, the composition contains about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight of the glidant based on the weight of the composition. In other embodiments, the composition may have a concentration of from about 0.1 to about 9, from about 0.1 to about 8, from about 0.1 to about 7, from about 0.1 to about 6, from about 0.1 to about 5, from about 0.1 to about 4, from about 0.1 to about 3, from about 0.1 to about 2, from about 0.1 to about 1, from about 0.1 to about 0.5, from about 0.5 to about 10, from about 0.5 to about 9, from about 0.5 to about 8, from about 0.5 to about 7, from about 0.5 to about 6, from about 0.5 to about 5, from about 0.5 to about 4, from about 0.5 to about 3, from about 0.5 to about 2, from about 0.5 to about 1, from about 1 to about 10, from about 1 to about 9, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10 weight % of a flow enhancer. In further embodiments, the composition contains about 1% by weight of the glidant, based on the weight of the composition. The ratio of aticaplant to glidant is from 0.5 to 50 by weight. In some embodiments, the ratio of aticaplant to glidant is about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 by weight.In other embodiments, the ratio of Atikaplant to glidant by weight is about 0.5 to about 50, about 0.5 to about 45, about 0.5 to about 40, about 0.5 to about 35, about 0.5 to about 30, about 0.5 to about 25, about 0.5 to about 20, about 0.5 to about 15, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 about 5, about 5 to about 50, about 5 to about 45, about 5 to about 40, about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 50, about 23 to about 40, about 40 to about 50, or about 45 to about 50. In a further embodiment, the ratio of acicaplant to flow enhancer is about 5 by weight.

[0069] In some embodiments, the composition further comprises one or more lubricants. Examples of lubricants useful in the composition include, for example, magnesium stearate. The composition comprises about 0.05% to about 5% by weight of the lubricant based on the weight of the composition. In further embodiments, the composition comprises about 0.05, about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5% by weight of the lubricant based on the weight of the composition. In other embodiments, the composition comprises about 0.05 to about 4.5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 wt% of lubricant based on the weight of the composition. In further embodiments, the composition comprises about 0.5% by weight of a lubricant, based on the weight of the composition. The ratio of aticaplant to lubricant is about 1 to about 100 by weight. In some embodiments, the ratio of aticaplant to lubricant is about 1, about 5, 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 by weight.In other embodiments, the ratio of Atikaplant to lubricant by weight is from 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 50, from about 1 to about 40, from about 1 to about 30, from about 1 to about 20, from about 1 to about 10, from about 1 to about 5, from about 5 to about 100, from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 50, from about 1 to about 40, from about 1 to about 30, from about 1 ~ about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40, to about 100, about 40 to about 90, about 40 to about 80 , about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 100, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 100, about 80 to about 90, or about 90 to about 100. In a further embodiment, the ratio of aticaplant to lubricant is about 10 by weight.

[0070] In some embodiments, the composition has one or more of an aticaplant to filler ratio of 0.005-9 by weight, a disintegrant to aticaplant ratio of 0.1-10 by weight, an aticaplant to glidant ratio of 0.5-50 by weight, and an aticaplant to lubricant ratio of 1-100 by weight.

[0071] In other embodiments, the composition has one or more of an aticaplant to filler ratio of about 0.06 by weight, an aticaplant to disintegrant ratio of about 1 by weight, an aticaplant to glidant ratio of about 5 by weight, and an aticaplant to lubricant ratio of about 10 by weight.

[0072] In a further embodiment, the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant, based on the weight of the composition.

[0073] Desirably, the composition is formulated as a solid composition. In some embodiments, the solid composition is a tablet, capsule, or caplet. In other embodiments, the solid composition is a tablet, such as an oral tablet. In further embodiments, the solid composition is a capsule, such as an oral capsule. In yet other embodiments, the solid composition is a caplet, such as an oral caplet. Optionally, the solid composition is coated. For example, the coating is an enteric coating. By doing so, the coating provides a film coat on the solid composition. In some embodiments, the film coat comprises a coating powder. In other embodiments, the film coat comprises Opadry II Orange. In a further embodiment, the coating powder is Opadry II Orange.

[0074] The tablet may include one or more layers. In some embodiments, the tablet includes a core tablet and a film coat to provide a film-coated tablet. The ratio of the film coat to the core tablet is about 0.03 to 10 by weight. In some embodiments, the ratio of the film coat to the core tablet is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 by weight, based on the weight of the composition. In other embodiments, the ratio of film coat to core tablet is about 0.03 to about 9, about 0.03 to about 8, about 0.03 to about 7, about 0.03 to about 6, about 0.03 to about 6, about 0.03 to about 5, about 0.03 to about 4, about 0.03 to about 3, about 0.03 to about 2, about 0.03 to about 1, about 0.03 to about 0.5, about 0.03 to about 0.1, about 0.05 to about 10, 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 10 ... 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 10, 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, 0.5 to about 9, about 0.5 to about about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10.

[0075] The core tablet may comprise one or more phases. In some embodiments, the core tablet comprises a first phase, such as an intragranular phase. In other embodiments, the core tablet comprises a second phase, such as an extragranular phase. In further embodiments, the core tablet comprises an intragranular phase and an extragranular phase.

[0076] The ratio of intragranular to extragranular phase in the core tablet is about 1.5 to about 3 by weight. In some embodiments, the ratio of intragranular to extragranular phase in the core tablet is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3 by weight. In other embodiments, the ratio of intragranular phase to extragranular phase in the core tablet is about 1.5 to about 2.8, about 1.5 to about 2.5, about 1.5 to about 2.3, about 1.5 to about 2, about 1.5 to about 1.8, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.5, about 1.8 to about 2.3, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.5, about 2 to about 2.3, about 2 to about 2.1, about 2.1 to about 3, about 2.1 to about 2.8, about 2.1 to about 2.5, about 2.1 to about 2.3, about 2.3 to about 3, about 2.3 to about 2.8, about 2.3 to about 2.5 to about 2.5 to about 3, about 2.5 to about 2.8, and about 2.8 to about 3. In a further embodiment, the ratio of intragranular to extragranular phase in the core tablet is about 2.1 by weight.

[0077] Regarding the composition, the solid composition contains aticaplant and one or more pharma- ceutically acceptable excipients. In some embodiments, the intragranular phase includes aticaplant, a filler, a disintegrant, and a glidant. In other embodiments, the intragranular phase includes one filler. In further embodiments, the intragranular phase includes two fillers.

[0078] The intragranular phase comprises about 10 to about 120 mg of filler. In some embodiments, the intragranular phase comprises about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg of filler. In other embodiments, the intragranular phase comprises about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 ~ about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about About 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 120, about 60 to about 110, about 60 to about 100, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120. In a further embodiment, the intragranular phase contains about 60 mg of filler. In yet another embodiment, the intragranular phase contains about 30 mg of microcrystalline cellulose. In yet a further embodiment, the intragranular phase contains about 30 mg of lactose monohydrate. In another embodiment, the intragranular phase contains about 60 mg of microcrystalline cellulose. In a further embodiment, the intragranular phase contains about 60 mg of lactose monohydrate.

[0079] The intragranular phase has an atticaprant to filler ratio of about 0.008 to 0.8 by weight. In some embodiments, the intragranular phase has an atticaprant to filler ratio of about 0.008, about 0.005, about 0.001, about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 by weight. In other embodiments, the intragranular phase is from about 0.008 to about 0.7 by weight, from about 0.008 to about 0.6, from about 0.008 to about 0.5, from about 0.008 to about 0.6, from about 0.008 to about 0.5, from about 0.008 to about 0.4, from about 0.008 to about 0.3, from about 0.008 to about 0.2, from about 0.008 to about 0.1, from about 0.008 to about 0.05, from about 0.008 to about 0.01, from about 0.01 to about 0.8, from about 0.01 to about 0.7, 0.01 to about 0.6, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01 to about 0.2, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 0.8, about 0.05 to about 0.7, about 0.05 to about 0.6, about 0.05 to about 0.6, about 0.05 to about 0 .5, about 0.05 to about 0.4, about 0.05 to about 0.3, about 0.05 to about 0.2, about 0.05 to about 0.1, about 0.1 to about 0.8, about 0.1 to about 0.7, about 0.1 to about 0.6, about 0.1 to about 0.5, about 0.1 to about 0.4, about 0.1 to about 0.3, about 0.1 to about 0.2, about 0.2 to about 0.8, about 0.2 to about 0.7, about 0.2 to about 0.6, about 0.2 to about 0.5, about 0.2 to about 0.4, about 0.2 to about The atticaprant to filler ratio is about 0.3, about 0.3 to about 0.8, about 0.3 to about 0.7, about 0.3 to about 0.6, about 0.3 to about 0.5, about 0.3 to about 0.4, about 0.4 to about 0.8, about 0.4 to about 0.7, about 0.4 to about 0.6, about 0.4 to about 0.5, about 0.5 to about 0.8, about 0.5 to about 0.7, about 0.5 to about 0.6, about 0.6 to about 0.8, about 0.6 to about 0.7, or about 0.7 to about 0.8. In a further embodiment, the intragranular phase has an atticaprant to filler ratio of about 0.08 by weight.

[0080] The intragranular phase may also contain a disintegrant. In some embodiments, the intragranular phase contains about 1 to about 10 mg of disintegrant. In other embodiments, the intragranular phase contains about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10 mg of disintegrant. In further embodiments, the intragranular phase is from about 1 to about 9, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, from about 2 to about 10, from about 2 to about 9, from about 2 to about 8, from about 2 to about 7, from about 2 to about 6, from about 2 to about 5, from about 2 to about 4, from about 2 to about 3, from about 2.5 to about 10, from about 2.5 to about 9, from about 2.5 to about 8, from about 2.5 to about 7, from about 2.5 to about 6, from about 2.5 to about 5, from about 2.5 to about 4, from about 2.5 to about 3, from about 3 about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 0 to about 10. In yet another embodiment, the intragranular phase contains about 2.5 mg of disintegrant. In yet a further embodiment, the intragranular phase contains about 5 mg of disintegrant. In another embodiment, the intragranular phase contains about 2.5 mg of croscarmellose sodium. In a further embodiment, the intragranular phase contains about 5 mg of croscarmellose sodium.

[0081] The intragranular phase may further comprise a glidant. In some embodiments, the intragranular phase comprises from about 0.1 to about 5 mg of a glidant. In other embodiments, the intragranular phase comprises about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg of a glidant. In further embodiments, the intragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of glidant. In yet other embodiments, the intragranular phase contains about 0.5 mg of glidant. In yet further embodiments, the intragranular phase contains about 1 mg of glidant. In other embodiments, the intragranular phase contains about 0.5 mg of colloidal anhydrous silica. In further embodiments, the intragranular phase contains about 1 mg of colloidal anhydrous silica.

[0082] The intragranular phase has an atticaprant to disintegrant ratio by weight of about 0.2 to 20. In some embodiments, the intragranular phase has an atticaprant to disintegrant ratio by weight of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20. In other embodiments, the intragranular phase is from about 0.2 to about 18 by weight, from about 0.2 to about 16, from about 0.2 to about 14, from about 0.2 to about 12, from about 0.2 to about 10, from about 0.2 to about 8, from about 0.2 to about 6, from about 0.2 to about 4, from about 0.2 to about 3, from about 0.2 to about 2, from about 0.2 to about 1, from about 0.2 to about 0.5, from about 0.5 to about 20, from about 0.5 to about 18, from about 0.5 to about 16, from about 0.5 to about 14 ... about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 1 to about 1.5, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 14, about 4 to about 12, about 4 to about 10, about 4 to about 6, about 4 to about 8, about 4 to about 6, about 5 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, The atticaprant to disintegrant ratio is about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20. In a further embodiment, the intragranular phase has an atticaprant to disintegrant ratio of about 2 by weight.

[0083] The intragranular phase has a ratio of atticaprant to glidant by weight of about 1 to 100. In some embodiments, the intragranular phase has a ratio of atticaprant to glidant by weight of about 1, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100. In other embodiments, the intragranular phase has a ratio of aticaplant to glidant of about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 15, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 80, about 40 to about 60, or about 60 to about 80 by weight. In a further embodiment, the intragranular phase has a ratio of atticaprant to glidant of 10 by weight.

[0084] The extragranular phase comprises one or more of a filler, a disintegrant, a glidant, and a lubricant. In some embodiments, the extragranular phase comprises a filler. In other embodiments, the extragranular phase comprises a disintegrant. In further embodiments, the extragranular phase comprises a glidant. In yet other embodiments, the extragranular phase comprises a lubricant.

[0085] The extragranular phase may include a filler. In some embodiments, the extragranular phase contains one filler. In other embodiments, the extragranular phase contains about 10 to about 80 mg of a filler. In further embodiments, the extragranular phase contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, or about 80 mg of a filler. In still other embodiments, the outer grain phase is about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 10 to about 15, about 15 to about 80, about 15 to about 70, about 15 to about 60, about 15 to about 50, about 15 to about 40, about 15 to about 30, about 15 to about 20, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 25 to about 80, about 25 to about 70, about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 30, about 30 to about 80, about 30 to about 70, about 30 to about 6 ... The composition contains 0 to about 50, about 30 to about 40, about 35 to about 80, about 35 to about 70, about 35 to about 60, about 35 to about 50, about 35 to about 40, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 40 to about 80, about 40 to about 70, about 45 to about 80, about 45 to about 70, about 45 to about 60, about 45 to about 50, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 50 to about 55, about 55 to about 80, about 55 to about 70, about 55 to about 60, about 60 to about 80, about 60 to about 70, about 65 to about 80, about 65 to about 80, about 70 to about 80, or about 75 to about 80 mg of filler. In yet a further embodiment, the extragranular phase contains about 28.5 mg of filler. In another embodiment, the extragranular phase contains about 28.5 mg of silicified microcrystalline cellulose. In a further embodiment, the extragranular phase contains about 57 mg of filler. In yet another embodiment, the extragranular phase contains about 57 mg of silicified microcrystalline cellulose.

[0086] The extragranular phase may further contain a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In other embodiments, the extragranular phase contains about 1 to about 10 mg of disintegrant. In further embodiments, the extragranular phase contains about 1, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 7.5, about 8, about 9, or about 10 mg of disintegrant. In yet another embodiment, the outer grain phase is from about 1 to about 10, from about 1 to about 9, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2.5, from about 1 to about 2, from about 2 to about 10, from about 2 to about 9, from about 2 to about 8, from about 2 to about 7, from about 2 to about 6, from about 2 to about 5, from about 2 to about 4, from about 2 to about 3, from about 2.5 to about 10, from about 2.5 to about 9, from about 2.5 to about 8, from about 2.5 to about 7, from about 2.5 to about 6, from about 2.5 to about 5, from about 2.5 to about 4, from about 2.5 to about 3, from about 3 to about 10, from about 3 to about 5 About 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 7.5 to about 10, about 7.5 to about 9, about 7.5 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10 mg of disintegrant. In yet a further embodiment, the extragranular phase contains about 2.5 mg of disintegrant. In another embodiment, the extragranular phase contains about 5 mg of disintegrant. In a further embodiment, the extragranular phase contains about 2.5 mg of croscarmellose sodium.In yet another embodiment, the extragranular phase contains about 5 mg of croscarmellose sodium.

