Compositions comprising atecatram

Abstract

The present disclosure relates to compositions comprising atecatram, including oral compositions in the form of tablets, and methods of using the compositions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 317,471, filed on March 7, 2022. Technical Field

[0003] The present disclosure relates to compositions, including oral compositions, comprising aticaprant and methods of use thereof. Background Art

[0004] The kappa opioid receptor (KOR) and its natural ligand, dynorphin, are located in areas of the brain that influence reward and stress and may play a key role in mood, stress, and addiction disorders. Chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, which activates KOR and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surges, which in turn induce negative affective states. Behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety and found to have meaningful effects, which may translate to therapeutic benefits in humans. KOR antagonists may be effective in treating patients with mood disorders by modulating negative affective states associated with stress responses.

[0005] Anhedonia is one of the core symptoms of depression. Approximately 90% of patients with major depressive disorder (MDD) experience at least mild anhedonia. Only approximately 50% of patients with MDD show a meaningful response (>50% improvement) to first-line antidepressant treatment, and thus many suffer substantial persistent impairment. Although treatment strategies such as switching antidepressants and using adjunctive pharmacotherapy can improve response, almost 40% of patients remain symptomatic and are unable to achieve complete remission.

[0006] What are needed are new compounds and treatments for patients suffering from depression and optionally anhedonia. Summary of the invention

[0007] In some aspects, the present disclosure provides a pharmaceutical composition comprising about 2 mg to about 20 mg of artikaplan and a filler, wherein the composition comprises between about 0.1 wt % to about 90 wt % artikaplan.

[0008] In other aspects, the present disclosure provides an oral tablet comprising about 5 mg of artikaplanam, wherein the oral tablet comprises about 100 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; 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 anhydrous colloidal silicon dioxide, and about 0.5 mg of magnesium stearate.

[0009] In a further aspect, the present disclosure provides an oral tablet comprising about 10 mg of artikaplanam, wherein the oral tablet comprises about 200 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silicon dioxide, and about 1 mg of magnesium stearate.

[0010] In yet other aspects, the present disclosure provides a pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplanam, wherein the composition has a pharmacokinetic (PK) profile comprising one or more of the following parameters following administration of the composition to a human (dose normalized to 10 mg) after at least 10 hours of fasting: (a) a mean C between about 20 ng / mL and 45 ng / mL; max ; (b) mean AUC between about 250 h*ng / mL and 450 h*ng / mL infinity ; (c) mean AUC between about 250 h*ng / mL and 450 h*ng / mL last ; and (d) a median t between about 1 hour and 4 hours max .

[0011] In yet another aspect, the present disclosure provides a method for treating major depressive disorder (MDD) in a human patient, the method comprising administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplan, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with artikaplan, and wherein administering the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the following PK parameters after administration of the composition to the human (dose normalized to 10 mg) after at least 10 hours of fasting: (a) a mean C between about 30 ng / mL and 40 ng / mL; (b) a mean C between about 10 ng / mL and 20 ng / mL; max ; (b) mean AUC between approximately 300 h*ng / mL and 430 h*ng / mL infinity; (c) mean AUC between approximately 280 h*ng / mL and 430 h*ng / mL last ; and (d) a median t between about 1 hour and 4 hours max .

[0012] In other aspects, the present disclosure provides a solid pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplan, wherein the composition has a dissolution curve comprising a Q value between about 60% and 90% at 45 minutes under the following dissolution operating conditions: equipment: 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 completion: UHPLC with UV detection at 247 nm.

[0013] In additional aspects, the present disclosure provides a method of treating major depressive disorder (MDD) in a human patient, the method comprising administering to the patient a pharmaceutical composition, oral tablet, or solid pharmaceutical composition described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is the x-ray powder diffraction (XRPD) pattern (transmission mode) of polymorphic Form III of Atikaplan.

[0015] Figure 2 is a differential scanning calorimetry (DSC) thermogram of polymorphic Form III of Atikaplan.

[0016] Figure 3 is the mDSC thermogram of polymorphic Form III of Atikaplan.

[0017] Figure 4 This is the experimental design of Example 1.

[0018] Figure 5 is a line graph showing the MADRS (Montgomery-Asberg Depression Rating Scale) total score: least squares mean change from baseline (± SE) during the treatment period for the enriched intention-to-treat (eITT) analysis set.

[0019] Figure 6 is a graph showing the change in MADRS total score at treatment week 6 for the enriched population and the entire population: MMRM Results—Estimated LS Means and Comparison with Placebo.

[0020] Figure 7 is a line graph showing the SHAPS (Snaith-Hamilton Hedonic Feeling Scale) Total Score: Least Squares Mean Change from Baseline (± SE) during the Treatment Period for the eITT Analysis Set.

[0021] Figure 8 Graphs showing the change in SHAPS total score at treatment week 6 for the enriched and full populations: MMRM (mixed effects model for repeated measures) results—estimated LS means and comparison with placebo.

[0022] Fig. 9 is a line graph showing the MADRS total score: mean (± SE) over time for the eITT analysis set.

[0023] Figure 10-A is a line graph showing MADRS total score: mean (± SE) over time for the full intention-to-treat (fITT) analysis set. Figure 10-B is an excerpt from Figure 10-A for treatment weeks 0 to 6.

[0024] Fig.11 is a line graph showing the MADRS total score: percentage of subjects with remission of depressive symptoms (total score ≤ 10) during the treatment period in the eITT analysis set.

[0025] Fig.12 is a line graph showing the MADRS total score: percentage of subjects with remission of depressive symptoms (total score ≤ 10) during the treatment period in the fITT analysis set.

[0026] Fig.13 is a line graph showing the MADRS total score: percentage of responders (≥30% improvement from baseline) during the treatment period for the eITT analysis set.

[0027] Fig.14 is a line graph showing the MADRS total score: percentage of responders (improvement ≥30% from baseline) during the treatment period for the fITT analysis set.

[0028] Fig.15 is a line graph showing the MADRS total score: percentage of responders (≥50% improvement from baseline) during the treatment period for the eITT analysis set.

[0029] Fig.16 is a line graph showing the MADRS total score: percentage of responders (≥50% improvement from baseline) during the treatment period for the fITT analysis set.

[0030] Fig.17 is a line graph showing the SHAPS total score: mean (± SE) over time for the eITT analysis set.

[0031] Fig.18 is a line graph showing SHAPS total score: mean (± SE) over time for the fITT analysis set.

[0032] Fig.19 Shown are the changes from baseline in MADRS according to anhedonia severity.

[0033] Figure 20-A is a line graph showing the change in MADRS from baseline for patients with high anhedonia (ie, SHAPS ≥ 38). Figure 20-B is a line graph showing the change in MADRS from baseline for patients with low anhedonia (ie, SHAPS < 38).

[0034] Fig.21 is a bar graph showing a comparison of MADRS for patients with low anhedonia and high anhedonia.

[0035] Fig. 22 is a line graph showing the change in mean ASEX total score from baseline.

[0036] Fig.23 is a bar graph showing the change from baseline in the ASEX item level change total score mean.

[0037] Fig.24 is a flow chart for a process for preparing a tablet containing artikaplan. In this figure, a It refers to micronized (ie ground) artikaplan.

[0038] Fig.25 is a schematic overview of part 1 of the study. In this figure, treatment A = 2 x 5 mg capsules; treatment B = 1 x 10 mg tablet concept 1; treatment C = 1 x 5 mg tablet concept 1; treatment D = 1 x 10 mg tablet concept 1, high fat diet.

[0039] Fig.26 is a schematic overview of Part 2 of the study. In this figure, a) Day 1 of the treatment period is the first day of the washout period. Treatment E: 2 x 5 mg oral capsules administered in the morning after at least 10 hours overnight fast. Treatment F: 1 x 10 mg formulation Concept 2 administered in the morning after at least 10 hours overnight fast. Treatment G: 1 x 5 mg formulation Concept 2 administered in the morning after at least 10 hours overnight fast. Treatment H: 1 x 10 mg formulation Concept 2 administered in the morning approximately 30 minutes after starting a standardized high-fat breakfast after at least 10 hours overnight fast.

[0040] Fig. 27 and Fig.28 Relative bioavailability results are shown for the artikaplan PK profile relative to the BA.

[0041] Fig.29 and Fig.30Relative bioavailability results (dose proportionality) of the artikaplanam PK profile are shown.

[0042] Figure 31 to Figure 33 Relative bioavailability results (food effect) of the artikaplan PK profile are shown.

[0043] Fig.34 This is the study protocol of Example 7. All patients will continue to take oral antidepressant SSRI / SNRI throughout the study. Approximately 34 additional elderly participants will be randomized.

[0044] Fig.35 This is the study protocol of Example 8. All patients will continue to take oral antidepressant SSRI / SNRI throughout the study. Approximately 68 additional elderly participants will be randomized.

[0045] Fig.36 Bar graph showing the SHAPS item: Change from baseline in LS mean of SHAPS total score at Week 6 for the fITT analysis set. In this graph, from top to bottom, the bars alternately represent placebo or artikaplanam. For example, the first bar refers to artikaplanam, the second bar refers to placebo, the third bar refers to artikaplanam, and so on.