[0087] The extragranular phase has a filler to disintegrant ratio by weight of about 1 to 100. In some embodiments, the extragranular phase has a filler to disintegrant ratio by weight of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100. In further embodiments, the extragranular phase has a filler to disintegrant ratio by weight of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 10 to about In still other embodiments, the filler to disintegrant ratio is about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 10 to about 15, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100. In still other embodiments, the extragranular phase has a filler to disintegrant ratio of about 11.4.

[0088] The extragranular phase may further comprise a glidant. In some embodiments, the glidant is colloidal anhydrous silica. In other embodiments, the extragranular phase contains about 0.1 to about 5 mg of a glidant. In further embodiments, the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 mg of a glidant. In yet another embodiment, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of glidant. In yet another embodiment, the extragranular phase contains about 0.5 mg of glidant. In another embodiment, the extragranular phase contains about 1 mg of glidant. In a further embodiment, the extragranular phase contains about 0.5 mg of colloidal anhydrous silica. In yet another embodiment, the extragranular phase contains about 1 mg of colloidal anhydrous silica.

[0089] The extragranular phase has a filler to glidant ratio, by weight, of about 5 to 500. In other embodiments, the extragranular phase has a filler to glidant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In further embodiments, the extragranular phase has a molecular weight of from about 5 to about 400, from about 5 to about 300, from about 5 to about 200, from about 5 to about 100, from about 5 to about 75, from about 5 to about 50, from about 10 to about 500, from about 10 to about 400, from about 10 to about 300, from about 10 to about 200, from about 10 to about 100, from about 10 to about 50, from about 25 to about 500, from about 25 to about 400, from about 25 to about 300, from about 25 to about 200, from about 25 to about 100, from about 25 to about 75, The filler to glidant ratio is from about 25 to about 50, from about 50 to about 500, from about 50 to about 400, from about 50 to about 300, from about 50 to about 200, from about 50 to about 100, from about 100 to about 500, from about 100 to about 400, from about 100 to about 300, from about 100 to about 200, from about 200 to about 500, from about 200 to about 400, from about 200 to about 300, from about 300 to about 500, from about 300 to about 400, or from about 400 to about 500. In yet a further embodiment, the extragranular phase has a filler to glidant ratio of about 57.

[0090] The extragranular phase may also contain a lubricant. In some embodiments, the lubricant is magnesium stearate. In other embodiments, the extragranular phase contains about 0.1 to about 5 mg of a lubricant. In further embodiments, the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 mg of a lubricant. In yet another embodiment, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of lubricant. In yet another embodiment, the extragranular phase contains about 0.5 mg of lubricant. In another embodiment, the extragranular phase contains about 1 mg of lubricant. In a further embodiment, the extragranular phase contains about 0.5 mg of magnesium stearate. In yet another embodiment, the extragranular phase contains about 1 mg of magnesium stearate.

[0091] The extragranular phase has a filler to lubricant ratio, by weight, of about 5 to 500. In other embodiments, the extragranular phase has a filler to lubricant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In further embodiments, the extragranular phase is from about 5 to about 400, from about 5 to about 300, from about 5 to about 200, from about 5 to about 100, from about 5 to about 75, from about 5 to about 50, from about 10 to about 500, from about 10 to about 400, from about 10 to about 300, from about 10 to about 200, from about 10 to about 100, from about 10 to about 50, from about 25 to about 500, from about 25 to about 400, from about 25 to about 300, from about 25 to about 200, from about 25 to about 100, from about 25 to about 75 by weight. , about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500. In yet a further embodiment, the extragranular phase has a filler to lubricant ratio of about 57.

[0092] In some embodiments, the intragranular phase has one or more of an atticaprant to filler ratio of about 0.008-0.8 by weight, an atticaprant to disintegrant ratio of about 0.2-20 by weight, and an atticaprant to glidant ratio of about 1-100 by weight.

[0093] In some embodiments, the extragranular phase has one or more of a filler to disintegrant ratio by weight of about 1-100, a filler to glidant ratio by weight of about 5-500, and a filler to lubricant ratio by weight of about 5-500. In other embodiments, the extragranular phase has a filler to disintegrant ratio by weight of about 11.4. In further embodiments, the extragranular phase has a filler to glidant ratio by weight of about 57. In yet other embodiments, the extragranular phase has a filler to lubricant ratio by weight of about 57.

[0094] In another embodiment, the core tablet comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0095] The oral tablet may be of a suitable weight for administration by a patient. In a further embodiment, the oral tablet has a core tablet weight of about 10 to about 1000 mg. In other embodiments, the core tablet is about 10, about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg. In a further embodiment, the core tablet is about 10 to about 900, about 10 to about 800, about 10 to about 700, about 10 to about 600, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 1000, about 25 to about 900, about 25 to about 80 0, about 25 to about 700, about 25 to about 600, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 50 to about 1000, about 50 to about 900, about 50 to about 800, about 50 to about 700, about 50 to about 600, about 50 to about 500, about 50 to About 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 700, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 10 In yet another embodiment, the core tablet is about 100 mg. In yet a further embodiment, the oral tablet comprises a core tablet of about 200 mg.

[0096] In some aspects, the core tablet contains a disintegrant. For example, the core tablet contains about 5 to about 100 mg of disintegrant. In some embodiments, the core tablet contains about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of disintegrant. In other embodiments, the core tablet contains about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of disintegrant. In a further embodiment, the core tablet contains about 5 mg of disintegrant. In yet another embodiment, the core tablet contains about 10 mg of disintegrant.

[0097] In other aspects, the core tablet contains a glidant. For example, the core tablet contains about 1 to about 100 mg of glidant. In some embodiments, the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of glidant. In other embodiments, the core tablet contains about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15 , about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of glidant. In a further embodiment, the core tablet contains about 1 mg of glidant. In yet another embodiment, the core tablet contains about 2 mg of glidant.

[0098] In a further aspect, the core tablet contains a lubricant. For example, the core tablet contains about 0.5 to about 100 mg of lubricant. In some embodiments, the core tablet contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of lubricant. In other embodiments, the core tablet has a molecular weight of about 0.5 to about 80, about 0.5 to about 60, about 0.5 to about 40, about 0.5 to about 20, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 10 The core tablet contains about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of lubricant. In a further embodiment, the core tablet contains about 0.5 mg of lubricant. In yet another embodiment, the core tablet contains about 1 mg of lubricant.

[0099] In a further aspect, the core tablet contains a filler. For example, the core tablet contains about 1 to about 200 mg of filler. In some embodiments, the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg of filler.In other embodiments, the core tablet is from about 1 to about 180, from about 1 to about 160, from about 1 to about 140, from about 1 to about 120, from 1 to about 100, from about 1 to about 80, from about 1 to about 60, from about 1 to about 40, from about 1 to about 20, from about 1 to about 10, from about 1 to about 5, from about 2 to about 200, from about 2 to about 180, from about 2 to about 160, from about 2 to about 140, from about 2 to about 120, from about 2 to about 100, from about 2 to about 80, from about 2 to about 60, from about 2 to about 40, from about 2 to about 20, from about 2 to about 10, from about 2 to about 5, from about 5 to about 200m, from about 5 to about 180, from about 5 to about 160, from about 5 to about 140, from about 5 to about 120, from about 5 to about 100, from about 5 to about 80, from about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 200, about 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about 20 to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, bout 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 80, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 About 120, about 80 to about 100 mg, about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 140 to about 200, about 140 to about 180, about 140 to about 160, about 160 to about 200, about 160 to about 180, or about 180 to about 200 mg of filler. In a further embodiment, the core tablet contains about 88.5 mg of filler. In yet another embodiment, the core tablet contains about 177 mg of filler.

[0100] In some preferred embodiments, the oral tablet comprises about 100 mg of core tablet, containing about 5 mg of aticaplant, about 5 mg of disintegrant, about 88.5 mg of filler, about 1 mg of glidant, and about 0.5 mg of lubricant.

[0101] In another preferred embodiment, the oral tablet comprises about 200 mg of a core tablet, the core tablet comprising about 10 mg of aticaplant, about 10 mg of disintegrant, about 177 mg of filler, about 2 mg of glidant, and about 1 mg of lubricant.

[0102] As mentioned above, the core tablet may be coated with a film coat. In some embodiments, the oral tablet comprises about 3 mg of film coat. In other embodiments, the oral tablet comprises about 6 mg of film coat.

[0103] In some aspects, the film-coated oral tablet comprises about 80 to about 99.9% by weight of the core tablet and about 0.1 to about 20% by weight of the core tablet based on the weight of the film-coated oral tablet. In some embodiments, the film-coated oral tablet comprises about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or 99.9% by weight based on the weight of the film-coated oral tablet. In another embodiment, the film-coated oral tablet has a molecular weight of about 80 to about 99, about 80 to about 96, about 80 to about 94, about 80 to about 92, about 80 to about 90, about 80 to about 88, about 80 to about 86, about 80 to about 84, about 80 to about 82, about 82 to about 99, about 82 to about 96, about 82 to about 94, about 82 to about 92, about 82 to about 90, about 82 to about 88, about 82 to about 86, about 82 to about 84, about 84 to about 99, about 84 to about 99, about 84 to about 96, about 84 to about 94, about 84 to about 92, about 84 to about 90, about 84 to about 88, about 84 to about 86, about 86 to about 99, about 86 to about 96, about 86 to about 94, about 86 to about 92, about 86 to about 90, about 86 to about 88, about 88 to about 99, about 88 to about 96, about 88 to about 94, about 88 to about 92, about 88 to about 90, about 90 to about 99, about 90 to about 96, about 90 to about 94, about 90 to about 92, about 92 to about 99, about 92 to about 96, about 92 to about 94, about 94 to about 99, about 94 to about 96, about 96 to about 99, or about 98 to about 99 weight percent of the core tablet. In a further embodiment, the film-coated oral tablet comprises about 97 weight percent of the core tablet, based on the weight of the film-coated oral tablet. In yet another embodiment, the film-coated oral tablet comprises about 0.1 to about 20% by weight of the film coat, based on the weight of the film-coated oral tablet. In yet further embodiments, the film-coated oral tablet comprises about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight of the film coat, based on the weight of the film-coated oral tablet.In other embodiments, the film-coated oral tablet has a molecular weight of about 0.1 to about 18, about 0.1 to about 16, about 0.1 to about 14, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 8, about 0.1 to about 6, about 0.1 to about 4, about 0.1 to about 2, about 0.1 to about 1, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 2, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 ~ about 12, about 2 to about 10, about 2 to about 8, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 12, about 4 to about 10, about 4 to about 8, about 4 to about 6, about 6 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to 18, about 8 to 16, about 8 About 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20% by weight of the film coat. In a further embodiment, the film-coated oral tablet comprises about 3% by weight of the film coat, based on the weight of the film-coated oral tablet. In yet another embodiment, the film-coated oral tablet comprises about 97% by weight of the core tablet and about 3% by weight of the film coat, based on the weight of the film-coated oral tablet.

[0104] In some embodiments, the present disclosure provides an oral tablet comprising about 5 mg of acicaplant, the oral tablet comprising about 100 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 30 mg of microcrystalline cellulose, about 30 mg of lactose monohydrate, about 2.5 mg of croscarmellose sodium, and about 0.5 mg of colloidal anhydrous silica, and the extragranular phase comprising about 28.5 mg of silicified microcrystalline cellulose, about 2.5 mg of croscarmellose sodium, about 0.5 mg of colloidal anhydrous silica, and about 0.5 mg of magnesium stearate.

[0105] In another embodiment, the present disclosure provides an oral tablet comprising about 10 mg of aticaplant, the oral tablet comprising about 200 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium, and about 1 mg of colloidal anhydrous silica, and the extragranular phase comprising about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of colloidal anhydrous silica, and about 1 mg of magnesium stearate.

[0106] The solid composition may also have a desirable dissolution profile that provides a desired release of Atikaplant. In some embodiments, the solid composition contains about 2 mg to 20 mg of Atikaplant and has a dissolution profile that includes a Q value of about 60% to 90% at 45 minutes under the following dissolution operating conditions: (i) apparatus: paddle (USP Type 2, Ph.Eur., JP), (ii) dissolution medium: 0.01 M hydrochloric acid, (iii) volume: 900 mL, (iv) temperature: 37±0.5° C., (v) rotation speed: 50 rpm, and (vi) analysis end: UHPLC with UV detection at 247 nm. In some embodiments, the Q value is about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, or about 95% at 45 minutes. In other embodiments, the Q value is about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90% at 45 minutes. In further embodiments, the Q value is about 70% to 80% at 45 minutes. In other aspects, the Q value is about 75% at 45 minutes.

[0107] Advantageously, Atikaplant may be administered in a single dose per day, or the total daily dose may be divided and administered two, three or four times per day. In some embodiments, Atikaplant-containing compositions are administered once per day. In other embodiments, Atikaplant-containing oral tablets are administered once per day. In further embodiments, Atikaplant-containing solid pharmaceutical compositions are administered once per day.

[0108] As described herein, in particular, the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Thus, in a particular embodiment, the present disclosure relates to aticaplant for use as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In a further particular embodiment, the present disclosure also relates to the use of aticaplant in the manufacture of a medicament as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In a further particular embodiment, the present disclosure further relates to the package or pharmaceutical product as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Such antidepressant therapy may in particular be selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or combinations thereof.

[0109] As described herein, aticaplant may be used as an adjunctive treatment, or in other words, in conjunction with, add-on to, or in combination with one or more antidepressants, for example, a patient may already be administered one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to aticaplant for the uses described herein, comprising administration of aticaplant as an adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant for the uses described herein, comprising administration of aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant in the manufacture of a medicament as described herein, wherein the treatment comprises administration of an effective amount of aticaplant as an adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the disclosure also relates to the use of aticaplant as described herein, wherein the treatment comprises administering an effective amount of aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the disclosure also relates to the use of aticaplant as described herein, wherein the treatment comprises administering an effective amount of aticaplant in combination with an effective amount of one or more antidepressants. In further specific embodiments, the disclosure also relates to the package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant as adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the disclosure also relates to the package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant in combination with an effective amount of one or more antidepressants.In a further specific embodiment, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant in combination with an effective amount of one or more antidepressants, which may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0110] As already mentioned, the present disclosure relates to aticaplant for the uses described herein. In a specific embodiment, the aticaplant is S-aticaplant. In a further embodiment of the present disclosure, aticaplant for the uses described herein, particularly S-aticaplant, is administered in an amount of about 2 to about 35 mg, more specifically about 10 mg. In yet a further embodiment, aticaplant for the uses described herein, particularly S-aticaplant, is administered orally. In yet a further specific embodiment, the present disclosure relates to aticaplant for the uses described herein, particularly S-aticaplant, 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 aticaplant is S-aticaplant. In a further embodiment of the uses described herein, about 2 to about 35 mg, more specifically about 10 mg of aticaplant is administered. In yet a further embodiment of the uses, aticaplant is administered orally. In yet further particular embodiments of the use, the aticaplant, particularly S-aticaplant, is administered once a day. In further particular embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the aticaplant is, particularly 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 aticaplant, more particularly about 10 mg. In further embodiments of the package or pharmaceutical product as described herein, the instructions for treatment with aticaplant, particularly S-aticaplant, are for oral administration. In further particular embodiments of the package or pharmaceutical product as described herein, the instructions for treatment with aticaplant, particularly S-aticaplant, are for administration once a day.