[0046] Fig.37 is a graph showing the MADRS total score: LS mean difference (60%) according to different subgroups for the fITT analysis set at Week 6. In this graph, <17 indicates mild severity; 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe. DETAILED DESCRIPTION

[0047] All individual features mentioned herein (e.g., specific embodiments or specific preferred features) may be considered alone or in combination with any other features mentioned herein (including specific embodiments or preferred features); thus, preferred features may be used in conjunction with other preferred features, or independently of them (and similarly in combination with specific embodiments).

[0048] The present disclosure provides compositions comprising pure crystalline Form III artikaplan that is anhydrous and stable in solid form.

[0049] The term "crystal" refers to a solid form of a chemical moiety containing a highly ordered intermolecular structure.

[0050] The term "polymorph" refers to a crystalline form of a molecule having a specific crystal structure. A crystalline compound may have one crystalline form, or may have two or more crystalline forms (i.e., polymorphs). As will be appreciated by those skilled in the art, polymorphs of a chemical compound may be distinguished from one another by comparing physicochemical properties such as solubility, dissolution rate, stability, bioavailability, etc. 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 adsorption.

[0051] The term "crystal" refers to a solid state form of a chemical moiety in which atoms, molecules or ions are assembled in a highly ordered structure extending in all directions. Therefore, "crystal" includes all crystalline forms of Compound I (including its salts). Characterization of the crystalline form can be performed by a person skilled in the art, including but not limited to XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This is in contrast to the XRPD pattern of the amorphous form, which typically contains a broad peak without an identifiable peak. The crystalline form may be completely crystalline or partially crystalline. In some aspects, the crystalline sample may be 100% w / w crystalline. The crystalline sample may also contain amorphous solids. In certain aspects, the crystalline form may contain solids such that the sample is at least about 99% w / w crystalline, at least about 95% w / w amorphous, at least about 90% w / w crystalline, at least about 85% w / w crystalline, at least about 80% w / w crystalline, etc.

[0052] As used herein, the term "anhydrous" or "anhydrate" refers to a substantially water-free crystal as described herein. In some aspects, the anhydrous form contains less than about 1% w / w water. In other aspects, the anhydrous form contains less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w / w water.

[0053] 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 defined, the temperatures described may vary. In some aspects, the temperatures described herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.

[0054] Similarly, the 2θ values ​​obtained from the XRPD pattern may also vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, samples (including particle size, impurities, etc.), and / or laboratory conditions. Unless otherwise defined, the XRPD pattern and / or 2θ peak value may vary. In certain aspects, the 2θ peak value changes (increases or decreases) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more 2θ peak values ​​increase by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more 2θ peak values ​​decrease by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.

[0055] As used herein, the term "corresponding to" can be used to refer to certain spectra. Therefore, "corresponding to" includes spectra that are identical or substantially similar to another spectrum. Those skilled in the art will be able to compare such spectra and determine whether one spectrum corresponds to another spectrum. Therefore, the term "corresponding to" is used herein to compare XRPD diagrams, DSC thermograms, etc. In some aspects, when their 2θ values ​​are within the error boundaries as described above, one XRPD diagram corresponds to another XRPD diagram. In other aspects, when the peaks have the same 2θ peak value, but one or more peaks have different heights (intensities), one XRPD diagram corresponds to another XRPD diagram. In other aspects, when the peaks have the same 2θ peak value, but one or more peaks have different peak areas, one XRPD diagram corresponds to another XRPD diagram. In yet other aspects, when the peaks have the same 2θ peak value, but one or more peaks are blurred, one XRPD diagram corresponds to another XRPD diagram. This blurred peak may be due to impurities, excipients, etc. This blurred peak does not usually hinder the characterization of the crystalline form.

[0056] Unless otherwise indicated, as used herein, the term "artikaplan" refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, ie, the following compound:

[0057]

[0058] Also known as JNJ-67953964, 67953964-AAA, CERC-501, and LY-2456302. In some embodiments, "artikaplan" refers to the (S)-enantiomer of artikaplan, i.e., the following compound:

[0059]

[0060] Also known as (S)-artikaplanam or (S)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide. In other embodiments, the artikaplanam used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-artikaplanam or (R)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide having the following structure:

[0061]

[0062] In other embodiments, artikaplank contains less than about 10% by weight of the (R)-enantiomer of artikaplank, based on the weight of artikaplank. In additional embodiments, artikaplank contains less than about 10% by weight, about 9% by weight, about 8% by weight, about 7% by weight, about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, about 0.005% by weight, or about 0.001% by weight of the (R)-enantiomer of artikaplank, based on the weight of artikaplank. In yet other embodiments, artikaplank contains from about 0.001% to about 10% by weight of the (R)-enantiomer of artikaplank, based on the weight of artikaplank. In yet other embodiments, the artikaplanm contains from about 0.001% to about 10%, from about 0.001% to about 5%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 0.1% to about 5%, or from about 0.5% to about 5% by weight of the (R)-enantiomer of artikaplanm, based on the weight of artikaplanm.

[0063] The present invention also contemplates pharmaceutically acceptable salts of artikaplanam, which salts can be readily selected by one skilled in the art. "Pharmaceutically acceptable salts" refers to salts of artikaplanam that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. Generally, see 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 pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0064] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromates (such as hydrobromide), iodates (such as hydroiodide), acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, and the like. , maleate, butyne-1,4-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.

[0065] In some embodiments, artikaplanam is crystalline form III of artikaplanam. Crystalline form III of artikaplanam can be characterized by a variety of techniques, including, but not limited to, x-ray diffraction and differential scanning calorimetry. In some embodiments, crystalline form III of artikaplanam is characterized by x-ray diffraction. In other embodiments, crystalline form III of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°. In other embodiments, crystalline form III of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°. In yet other embodiments, the crystalline Form III of Artikaplanam 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 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°. In yet further embodiments, the crystalline Form III of Artikaplanam 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, the crystalline Form III of Artikaplanam 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 of Table 1.

[0066]

[0067] In yet other embodiments, the crystalline Form III of Atikaplan is characterized by the x-ray diffraction pattern peaks in Table 2.

[0068]

[0069] In yet other embodiments, the crystalline Form III of Atikaplan is characterized by the x-ray diffraction pattern peaks in Table 3.

[0070]

[0071]

[0072] In another embodiment, the crystalline form III of atikaplan is characterized by corresponding to Figure 1 X-ray powder diffraction pattern of .

[0073] Crystalline Form III of artikaplanam may also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram comprises a peak temperature (T m In other embodiments, the crystalline form III of atikaplan is characterized by corresponding to Figure 2 Differential scanning calorimetry thermogram of .

[0074] Pharmaceutical composition

[0075] The present disclosure also contemplates pharmaceutical compositions comprising artikaplan and one or more pharmaceutically acceptable excipients. As used herein, the term "composition" is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product obtained directly or indirectly by combining specified ingredients in specified amounts. A preferred pharmaceutical composition contains crystalline Form III of artikaplan as the active ingredient, intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a variety of forms depending on the form of the preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0076] The amount of artikaplanam present in the composition is from about 2 mg to about 60 mg. In some embodiments, the composition contains about 2 mg to about 20 mg of artikaplanam. In some embodiments, the composition contains about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of artikaplanam. In other embodiments, the composition contains about 5 mg to about 20 mg, about 10 mg to about 20 mg, about 15 mg to about 20 mg, about 1 mg to about 15 mg, about 2 mg to about 15 mg, about 5 mg to about 15 mg, about 10 mg to about 15 mg, about 1 mg to about 10 mg, about 2 mg to about 10 mg, or about 5 mg to about 10 mg of artikaplanam. In yet other embodiments, the effective amount of artikaplank is from about 5 mg to about 15 mg. In other embodiments, the amount of artikaplank is about 5 mg or 10 mg. In other embodiments, the amount of artikaplank is about 5 mg. In yet other embodiments, the amount of artikaplank is about 10 mg. The composition contains about 0.1% by weight to about 90% by weight of artikaplank. In some embodiments, the composition contains about 0.1% by weight, about 0.5% by weight, about 1% by weight, 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight of artikaplank based on the weight of the composition.In other embodiments, the composition comprises, based on the weight of the composition, from about 0.1 wt % to about 80 wt %, from about 0.1 wt % to about 70 wt %, from about 0.1 wt % to about 60 wt %, from about 0.1 wt % to about 50 wt %, from about 0.1 wt % to about 40 wt %, from about 0.1 wt % to about 30 wt %, from about 0.1 wt % to about 20 wt %, from about 0.1 wt % to about 10 wt %, from about 0.1 wt % to about 5 wt %, from about 0.1 wt % to about 1 wt %, from about 0.1 wt % to about 0.5 wt %, from about 1 wt % to about 90 wt %, from about 1 wt % to about 80 wt %, from about 1 wt % to about 70 wt %, from about 1 wt % to about 60 wt %, From about 1 wt % to about 50 wt %, from about 1 wt % to about 40 wt %, from about 1 wt % to about 30 wt %, from about 1 wt % to about 20 wt %, from about 1 wt % to about 10 wt %, from about 1 wt % to about 5 wt %, from about 5 wt % to about 90 wt %, from about 5 wt % to about 80 wt %, from about 5 wt % to about 70 wt %, from about 5 wt % to about 60 wt %, from about 5 wt % to about 50 wt %, from about 5 wt % to about 40 wt %, from about 5 wt % to about 30 wt %, from about 5 wt % to about 20 wt %, from about 5 wt % to about 10 wt %, from about 10 wt % to about 90 wt %, from about 10 wt % to about 80 wt %, from about 10 wt % to about 70 wt %, from about 10 wt % to about % to about 60% by weight, about 10% to about 60% 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 90% by weight, about 20% to about 80% by weight, about 20% to about 70% by weight, about 20% to about 60% 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 90% by weight, about 30% to about 80% by weight, about 30% to about 70% by weight, about 30% to about 60% by weight, about 30% to about 60% by weight, about 30% to about 40% by weight, about 20% to about 30% by weight, about 30% to about 90% by weight, about 30% to about 80% by weight, about 30% to about 70% by weight, about 30% to about 60% by weight, about 30% to about In another embodiment, the composition contains about 5% by weight of artikaplanam.In yet other embodiments, the composition contains about 6% by weight of artikaplanam. In yet other embodiments, the composition contains about 7% by weight of artikaplanam. In other embodiments, the composition contains about 8% by weight of artikaplanam. In other embodiments, the composition contains about 9% by weight of artikaplanam. In still other embodiments, the composition contains about 10% by weight of artikaplanam. The amount of artikaplanam administered according to the methods described herein can be determined by one skilled in the art, and unless otherwise indicated, the amount is stated based on the artikaplanam free base. That is, the amount indicates the amount of artikaplanam molecules administered in addition to, for example, solvent (such as in a solvate) or counter ions (such as in a pharmaceutically acceptable salt).