[0111] Advantageously, administration of Atikaplant does not result in weight gain during treatment, including clinically relevant weight gain. In further particular embodiments, the present disclosure relates to Atikaplant for use as defined herein, where the patient does not experience weight gain during treatment with Atikaplant. In further particular embodiments, the present disclosure relates to use as defined herein, where the patient does not experience weight gain during treatment with Atikaplant. In further particular embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, where the patient does not experience weight gain during treatment with Atikaplant. The patient's weight can be assessed, in particular, upon the first administration of Atikaplant.

[0112] Also, unexpectedly, it was observed that patients do not experience a decline in sexual function during treatment with Atikaplant based on the evaluation at the first administration. In a further specific embodiment, the present disclosure relates to Atikaplant for use as described herein, where the patient does not experience a decline in sexual function during treatment with Atikaplant. In a further specific embodiment, the present disclosure relates to the use as described herein, where the patient does not experience a decline in sexual function during treatment with Atikaplant. In a further specific embodiment, the present disclosure relates to the package or pharmaceutical product as described herein, where the patient does not experience a decline in sexual function during treatment with Atikaplant. Such term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to those skilled in the art, for example by applying the Arizona Sexual Experience Scale (ASEX).

[0113] 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, for example, the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the present disclosure relates to an acica plant for use as described herein, wherein after 6 weeks of treatment with the acica plant, 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, and more specifically, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the anhedonia scale. In further specific embodiments, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the disclosure relates to a use as described herein, wherein after 6 weeks of treatment with Atika plant, the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in the total score on the Anhedonia Scale. In further particular embodiments, the Anhedonia Scale is the Snaith-Hamilton Pleasure Scale (SHAPS). In further particular embodiments, the disclosure relates to a package or pharmaceutical product as described herein, wherein the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale after 6 weeks of treatment with Atika plant, more particularly, the 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 a further particular embodiment, the anhedonia scale is the Snaith-Hamilton Anhedonia Scale (SHAPS).

[0114] Treatment method In one aspect of the present invention, a method is provided for treating patients with more severe types of depression, i.e., major depressive disorder, using the compounds, compositions, e.g., solid compositions, and tablets, e.g., oral tablets, described herein. The patient may also experience 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, among other things, ineffective medication, repeated unnecessary medical appointments, lack of patient compliance, and overall patient frustration. Furthermore, antidepressants are known to have various side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among other things. Thus, patients may choose to refrain from or discontinue taking antidepressants to avoid or prevent any side effects.

[0115] The methods described herein are effective in managing depression and anhedonia in patients using Atikaplant. Desirably, the methods allow patients to successfully manage their depression and simultaneously reduce anhedonia. In certain embodiments, patients treated according to the methods described have moderate to severe anhedonia. The term "anhedonia" as used herein refers to a lack or diminished 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 phases: the appetitive phase (governed by desire), the consummatory phase (governed by liking), and the satisfaction phase (governed by learning). The appetitive phase is characterized by an initial expenditure of energy to obtain a reward. The consummatory stage is the enjoyment of rewards, and the satisfaction stage is characterized by learning and feedback integration.

[0116] 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.

[0117] 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.

[0118] In some embodiments, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet further embodiments, in still other embodiments, the patient's anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 to about 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant. In other embodiments, the patient's anhedonia is improved, i.e., reduced by 100%, as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant.

[0119] The reduction in anhedonia after starting treatment with Atika Plant can be measured relative to the patient's anhedonia measured before treatment with Atika Plant, i.e., baseline anhedonia measurement. In this way, the treating clinician can calculate the change in anhedonia from baseline to real-time anhedonia measurement at any time after treatment with Atika Plant. Thus, a standard method for measuring anhedonia can be used, such as an anhedonia scale, e.g., SHAPS.

[0120] Desirably, the baseline anhedonia measurements are obtained within about one week of initiating treatment with Atikaplant. In some embodiments, the baseline anhedonia measurements are obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to initiating treatment with Atikaplant. In further embodiments, the baseline anhedonia measurements are obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiating treatment with Atikaplant.

[0121] The change in the patient's anhedonia depends on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to the Atika plant, and other medications being administered, among others. In some embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In other embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In further embodiments, the patient's anhedonia is reduced about 3 to about 6 weeks after Atika plant treatment, and in certain embodiments by the 6th week. In certain embodiments, the patient's anhedonia is reduced by at least about 40% after about 6 weeks of Atika plant treatment, as measured by the change from baseline in the total score on the Anhedonia Scale. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and in some embodiments, within about 3 to about 6 weeks, as measured by the change from baseline in the total score on the Anhedonia Scale and / or by physician / clinical judgment.

[0122] 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.

[0123] In some embodiments, the present disclosure provides a method of treating MDD in a patient by administering to a human patient a pharmaceutical composition comprising about 2 mg to 20 mg of aticaplant, the patient having had an inadequate response to other antidepressant therapies prior to treatment with aticaplant. In some embodiments, administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile (dose normalized to 10 mg) comprising one or more of the PK parameters described above following administration of the composition to a human following at least a 10 hour fast.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] As is known in the art, a patient is considered to have major depressive disorder if they exhibit five or more symptoms during the same two-week period that are a change from previous functioning, and depressed mood and / or loss of interest / pleasure must be present, excluding symptoms clearly attributable to another physical illness. See, e.g., Table 4.

[0128] [Table 4]

[0129] In some embodiments, the following criteria are also met to be diagnosed with MDD:

[0130] [Table 5]

[0131] Major depressive disorder may be classified as mild, moderate, or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In further embodiments, MDD is severe. As used herein, "mild MDD" applies to patients who have few, if any, symptoms beyond those required to make a diagnosis, the intensity of symptoms is distressing but manageable, and the symptoms result in mild impairment in social or occupational functioning. Mild MDD may be a single episode (ICD-10F32.0) or recurrent episodes (ICD-10F33.0). "Moderate MDD" applies to patients who have a number of symptoms, intensity of symptoms, and / or functional impairment that is between those designated as "mild" and those designated as "severe." Moderate MDD may be a single episode (ICD-10F32.1) or recurrent episodes (ICD-10F33.1). "Severe MDD" refers to patients whose number of symptoms significantly exceeds that required to make a diagnosis, the intensity of symptoms is severely distressing, the symptoms significantly interfere with social and occupational functioning, and emergency symptom management is required. In some embodiments, severe MDD can be single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition in Table 5.

[0132] [Table 6]

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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 6.

[0138] [Table 7]

[0139] The MGH-ATRQ is a self-assessment scale used to determine treatment resistance in patients with MDD. This questionnaire examines antidepressant therapy history, using specific anchor points to define the appropriateness of both the dose and duration of each antidepressant trial, as well as the degree of symptom improvement. The MGH-ATRQ allows for the determination of treatment resistance in depression and is known to those skilled in the art.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] In certain embodiments, the patient has been treated with other antidepressant therapy prior to receiving Atikaplant. In some embodiments, the patient has been treated with other antidepressant therapy, including an SSRI, an SNRI, or a combination thereof. In other embodiments, the patient has stopped other antidepressant therapy prior to initiating treatment with Atikaplant.

[0148] The methods described herein also include adjunctive treatment with a therapeutically effective amount of one or more antidepressants. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" refer to the treatment of a patient in need thereof by administering Aticaplant in combination with one or more antidepressants, where Aticaplant and the antidepressants are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.

[0149] In some aspects, Atikaplant is administered adjunctively with other antidepressant(s) currently administered to the patient, including current antidepressants to which the patient has had an inadequate response, i.e., which have failed to treat the patient's depression. In other embodiments, Atikaplant is administered adjunctively with antidepressant(s) not previously administered to the patient, i.e., new antidepressants. In yet other embodiments, Atikaplant is administered in a regimen with an antidepressant previously administered to the patient.

[0150] When acicaplant and other antidepressants are administered in separate dosage forms, the number of doses administered per day for each active compound may be the same or different, and more typically, different.Antidepressants may be administered as prescribed by the attending physician and / or by its label, and acicaplant is administered as described herein.Typically, patients are under concurrent treatment with both antidepressants and acicaplant, both of which are administered according to their prescribed dosing regimen.Aticaplant and antidepressants may be administered simultaneously in divided or single forms, at the same or different times during the course of therapy, according to simultaneous or alternating regimens.

[0151] Aticaplant and antidepressant can be administered via the same or different administration routes.Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.In some embodiments, Aticaplant is administered orally.

[0152] Treatment with Atikaplant as described herein has several advantages over treatments in the art. In some embodiments, patients do not experience many of the side effects associated with other antidepressants (i.e., antidepressants other than Atikaplant). In certain aspects, patients do not experience weight gain during treatment with Atikaplant. As used herein, the term "weight gain" refers to an increase in a patient's weight compared to the subject's weight prior to taking Atikaplant or the patient's weight assessed at the time of the first administration of Atikaplant. In certain embodiments, patients can actually see a decrease in overall weight compared to the patient's weight prior to receiving Atikaplant. In further embodiments, the patient's weight is stable, i.e., it neither increases nor decreases. In certain embodiments, patients do not experience clinically relevant weight gain, characterized as a weight gain of ≧7%.

[0153] This is in contrast to many other antidepressants for which weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[0154] In a further aspect, the patient does not experience a decrease in sexual function during treatment with Atikaplant. As used herein, the term "decrease in sexual function" refers to a decrease or reduction in one or more components of human sexual activity (i.e., sexual function). In some embodiments, sexual function includes one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. In other embodiments, sexual function includes sexual drive. In further embodiments, sexual function includes vaginal lubrication satisfaction. In further embodiments, sexual function includes orgasmic achievement. In yet other embodiments, sexual function includes orgasmic satisfaction. Desirably, the patient's sexual function is assessed upon the first administration of Atikaplant. Thus, the patient's sexual function during Atikaplant intake can be compared to the subject's sexual function prior to Atikaplant administration. Sexual function can be assessed by using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). The ASEX is used to investigate whether Atikaplant has an additional positive or negative effect on sexual function. The ASEX is a five-item rating scale administered to patients that quantifies sexual drive, sexual arousal, vaginal lubrication or erection, ability to achieve orgasm, and satisfaction. Scores range from 5 to 30, and two different versions of the scale (male and female) are available.

[0155] 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.

[0156] The methods described herein include administering an effective amount of Aticaplant to a patient. 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, Aticaplant is utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressants are utilized in effective amounts, separately or in combination with Aticaplant.

[0157] Embodiments: The present invention also provides the following non-limiting embodiments.

[0158] Embodiment 1 is a pharmaceutical composition comprising about 2 mg to about 20 mg of acutiloplant and a filler, the composition comprising about 0.1% to about 90% by weight of acutiloplant.

[0159] Embodiment 2 is the pharmaceutical composition of embodiment 1, further comprising one or more of a disintegrant, a glidant, a lubricant, a solvent, a colorant, and a binder.

[0160] Embodiment 3 is the pharmaceutical composition of embodiment 1 or 2, wherein the composition comprises about 10% to about 99.9% by weight of a filler.

[0161] Embodiment 4 is a pharmaceutical composition according to any one of embodiments 1 to 3, wherein the composition comprises a disintegrant.

[0162] Embodiment 5 is the pharmaceutical composition of embodiment 4, wherein the composition comprises about 0.5% to about 50% by weight of a disintegrant.

[0163] Embodiment 6 is a pharmaceutical composition according to any one of embodiments 1 to 5, comprising a glidant.

[0164] Embodiment 7 is the pharmaceutical composition of embodiment 6, comprising about 0.1% to about 10% by weight of a glidant.

[0165] Embodiment 8 is a pharmaceutical composition according to any one of embodiments 1 to 7, wherein the composition is a lubricant.

[0166] Embodiment 9 is the pharmaceutical composition of embodiment 8, wherein the composition comprises about 0.05% to about 5% by weight of a lubricant.

[0167] Embodiment 10 is a pharmaceutical composition according to any one of embodiments 1 to 9, wherein the composition has one or more of an aticaplant to filler ratio of 0.005 to 9 by weight, an aticaplant to disintegrant ratio of 0.1 to 10 by weight, an aticaplant to glidant ratio of 0.5 to 50 by weight, and an aticaplant to lubricant ratio of 1 to 100 by weight.

[0168] Embodiment 11 is a pharmaceutical composition according to any one of embodiments 1 to 10, wherein the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0169] Embodiment 12 is a pharmaceutical composition according to any one of embodiments 1 to 11, wherein the composition is an oral tablet.

[0170] Embodiment 13 is the pharmaceutical composition of embodiment 12, wherein the oral tablet is a film-coated oral tablet comprising (a) a core tablet and (b) a film coat.

[0171] Embodiment 14 is a pharmaceutical composition according to embodiment 13, wherein the ratio of film coat to core tablet is about 0.03-10 by weight.

[0172] Embodiment 15 is a pharmaceutical composition according to embodiment 13 or 14, wherein the film coat comprises a coating powder.

[0173] Embodiment 16 is a pharmaceutical composition according to any one of embodiments 13 to 15, wherein the core tablet comprises an intragranular phase and an extragranular phase.

[0174] Embodiment 17 is a pharmaceutical composition according to embodiment 16, wherein the ratio of intragranular phase to extragranular phase in the core tablet is about 1.5-3.

[0175] Embodiment 18 is a pharmaceutical composition according to embodiment 16, wherein the intragranular phase comprises aticaplant, a filler, a disintegrant, and a glidant.

[0176] Embodiment 19 is the pharmaceutical composition of embodiment 18, wherein the intragranular phase has one or more of: an atticaprant to filler ratio of about 0.008-0.8 by weight; an atticaprant to disintegrant ratio of about 0.2-20 by weight; and an atticaprant to glidant ratio of about 1-100 by weight.

[0177] Embodiment 20 is a pharmaceutical composition according to embodiment 16 or 17, wherein the extragranular phase comprises a filler, a disintegrant, a glidant, and a lubricant.

[0178] Embodiment 21 is the pharmaceutical composition of embodiment 20, wherein the extragranular phase has one or more of a filler to disintegrant ratio of about 1-100 by weight, a filler to glidant ratio of about 5-500 by weight, and a filler to lubricant ratio of about 5-500 by weight.

[0179] Embodiment 22 is a pharmaceutical composition according to any one of embodiments 13 to 21, wherein the film-coated oral tablet comprises about 97% by weight of the core tablet and about 3% by weight of the film coat, the core tablet comprising about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0180] Embodiment 23 is a pharmaceutical composition according to any one of embodiments 1 to 22, wherein the composition is an oral tablet comprising about 100 mg of a core tablet, the core tablet comprising about 5 mg of aticaplant, about 5 mg of disintegrant, about 88.5 mg of filler, about 1 mg of glidant, and about 0.5 mg of lubricant.

[0181] Embodiment 24 is a pharmaceutical composition according to embodiment 23, further comprising about 3 mg of a film coat.

[0182] Embodiment 25 is a pharmaceutical composition according to any one of embodiments 1 to 24, wherein the composition is an oral tablet comprising about 200 mg of a core tablet, the core tablet comprising about 10 mg of aticaplant, about 10 mg of disintegrant, about 177 mg of filler, about 2 mg of glidant, and about 1 mg of lubricant.

[0183] Embodiment 26 is a pharmaceutical composition according to embodiment 25, further comprising about 6 mg of a film coat.

[0184] Embodiment 27 is a pharmaceutical composition according to any one of embodiments 1 to 26, wherein the filler is selected from microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose.

[0185] Embodiment 28 is a pharmaceutical composition according to any one of embodiments 2 to 27, wherein the disintegrant is croscarmellose sodium.

[0186] Embodiment 29 is a pharmaceutical composition according to any one of embodiments 2 to 28, wherein the glidant is colloidal anhydrous silica.

[0187] Embodiment 30 is a pharmaceutical composition according to any one of embodiments 2 to 29, wherein the lubricant is magnesium stearate.

[0188] Embodiment 31 is a pharmaceutical composition according to any one of embodiments 15 to 30, wherein the coating powder is Opadry II Orange.

[0189] Embodiment 32 is an oral tablet comprising about 5 mg of aticaplant, wherein the oral tablet comprises about 100 mg of a core tablet, wherein the core tablet comprises an intragranular phase and an extragranular phase, wherein the intragranular phase comprises about 30 mg of microcrystalline cellulose, about 30 mg of lactose monohydrate, about 2.5 mg of croscarmellose sodium, and about 0.5 mg of colloidal anhydrous silica, and wherein the extragranular phase comprises about 28.5 mg of silicified microcrystalline cellulose, about 2.5 mg of croscarmellose sodium, about 0.5 mg of colloidal anhydrous silica, and about 0.5 mg of magnesium stearate.

[0190] Embodiment 33 is an oral tablet according to embodiment 32, further comprising about 3 mg of a film coat.

[0191] Embodiment 34 is an oral tablet according to embodiment 33, wherein the film coat comprises Opadry II Orange.

[0192] Embodiment 35 is an oral tablet comprising about 10 mg of aticaplant, wherein the oral tablet comprises about 200 mg of a core tablet, wherein the core tablet comprises an intragranular phase and an extragranular phase, wherein the intragranular phase comprises about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium, and about 1 mg of colloidal anhydrous silica, and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of colloidal anhydrous silica, and about 1 mg of magnesium stearate.

[0193] Embodiment 36 is an oral tablet according to embodiment 35, further comprising 3 mg of a film coat.

[0194] Embodiment 37 is an oral tablet according to embodiment 36, wherein the film coat comprises Opadry II orange.

[0195] Embodiment 38 is a pharmaceutical composition comprising about 2 mg to 20 mg of aticaplant, wherein the composition has a pharmacokinetic (PK) profile (dose normalized to 10 mg) comprising one or more of the following parameters following administration of the composition to a human following at least a 10 hour fast: a. Average C of about 30-40 ng / mL max ; b.About 300~430h * Mean AUC in ng / mL infinity ; c.About 280~430h * Mean AUC in ng / mL last ; d. Median t of approximately 1 to 4 hours max , a pharmaceutical composition.

[0196] Embodiment 39 is the pharmaceutical composition of embodiment 38, wherein the mean Cmax is about 30-35 ng / mL.

[0197] In embodiment 40, the average AUCinfinity is about 300 to 320 h * 40. The pharmaceutical composition according to embodiment 38 or 39, wherein the .alpha.-tocopherol concentration is 100 ng / mL.

[0198] In embodiment 41, the average AUClast is about 280 to 310 h * ng / mL.

[0199] In embodiment 42, the median t max is about 1.5 hours.

[0200] Embodiment 43 is a pharmaceutical composition according to any one of embodiments 38 to 42, wherein the composition is an oral tablet.

[0201] Embodiment 44 is a pharmaceutical composition according to any one of embodiments 38 to 43, wherein the composition further comprises one or more of a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.

[0202] Embodiment 45 is a pharmaceutical composition according to any one of embodiments 38 to 44, wherein the composition comprises about 0.1% to 90% by weight of aticaplant.

[0203] Embodiment 46 is a pharmaceutical composition according to any one of embodiments 38 to 45, wherein the composition contains about 5 mg of aticaplant or about 10 mg of aticaplant.

[0204] Embodiment 47 is a pharmaceutical composition according to any one of embodiments 38 to 46, wherein the composition has one or more of the following ratios: aticaplant to filler from 0.005 to 9 by weight; aticaplant to disintegrant from 0.1 to 10 by weight; aticaplant to glidant from 0.5 to 50 by weight; and aticaplant to lubricant from 1 to 100 by weight.

[0205] Embodiment 48 is a pharmaceutical composition according to any one of embodiments 38 to 47, wherein the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0206] Embodiment 49 is a method for treating major depressive disorder (MDD), comprising administering to a patient a pharmaceutical composition comprising about 2 mg to 20 mg of aticaplant, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with aticaplant, and wherein administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile (dose normalized to 10 mg) comprising one or more of the following PK parameters following administration of the composition to a human following at least a 10 hour fast: e. Average C of about 30-40 ng / mL max ; f.About 300~430h * Mean AUC in ng / mL infinity ; g.About 280~430h * Mean AUC in ng / mL last ; h. Median time t: approx. 1-4 hours max , a method.

[0207] In embodiment 50, the average C max 50. The method according to embodiment 49, wherein the concentration of β-glutamic acid in the blood is about 30 to 35 ng / mL.

[0208] In embodiment 51, the mean AUC infinity However, about 300 to 320 hours * 51. The method according to embodiment 49 or 50, wherein the concentration is 1 ng / mL.

[0209] In embodiment 52, the mean AUC last However, about 280 to 310 hours * 52. The method according to any one of embodiments 49 to 51, wherein the concentration is 1 ng / mL.

[0210] In embodiment 53, the median t max is about 1.5 hours.

[0211] Embodiment 54 is the method of any one of embodiments 49-53, wherein the composition is an oral tablet.

[0212] Embodiment 55 is the method of any one of embodiments 49-54, wherein the composition further comprises one or more of a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.

[0213] Embodiment 56 is the method of any one of embodiments 49 to 55, wherein the composition comprises about 0.1% to 90% by weight of Atica plant.

[0214] Embodiment 57 is the method of any one of embodiments 49 to 56, wherein the composition comprises about 10% to 99.9% by weight of the filler.

[0215] Embodiment 58 is the composition of any one of embodiments 49-57, wherein the composition has one or more of an aticaplant to filler ratio of 0.005-9 by weight, an aticaplant to disintegrant ratio of 0.1-10 by weight, an aticaplant to glidant ratio of 0.5-50 by weight, and an aticaplant to lubricant ratio of 1-100 by weight.

[0216] Embodiment 59 is the method of any one of embodiments 49 to 58, wherein the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0217] Embodiment 60 is the method of any one of embodiments 49 to 59, wherein the patient has anhedonia.

[0218] Embodiment 61 is the method of any one of embodiments 49 to 60, wherein the pharmaceutical composition comprises about 5 mg of aticaplant.

[0219] Embodiment 62 is the method of any one of embodiments 49 to 60, wherein the pharmaceutical composition comprises about 10 mg of aticaplant.

[0220] Embodiment 63 is the method of any one of embodiments 49-60, wherein the other antidepressant therapy comprises one or more antidepressants.

[0221] Embodiment 64 is the method of embodiment 63, wherein the one or more antidepressants comprises an SSRI, an SNRI, or a combination thereof.

[0222] Embodiment 65 is the method of any one of embodiments 49 to 64, wherein the atica plant is S-atica plant.

[0223] Embodiment 66 is the method of any one of embodiments 49-65, further comprising treatment with an effective amount of one or more antidepressants.

[0224] Embodiment 67 is the method of embodiment 66, wherein the one or more antidepressants is an SSRI, an SNRI, or a combination thereof.

[0225] Embodiment 68 is a method according to any one of embodiments 49 to 67, wherein the pharmaceutical composition comprising aticaplant is administered once a day.

[0226] Embodiment 69 is a solid pharmaceutical composition comprising about 2 mg to 20 mg of aticaplant, the composition having a dissolution profile comprising a Q value of about 60% to 90% at 45 minutes under the following dissolution operating conditions: Apparatus: Paddle (USP Type 2, Ph.Eur.,JP) Dissolution medium: 0.01M hydrochloric acid Capacity: 900mL Temperature: 37+ / -0.5 degrees Celsius Rotation speed: 50 rpm Analysis completed: UHPLC with UV detection at 247 nm.

[0227] Embodiment 70 is a solid pharmaceutical composition according to embodiment 69, wherein the composition comprises about 5 mg or about 10 mg of aticaplant.

[0228] Embodiment 71 is a solid pharmaceutical composition according to embodiment 69 or 70, wherein the Q value is about 70% to 80% at 45 minutes.

[0229] Embodiment 72 is a stable solid pharmaceutical composition according to embodiment 71, wherein the Q value is about 75% at 45 minutes.

[0230] Embodiment 73 is a solid pharmaceutical composition according to any one of embodiments 69 to 72, wherein the composition is an oral tablet.

[0231] Embodiment 74 is a solid pharmaceutical composition according to any one of embodiments 69 to 73, wherein the composition further comprises one or more of a filler, a disintegrant, a glidant, a lubricant, a binder, and a colorant.

[0232] Embodiment 75 is a solid pharmaceutical composition according to any one of embodiments 69 to 74, wherein the composition comprises about 0.1% to 90% by weight of aticaplant.

[0233] Embodiment 76 is a solid pharmaceutical composition according to any one of embodiments 69 to 75, wherein the composition comprises about 10% to 99.9% by weight of a filler.

[0234] Embodiment 77 is a solid pharmaceutical composition according to any one of embodiments 69 to 76, wherein the composition has one or more of the following ratios: aticaplant to filler from 0.005 to 9 by weight; aticaplant to disintegrant from 0.1 to 10 by weight; aticaplant to glidant from 0.5 to 50 by weight; and aticaplant to lubricant from 1 to 100 by weight.

[0235] Embodiment 78 is a solid pharmaceutical composition according to any one of embodiments 69 to 77, wherein the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0236] Embodiment 79 is a method for treating major depressive disorder (MDD) in a human patient, comprising administering to the patient a pharmaceutical composition according to any one of embodiments 1 to 32 or 38 to 48, an oral tablet according to any one of embodiments 33 to 37, or a solid pharmaceutical composition according to any one of embodiments 69 to 78.

[0237] Embodiment 80 is the method of embodiment 79, wherein the patient has anhedonia.

[0238] Embodiment 81 is the method of any one of embodiments 79-80, wherein the pharmaceutical composition, oral tablet, or solid pharmaceutical composition comprises about 5 mg of aticaplant.

[0239] Embodiment 82 is the method of any one of embodiments 79 to 81, wherein the pharmaceutical composition, oral tablet, or solid pharmaceutical composition comprises about 10 mg of aticaplant.

[0240] Embodiment 83 is the method of any one of embodiments 79 to 82, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with Aticaplant.

[0241] Embodiment 84 is the method of embodiment 83, wherein the other antidepressant therapy comprises one or more antidepressants.

[0242] Embodiment 85 is the method of embodiment 84, wherein the one or more antidepressants comprises an SSRI, an SNRI, or a combination thereof.

[0243] Embodiment 86 is the method of any one of embodiments 79 to 85, wherein the atica plant is S-atica plant.

[0244] Embodiment 87 is the method of any one of embodiments 79-86, further comprising treatment with an effective amount of one or more antidepressants.

[0245] Embodiment 88 is the method of embodiment 87, wherein the one or more antidepressants is an SSRI, an SNRI, or a combination thereof.

[0246] Embodiment 89 is the method of any one of embodiments 79 to 88, wherein the pharmaceutical composition, oral tablet, or solid pharmaceutical composition comprising aticaplant is administered once a day.

[0247] Embodiment 90 is a method of treating major depressive disorder in a human patient, comprising administering to the human patient a pharmaceutical composition comprising aticaplant and one or more pharma- ceutical acceptable excipients, wherein the patient has had a previous inadequate response to other antidepressant therapies, and wherein the pharmaceutical composition is administered orally once daily with or without food.

[0248] Embodiment 91 is the method of embodiment 90, wherein the pharmaceutical composition is an oral tablet.

[0249] Embodiment 92 is the method of embodiment 90 or 91, wherein the pharmaceutical composition comprises about 5 mg to 10 mg of aticaplant, about 5 mg of aticaplant, or about 10 mg of aticaplant.

[0250] Embodiment 93 is the method of any one of embodiments 90-92, wherein the other antidepressant therapy comprises one or more antidepressants.

[0251] Embodiment 94 is the method of embodiment 93, wherein the one or more antidepressants comprises an SSRI, an SNRI, or a combination thereof.

[0252] Embodiment 95 is the method of any one of embodiments 90 to 94, wherein the attic plant is S-attic plant or the attic plant is crystalline attic plant.

[0253] Embodiment 96 is the method of any one of embodiments 90-95, further comprising treatment with an effective amount of one or more antidepressants.

[0254] Embodiment 97 is the method of embodiment 96, wherein the one or more antidepressants is an SSRI, an SNRI, or a combination thereof.

[0255] Embodiment 98 is the method of any one of embodiments 90 to 97, wherein the patient has anhedonia, optionally moderate to severe anhedonia.

[0256] Embodiment 99 is the method of any one of embodiments 90 to 98, wherein the pharmaceutical composition comprises one or more of a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.

[0257] Embodiment 100 is the method of embodiment 99, wherein the filler is selected from microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is colloidal anhydrous silica, and the lubricant is magnesium stearate.

[0258] Embodiment 101 is the method of any one of embodiments 90 to 100, wherein the pharmaceutical composition comprises about 0.1% to 90% by weight of aticaplant.

[0259] Embodiment 102 is the method of any one of embodiments 90 to 101, wherein the pharmaceutical composition comprises about 10% to 99.9% by weight of a filler.

[0260] Embodiment 103 is the method of any one of embodiments 90 to 102, wherein the pharmaceutical composition is a film-coated oral tablet comprising (i) a film coat and (ii) a core tablet, the core tablet comprising about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

[0261] Embodiment 104 is a method, wherein the film-coated oral tablet comprises about 97% by weight of the core tablet and about 3% by weight of the film coating.

[0262] Embodiment 105 is the method of any one of embodiments 90 to 104, wherein the pharmaceutical composition is an oral tablet comprising about 10 mg of acicaplant, the oral tablet comprising about 200 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium, and about 1 mg of colloidal anhydrous silica, and the extragranular phase comprising about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of colloidal anhydrous silica, and about 1 mg of magnesium stearate.

[0263] 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.

[0264] [Table 8-1]

[0265] [Table 8-2]

[0266] 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.

[0267] 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.

[0268] Details of the standard Pharmorphix data collection method are as follows. Angle range: 2~42°2θ Step size: 0.05°2θ Collection time: 0.5 seconds / step (total collection time: 6.40 minutes)

[0269] If required, other methods for data collection will be used with details as shown in Table 7.