[0077] In some embodiments, the pharmaceutical composition has a specific pharmacokinetic (PK) profile at a specific dose. In some embodiments, the pharmaceutical composition has a PK profile that is proportional to the dose. In other embodiments, the pharmaceutical composition has a PK profile that is proportional to the dose, including parameters (e.g., exposure parameters, such as C max In other embodiments, the pharmaceutical composition has a PK profile or PK parameters that are proportional to a dose between about 1 mg and 60 mg of artikaplanam, between about 2 mg and 60 mg of artikaplanam, between about 2 mg and 40 mg of artikaplanam, between about 2 mg and 20 mg of artikaplanam, between about 2 mg and 15 mg of artikaplanam, between about 2 mg and 10 mg of artikaplanam, and between about 5 mg and 10 mg of artikaplanam.

[0078] Some embodiments include pharmaceutical compositions comprising artikaplan that are bioequivalent to any of the pharmaceutical compositions described herein. In some embodiments, the pharmaceutical composition comprises between about 2 mg and about 60 mg of artikaplan, between about 2 mg and about 20 mg of artikaplan, between about 5 mg and about 10 mg of artikaplan, or about 5 mg or about 10 mg of artikaplan, wherein the composition is bioequivalent to a pharmaceutical composition comprising artikaplan that, when administered to a human after at least 10 hours of fasting, produces a PK profile comprising one or more of: a mean Cmax between about 30 ng / mL and 35 ng / mL, a mean AUCinfinity between about 300 ng / mL and 320 ng / mL, and a median t of about 1.5 hours max(Doses were normalized to 10 mg). Bioequivalence can be demonstrated by any method known to those skilled in the art, such 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.

[0079] In some embodiments, the pharmaceutical composition comprises between about 2 mg and about 20 mg of artikaplanm, about 5 mg of artikaplanm, or about 10 mg of artikaplanm, wherein when the pharmaceutical composition is compared to a reference composition, the 90% confidence interval for the ratio of the geometric means of one or more PK parameters of the pharmaceutical composition and the reference composition is within the bioequivalence limits of 80% and 125%. In some embodiments, the reference composition is a composition comprising artikaplanm that, when administered to a human after at least 10 hours of fasting, produces a PK profile comprising one or more of: a mean Cmax between about 30 ng / mL and 35 ng / mL, a mean AUCinfinity between about 300 ng / mL and 320 ng / mL, and a median tmax of about 1.5 hours. max (Dose normalized to 10 mg). In some other embodiments, the reference composition has a PK profile of any of Treatment A, Treatment B, Treatment C, or Treatment D described in Table 69.

[0080] In some embodiments, the PK profile is based on administering a composition containing about 2 mg to about 60 mg of artikaplan to a human after at least 10 hours of fasting. In some other embodiments, the PK profile is based on administering a composition containing about 2 mg to about 60 mg of artikaplan to a human about 30 minutes after starting a high fat meal after at least 10 hours of fasting. As another example, the PK profile is based on administering a composition containing about 2 mg to about 20 mg of artikaplan to a human after at least 10 hours of fasting. In some embodiments, the PK profile is based on administering a composition containing about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of artikaplan to a human. In further embodiments, the PK profile is based on a combination of a pharmaceutical composition comprising about 2 mg to about 19 mg, about 2 mg to about 18 mg, about 2 mg to about 16 mg, about 2 mg to about 14 mg, about 2 mg to about 12 mg, about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, about 4 mg to about 20 mg, about 4 mg to about 18 mg, about 4 mg to about 16 mg, about 4 mg to about 14 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 8 mg, about 4 mg to about 6 mg, about 6 mg to about 20 mg, about 6 mg to about 18 mg, about 6 mg to about 16 mg, about 6 mg to about 14 mg, about 6 mg to about 12 mg, about 6 mg to about 10 mg, about 6 mg to about 8 mg, about 2 mg to about 6 mg The compositions of artikaplanam in an amount of 6 mg to about 8 mg, about 8 mg to about 20 mg, about 8 mg to about 18 mg, about 8 mg to about 16 mg, about 8 mg to about 14 mg, about 8 mg to about 12 mg, about 8 mg to about 10 mg, about 10 mg to about 20 mg, about 10 mg to about 18 mg, about 10 mg to about 16 mg, about 10 mg to about 14 mg, about 10 mg to about 12 mg, about 12 mg to about 20 mg, about 12 mg to about 18 mg, about 12 mg to about 16 mg, about 12 mg to about 14 mg, about 14 mg to about 20 mg, about 14 mg to about 18 mg, about 14 mg to about 16 mg, about 16 mg to about 20 mg, about 16 mg to about 18 mg, or about 18 mg to about 20 mg are administered to a human.

[0081] In certain aspects, the PK curve is determined after at least 10 hours of fasting. In some embodiments, the food fast is at least about 1 hour, about 2 hours, about 4 hours, about 5 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, about 22 hours, 24 hours, about 28 hours, or about 32 hours.

[0082] For example, the PK profile may include a range between about 1 ng / mL and about 100 ng / mL, between about 5 ng / mL and about 70 ng / mL, between about 5 ng / mL and about 65 ng / mL, between about 5 ng / mL and about 60 ng / mL, between about 5 ng / mL and about 55 ng / mL, between about 5 ng / mL and about 50 ng / mL, between about 5 ng / mL and about 45 ng / mL, between about 10 ng / mL and about 70 ng / mL, between about 10 ng / mL and about 65 ng / mL, between about 10 ng / mL and about The C of about 10 ng / mL to about 60 ng / mL, about 10 ng / mL to about 55 ng / mL, about 10 ng / mL to about 50 ng / mL, about 10 ng / mL to about 45 ng / mL, about 13 ng / mL to about 60 ng / mL, about 13 ng / mL to about 55 ng / mL, about 13 ng / mL to about 50 ng / mL, about 20 ng / mL to about 70 ng / mL, about 20 ng / mL to about 65, or about 20 ng / mL to about 63 ng / mL (dose normalized to 10 mg) is preferably between about 10 ng / mL and about 55 ng / mL, about 10 ng / mL to about 50 ng / mL, about 10 ng / mL to about 45 ng / mL, about 13 ng / mL to about 60 ng / mL, about 13 ng / mL to about 55 ng / mL, about 13 ng / mL to about 50 ng / mL, about 20 ng / mL to about 70 ng / mL, about 20 ng / mL to about 65, or about 20 ng / mL to about 63 ng / mL (dose normalized to 10 mg) max In some embodiments, when administered after at least 10 hours of fasting, the PK profile includes a C ranging between about 20 ng / mL and about 45 ng / mL, between about 22 ng / mL and about 45 ng / mL, between about 23 ng / mL and about 45 ng / mL, or between about 24 ng / mL and about 44 ng / mL (dose normalized to 10 mg). max In some embodiments, the PK profile includes a C ranging between about 25 ng / mL and about 50 ng / mL, between about 27 ng / mL and about 38 ng / mL, between about 25 ng / mL and about 40 ng / mL, or between about 28 ng / mL and about 38 ng / mL (dose normalized to 10 mg) when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting. max .

[0083] In some embodiments, the PK profile comprises a range between about 50 h*ng / mL and about 800 h*ng / mL, between about 100 h*ng / mL and about 500 h*ng / mL, between about 100 h*ng / mL and about 480 h*ng / mL, between about 100 h*ng / mL and about 450 h*ng / mL, between about 100 h*ng / mL and about 400 h*ng / mL, between about 110 h*ng / mL and about 500 h*ng / mL, between about 110 h*ng / mL and about 480 h*ng / mL, between about 110 h*ng / mL and about 450 h*ng / mL, AUC between about 110 h*ng / mL and about 400 h*ng / mL, between about 150 h*ng / mL and about 700 h*ng / mL, between about 200 h*ng / mL and about 700 h*ng / mL, between about 200 h*ng / mL and about 650 h*ng / mL, between about 250 h*ng / mL and about 450 h*ng / mL, between about 280 h*ng / mL and about 420 h*ng / mL, between about 290 h*ng / mL and about 410 h*ng / mL, or between about 210 h*ng / mL and about 650 h*ng / mL (dose normalized to 10 mg) infinity In some embodiments, when administered after at least 10 hours of fasting, the PK profile includes an AUC ranging between about 200 h*ng / mL and about 400 h*ng / mL, between about 210 h*ng / mL and about 400 h*ng / mL, between about 210 h*ng / mL and about 398 h*ng / mL, between about 220 h*ng / mL and about 400 h*ng / mL, or between about 220 h*ng / mL and about 398 h*ng / mL (dose normalized to 10 mg). infinity In some embodiments, when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting, the PK profile includes an AUC ranging between about 300 h*ng / mL and about 600 h*ng / mL, between about 300 h*ng / mL and 550 h*ng / mL, or between about 320 h*ng / mL and about 530 h*ng / mL (dose normalized to 10 mg). infinity .

[0084] In some embodiments, the PK profile comprises a range between about 50 h*ng / mL and about 800 h*ng / mL, between about 100 h*ng / mL and about 500 h*ng / mL, between about 100 h*ng / mL and about 480 h*ng / mL, between about 100 h*ng / mL and about 450 h*ng / mL, between about 100 h*ng / mL and about 400 h*ng / mL, between about 110 h*ng / mL and about 500 h*ng / mL, between about 110 h*ng / mL and about 480 h*ng / mL, between about 110 h*ng / mL and about 450 h*ng / mL, AUC between about 110 h*ng / mL and about 400 h*ng / mL, between about 150 h*ng / mL and about 700 h*ng / mL, between about 200 h*ng / mL and about 700 h*ng / mL, between about 200 h*ng / mL and about 650 h*ng / mL, between about 250 h*ng / mL and about 450 h*ng / mL, between about 280 h*ng / mL and about 420 h*ng / mL, between about 290 h*ng / mL and about 410 h*ng / mL, or between about 210 h*ng / mL and about 650 h*ng / mL (dose normalized to 10 mg) last In some embodiments, the PK profile includes an AUC ranging between about 300 and about 400 (dose normalized to 10 mg). last .

[0085] In some embodiments, the PK profile comprises a t ranging between about 0.5 hours and about 5 hours, between about 1 hour and about 4.5 hours, between about 1 hour and about 4 hours, between about 1 hour and about 3 hours, between about 1 hour and about 2.5 hours, or between about 1 hour and about 2 hours. max In some embodiments, when administered after at least 10 hours of fasting, the PK profile includes a t ranging between about 1 hour and about 2.5 hours, between about 1 hour and about 2 hours, or between about 1 hour and about 3 hours. max In some embodiments, when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting, the PK profile includes a t range of between about 1 hour and about 4 hours. max .

[0086] In some embodiments, the PK profile comprises a t ranging between about 5 hours and about 60 hours, between about 5 hours and about 55 hours, between about 5 hours and about 50 hours, between about 5 hours and about 45 hours, between about 5 hours and about 40 hours, between about 9 hours and about 60 hours, between about 9 hours and about 55 hours, between about 9 hours and about 50 hours, between about 9 hours and about 45 hours, or between about 9 hours and about 40 hours. 1 / 2 .

[0087] In some embodiments, the PK profile comprises a range between about 0.010 1 / hour and about 0.080 1 / hour, between about 0.010 1 / hour and about 0.075 1 / hour, between about 0.010 1 / hour and about 0.070 1 / hour, between about 0.015 1 / hour and about 0.080 1 / hour, between about 0.015 1 / hour and about 0.075 1 / hour, between about 0.015 1 / hour and about 0.070 1 / hour, between about 0.015 1 / hour and about 0.065 1 / hour, between about 0.015 1 / hour and about 0.060 1 / hour, between about 0.015 1 / hour and about 0.055 1 / hour, or between about 0.015 λ between 1 / hour and about 0.0501 / hour z .

[0088] In some other embodiments, the PK profile includes a range between about 10 L / h and about 90 L / h, between about 10 L / h and about 85 L / h, between about 10 L / h and about 80 L / h, between about 10 L / h and about 75 L / h, between about 10 L / h and about 70 L / h, between about 10 L / h and about 60 L / h, between about 10 L / h and about 50 L / h, between about 15 L / h and about 90 L / h, between about 15 L / h and about In some embodiments, the present invention provides a CL / F of between about 20 L / h and about 80 L / h, between about 15 L / h and about 70 L / h, between about 15 L / h and about 60 L / h, between about 15 L / h and about 50 L / h, between about 20 L / h and about 90 L / h, between about 20 L / h and about 80 L / h, between about 20 L / h and about 75 L / h, between about 20 L / h and about 70 L / h, between about 20 L / h and about 60 L / h, or between about 20 L / h and about 50 L / h.

[0089] In some other embodiments, the PK profile includes a range between about 400L and about 6000L, between about 400L and about 5500L, between about 400L and about 5000L, between about 400L and about 4000L, between about 400L and about 3500L, between about 400L and about 3400L, between about 450L and about 3500L, between about 450L and about 3000L, between about 5 ... Vd / F between about 500L and about 3000L, between about 400L and about 2000L, between about 400L and about 1500L, between about 400L and about 1200L, between about 550L and about 3500L, between about 550L and about 3000L, between about 600L and about 3500L, between about 600L and about 3000L, between about 600L and about 2500L, or between about 450L and about 1200L.

[0090] For example, when the dose is normalized to 10 mg, the PK profile may include a mean C between about 20 ng / mL and 45 ng / mL. max In some embodiments, the average C max In other embodiments, the average C is about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 34 ng / mL, about 35 ng / mL, about 36 ng / mL, about 37 ng / mL, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, or about 55 ng / mL (dose normalized to 10 mg). In other embodiments, the average C maxIn another embodiment, the average C is about 20 ng / mL to about 40 ng / mL, about 20 ng / mL to about 35 ng / mL, about 20 ng / mL to about 30 ng / mL, about 20 ng / mL to about 25 ng / mL, about 25 ng / mL to about 45 ng / mL, about 25 ng / mL to about 40 ng / mL, about 25 ng / mL to about 35 ng / mL, about 25 ng / mL to about 30 ng / mL, about 30 ng / mL to about 45 ng / mL, about 30 ng / mL to about 40 ng / mL, about 30 ng / mL to about 35 ng / mL, about 35 ng / mL to about 45 ng / mL, about 35 ng / mL to about 40 ng / mL, or about 40 ng / mL to about 45 ng / mL (dose normalized to 10 mg). In another embodiment, when administered after at least 10 hours of fasting, the average C max Between about 30 ng / mL and 35 ng / mL, between about 31 ng / mL and 35 ng / mL, or between about 31 ng / mL and 34 ng / mL (dose normalized to 10 mg). In other embodiments, when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting, the mean C max Between about 35 ng / mL and 40 ng / mL, between about 36 ng / mL and 39 ng / mL, or between about 37 ng / mL and 38 ng / mL (dose normalized to 10 mg).

[0091] The PK profile may also have a mean AUC between about 250 h*ng / mL and 450 h*ng / mL. infinity (Dose normalized to 10 mg). In some embodiments, AUC infinity is about 250 h*ng / mL, about 260 h*ng / mL, about 270 h*ng / mL, about 280 h*ng / mL, about 290 h*ng / mL, about 300 h*ng / mL, about 310 h*ng / mL, about 320 h*ng / mL, about 330 h*ng / mL, about 340 h*ng / mL, about 350 h*ng / mL, about 360 h*ng / mL, about 370 h*ng / mL, about 380 h*ng / mL, about 390 h*ng / mL, about 400 h*ng / mL, about 410 h*ng / mL, about 420 h*ng / mL, about 430 h*ng / mL, about 440 h*ng / mL, or about 450 h*ng / mL (dose normalized to 10 mg). In other embodiments, the average AUC infinityThe range of about 250 h*ng / mL to about 400 h*ng / mL, about 250 h*ng / mL to about 375 h*ng / mL, about 250 h*ng / mL to about 350 h*ng / mL, about 250 h*ng / mL to about 325 h*ng / mL, about 250 h*ng / mL to about 300 h*ng / mL, about 250 h*ng / mL to about 275 h*ng / mL, about 275 h*ng / mL to about 450 h*ng / mL, about 275 h*ng / mL to about 425 h*ng / mL, about 275 h*ng / mL to about 400 h*ng / mL, about 275 h*ng / mL to about 375 h*ng / mL, about 2 75 h*ng / mL to about 350 h*ng / mL, about 275 h*ng / mL to about 325 h*ng / mL, about 275 h*ng / mL to about 300 h*ng / mL, about 300 h*ng / mL to about 450 h*ng / mL, about 300 h*ng / mL to about 425 h*ng / mL, about 300 h*ng / mL to about 400 h*ng / mL, about 300 h*ng / mL to about 390 h*ng / mL, about 300 h*ng / mL to about 380 h*ng / mL, about 300 h*ng / mL to about 370 h*ng / mL, about 300 h*ng / mL to about 360 h*ng / mL, about 300 h*ng / mL to about 365 h*ng / mL, about 300 h*ng / mL to about ng / mL to about 350h*ng / mL, about 300h*ng / mL to about 340h*ng / mL, about 300h*ng / mL to about 330h*ng / mL, about 300h*ng / mL to about 320h*ng / mL, about 300h*ng / mL to about 310h*ng / mL, about 325h*ng / mL to about 450h*ng / mL, about 325h*ng / mL to about 425h*ng / mL, about 325h*ng / mL to about 400h*ng / mL, about 325h*ng / mL to about 375h*ng / mL, about 325h*ng / mL to about 350h*ng / mL, about 350h*ng / mL mL to about 450 h*ng / mL, about 350 h*ng / mL to about 425 h*ng / mL, about 350 h*ng / mL to about 400 h*ng / mL, about 350 h*ng / mL to about 375 h*ng / mL, about 375 h*ng / mL to about 450 h*ng / mL, about 375 h*ng / mL to about 425 h*ng / mL to about 375 h*ng / mL to about 400 h*ng / mL, about 400 h*ng / mL to about 450 h*ng / mL, about 400 h*ng / mL to about 425 h*ng / mL, or about 425 h*ng / mL to about 450 h*ng / mL (dose normalized to 10 mg).In further embodiments, when administered after at least 10 hours of fasting, the mean AUC. infinity Between about 300 h*ng / mL and 320 h*ng / mL (dose normalized to 10 mg). In another embodiment, when administered about 30 minutes after starting a high fat meal after at least 10 hours of fasting, the mean AUC infinity Between approximately 320 h*ng / mL and 530 h*ng / mL (dose normalized to 10 mg).