[0270] [Table 9]

[0271] 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.

[0272] 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.

[0273] The scanning mode for the metal plates used the gonioscan axis, whereas for the Millipore plates 2θ scanning was utilized.

[0274] Details of standard screening data collection methods are as follows: Angle range: 2.5~32.0°2θ Step size: 0.0130°2θ Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0275] The software used for data collection was X'Pert Data Collector and data was analyzed and presented using Diffrac Plus EVA.

[0276] B. Differential Scanning Calorimetry (DSC) TA Instruments Q2000 DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample in a pinhole aluminum pan was heated from 25 °C to 275 °C at 10 °C / min. A dry nitrogen purge at 50 mL / min was maintained over the sample.

[0277] 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.

[0278] The instrument control software was Advantage for Q Series and Thermal Advantage and data was analyzed using Universal Analysis or TRIOS.

[0279] 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.

[0280] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0281] C. Determination of Chemical Purity by HPLC Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector using OpenLAB software. Complete method details are shown in Table 8.

[0282] [Table 10]

[0283] Example 2 - Preparation of Atikaplant THF solvate

[0284] [ka]

[0285] Aqueous sodium hydroxide was added to compound 1 in 2-methyltetrahydrofuran. After phase separation, compound 2 in 2-MeTHF, i.e., the free base of compound 1, was solvent exchanged into tetrahydrofuran (THF). Reductive amination of compound 3 with compound 2 was carried out by adding sodium triacetoxyborohydride and THF. Upon completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 was concentrated and ethanol and water were added. The product was crystallized using THF, ethanol, and water to yield compound 4 as a solid.

[0286] Charge 7.3 L / kg water to reactor. Charge 6.6 L / kg 2-MeTHF to reactor. Charge 1.15 mol / mol compound 1 to reactor. Charge 2.3 mol / mol 50% aqueous NaOH at 22°C with stirring for a minimum of 20 minutes. Rinse with 1.0 L / kg water. Stir for a minimum of 30 minutes at 22°C. Allow to settle for a minimum of 30 minutes. Separate and discard bottom aqueous layer. Concentrate under vacuum at a maximum of 45°C to a minimum volume. Charge a portion of THF to reactor and distill back to a minimum volume to complete the solvent exchange. Adjust reactor to 20°C. Charge 5.0 L / kg THF to reactor. Charge 1.00 mol compound 3 to reactor. Charge 10.0 L / kg THF to reactor. Adjust R1 to 32°C and stir for a minimum of 1 hour. Adjust the reactor to 15°C. Charge 1.50 mol / mol NaBH(OAc)3 in portions to the reactor at 15°C. Stir at 15°C for a minimum of 1 hour. Charge 5.0 L / kg water to the reactor at 15°C. Charge 3.05 mol / mol 50% aqueous NaOH to the reactor at 15°C and stir for a minimum of 2 hours. Rinse with 0.5 L / kg water. Allow to settle for a minimum of 30 minutes. Separate and discard the bottom aqueous layer. Charge 6.2 L / kg 20% ​​aqueous NaCl to the reactor at 15°C and stir for a minimum of 30 minutes. Allow to settle for a minimum of 30 minutes. Separate and discard the bottom aqueous layer. Concentrate under vacuum to 8.0 L / kg at a maximum of 45°C. Adjust the reactor to 25°C. Charge 8.0 L / kg EtOH (2% MeOH) and 8.0 L / kg water to the reactor at 25° C. Dose 2.0 L / kg water at 25° C. over a minimum of 2.5 hours. Charge 0.03 kg / kg crude Compound 4 seed to the reactor at 25° C. Stir at 25° C. for a minimum of 2 hours. Charge 6.0 L / kg water to the reactor at 25° C. over a minimum of 7.5 hours. Cool to 2.5° C. over a minimum of 7 hours. Stir at 2.5° C. for a minimum of 6 hours. Isolate the product and wash with THF / EtOH / water 1:1:2 (volume ratio). Dry the product at 25° C.

[0287] Example 3 - Preparation of pure Aticaplant

[0288] [ka]

[0289] Charge 1.0 mol of crude compound 4 to the dissolution reactor. Add 1.91 L / mol of 2-MeTHF. Add 2.39 L / mol of n-heptane. Stir reactor contents. Adjust temperature to 42° C. and stir for a minimum of 10 minutes until complete dissolution. Filter solution through a polishing filter into the crystallization reactor to remove possible insoluble material. Rinse the polishing filter. Stir at 40° C. for a minimum of 10 minutes. Cool to 20° C. over a minimum of 1 hour. Stir at 20° C. for a minimum of 10 minutes. Dose 1.23 L / mol of n-heptane over a minimum of 30 minutes at 20° C. Stir at 20° C. for a minimum of 10 minutes. Seed at 20° C. with 0.02 mol / mol of JNJ 67953964 AAA. Stir at 20° C. for a minimum of 8 hours. Dosing 3.68 L / mol n-heptane at 20° C. over a minimum of 12 hours. Stir at 20° C. for a minimum of 2 hours. Cool to 10° C. over a minimum of 3 hours. Stir at 10° C. for a minimum of 4 hours. Isolate compound 5. Wash the wet cake with 2-MeTHF / n-heptane (25 / 75 w / w%). Dry compound 5 at 50° C.

[0290] Compound 5 was characterized and the results are shown in Table 9.

[0291] [Table 11]

[0292] Atikaplant Form III was found to be crystalline by XRPD. 1 H NMR showed the material to be consistent with the proposed structure with residual ethyl acetate present. Ion chromatography showed no cations / anions present and HPLC showed 99.8% purity. DSC (heating 20° C. to 131° C. at 10° C. / min) showed a peak temperature at 121° C. See FIG. 3.

[0293] Example 4 - Tablets containing Atikaplant Tablets containing Aticaplant were prepared according to the scheme in FIG. 24 containing the ingredients in Table 10.

[0294] [Table 12]

[0295] Tablets were prepared as follows. 1. Using a suitable blender, combine the following screened ingredients in a blend: a. Atika Plant or Atika Plant Ultrafine Particles B microcrystalline cellulose c. Colloidal anhydrous silica D. Lactose monohydrate 2. Screen the blend using a suitable sieve. 3. Add the following sifted ingredients to the blend. Mix further using a suitable blender. Microcrystalline cellulose B lactose monohydrate 4. Screen the blend using a suitable sieve. 5. Add the following sifted ingredients to the blend. Mix further using a suitable blender. Microcrystalline cellulose B lactose monohydrate 6. Screen the blend using suitable sieves. 7. Add the following screened ingredients to the blend. Further mix using a suitable blender. Microcrystalline cellulose Lactose Monohydrate Croscarmellose sodium 8. Make dry granules using any suitable compression technique. 9. Add the following sieved ingredients to the dry granules and mix using a suitable blender: a. Silicified microcrystalline cellulose b. Croscarmellose sodium c. Colloidal anhydrous silica 10. Add the following sieved ingredients to the blend and mix using a suitable blender: a. Magnesium stearate 11. Compress the blend into core tablets using a suitable tablet press. 12. Suspend the coating powder in the purified water using a suitable container. 13. Spray the coating suspension onto the core tablets using a suitable coater. 14. Collect the film coated tablets and package them in suitable containers.

[0296] Example 5 - Testing of tablets containing Atikaplant The tablets of Example 3 are tested to determine dissolution characteristics and chemical stability. See Table 11 for dissolution conditions and Tables 12-13 for results.

[0297] [Table 13]

[0298] [Table 14]

[0299] [Table 15]

[0300] The chemical stability of the tablets is evaluated over a 28 day period using a Risk Based Predictive Stability (RiBPS) study. The stability protocol for the study is provided in Tables 14-15.

[0301] [Table 16]

[0302] [Table 17]

[0303] The ICH stability protocol is shown in Table 16.

[0304] [Table 18]

[0305] During the RiBPS study, the three major degradation products (RRT0.399, RRT0.466, and RRT0.874) showed an increasing trend over the storage period. The degradation levels ranged from 0.06% to 0.98% for RRT0.399, <0.05% to 0.39% for RRT0.466, and <0.05% to 0.99% for RRT0.874.

[0306] The results of the RiBPS study showed that the degradant RRT 0.466 is the shelf-life limiting attribute of the drug product.

[0307] The results demonstrated that for drug product stored in open dishes when stored at 25°C / 60% RH and 30°C / 75% RH, the probability of aging for 12 months was 99% with a specification limit of 0.30%.

[0308] Example 6 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).

[0309] 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.

[0310] Secondary objectives are to: To evaluate the efficacy of Aticaplant compared to placebo when administered as an adjunctive treatment in subjects with MDD who are partially responsive to SSRI / SNRI treatment, in reducing symptoms of depression as assessed by change from baseline in MADRS in both responders and non-responders during the placebo run-in period. ii. To investigate the overall safety and tolerability of adjunctive Aticaplant treatment in subjects with MDD when used in combination with an SSRI or SNRI. iii.To investigate the effects of Aticaplant versus placebo on depression-related anhedonia as assessed by SHAPS. iv. To investigate the effect of Aticaplant on symptoms of depression using the Clinical Global Impression-Severity (CGI-S), patient reported symptoms scale for Major Depressive Disorder (SMDDS) and Self-Evaluation of Treatment Experience (SATE). v. To investigate the effects of Aticaplant on symptoms of anxiety using the HAM-A and on core symptoms of anxiety using the HAM-A6 subscale. vi. To evaluate the plasma PK of Atikaplant in subjects with MDD and investigate its relationship with efficacy and safety parameters.

[0311] Secondary exploration objectives are to: To investigate the effects of Aticaplant on aspects of cognition and executive function using the CPFQ. ii. To explore mood-related biomarkers (including but not limited to growth factors, HPA axis markers, immune system activation, metabolic markers) and genetic / epigenetic variations that may be associated with clinical response, non-response, or safety and tolerability parameters of the Atticaplant.

[0312] B. Study Design For each subject, the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. See Figure 4.

[0313] 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.

[0314] The treatment phase consisted of three periods: a concealed placebo run-in period, after which subjects were randomly assigned to 10 mg of aticaplant (two 5 mg capsules) or placebo, lasting 6 weeks. Each capsule contained aticaplant (5 mg), microcrystalline cellulose (94.95 mg) and magnesium stearate (0.05 mg) in a hard gelatin capsule. Subjects who completed the treatment period entered a withdrawal period and were treated with placebo for the remainder of the treatment phase. The total duration of each subject was approximately 16 weeks. There were 11 scheduled visits, including screening. The overall flow is shown in Figure 4.

[0315] 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.

[0316] 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 17.

[0317] [Table 19]

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] If Visit 11 was scheduled for 3 days later, subjects continued taking medication until Visit 11.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] D. Clinical Evaluation (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Major Depressive Disorder Symptom Scale (SMDDS), and Self-Evaluation of Treatment Experience (SATE). (ii) Anhedonia: Snaith-Hamilton Pleasure Scale (SHAPS) (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and HAM-A6 (iv) Effects on cognition: Cognitive and Physical Functioning Questionnaire (CPFQ) (v) Safety assessment Standard safety evaluations were performed, including physical and neurological examinations, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI complaints in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical test panel to test for gastric mucosal status. (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Central sedative effect: Karolinska Sleepiness Scale (ix) Sexual dysfunction: ASEX

[0328] 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 18 and 19.

[0329] [Table 20]

[0330] [Table 21]

[0331] 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).

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] Efficacy endpoints were presented for both eITT and fITT.

[0337] 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.

[0338] 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

[0339] Enriched ITT analysis population The mean (SD) MADRS total score at treatment baseline was 29.0 (4.61) with a range of 19 to 41. See Figure 5. The mean change from treatment baseline (SD) in MADRS total score at week 6 of treatment was -10.2 (8.44) for Aticaplant and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 20-22 and Figure 8.

[0340] [Table 22]

[0341] [Table 23]

[0342] [Table 24]

[0343] Based on the results of the MMRM model with subject as a random effect; country, treatment, time, and treatment-by-time interactions as factors; and baseline MADRS total score as a continuous covariate. A significant positive efficacy signal was detected for Atikaplant versus placebo at the one-sided 0.20 significance level. The estimated LS mean difference between Atikaplant and placebo at week 6 of treatment was -2.1, with an upper 80% one-sided CI limit of -1.09. The corresponding p-value was 0.044. The treatment effect was larger in the fITT population than in the eITT population: -3.1, with an upper 80% one-sided CI limit of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figures 2 and 3.

[0344] Complete ITT Analysis Set The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86) with a range of 0 to 41. See Figures 7A and 7B. The mean change from treatment baseline in MADRS total score at treatment week 6 for fITT was smaller than for eITT: -9.7 (8.02) for Aticaplant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results indicate a statistical advantage over placebo with a persistence of effect with the largest difference seen at week 6. See Table 23.

[0345] [Table 25]

[0346] 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 24-25 and Figure 6.

[0347] [Table 26]

[0348] [Table 27]

[0349] 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.

[0350] (ii) Secondary Endpoints MADRS remission rate over the treatment period At week 6 of treatment, the percentage of subjects with MADRS remission (MADRS total score ≦10) in the eITT population was 16.9% for Atika plant and 16.9% for placebo. At week 6 of treatment, the remission rate in the fITT population was 31.2% for Atika plant and 22.2% for placebo. No significant treatment differences were detected at week 6 of treatment for both populations (eITT and fITT) using a chi-square test (two-tailed p=0.999 and p=0.203, respectively). See Figures 11 and 12.

[0351] 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).

[0352] MADRS response rate (at least 50% improvement) over the treatment period The proportion of subjects with a ≥ 50% improvement in MADRS total score at week 6 in the eITT population was 35.6% for the Atika plant and 22.0% for the placebo. The response rate at week 6 in the fITT population was 38.2% for the Atika plant and 23.5% for the 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 26 and Figures 13-16.

[0353] [Table 28]

[0354] 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.

[0355] 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 27 and Figures 17 and 37.

[0356] [Table 29]

[0357] The change in SHAPS total score was analyzed using the same MMRM model used for the MADRS total score. The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.7 [-1.81, 0.41]. See Figure 7 and Tables 28 and 29 and Figure 18. The corresponding p-value was 0.419.

[0358] [Table 30]

[0359] [Table 31]

[0360] The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.8 [-1.79, 0.10]. The corresponding p-value was 0.250. See Figures 7 and 8.

[0361] 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 30.

[0362] [Table 32]

[0363] 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 < 38, 20 ≤ 20), 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 31). The observed effect sizes were 0.38 and 0.11, respectively.

[0364] [Table 33]

[0365] 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% two-sided CI of [-8.4, -0.8] for subjects with high anhedonia levels (n=63) and -2.3 with a 90% two-sided CI of [-5.0, 0.4] for subjects with low anhedonia levels (n=94). See Table 32. The observed effect sizes were 0.51 and 0.29, respectively.

[0366] [Table 34]

[0367] 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.