[0092] In other aspects, the pharmaceutical composition has a mean AUC comprised between about 250 h*ng / mL and 450 h*ng / mL (dose normalized to 10 mg). last In some embodiments, AUC last In some embodiments, the average AUC is about 250 h*ng / mL, about 260 h*ng / mL, about 270 h*ng / mL, about 280 h*ng / mL, about 290 h*ng / mL, about 300 h*ng / mL, about 310 h*ng / mL, about 320 h*ng / mL, about 330 h*ng / mL, about 340 h*ng / mL, about 350 h*ng / mL, about 360 h*ng / mL, about 370 h*ng / mL, about 380 h*ng / mL, about 390 h*ng / mL, about 400 h*ng / mL, about 410 h*ng / mL, about 420 h*ng / mL, about 430 h*ng / mL, about 440 h*ng / mL or about 450 h*ng / mL. In other embodiments, the average AUC lastThe range of about 250 h*ng / mL to about 400 h*ng / mL, about 250 h*ng / mL to about 375 h*ng / mL, about 250 h*ng / mL to about 350 h*ng / mL, about 250 h*ng / mL to about 325 h*ng / mL, about 250 h*ng / mL to about 300 h*ng / mL, about 250 h*ng / mL to about 275 h*ng / mL, about 275 h*ng / mL to about 450 h*ng / mL, about 275 h*ng / mL to about 425 h*ng / mL, about 275 h*ng / mL to about 400 h*ng / mL, about 275 h*ng / mL to about 375 h*ng / mL, about 2 75 h*ng / mL to about 350 h*ng / mL, about 275 h*ng / mL to about 325 h*ng / mL, about 275 h*ng / mL to about 300 h*ng / mL, about 300 h*ng / mL to about 450 h*ng / mL, about 300 h*ng / mL to about 425 h*ng / mL, about 300 h*ng / mL to about 400 h*ng / mL, about 300 h*ng / mL to about 390 h*ng / mL, about 300 h*ng / mL to about 380 h*ng / mL, about 300 h*ng / mL to about 370 h*ng / mL, about 300 h*ng / mL to about 360 h*ng / mL, about 300 h*ng / mL to about 365 h*ng / mL, about 300 h*ng / mL to about ng / mL to about 350h*ng / mL, about 300h*ng / mL to about 340h*ng / mL, about 300h*ng / mL to about 330h*ng / mL, about 300h*ng / mL to about 320h*ng / mL, about 300h*ng / mL to about 310h*ng / mL, about 325h*ng / mL to about 450h*ng / mL, about 325h*ng / mL to about 425h*ng / mL, about 325h*ng / mL to about 400h*ng / mL, about 325h*ng / mL to about 375h*ng / mL, about 325h*ng / mL to about 350h*ng / mL, about 350h*ng / mL mL to about 450 h*ng / mL, about 350 h*ng / mL to about 425 h*ng / mL, about 350 h*ng / mL to about 400 h*ng / mL, about 350 h*ng / mL to about 375 h*ng / mL, about 375 h*ng / mL to about 450 h*ng / mL, about 375 h*ng / mL to about 425 h*ng / mL to about 375 h*ng / mL to about 400 h*ng / mL, about 400 h*ng / mL to about 450 h*ng / mL, about 400 h*ng / mL to about 425 h*ng / mL, or about 425 h*ng / mL to about 450 h*ng / mL (dose normalized to 10 mg).In further embodiments, the PK profile has a mean AUC between about 280 h*ng / mL and 310 h*ng / mL. last (Doses normalized to 10 mg).

[0093] In yet another aspect, the pharmaceutical composition has a median t included between about 1 hour and 4 hours. max In some embodiments, the median t max t is about 1 hour, about 1.1 hours, about 1.2 hours, about 1.3 hours, about 1.4 hours, about 1.5 hours, about 1.6 hours, about 1.7 hours, about 1.8 hours, about 1.9 hours, about 2 hours, about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, about 2.9 hours, about 3 hours, about 3.1 hours, about 3.2 hours, about 3.3 hours, about 3.4 hours, about 3.5 hours, about 3.6 hours, about 3.7 hours, about 3.8 hours, about 3.9 hours, or about 4 hours. In other embodiments, the median t max In another embodiment, the median t is about 1 hour to about 3.5 hours, about 1 hour to about 3 hours, about 1 hour to about 2.5 hours, about 1 hour to about 2 hours, about 1 hour to about 1.5 hours, about 1.5 hours to about 4 hours, about 1.5 hours to about 3.5 hours, about 1.5 hours to about 3 hours, about 1.5 hours to about 2.5 hours, about 1.5 hours to about 2 hours, about 2 hours to about 4 hours, about 2 hours to about 3.5 hours, about 2 hours to about 3 hours, about 2 hours to about 2.5 hours, about 2.5 hours to about 4 hours, about 2.5 hours to about 3.5 hours, about 2.5 hours to about 3 hours, about 3 hours to about 4 hours, about 3 hours to about 3.5 hours, or about 3.5 hours to about 4 hours. In another embodiment, the median t max For about 1.5 hours.

[0094] In some embodiments, the pharmaceutical composition comprises a PK profile for Treatment A, Treatment B, Treatment C, or Treatment D as shown in Table 69.

[0095] In some embodiments, the pharmaceutical composition has a mean C of about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 34 ng / mL, or about 35 ng / mL (dose normalized to 10 mg) when administered after at least 10 hours of fasting. max In some embodiments, the pharmaceutical composition has a mean C of about 31.2 ng / mL. maxand a standard deviation of about 6.9 ng / mL (dose normalized to 10 mg). In some embodiments, the pharmaceutical composition comprises about 10 mg of artikaplanam and has a mean C of about 34.1 ng / mL when administered after at least 10 hours of fasting. max In some embodiments, the pharmaceutical composition comprises about 5 mg of artikaplanam 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 10 hours of fasting.

[0096] In some embodiments, the pharmaceutical composition has a PK profile (dose normalized to 10 mg) comprising a mean Cmax of about 36 ng / mL, about 37 ng / mL, about 38 ng / mL, about 39, or about 35 ng / mL when administered about 30 minutes after a high fat meal is initiated after at least 10 hours of fasting. In some embodiments, the pharmaceutical composition comprises about 10 mg of artikaplanam 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 a high fat meal is initiated after at least 10 hours of fasting.

[0097] In some embodiments, the pharmaceutical composition has a PK profile (dose normalized to 10 mg) comprising a mean AUCinfinity of about 300 h*ng / mL, about 305 h*ng / mL, about 310 h*ng / mL, about 315 h*ng / mL, or about 320 h*ng / mL when administered after at least 10 hours of fasting.

[0098] In some embodiments, the pharmaceutical composition has a PK profile (dose normalized to 10 mg) comprising a mean AUCinfinity of about 400 h*ng / mL, about 420 h*ng / mL, about 425 h*ng / mL, about 430 h*ng / mL, about 440 h*ng / mL, or about 450 h*ng / mL when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting.

[0099] In some embodiments, the pharmaceutical composition has a median t of about 1.0 hours, about 1.1 hours, about 1.2 hours, about 1.3 hours, about 1.4 hours, about 1.5 hours, about 1.6 hours, about 1.7 hours, about 1.8 hours, about 1.9 hours, or about 2.0 hours when administered after at least 10 hours of fasting. max In some embodiments, when administered after at least 10 hours of fasting, the pharmaceutical composition has a median t max PK curve.

[0100] In some embodiments, the pharmaceutical composition has a median t of about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, about 2.9 hours, or about 3.0 hours when administered about 30 minutes after initiation of a high fat meal after at least 10 hours of fasting. max In some embodiments, when administered about 30 minutes after initiation of a high-fat meal after at least 10 hours of fasting, the pharmaceutical composition has a median t value of about 2.75 hours. max PK curve.