[0368] Change from treatment baseline in CGI-S total score upon treatment

[0369] [Table 35]

[0370] Change from baseline in SMDDS total score at week 6 of treatment

[0371] [Table 36]

[0372] Number of subjects with SATE score at 6 weeks of treatment

[0373] [Table 37]

[0374] Change from baseline in HAM-A6 total score at week 6 of treatment

[0375] [Table 38]

[0376] These data show greater improvements in HAMA6 scores in Atticaplant treated patients versus placebo.

[0377] Change from treatment baseline in structured interview guide for SIGH-A scores at week 6 of treatment

[0378] [Table 39]

[0379] 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.

[0380] [Table 40]

[0381] (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 39.

[0382] [Table 41]

[0383] 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 40.

[0384] [Table 42]

[0385] 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.

[0386] 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 41.

[0387] [Table 43]

[0388] 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.

[0389] No deaths were reported.

[0390] (iv) Anhedonia analysis Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 42-44.

[0391] [Table 44]

[0392] The results show that the treatment effect was greater in patients with more anhedonia at baseline. See Figure 19.

[0393] [Table 45]

[0394] [Table 46]

[0395] The results show that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 20-A and 20-B. In Figure 20-A, i.e., in the high anhedonia group, the placebo + oral antidepressant group shows less placebo response compared to the low anhedonia group in Figures 7-8. Similarly, the treatment effect of the Aticaplant + oral antidepressant group is higher in the high anhedonia group compared to the low anhedonia group. Overall, the effect size is greater at all single time points (week 1 onwards) in the high anhedonia group. The LSMD in the high anhedonia group is more than twice that of the low anhedonia group at week 6. Furthermore, looking at symptom levels, there is a greater improvement in anhedonia and dysphoria-related items in the subgroup with high vs. low anhedonia. See Figure 21.

[0396] (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 45.

[0397] [Table 47]

[0398] (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.

[0399] 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 46 and 47.

[0400] [Table 48]

[0401] [Table 49]

[0402] (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.

[0403] 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.

[0404] Patients had sexual function measured using the ASEX, a standard, familiar rating scale. See Table 48.

[0405] [Table 50]

[0406] The mean change from treatment baseline (SD) in ASEX total score by week 6 was -1.5 (4.02) points for Atika Plant compared to -0.7 (2.98) points for placebo. Lower scores in ASEX indicate improvement. The score reduction at week 6 was greater in the Atika Plant group compared to placebo. This is unexpected, since adjunctive treatment with other drugs is expected to worsen sexual function, i.e., increase ASEX score over time. See Figure 22.

[0407] 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 attainment, and vaginal lubrication / erection. Most of the improvement is seen in items 3, 4, and 5 in Figure 23.

[0408] (viii) Onset of Effect The onset of effect for Atikaplant can be estimated from the study. Figure 10B shows the least squares mean change from baseline. A significant treatment effect in favor of Atikaplant was seen as early as week 3. At this time point, Atikaplant showed a statistically superior effect compared to placebo.

[0409] Example 7: Single-dose Aticaplant as adjunctive antidepressant therapy Study Design: A 6-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia (MDD ANH+) and who had an inadequate response to SSRIs or serotonin and SNRIs in the current depressive episode. See Figure 34.

[0410] For all subjects, the study will consist of three phases: an eligibility screening phase (up to 4 weeks prior to administration of the first dose), a 6-week double-blind treatment phase, and a 1-2 week follow-up. Subjects who complete the double-blind phase may enter an open-label long-term safety study.

[0411] Sample size and randomization: Approximately 544 subjects with MDD with prominent anhedonia (MDD ANH+) and MDD without prominent anhedonia (MDD ANH-) will be randomized in a 1:1 ratio to adjunctive placebo or acicaplant to achieve a minimum of 314 adult subjects meeting predefined criteria for MDD ANH+ eligible for inclusion in the primary analysis. Randomization will be stratified by study center, age group (adult [<65 years], elderly [>=65 years]), baseline anhedonia, and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0412] Dose and Administration All eligible subjects will receive either aticaplant or placebo in addition to their baseline SSRI / SNRI which will be continued throughout the study. Study medication will be taken daily.

[0413] Inclusion Criteria:

[0414] [Table 51]

[0415] Exclusion criteria:

[0416] [Table 52-1]

[0417] [Table 52-2]

[0418] A. Efficacy Objectives and Endpoints Assessment of primary and secondary (primary and other) endpoints will be performed on the FAS, which includes adult (non-elderly) subjects with MDD ANH+ who have taken at least one dose of study medication.

[0419] Primary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects with MDD ANH+ and an inadequate response to current antidepressants, as assessed by change from baseline in MADRS total score from Day 1 (pre-randomization) to the end of the 6-week double-blind treatment phase (Day 43): - Change from baseline to week 43 in MADRS total score.

[0420] Primary Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as adjunctive therapy to antidepressants on patient-reported assessment of anhedonia outcomes: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0421] Other Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as an adjunctive treatment for: Proportion of responders at Day 43 (≥ 50% reduction in MADRS total score). Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43. - Change in MADRS 6 from baseline to day 43. - Change in PHQ-9 score from baseline to week 43. - Change in SHAPS score from baseline to week 43. - Change in symptoms of anxiety using GAD-7 from baseline to day 43.

[0422] Exploratory: To evaluate the efficacy of Aticaplant as an adjunctive treatment compared to placebo in adult subjects with MDD ANH+ and all MDD subjects (adults and elderly subjects with MDD ANH+ and MDD ANH-) on: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to week 43 in SDS total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0423] To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH- as an adjunctive treatment for: -Change from baseline over time in MADRS total score. -Change from baseline over time in DARS total score.

[0424] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. ·AE includes AESI. An AE may be any untoward or unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product (investigational or non-investigational medicinal product), whether or not it is causally related to the medicinal product (investigational or non-investigational medicinal product). A TEAE was an AE that occurred during the treatment phase that worsened from baseline. The full safety analysis set included all enrolled subjects who received at least one dose of the investigational product during the treatment period. Vital signs ECG, laboratory data ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0425] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0426] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, except to treat AEs or breakthrough symptoms, as indicated, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening until first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin / agomelatine. Subjects taking benzodiazepine and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to and including 6 mg / day lorazepam) during the double-blind treatment phase. Dose escalation beyond the equivalent of 6 mg / day lorazepam or new benzodiazepine medications will not be permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. Any form of new psychotherapy or change in current psychotherapy is prohibited during the screening and double-blind phases. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0427] Example 8 - A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety, and tolerability of fixed doses of Aticaplant 5 mg and 10 mg as adjunctive therapy in adult and geriatric subjects with MDD with prominent anhedonia and inadequate response to current antidepressant therapy Study Design: An 8-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia and who have had an inadequate response to SSRIs or SNRIs in the current depressive episode. See Figure 35.

[0428] For all subjects, the study consisted of three phases: Eligibility Screening Phase (up to 4 weeks prior to first dose administration) 8-week double-blind treatment phase · and a 1-2 week follow-up phase.

[0429] Approximately 624 subjects (randomized in a 2:1:1 ratio to placebo, 5 mg acetaminophen, and 10 mg acetaminophen) will be enrolled in the study with the goal of achieving a minimum of 556 adult subjects with MDD with prominent anhedonia and approximately 68 elderly subjects (>= 65 years) with MDD with prominent anhedonia.

[0430] Subjects who complete the double-blind treatment phase may enter an open-label long-term safety study.

[0431] Sample size and randomization: Approximately 624 adult (<65 years) and elderly (>65 years) subjects with MDD with prominent anhedonia will be randomized in a 2:1:1 ratio to adjunctive placebo, 5 mg ataticaplant, or 10 mg ataticaplant to achieve a minimum of 556 adult subjects who meet the predefined criteria for MDD with prominent anhedonia eligible for inclusion in the primary efficacy analysis set. Randomization will be stratified by study center, age group (adult, elderly), and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0432] Dose and Administration: All eligible subjects will receive Aticaplant 5 mg, Aticaplant 10 mg, or placebo in addition to their baseline SSRI / SNRI, which will be continued for the entire study. Study medication will be taken daily.

[0433] Inclusion Criteria:

[0434] [Table 53]

[0435] Exclusion criteria:

[0436] [Table 54-1]

[0437] [Table 54-2]

[0438] A. Efficacy Objectives and Endpoints Assessment of the primary and secondary (primary and other) endpoints will be performed on the full analysis set (FAS), which includes adult (non-elderly) subjects with MDD with significant anhedonia who have taken at least one dose of study medication.

[0439] Primary: To evaluate the efficacy of two fixed doses of Aticaplant (5 mg and 10 mg) compared with placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects (18-64 years) with MDD with prominent anhedonia and inadequate response to current antidepressants. - Change from baseline to week 43 in MADRS total score.

[0440] Primary Secondary: To evaluate the efficacy of Aticaplant 10 mg compared with placebo as adjunctive therapy to antidepressants on patient-reported assessments of anhedonia outcomes in adult subjects with MDD with prominent anhedonia: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0441] Other secondary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in adult subjects with MDD with prominent anhedonia. Proportion of responders (≥ 50% reduction in MADRS total score) at Day 43 and Day 57. Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43 and Day 57. Changes from baseline to days 43 and 57 in MADRS-6 Change from baseline to Day 43 and Day 57 in the Patient Health Questionnaire, 9-item (PHQ-9) total score.

[0442] Exploratory: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD with prominent anhedonia as an adjunctive treatment: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to Day 43 in Sheehan Disability Scale (SDS) total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0443] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. AE includes AESI Vital signs ECG Test values ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0444] Other objectives (exploratory): To identify diagnostic biomarkers and investigate changes in MDD-related biomarkers in relation to clinical response to depression and anhedonia during monotherapy with Aticaplant. To identify genetic and other factors that may affect the pharmacokinetics (PK), safety, or tolerability of Atikaplant.

[0445] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0446] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, as indicated, except to treat AEs or breakthrough symptoms, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening until first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedative antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin. Subjects taking benzodiazepine and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to and including the 6 mg / day dose of lorazepam). Dose escalation beyond the equivalent of 6 mg / day lorazepam or new benzodiazepine medications will not be permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. During the screening and double-blind phases of the study, any form of new psychotherapy or change in current psychotherapy is prohibited. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0447] Example 9 This is a Phase 1, open-label, single-dose, multicenter, four-part study in healthy adult participants.

[0448] A total of approximately 80 eligible, healthy adult participants are planned to be enrolled in this study. 24 participants in each part will be enrolled to ensure that at least 20 participants in each part complete all required PK evaluations. Eligible participants may be enrolled in more than one part of the study, provided sufficient washout periods are completed between the participants' periods.

[0449] Potential participants will be screened from day -28 to day -2 to determine participant eligibility for study participation. For part 1, eligible participants will be admitted on day -1 of each treatment period and remain in the hospital for the entire duration of treatment (days -1 to 5, with single dose treatment on day 1 and 96 hours of PK), whereas for part 2, PK sampling will occur until 120 hours (day 6). Each dosed participant will undergo safety follow-up on days 10-14 after the last dose of study intervention.

[0450] Part 1 Part 1 of the study included the determination of the relative bioavailability for the tablet (formulation concept 1, i.e., unground Attica plant formulation, see Table 10) and capsule formulations (see Example 6, Study Design for description of capsule formulation) in healthy adult participants, as well as the dose proportionality and food effect for the tablet formulation (formulation concept 1) (Figure 25). Part 1 is comprised of subparts 1A and 1B, consisting of a total of four periods. Subpart 1A is a randomized, open-label, three-way crossover, three-period study conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg Atikaplant administered as a 1 x 10 mg oral tablet (formulation concept 1) under fasting conditions (treatment B) compared to 10 mg Atikaplant administered as a 2 x 5 mg oral capsule under fasting conditions (treatment A), and to evaluate the dose proportionality of a single dose of 5 mg Atikaplant administered as a 1 x 5 mg oral tablet (formulation concept 1) under fasting conditions (treatment C) compared to a potential Phase 3 oral tablet (formulation concept 1) under fasting conditions (1 x 10 mg, treatment B; Table 49). Participants will be assigned to one of six treatment sequences (Table 51) and will receive the three treatments in a three-way crossover. The same 24 participants who completed subpart 1A will be enrolled in subpart 1B. Subpart 1B consisted of a fourth period to evaluate the food effect of a single dose of 10 mg Aticaplant administered as a 1 x 10 mg oral tablet (Formulation Concept 1) under fed conditions (Treatment D; Tables 50 and 52). Preliminary PK analyses were performed at the end of the food effect part (Subpart 1B) for all periods from Part 1 and include food effect data.

[0451] [Table 55]

[0452] [Table 56]

[0453] [Table 57]

[0454] [Table 58]

[0455] ·Main purpose: -To evaluate the relative oral bioavailability of a potential Phase 3 tablet concept formulation (unmilled API formulation concept; 1 x 10 mg) compared to an oral capsule formulation of Achikaplant (2 x 5 mg) when administered as a single oral dose of 10 mg Achikaplant to healthy adult participants under fasting conditions. -To evaluate the dose proportionality of a potential Phase 3 tablet concept formulation (unmilled API formulation concept; 1 x 5 mg) against Atika Plant's potential Phase 3 tablet concept formulation (unmilled API formulation concept; 1 x 10 mg) when administered to healthy adult participants under fasting conditions. -To evaluate the PK of a single oral dose of Aticaplant in a potential Phase 3 tablet formulation (unmilled API formulation; 1 x 10 mg) in healthy adult participants under fasted and fed (high fat meal) conditions.

[0456] ·Secondary purpose: -To evaluate the safety and tolerability of oral administration of Atikaplant in healthy adult participants.

[0457] Part 2 Part 2 of the study included the determination of the relative bioavailability for the tablet (formulation concept 2, i.e., milled (ultrafine) Atica plant formulation; see Table 10) and capsule formulations (see Example 6, Study Design for description of capsule formulation), as well as the dose proportionality and food effect for the tablet formulation (formulation concept 2) in healthy adult participants (Figure 26). Part 2 consisted of subparts 2A and 2B, which consisted of a total of four periods. Subpart 2A is a randomized, open-label, three-way crossover, three-period study conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg Atikaplant (formulation concept 2) administered as a 1 x 10 mg oral tablet under fasting conditions (treatment F) compared with 10 mg Atikaplant administered as a 2 x 5 mg oral capsule under fasting conditions (treatment E), and to evaluate the dose proportionality of a single dose of 5 mg Atikaplant (formulation concept 2) administered as a 1 x 5 mg oral tablet under fasting conditions (treatment G) compared with a potential Phase 3 oral tablet (formulation concept 2) under fasting conditions (1 x 10 mg, treatment F; Table 53). Participants will be assigned to one of six treatment sequences (Table 55) and will receive the three treatments in a three-way crossover. The same 24 participants who completed subpart 2A will be enrolled in subpart 2B. Subpart 2B consists of a fourth period to evaluate the food effect of a single dose of 10 mg Aticaplant administered as a 1 x 10 mg oral tablet (formulation concept 2) under fed conditions (Treatment H; Tables 54 and 56). Preliminary PK analyses will be performed at the end of the food effect part (Subpart 2B) for all periods from Part 2 and will include food effect data.