[0101] As described, the composition contains a pharmaceutically acceptable excipient, one of which is 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 additional embodiments, the filler is lactose monohydrate. In yet other embodiments, the filler is silicified microcrystalline cellulose. Based on the weight of the composition, the composition includes a filler in about 10% by weight to about 99.9% by weight. 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% filler by weight, based on the weight of the composition.In other embodiments, the composition comprises from about 10% to about 90% by weight, from about 10% to about 80% by weight, from about 10% to about 70% by weight, from about 10% to about 60% by weight, from about 10% to about 50% by weight, from about 10% to about 40% by weight, from about 10% to about 30% by weight, from about 10% to about 20% by weight, from about 20% to about 99.9% by weight, from about 20% to about 90% by weight, from about 20% to about 99.9% by weight, from about 20% to about 90% by weight, from about 20% to about 50% by weight, from about 10% to about 40% by weight, from about 10% to about 30% by weight, from about 10% to about 20% by weight, from about 20% to about 99.9% by weight, from about 20% to about 9 ...10% to about 100% by weight, from about 10% to about 100% by weight, from about 10% to about to about 80 wt%, about 20 wt% to about 70 wt%, about 20 wt% to about 60 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, about 30 wt% to about 99.9 wt%, about 30 wt% to about 90 wt%, about 30 wt% to about 80 wt%, about 30 wt% to about 70 wt%, about 30 wt% to about 60 wt%, about 30 wt% to about 50 wt% %, about 30 wt % to about 40 wt %, about 40 wt % to about 99.9 wt %, about 40 wt % to about 90 wt %, about 40 wt % to about 80 wt %, about 40 wt % to about 70 wt %, about 40 wt % to about 60 wt %, about 40 wt % to about 50 wt %, about 50 wt % to about 99.9 wt %, about 50 wt % to about 90 wt %, about 50 wt % to about 80 wt %, about 50 wt % to about 70 wt %, about 5 ... In some embodiments, the composition comprises about 60% by weight, about 60% by weight to about 99.9% by weight, about 60% by weight to about 90% by weight, about 60% by weight to about 80% by weight, about 60% by weight to about 70% by weight, about 70% by weight to about 99.9% by weight, about 70% by weight to about 90% by weight, about 70% by weight to about 80% by weight, about 80% by weight to about 99.9% by weight, about 80% by weight to about 90% by weight, or about 90% by weight to about 99.9% by weight of filler. In other embodiments, based on the weight of the composition, the composition comprises about 90% by weight of filler. In other embodiments, based on the weight of the composition, the composition comprises about 88.5% by weight of filler.

[0102] The weight ratio of artikaplanam to filler is between about 0.005 and about 9. In some embodiments, the weight ratio of artikaplanam to filler is between about 0.008 and about 0.8. In other embodiments, the weight ratio of artikaplanam 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 0.0 1 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 In some embodiments, the weight ratio of artikaplanam to filler is about 0.056.

[0103] The composition may also contain one or more of a filler, a disintegrant, a glidant, a lubricant, a solvent, a colorant, a binder, a buffer, a preservative, a osmotic agent, a wetting agent, a surfactant, a solubilizer, a thickener, a colorant, an antioxidant, an emulsifier, an isotonic agent, a suspending agent and / or a viscosity increasing agent.

[0104] In some embodiments, the composition further comprises one or more disintegrants. Examples of disintegrants that can be used in the composition include, for example, a disintegrant that is cross-linked sodium carboxymethyl cellulose. Based on the weight of the composition, the composition comprises a disintegrant of about 0.5% by weight to about 50% by weight. In some embodiments, based on the weight of the composition, the composition comprises about 0.5% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of a disintegrant. In other embodiments, the composition comprises, based on the weight of the composition, from about 0.5 wt % to about 40 wt %, from about 0.5 wt % to about 30 wt %, from about 0.5 wt % to about 20 wt %, from about 0.5 wt % to about 10 wt %, from about 0.5 wt % to about 5 wt %, from about 0.5 wt % to about 4 wt %, from about 0.5 wt % to about 3 wt %, from about 0.5 wt % to about 2 wt %, from about 0.5 wt % to about 1 wt %, from about 5 wt % to about 50 wt %, from about 5 wt % to about 40 wt %, from 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 a disintegrant. In another embodiment, the composition comprises about 5% by weight of a disintegrant based on the weight of the composition. The weight ratio of artikaplank to disintegrant is between about 0.1 and 10. In some embodiments, the weight ratio of artikaplank to 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.In other embodiments, the weight ratio of artikaplanam to disintegrant is 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 0.1 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 0.5 to about 2. In some embodiments, the weight ratio of artikaplank to disintegrant is 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 other embodiments, the weight ratio of artikaplank to disintegrant is about 5. In other embodiments, the weight ratio of artikaplank to disintegrant is about 1.

[0105] In other embodiments, the composition also includes one or more glidants. Examples of glidants that can be used in the composition include, for example, anhydrous colloidal silicon dioxide. Based on the weight of the composition, the composition includes a glidant between about 0.1 wt % and about 10 wt %. In some embodiments, based on the weight of the composition, the composition contains about 0.1 wt %, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt % of a glidant.In other embodiments, the composition contains, based on the weight of the composition, 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 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 10%, from about 0.5% to about 15 ... % to about 7 weight %, about 0.5 weight % to about 6 weight %, about 0.5 weight % to about 5 weight %, about 0.5 weight % to about 4 weight %, about 0.5 weight % to about 3 weight %, about 0.5 weight % to about 2 weight %, about 0.5 weight % to about 1 weight %, about 1 weight % to about 10 weight %, about 1 weight % to about 9 weight %, about 1 weight % to about 8 weight %, about 1 weight % to about 7 weight %, about 1 weight % to about 6 weight %, about 1 weight % to about 5 weight %, about 1 weight % to about 4 weight %, about 1 weight % to about 3 weight %, about 1 weight % to about 2 weight %, about 2 weight % to about 10 weight %, From about 2 wt % to about 9 wt %, from about 2 wt % to about 8 wt %, from about 2 wt % to about 7 wt %, from about 2 wt % to about 6 wt %, from about 2 wt % to about 5 wt %, from about 2 wt % to about 4 wt %, from about 2 wt % to about 3 wt %, from about 3 wt % to about 10 wt %, from about 3 wt % to about 9 wt %, from about 3 wt % to about 8 wt %, from about 3 wt % to about 7 wt %, from about 3 wt % to about 6 wt %, from about 3 wt % to about 5 wt %, from about 3 wt % to about 4 wt %, from about 4 wt % to about 10 wt %, from about 4 wt % to about 9 wt %, from about 4 wt % to about 8 wt %, from about 4 wt % to about 7 %, about 4 wt % to about 6 wt %, about 4 wt % to about 5 wt %, about 5 wt % to about 10 wt %, about 5 wt % to about 9 wt %, about 5 wt % to about 8 wt %, about 5 wt % to about 7 wt %, about 5 wt % to about 6 wt %, about 6 wt % to about 10 wt %, about 6 wt % to about 9 wt %, about 6 wt % to about 8 wt %, about 6 wt % to about 7 wt %, about 7 wt % to about 10 wt %, about 7 wt % to about 9 wt %, about 7 wt % to about 8 wt %, about 8 wt % to about 10 wt %, about 8 wt % to about 9 wt %, or about 9 wt % to about 10 wt %. In another embodiment, the composition contains about 1 wt % of the glidant based on the weight of the composition. The weight ratio of artikaplanam to the glidant is between 0.5 and 50.In some embodiments, the weight ratio of artikaplanam to the 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. In other embodiments, the weight ratio of artikaplanam to the glidant 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. In some embodiments, the weight ratio of artikaplanam to the glidant is 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 other embodiments, the weight ratio of artikaplanam to the glidant is about 5.

[0106] In other embodiments, the composition also includes one or more lubricants. Examples of lubricants that can be used in the composition include, for example, magnesium stearate. Based on the weight of the composition, the composition is included in about 0.05 wt % to about 5 wt % of lubricant. In some embodiments, based on the weight of the composition, the composition includes about 0.05 wt %, about 0.1 wt %, about 0.5 wt %, about 1 wt %, about 1.5 wt %, about 2 wt %, about 2.5 wt %, about 3 wt %, about 3.5 wt %, about 4 wt %, about 4.5 wt % or about 5 wt % of lubricant. In other embodiments, the composition comprises, based on the weight of the composition, from about 0.05% to about 4.5% by weight, from about 0.05% to about 4% by weight, from about 0.05% to about 3% by weight, from about 0.05% to about 2% by weight, from about 0.05% to about 1% by weight, from about 0.05% to about 0.5% by weight, from about 0.05% to about 0.1% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 4% by weight, from about 0.1% to about 3% by weight, from about 0.1% to about 2% by weight, from about 0.1% to about 1% by weight, from about 0.05% to about 0.5% by weight, from about 0.05% to about 0.1% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 4% by weight, from about 0.1% to about 3% by weight, from about 0.1% to about 2% by weight. In another embodiment, the composition comprises about 0.5 wt % of lubricant. The weight ratio of artikaplank to lubricant is between about 1 and about 100. In some embodiments, the weight ratio of artikaplan 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.In other embodiments, the weight ratio of artikaplanam to lubricant 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 to about 20, from about 1 to about 10, from about 1 to about 5, from about 5 to about 100. 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 In some embodiments, the weight ratio of artikaplanam to lubricant is about 10. In some embodiments, the weight ratio of artikaplanam to lubricant is about 10.