[0458] [Table 59]

[0459] [Table 60]

[0460] [Table 61]

[0461] [Table 62]

[0462] ·Main purpose: -To evaluate the relative oral bioavailability of a potential Phase 3 tablet concept formulation (crushed ATICAPLANT formulation concept; 1 x 10 mg) compared to an oral capsule formulation of ATICAPLANT (2 x 5 mg) when administered as a single oral dose of 10 mg ATICAPLANT to healthy adult participants under fasting conditions. -To evaluate the dose proportionality of a potential Phase 3 tablet concept formulation (milled API formulation concept; 1 x 5 mg) against a potential Phase 3 tablet concept formulation of Atticaplant (milled Atticaplant formulation concept; 1 x 10 mg) when administered to healthy adult participants under fasting conditions. -To evaluate the PK of a single oral dose of ATIKAPLANT in a potential Phase 3 tablet concept formulation (crushed ATIKAPLANT formulation concept; 1 x 10 mg) in healthy adult participants under fasted and fed (high fat meal) conditions.

[0463] Additional points For each individual participant, there will be a washout period between subsequent intakes of the study intervention of at least 7 days for Part 1 and at least 8 days for Part 2. Day 1 of the treatment period (day of study intervention intake) will be the first day of the washout period (as well as between study parts, if applicable).

[0464] Participants will fast in Part 1A and Part 2A. Participants will be fed in Parts 1B and 2B. In the fasting condition, participants will fast overnight (eat nothing but drink nothing except non-carbonated water) for at least 10 hours prior to and 4 hours after study intervention administration during each fasting treatment period. A standardized lunch will be provided at the investigational site approximately 4 hours post-dose and after 4-hour PK sampling. Water intake will be permitted until 2 hours prior to study intervention intake. Thereafter, water intake will be permitted only for study intervention intake and breakfast portions, if applicable. Water will be available ad libitum beginning approximately 2 hours post-dose. In the fed condition, participants will consume a standardized high-fat breakfast within 20 minutes after an overnight fast (at least 10 hours). A high-fat meal (approximately 50 percent of the total caloric content of the diet) and a high-calorie meal (approximately 800-1000 calories) is recommended for food effect bioavailability testing (e.g., 2 strips of fried bacon, 2 buttered eggs, 4 ounces (120 grams) of buttered hash brown potatoes, 2 pieces of whole wheat bread, and 240 mL of whole milk). The study intervention will be administered approximately 30 minutes after the start of breakfast.

[0465] In Parts 1 and 2, plasma concentrations will be determined for Atikaplant. Blood draws to determine plasma concentrations of Atikaplant will be performed at pre-dose and post-dose time points beginning on Day 1 as shown in Tables 57-58.

[0466] Parts 1 and 2 of the exam may begin at any time, regardless of the other parts of the exam.

[0467] For parts 1 and 2, the study consisted of a screening phase (within 28 days prior to administration of the study intervention), an open-label treatment phase (days -1 to 5, with single-dose treatment on day 1, and at least 96-hour PK for part 1 and 120-hour PK (day 6) for part 2).

[0468] [Table 63]

[0469] [Table 64]

[0470] [Table 65]

[0471] [Table 66]

[0472] Definitions for Tables 57-58 (a) If scheduled procedures coincide, they should preferably be performed in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse / heart rate), blood / CSF collection for PK or laboratory measurements, and C-SSRS. (b) For all female participants. (c) Period 1 only. (d) Fed dosing period only. A standardized high-fat breakfast should be consumed within 20 minutes. (e) After an overnight fast of at least 10 hours, the study intervention will be administered in the morning under fasting conditions if dosing is under fasting conditions, and 30 minutes after breakfast during periods when dosing is under fed conditions. (f) For all postmenopausal women, FSH is performed to confirm the postmenopausal status in women without another medical cause. (g) After collection of 4-hour PK blood samples and / or CSF samples. (h) An additional 6 mL of blood will be drawn from each participant prior to dosing for experimental work related to parent and metabolite protein binding. (i) Severe acute respiratory syndrome (SARS-CoV-2) testing may be performed in accordance with region-specific guidelines or practices. (j) There are two versions of the C-SSRS. A baseline / screening version of the C-SSRS will be completed at screening, followed by a last visit version of the C-SSRS to be completed pre-dose on Day -1, prior to discharge on Day 5 of each treatment period (for Part 1), and prior to discharge on Day 6 of each treatment period (for Part 2), and at the end of the study or early withdrawal. (k) After discharge from the clinic, participants may be contacted by telephone for evaluation of adverse events. (l) Free and total plasma concentrations of Aticaplant are assayed. (m) (n) Blood pressure and respiratory rate are measured after 5 minutes of rest in the supine position. (o) Either urine alcohol testing or alcohol breath testing may be used for alcohol screening per locality-specific guidelines or practices. (p) Before insertion of the spinal catheter. (q) The catheter tip will be used for culture analysis whenever the catheter is kept in place for more than 24 hours.

[0473] A. Study Population A total of approximately 80 eligible, healthy adult participants are planned to be enrolled in this study. 24 participants each will be enrolled in Parts 1 and 2 to ensure that at least 20 participants in each part complete all required PK evaluations. Eligible participants may enroll in more than one part of the study, provided sufficient washout periods are completed between the participants' periods.

[0474] Screening of eligible participants will occur within 28 days prior to administration of the study intervention.

[0475] (i) Inclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study:

[0476] About all participants

[0477] [Table 67]

[0478] Other inclusions

[0479] [Table 68]

[0480] (ii) Exclusion criteria Potential participants who meet any of the following criteria will be excluded from participating in the study: For all participants:

[0481] [Table 69]

[0482] Other Exclusions Donation of blood or blood products or plasma or substantial loss of blood (>500 mL) within 3 months prior to the first administration of the study intervention in any part of the study, or any intention to donate blood or blood products during the study. Inability to swallow solid oral dosage forms with the aid of water (participant is unable to chew, disintegrate, dissolve, or crush the study intervention). History of smoking or use of nicotine-containing substances within the past 3 months prior to screening, as determined by medical history or participant's verbal report. · Vulnerable participants (e.g., people in custody). Drinking, on average, more than 8 cups of tea / coffee / hot chocolate / cola or other caffeinated beverages per day - Clinically significant acute illness within 7 days prior to administration of the study intervention. History of clinically significant drug and / or food allergies.

[0483] (iii) Meals and dietary restrictions 1. Participants must not consume grapefruit juice, bitter orange (including orange tangerines), or any food or beverage containing quinine (e.g., tonic water) from 48 hours (72 hours for grapefruit juice and bitter orange) prior to the first dose of study intervention until the last dose of study intervention. 2. No water is permitted within 2 hours prior to study intervention, except for 240 mL of non-carbonated water for receiving oral study intervention and water given with a high-fat breakfast. No water is permitted until 2 hours post-dose, after which water is available ad libitum. 3. Not to consume any food or beverages (including added salt or sugar) other than those provided by investigational site personnel during the hospital stay. 4. Must refrain from consuming methylxanthine-containing products (e.g., chocolate bars or beverages, coffee, tea, or cola) for 48 hours prior to administration of the study intervention and during hospitalization, and must avoid excessive caffeine intake (i.e., no more than approximately 500 mg / day, or no more than 5 cups of tea or coffee or 8 cans of cola) throughout the entire study period (including screening period and follow-up visits). 5. Not consume any food containing poppy seeds during the study beginning 72 hours prior to screening or 72 hours prior to admission to the study site during each treatment period (to avoid false positive urine drug tests for codeine).

[0484] Caffeine, alcohol, tobacco, and addictive drugs 1. Smoking tobacco (or equivalent) and / or use of nicotine-based products is not permitted from 3 months prior to study drug administration until completion of the follow-up visit. 2. Alcohol use should be limited to an absolute minimum. The best practice is to consume no alcohol at all from the initial screening visit until the follow-up visit. If any alcohol is consumed, consumption of up to two standard drinks per day is permitted. A standard drink is defined as a 350 mL glass of 5% ABV beer, a 150 mL glass of 12% ABV wine, or a 45 mL glass of 40% ABV (80 proof) spirits.

[0485] Activity 1. Strenuous exercise may affect study-specified assessments and safety test results. For this reason, strenuous exercise should be avoided within 48 hours prior to all scheduled study visits and throughout the stay at the CRC. Pre-exercise is permitted if the participant's serum creatinine concentration is within the normal range. Minor abnormalities not considered to be clinically relevant are acceptable. 2. Participants will be advised not to donate blood for at least 3 months after completion of the study or to participate in any investigational medicinal product trials for at least 1 month after completion of the study.

[0486] B. Study Intervention All study interventions will be administered with 240 mL of non-carbonated water on the morning of Day 1 of each treatment period. Study interventions must be swallowed whole, without chewing, cracking, dissolving, or crushing.

[0487] For each participant, all doses must be administered at approximately the same time.

[0488] Participants receiving the study intervention under fasting conditions will fast overnight for at least 10 hours.

[0489] Participants receiving the study intervention in the fed condition will fast overnight (at least 10 hours) followed by consuming a high-fat breakfast within 20 minutes. The high-fat breakfast will be the same as on dosing days of the fed period (Period 4 for Parts 1 and 2). The study intervention will be administered approximately 30 minutes after the start of breakfast.

[0490] Non-carbonated water will be allowed up to 2 hours prior to study intervention administration. Participants will continue to fast until at least 4 hours after study intervention administration. Water will be available ad libitum approximately 2 hours (but not earlier) after dosing. A standardized lunch will be provided to all participants on Day 1 following collection of the 4-hour PK blood sample. Participants may resume their usual diet 4 hours later.

[0491] The exact composition of breakfast and lunch is recorded. Lunch is the same for all intervention periods. The exact start and end times of breakfast and the start time of lunch are recorded along with any deviations regarding the timing of the meals.

[0492] Atikaplant will be supplied as a 5 mg capsule and 5 mg and 10 mg tablet formulations for this study.

[0493] Combination therapy Pre-study therapy administered up to 30 days prior to the first dose of study intervention must be recorded at screening.

[0494] All therapies different from the study drug (prescription or over-the-counter medications including vaccines, vitamins, herbal dietary supplements, non-pharmacological therapies such as electrical stimulation, acupuncture, special diets, exercise regimens, or other specific target categories) must be recorded. Information recorded includes a description of the type of therapy, duration of use, dosing regimen, route of administration, and its indication. Modification of active existing therapy should not be made for the express purpose of the participant entering the trial.

[0495] Any concomitant therapy that is considered to be a CYP inhibitor or inducer or a transport inhibitor or inducer will not be permitted during the study and will not be permitted for at least 1 month prior to receiving the first intake of the study intervention.

[0496] Throughout the study, prescription or non-prescription medications (including vitamins and herbal supplements) other than the study intervention are prohibited, with the exception of paracetamol. A maximum of three doses of 500 mg paracetamol per day, and no more than 3 g per week, will be permitted throughout the study for the treatment of headache or other pain.

[0497] Women who used hormonal contraceptives as a means of birth control must continue to use the same hormonal contraceptives throughout the study.Women who used hormone replacement therapy must continue to use the same hormone replacement therapy throughout the study.

[0498] C. Research Evaluation Tables 59 and 60 summarize the frequency and timing of PK measurements applicable to this study.

[0499] If multiple assessments are scheduled for the same time point, they should preferably be performed in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse / heart rate), blood / CSF draws for PK or laboratory measurements, and C-SSRS. Blood draws for PK assessments should be kept as close as possible to the designated time. Other measurements may be performed prior to the designated time point, if necessary.

[0500] The maximum amount of blood drawn in this study for each participant will not exceed 500 mL.

[0501] The total volume of CSF collected per participant enrolled in the CSF PK did not exceed 52.3 mL, which is considered acceptable given the daily CSF production rate.

[0502] [Table 70]

[0503] [Table 71]

[0504] (i) Vital signs Temperature, pulse / heart rate, respiratory rate, and blood pressure are assessed.

[0505] Blood pressure and pulse / heart rate measurements are assessed using a fully automated device consisting of an inflatable cuff and a vibration detection system. All values ​​are recorded on a built-in recorder to ensure that measurements are observer independent. Blood pressure and pulse / heart rate measurements are recorded after at least 5 minutes of rest in a quiet environment without distractions (e.g., television, mobile phones).

[0506] (ii) Electrocardiogram During ECG collection, subjects should be in a quiet environment free of distractions (e.g., television, cell phone). Subjects should rest in a supine position for at least 5 minutes prior to ECG collection and refrain from talking or moving their arms or legs. If blood draws or vital sign measurements are scheduled at the same time points as ECG recording, they should preferably be performed in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse / heart rate), blood draw / CSF collection for PK or laboratory measurements, and C-SSRS.

[0507] (iii) Columbia Suicide Severity Rating Scale (C-SSRS) The C-SSRS is a spectrum of suicidal thoughts and behaviors scale developed to assess the severity and track suicidal events throughout any treatment trial. It is a clinical interview to assess the risk of treatment-emergent suicidal thoughts / behaviors.

[0508] There are two versions of the C-SSRS: a baseline / screening version of the C-SSRS is completed at screening, followed by a last visit version of the C-SSRS completed pre-dose on day -1, prior to discharge on day 5 of each treatment period (for part 1), and prior to discharge on day 6 of each treatment period (for part 2), and at the end of the study or early withdrawal.

[0509] (iv) Fundus examination Fundusoscopy is a form of examination of the fundus of the eye. A WelChAllyn® PanOptic™ ophthalmoscope (Model 11810) is used according to internal standard operating procedures.

[0510] (v) Pharmacokinetics Plasma and CSF samples will be used to assess the PK of Aticaplant.

[0511] evaluation Blood samples (4 mL each) for determination of Aticaplant plasma concentrations are collected at the time points indicated in Tables 59-60.

[0512] Analytical procedures During the study, serial blood draws (4 mL each) for determination of ATC plasma concentrations will be taken at the time points shown in Tables 59-60.

[0513] To determine the concentrations of Atticaplants, plasma samples are analyzed using a validated, specific and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) method.

[0514] Parameters The following plasma PK parameters of Atikaplant will be determined: A non-compartmental model with extravascular input will be used for the pharmacokinetic analysis.

[0515] Based on the individual concentration-time data, using actual sampling times, the following PK parameters are derived for the Atika plant:

[0516] [Table 72]

[0517] t 1 / 2 , λ z , and AUC ∞ For an acceptable calculation of the following requirements should be met: A) At least three data points are used in the calculation, otherwise, t 1 / 2 , λ z and AUC ∞ cannot be evaluated. B) Coefficient of determination (r 2 adj) is at least 0.90.

[0518] If requirement (B) is not met, t 1 / 2 , λ z , and AUC ∞ are reported as approximations.

[0519] The actual sampling times are checked for major aberrations. If a major anomaly occurs for the actual sampling time with a deviation from the scheduled time of >20.00%, this plasma concentration is excluded from the descriptive statistics in the plasma concentration table.

[0520] Determining sample size PK parameters (AUC ∞ and C max The within-participant coefficient of variation (CV) for AUC ∞ For C, the rate is 8.3% to 10.4%. max The estimated CV for CI was 14.4%–24.3%. Therefore, a within-participant CV of 25% was used for this sample size justification.