[0107] In some aspects, the composition comprises one or more of: a weight ratio of artikaplank to filler between 0.005 and 9; a weight ratio of artikaplank to disintegrant between 0.1 and 10; a weight ratio of artikaplank to glidant between 0.5 and 50; and a weight ratio of artikaplank to lubricant between 1 and 100.

[0108] In other aspects, the composition comprises one or more of: a weight ratio of artikaplank to filler of about 0.06; a weight ratio of artikaplank to disintegrant of about 1; a weight ratio of artikaplank to glidant of about 5; and a weight ratio of artikaplank to lubricant of about 10.

[0109] In a further aspect, the composition comprises about 5 wt % artikaplanam, about 88.5 wt % filler, about 5 wt % disintegrant, about 1 wt % glidant, and about 0.5 wt % lubricant, based on the weight of the composition.

[0110] Ideally, the composition is formulated as a solid composition. In some embodiments, the solid composition is a tablet, a capsule, or a 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 coating on the solid composition. In some embodiments, the film coating comprises a coating powder. In other embodiments, the film coating comprises Opadry II orange. In further embodiments, the coating powder is Opadry II orange.

[0111] The tablet may comprise one or more layers. In some embodiments, the tablet comprises a tablet core and a film coating to provide a film-coated tablet. The weight ratio of the film coating to the tablet core is between about 0.03 and 10. In some embodiments, the weight ratio of the film coating to the tablet core is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 based on the weight of the composition. In other embodiments, the ratio of film coating to core tablet is from about 0.03 to about 9, from about 0.03 to about 8, from about 0.03 to about 7, from about 0.03 to about 6, from about 0.03 to about 6, from about 0.03 to about 5, from about 0.03 to about 4, from about 0.03 to about 3, from about 0.03 to about 2, from about 0.03 to about 1, from about 0.03 to about 0.5, from about 0.03 to about 0.1, from about 0.05 to about 10, from about 0.05 to about 9, from about 0.05 to about 8, from about 0.05 to about 7, from about 0.05 to about 6, from about 0.0 5 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 10 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, From about 3 to about 10, from about 3 to about 9, from about 3 to about 8, from about 3 to about 7, from about 3 to about 6, from about 3 to about 6, from about 3 to about 5, from about 3 to about 4, from about 4 to about 10, from about 4 to about 9, from about 4 to about 8, from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 10, from about 5 to about 9, from about 5 to about 8, from about 5 to about 7, from about 5 to about 6, from about 6 to about 10, from about 6 to about 9, from about 6 to about 8, from about 6 to about 7, from about 7 to about 10, from about 7 to about 9, from about 7 to about 8, from about 8 to about 10, from about 8 to about 9, or from about 9 to 10.

[0112] The tablet core may contain one or more phases. In some embodiments, the tablet core comprises a first phase, such as an intragranular phase. In other embodiments, the tablet core comprises a second phase, such as an extragranular phase. In other embodiments, the tablet core comprises an intragranular phase and an extragranular phase.

[0113] The weight ratio of the intragranular phase to the extragranular phase in the tablet core is between about 1.5 and about 3. In some embodiments, the weight ratio of the intragranular phase to the extragranular phase in the tablet core 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. In other embodiments, the weight ratio of the intragranular phase to the extragranular phase in the tablet core is from about 1.5 to about 2.8, from about 1.5 to about 2.5, from about 1.5 to about 2.3, from about 1.5 to about 2, from about 1.5 to about 1.8, from about 1.8 to about 3, from about 1.8 to about 2.8, from about 1.8 to about 2.5, from about 1.8 to about 2.3, from about 2 to about 3, from about 2 to about 2.8, from about 2 to about 2.5, from about 2 to about 2.3, from about 2 to about 2.1, from about 2.1 to about 3, from about 2.1 to about 2.8, from about 2.1 to about 2.5, from about 2.1 to about 2.3, from about 2.3 to about 3, from about 2.3 to about 2.8, from about 2.3 to about 2.5 to about 2.5 to about 3, from about 2.5 to about 2.8, and from about 2.8 to about 3. In yet other embodiments, the weight ratio of the intragranular phase to the extragranular phase in the tablet core is about 2.1.

[0114] Regarding the composition, the solid composition contains artikaplan and one or more pharmaceutically acceptable excipients. In some aspects, the intragranular phase comprises artikaplan, a filler, a disintegrant, and a glidant. In other aspects, the intragranular phase comprises one filler. In other aspects, the intragranular phase comprises two fillers.

[0115] The intragranular phase comprises from about 10 mg to about 120 mg of filler. In some embodiments, the intragranular phase comprises from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of filler. In other embodiments, the particle inner phase comprises from about 10 to about 110, from about 10 to about 100, from about 10 to about 90, from about 10 to about 80, from about 10 to about 70, from about 10 to about 60, from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, from about 10 to about 20, from about 20 to about 120, from about 20 to about 110, from about 20 to about 100, from about 20 to about 90, from about 20 to about 80, from about 20 to about 70, from about 20 to about 60, from about 20 to about 50, from about 20 to about 40, from about 10 to about 30, from about 10 to about 20, from about 20 to about 120, 0 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 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 In another embodiment, the intragranular phase contains about 60 mg of filler. In another embodiment, the intragranular phase contains about 30 mg of microcrystalline cellulose. In another 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 another embodiment, the intragranular phase contains about 60 mg of lactose monohydrate. In another embodiment, the intragranular phase contains about 60 mg of microcrystalline cellulose. In another embodiment, the intragranular phase contains about 60 mg of lactose monohydrate.

[0116] The intragranular phase comprises artikaplankton in a weight ratio to the filler of between about 0.008 and 0.8. In some embodiments, the intragranular phase comprises artikaplankton in a weight ratio to the filler 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. In other embodiments, the internal phase of the granules comprises artikaplankton in a weight ratio to filler of about 0.008 to about 0.7, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.4, about 0.008 to about 0.3, about 0.008 to about 0.2, about 0.008 to about 0.1, about 0.008 to about 0.05, about 0.008 to about 0.01, about 0.01 to about 0.8, about 0.01 to about 0.7, about 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. 0.5 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 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 other embodiments, the internal phase of the granules comprises artikaplankton in a weight ratio of about 0.08 to the filler.

[0117] The intragranular phase may also contain a disintegrant. In some embodiments, the intragranular phase contains from about 1 mg to about 10 mg of a disintegrant. In other embodiments, the intragranular phase contains from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 or about 10 mg of a disintegrant. In other embodiments, the intragranular phase contains 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 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 0 to about 10. In yet other embodiments, the intragranular phase contains about 2.5 mg of disintegrant. In yet other embodiments, the intragranular phase contains about 5 mg of disintegrant. In other embodiments, the intragranular phase contains about 2.5 mg of crosslinked carboxymethyl cellulose sodium. In other embodiments, the intragranular phase contains about 5 mg of crosslinked carboxymethyl cellulose sodium.

[0118] The intragranular phase may also contain a glidant. In some embodiments, the intragranular phase contains about 0.1 mg to about 5 mg of a glidant. In other embodiments, the intragranular phase contains about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of a glidant. In other embodiments, the intragranular phase contains about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, or about 4 mg to about 5 mg of a glidant. In other embodiments, the intragranular phase contains about 0.5 mg of a glidant. In yet other embodiments, the intragranular phase contains about 1 mg of a glidant. In other embodiments, the intragranular phase contains about 0.5 mg of anhydrous colloidal silicon dioxide. In other embodiments, the internal phase of the particle contains about 1 mg of anhydrous colloidal silicon dioxide.

[0119] The weight ratio of artikaplanm to disintegrant in the intragranular phase is between about 0.2 and 20; in some embodiments, the weight ratio of artikaplanm to disintegrant in the intragranular phase is 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 granular internal phase comprises artikaplanam to disintegrant in a weight ratio of about 0.2 to about 18, about 0.2 to about 16, about 0.2 to about 14, about 0.2 to about 12, about 0.2 to about 10, about 0.2 to about 8, about 0.2 to about 6, about 0.2 to about 4, about 0.2 to about 3, about 0.2 to about 2, about 0.2 to about 1, about 0.2 to about 0.5, 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 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 1 8, 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 In another embodiment, the intragranular phase comprises artikaplanam in a weight ratio of about 2 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. In another embodiment, the intragranular phase comprises artikaplanam in a weight ratio of about 2 to about 18.

[0120] The intragranular phase comprises artikaplankton to the glidant in a weight ratio of between about 1 and 100. In some embodiments, the intragranular phase comprises artikaplankton to the glidant in a weight ratio 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 comprises artikaplankton in a weight ratio to the 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. In yet other embodiments, the intragranular phase comprises artikaplankton in a weight ratio to the glidant of 10.

[0121] 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.