[0521] Using a selected within-participant CV of 25% and N=20 or 24 completers, point estimates of geometric mean ratios for PK parameters of relative bioavailability (test vs. reference formulation), food effect (fed vs. fasted conditions), and dose proportionality with normalized PK parameters (AUC ∞ and C max The limits at which the concentration can be reduced are shown in Table 61.

[0522] [Table 73]

[0523] To ensure that 20 participants complete the study, 24 participants will be enrolled. If 20 participants do not complete the study, additional participants may be recruited.

[0524] Analysis set population For the purposes of the analysis, the following populations are defined:

[0525] [Table 74]

[0526] statistical analysis The statistical analysis plan was completed prior to DBL and includes a more technical and detailed description of the statistical analyses described in this section. This section is an overview of the planned statistical analyses of the most important endpoints.

[0527] Characteristics of early participants For all participants who received at least one dose of study intervention, descriptive statistics (mean, standard deviation, median, minimum, maximum) will be performed for age, BMI, weight, and height. Gender and race will be listed and tabulated.

[0528] Pharmacokinetic analysis Data will be listed for all participants with available plasma concentrations per intervention. All concentrations below the limit of quantification (LOQ) or missing data will be labeled as such in the concentration data listing. Concentrations below the LOQ will be treated as 0 in summary statistics and for calculation of pharmacokinetic parameters. All participants and samples excluded from analysis will be clearly documented in the clinical trial report.

[0529] Check for factors that may affect plasma concentrations (e.g., vomiting, high pre-dose concentrations).

[0530] Reasons for excluding a participant or sample from the analysis include, but are not limited to: C max Pre-dose aticaplant plasma concentrations higher than 5% Vomiting after study intervention administration of immediate release product (within 3 hours after administration under fasting conditions and within 8 hours after administration under fed conditions). (median T of 1.5 hours under fasting conditions) max and median T at 4 h under fed conditions max (Consider this). %AUC ∞ex If exceeds 20% for a given participant, the participant is excluded from the statistical analysis of AUC∞. Too little data (more than 10% missing values ​​per participant) Non-compliance with study procedures that affect pharmacokinetics (e.g., co-medication)

[0531] All participants and samples excluded from the analysis will be clearly documented in the study report.

[0532] For each intervention, statistics including arithmetic mean, standard deviation (SD), coefficient of variation (CV), geometric mean, median, minimum, and maximum will be calculated for ATIKAPLANT plasma concentrations at each sampling time and all PK parameters of ATIKAPLANT.

[0533] For relative bioavailability, graphical representations of the results include (but are not limited to) the following graph for Atika Plant: Log-linear and linear-linear plasma concentration-time profiles for each individual. Log-linear and linear-linear plasma concentration-time profiles for the mean values ​​per intervention. Log-linear and linear-linear plasma concentration-time profiles for the median values ​​per intervention. Log-linear and linear-linear overlay plots of individual plasma concentration-time profiles per intervention. Graph comparing individual and mean (±SD) primary PK parameters of Atikaplant by intervention.

[0534] For dose proportionality, graphical representations of the results include (but are not limited to) the following graph for Aticaplant: Log-linear and linear-linear plasma concentration-time profiles for each individual for all dose levels. Overlay graphs with observed mean plasma concentration-time profiles on log-linear and linear-linear scales for all dose levels. Overlay graphs with mean dose-normalized plasma concentration-time profiles on log-linear and linear-linear scales. C max ,AUC ∝ ,AUC last , and / or graphs of observed individual values ​​of AUC truncated to a common time point for dose. C max ,AUC ∝ ,AUC last , and / or graphs of observed dose-normalized individual values ​​of AUC truncated to a common time point.

[0535] The primary objectives of the statistical analysis are to estimate the relative bioavailability of the Atika Plant test formulation to the Atika Plant reference formulation, the dose proportionality of the Atika Plant test formulation, and the effect of food on the PK of the Atika Plant test formulation.

[0536] The primary parameters of interest in statistical analysis were log-transformed estimated AUC, AUC last , AUC ∞ , and C max If more than half of the participants do not have reliable values, the AUC ∞ is rejected as the primary parameter for the group. If one of the PK parameters of interest is not estimable for a given participant at one or more time periods, the participant's data will not be included in the statistical analysis for that particular PK parameter.

[0537] For relative bioavailability and dose proportionality in subpart 1A (i.e., only the first 3 periods were included in this analysis), dose-normalized AUC last , AUC ∞ , and C max Then, least squares means and within-participant variances are estimated using a mixed effects model that includes treatment, period, and treatment sequence as fixed effects and participant as a random effect. These estimated least squares means and within-participant variances are used to construct point estimates and 90% confidence intervals for the difference in means on the log scale between treatment B (test) and treatment A (reference), and between treatment C (test) and treatment B (reference). The limits of the confidence intervals are back transformed using antilogarithms to estimate the mean AUC and C of the test formulation relative to the reference formulation. max Obtain 90% confidence intervals for the ratios (Treatment B / Treatment A and Treatment C / Treatment B). Similar analyses for relative bioavailability and dose proportionality in Subpart 2A will be performed for Treatments E, F, and G.

[0538] For food effects in both Subpart 1B (Treatment D vs. Treatment B) and Subpart 2B (Treatment H vs. Treatment F), a mixed-effects model is fitted to the data with the logarithm of the PK parameters as the dependent variable, treatment (fed vs. fasted) as a fixed effect, and participant as a random effect. These estimated least squares means and within-participant variances from the mixed-effects model are used to construct point estimates and 90% confidence intervals for the difference in means on the log scale between Treatment D (fed) and Treatment B (fasted), and between Treatment H (fed) and Treatment F (fasted). The limits of the confidence intervals are back transformed using the antilogarithm to estimate the mean AUC and C under fed versus fasted conditions. max Obtain 90% confidence intervals for the corresponding ratios.

[0539] D. Results This study included two parts with a similar study design to investigate two different tablet formulation concepts with part 1 (uncrushed API tablet) and part 2 (crushed API tablet). Within each part, evaluations included the relative bioavailability of the immediate release tablet formulation (1 x 10 mg) versus the API in capsule formulation (2 x 5 mg), dose proportionality between 10 mg and 5 mg tablet strengths, and food effect evaluation at 10 mg tablet strength. Each part consisted of subpart A and subpart B with a total of four periods. Subpart A was a randomized, open-label, three-way, crossover, three-period study conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg of ATICAPLANT administered as a 1 x 10 mg oral tablet under fasting conditions compared to 10 mg of ATICAPLANT administered as a 2 x 5 mg oral capsule under fasting conditions, and to evaluate the dose proportionality of a single dose of 5 mg of ATICAPLANT administered as a 1 x 5 mg oral tablet under fasting conditions compared to 1 x 10 mg oral tablet under fasting conditions. The same 24 participants who completed subpart A were enrolled in subpart B, which consisted of a fourth period to evaluate the food effect of a single dose of 10 mg of Aticaplant administered as a 1 × 10 mg oral tablet under fed conditions.

[0540] The PK analysis results for Part 1 (uncrushed API tablet formulation), including PK parameters across treatments and statistical comparisons between treatments of interest, are shown in Tables 62-65. Table 62 summarizes the PK parameters across treatments in Part 1. Table 63 shows the statistical comparison results of the relative bioavailability of the 1×10 mg uncrushed API tablet and 2×5 mg API in capsule formulations. Table 64 shows the statistical comparison results of the dose proportionality between the 1×10 mg uncrushed API tablet and 1×5 mg uncrushed API tablet formulations. Table 65 shows the statistical comparison results of the food effect assessment with the 1×10 mg uncrushed API tablet when administered in the presence of a high-fat meal and that in the fasted state. The PK parameter results were comparable between the uncrushed API tablet (1×10 mg) and API in capsule (2×5 mg) formulations, and statistical evaluation using calculated geometric mean ratios showed that these two formulations were comparable and within the BE limits of the criteria. Dose proportionality was established between the 10 mg and 5 mg uncrushed API tablet formulation strengths based on dose-dependent increases in PK parameters, comparison of dose-normalized PK parameters, and statistical evaluation of calculated geometric mean ratios that were within the BE limits of 0.8 to 1.25. Finally, the uncrushed API tablet formulation demonstrated approximately a 40% increase in AUC when given at 10 mg in the presence of a high-fat meal compared to fasted condition dosing, as evidenced by the calculated geometric mean ratios for AUC.

[0541] The PK analysis results for Part 2 (crushed API tablet formulation), including PK parameters across treatments and statistical comparisons between treatments of interest, are shown in Tables 66-73. Table 70 summarizes the PK parameters across treatments in Part 2. Table 71 shows the statistical comparison results of the relative bioavailability of the 1 x 10 mg crushed API tablet and 2 x 5 mg API in capsule formulations. Table 72 shows the statistical comparison results of the dose proportionality between the 1 x 10 mg crushed API tablet and 1 x 5 mg crushed API tablet formulations. Table 73 shows the statistical comparison results of the food effect assessment with the 1 x 10 mg crushed API tablet when administered in the presence of a high fat meal versus fasted conditions. The PK parameter results were comparable between the crushed API tablet (1 x 10 mg) and API in capsule (2 x 5 mg) formulations, and statistical evaluation using calculated geometric mean ratios showed that these two formulations were comparable and within the BE limits of the criteria. Dose proportionality was established between the 10 mg and 5 mg crushed API tablet formulation strengths based on dose-dependent increases in PK parameters, comparison of dose-normalized PK parameters, and statistical evaluation of calculated geometric mean ratios that were within the BE limits of 0.8 to 1.25. Finally, the crushed API tablet formulation demonstrated approximately a 30% increase in AUC when 10 mg was given in the presence of a high-fat meal compared to fasted condition dosing, as evidenced by the calculated geometric mean ratios for AUC.

[0542] In summary, both the 1 x 10 mg crushed and uncrushed API tablet formulations were bioequivalent, demonstrating exposure to ATCAPLANT similar to that observed with the 10 mg reference API in capsule formulation (2 x 5 mg API in capsule). Dose proportionality was observed between the 10 mg and 5 mg tablet formulation strengths of each of the uncrushed and crushed API tablet formulation concepts. A moderate food effect of approximately 30% (crushed API tablet) and approximately 40% (uncrushed API tablet) in AUC was observed at 10 mg, with a slightly delayed median T of 2.00 h (crushed API tablet) and 2.75 h (uncrushed API tablet) in the presence of a high-fat meal versus 1.5 h under fasting conditions administration. maxA 40% food effect is not considered clinically important for many drugs, given that it is part of the PK variability and that there are no safety concerns at higher Akticaplant exposures. Therefore, Akticaplant can be administered with or without food.

[0543] (i) PK parameters

[0544] [Table 75]

[0545] (ii) Relative BA rating The 1 x 10 mg uncrushed API tablet concept may demonstrate exposure to Aticaplant similar to that observed with the 10 mg reference API in a capsule formulation (2 x 5 mg API in capsule).

[0546] [Table 76]

[0547] (iii) dose proportionality; Dose proportionality can be observed between 1 x 10 mg uncrushed API tablets versus 1 x 5 mg uncrushed API tablets.

[0548] [Table 77]

[0549] (iv) Food effect For a 10 mg uncrushed API tablet, T increased to approximately 3 hours in the presence of a high-fat meal versus 1.5 hours in the absence of a high-fat meal. max was delayed and a food effect (high fat meal) was observed (approximately 44% increase in AUC).

[0550] [Table 78]

[0551]

Table 79

[0552]

Table 80

[0553]

Table 81

[0554]

Table 82

Claims

1. A pharmaceutical composition comprising about 2 mg to about 20 mg of aticaplant and a filler, said composition comprising about 0.1% to about 90% by weight of aticaplant.

2. 10. The pharmaceutical composition of claim 1, further comprising one or more of a disintegrant, a glidant, a lubricant, a solvent, a colorant, and a binder.

3. 3. The pharmaceutical composition of claim 1, wherein the composition comprises from about 10% to about 99.9% by weight of a filler.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition comprises a disintegrant.

5. The pharmaceutical composition of claim 4, wherein the composition comprises from about 0.5% to about 50% by weight of a disintegrant.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition comprises a glidant.

7. The pharmaceutical composition of claim 6, wherein the composition comprises from about 0.1% to about 10% by weight of a glidant.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the composition comprises a lubricant.

9. 9. The pharmaceutical composition of claim 8, wherein the composition comprises from about 0.05% to about 5% by weight of a lubricant.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the composition comprises about 5% by weight of aticaplant, about 88.5% by weight of a filler, about 5% by weight of a disintegrant, about 1% by weight of a glidant, and about 0.5% by weight of a lubricant.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the composition is an oral tablet.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the composition is an oral tablet comprising about 200 mg of a core tablet, the core tablet comprising about 10 mg of aticaplant, about 10 mg of a disintegrant, about 177 mg of a filler, about 2 mg of a glidant, and about 1 mg of a lubricant.

13. 13. The pharmaceutical composition of claim 12, further comprising about 6 mg of a film coat.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the filler is selected from microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose.

15. The pharmaceutical composition according to any one of claims 2 to 14, wherein the disintegrant is croscarmellose sodium.

16. The pharmaceutical composition according to any one of claims 2 to 14, wherein the glidant is colloidal anhydrous silica.

17. The pharmaceutical composition according to any one of claims 2 to 16, wherein the lubricant is magnesium stearate.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the pharmaceutical composition is an oral tablet comprising about 10 mg of aticaplant, the oral tablet comprising about 200 mg of a core tablet, the core tablet comprising an intragranular phase and an extragranular phase, the intragranular phase comprising about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium, and about 1 mg of colloidal anhydrous silica, and the extragranular phase comprising about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of colloidal anhydrous silica, and about 1 mg of magnesium stearate.

19. A method for treating major depressive disorder (MDD) in a human patient, comprising administering to said patient a pharmaceutical composition according to any one of claims 1 to 18.

20. 20. The method of claim 19, wherein the patient has anhedonia.

21. The method according to any one of claims 19 to 20, wherein the pharmaceutical composition comprises about 5 mg to about 10 mg of aticaplant, about 5 mg of aticaplant, or about 10 mg of aticaplant.

22. The method of any one of claims 19 to 21, wherein the patient has had an inadequate response to other antidepressant therapies prior to said treatment with Aticaplant.

23. 23. The method of claim 22, wherein the other antidepressant therapy comprises one or more antidepressants.

24. 24. The method of claim 23, wherein the one or more antidepressants comprises an SSRI, an SNRI, or a combination thereof.

25. The method according to any one of claims 19 to 24, wherein the atica plant is S-atica plant.

26. The method according to any one of claims 19 to 25, wherein the attic plant is a crystalline attic plant.

27. 27. The method of any one of claims 19 to 26, further comprising treatment with an effective amount of one or more antidepressants.

28. 28. The method of claim 27, wherein the one or more antidepressants is an SSRI, an SNRI, or a combination thereof.

29. The method of any one of claims 19 to 28, wherein the pharmaceutical composition comprising aticaplant is orally administered once daily.

30. 30. The method of claim 29, wherein the pharmaceutical composition comprising Aticaplant is administered with or without food.

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