[0122] The extragranular phase may include a filler. In some embodiments, the extragranular phase contains a filler. In other embodiments, the extragranular phase contains from about 10 mg to about 80 mg of filler. In other embodiments, the extragranular phase contains from about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 70 mg, or about 80 mg of filler. In still other embodiments, the extragranular phase contains from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 15 mg to about 80 mg, from about 15 mg to about 70 mg, from about 15 mg to about 60 mg, from about 15 mg to about 50 mg, from about 15 mg to about 40 mg, from about 15 mg to about 30 mg, from about 15 mg to about 20 mg. g, about 20 mg to about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 25 mg to about 80 mg, about 25 mg to about 70 mg, about 25 mg to about 60 mg, about 25 mg to about 50 mg, about 25 mg to about 40 mg, about 25 mg to about 30 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 35 mg to about 80 mg, about 35 mg to about 70 mg, about 35 mg to about 60 mg, about 35 mg to about 50 mg, about 35 mg to about 40 mg, about 40 mg to about 80 mg, about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 80 mg, about 40 mg to about 70 mg, about 45 mg to about 80 mg, about 45 mg to about 70 mg, about 40 mg to about 50 mg In another embodiment, the extragranular phase contains about 28.5 mg of filler. In other embodiments, the extragranular phase contains about 28.5 of silicified microcrystalline cellulose. In other embodiments, the extragranular phase contains about 57 mg of filler.In still other embodiments, the extragranular phase contains about 57 mg of silicified microcrystalline cellulose.

[0123] In addition, the extragranular phase may contain a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In other embodiments, the extragranular phase contains from about 1 mg to about 10 mg of a disintegrant. In other embodiments, the extragranular phase contains about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, or about 10 mg of a disintegrant. In yet other embodiments, the extragranular phase contains from about 1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 1 mg to about 8 mg, from about 1 mg to about 7 mg, from about 1 mg to about 6 mg, from about 1 mg to about 5 mg, from about 1 mg to about 4 mg, from about 1 mg to about 3 mg, from about 1 mg to about 2.5 mg, from about 1 mg to about 2 mg, from about 2 mg to about 10 mg, from about 2 mg to about 9 mg, from about 2 mg to about 8 mg, from about 2 mg to about 7 mg, from about 2 mg to about 6 mg, from about 2 mg to about 5 mg, from about 2 mg to about 4 mg, from about 2 mg to about 3 mg, from about 2.5 mg to about 10 mg, from about 2.5 mg to about 9 mg, from about 2.5 mg to about 8 mg, from about 2.5 mg to about 7 mg, from about 2.5 mg to about 6 mg, from about 2.5 mg to about 5 mg, from about 2.5 mg to about 4 mg, from about 2.5 mg to about 3 mg, from about 3 mg to about 10 mg. In some embodiments, the extragranular phase contains about 2.5 mg of disintegrant. In other embodiments, the extragranular phase contains about 5 mg of a disintegrant. In additional embodiments, the extragranular phase contains about 2.5 mg of croscarmellose sodium. In still other embodiments, the extragranular phase contains about 5 mg of croscarmellose sodium.

[0124] The extragranular phase comprises a filler to disintegrant weight ratio of between about 1 and 100. In some embodiments, the extragranular phase comprises a filler to disintegrant weight ratio of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100. In further embodiments, the extragranular phase comprises filler to disintegrant in a weight ratio 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 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 yet other embodiments, the extragranular phase comprises a ratio of filler to disintegrant of about 11.4.

[0125] The extragranular phase may also contain a glidant. In some embodiments, the glidant is anhydrous colloidal silicon dioxide. In other embodiments, the extragranular phase contains about 0.1 mg to about 5 mg of a glidant. In other embodiments, the extragranular phase contains about 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of a glidant. In yet other embodiments, the extragranular phase contains about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, or about 4 mg to about 5 mg of a glidant. In yet other embodiments, the extragranular phase contains about 0.5 mg of a glidant. In other embodiments, the extragranular phase contains about 1 mg of a glidant. In other embodiments, the extragranular phase contains about 0.5 mg of anhydrous colloidal silicon dioxide. In yet other embodiments, the extragranular phase contains about 1 mg of anhydrous colloidal silicon dioxide.

[0126] The extragranular phase comprises a filler to glidant weight ratio of between about 5 and 500. In other embodiments, the extragranular phase comprises 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 additional embodiments, the extragranular phase comprises a filler to glidant weight ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, 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 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 From about 100 to about 100, about 25 to about 75, 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 still other embodiments, the extragranular phase comprises a ratio of filler to glidant of about 57.

[0127] The extragranular phase may also contain a lubricant. In some embodiments, the lubricant is magnesium stearate. In other embodiments, the extragranular phase contains from about 0.1 mg to about 5 mg of lubricant. In other embodiments, the extragranular phase contains about 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of lubricant. In other embodiments, the extragranular phase contains about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, or about 4 mg to about 5 mg of lubricant. In yet other embodiments, the extragranular phase contains about 0.5 mg of lubricant. In other embodiments, the extragranular phase contains about 1 mg of lubricant. In other embodiments, the extragranular phase contains about 0.5 mg of magnesium stearate. In yet other embodiments, the extragranular phase contains about 1 mg of magnesium stearate.

[0128] The extragranular phase comprises a filler to lubricant weight ratio of between about 5 and 500. In other embodiments, the extragranular phase comprises 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 additional embodiments, the extragranular phase comprises a filler to lubricant weight ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, 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 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 From about 100 to about 100, from about 25 to about 75, 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 still other embodiments, the extragranular phase comprises a ratio of filler to lubricant of about 57.

[0129] In some embodiments, the intragranular phase comprises one or more of: a weight ratio of artikaplank to filler between about 0.008 and 0.8; a weight ratio of artikaplank to disintegrant between about 0.2 and 20; and a weight ratio of artikaplank to glidant between about 1 and 100.

[0130] In some embodiments, the extragranular phase comprises one or more of the following: a weight ratio of filler to disintegrant between about 1 and 100; a weight ratio of filler to glidant between about 5 and 500; and a weight ratio of filler to lubricant between about 5 and 500. In other embodiments, the extragranular phase comprises a weight ratio of filler to disintegrant of about 11.4. In additional embodiments, the extragranular phase comprises a weight ratio of filler to glidant of about 57. In yet other embodiments, the extragranular phase comprises a weight ratio of filler to lubricant of about 57.

[0131] In other aspects, the tablet core comprises about 5 weight % artikaplanam, about 88.5 weight % filler, about 5 weight % disintegrant, about 1 weight % glidant, and about 0.5 weight % lubricant.

[0132] Oral tablets can have a weight suitable for patient administration. In some embodiments, oral tablets have a core of about 10 mg to about 1000 mg. In other embodiments, the core is about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In other embodiments, the core is about 10 mg to about 900 mg, about 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 25 mg to about 1000 mg, about 25 mg to about 900 mg, about 25 mg to about 800 mg, about 25 mg to about 700 mg, about 25 mg to about 600 mg, about 25 mg to about 500 mg, about 25 mg to about 400 mg, about 25 mg to about 300 mg, about 25 mg to about 200 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 50 mg to about 1000 mg, about 50 mg to about 900 mg, about 50 mg to about 800 mg, about 50 mg to about 700 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 20 In some embodiments, the tablet core is about 100 mg. In yet other embodiments, the oral tablet comprises about 200 mg of the tablet core.

[0133] In some aspects, the tablet core contains a disintegrant. For example, the tablet core contains about 5 mg to about 100 mg of a disintegrant. In some embodiments, the tablet core contains about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of a disintegrant. In other embodiments, the tablet core contains about 5 mg to about 80 mg, about 5 mg to about 60 mg, about 5 mg to about 40 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 80, or about 80 mg to about 100 mg of disintegrant. In other embodiments, the tablet core contains about 5 mg of disintegrant. In yet other embodiments, the tablet core contains about 10 mg of disintegrant.

[0134] In other aspects, the tablet core contains a glidant. For example, the tablet core contains about 1 mg to about 100 mg of a glidant. In some embodiments, the tablet core contains about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of a glidant. In other embodiments, the tablet core contains from about 1 mg to about 100 mg, from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 2 mg to about 100 mg, from about 2 mg to about 80 mg, from about 2 mg to about 60 mg, from about 2 mg to about 40 mg, from about 2 mg to about 20 mg, from about 2 mg to about 10 mg, from about 2 mg to about 5 mg, from about 5 mg to about 80 mg, from about 5 mg to about 60 mg, from about 5 mg to about 40 mg, from about 5 mg to about 20 mg, In some embodiments, the tablet core contains about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, or about 80 mg to about 100 mg of a glidant. In other embodiments, the tablet core contains about 1 mg of a glidant. In yet other embodiments, the tablet core contains about 2 mg of a glidant.

[0135] In other aspects, the tablet core contains a lubricant. For example, the tablet core contains about 0.5 mg to about 100 mg of lubricant. In some embodiments, the tablet core contains about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of lubricant. In other embodiments, the tablet core contains from about 0.5 mg to about 80 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 40 mg, from about 0.5 mg to about 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 2 mg to about 100 mg, from about 2 mg to about 80 mg, from about 2 mg to about 60 mg, from about 2 mg to about 40 mg, from about 2 mg to about 20 mg, from about 2 mg to about 10 mg, from about 2 mg to about 5 mg, In some embodiments, the tablet core contains about 0.5 mg of lubricant. In other embodiments, the tablet core contains about 1 mg of lubricant.

[0136] In other aspects, the tablet core contains a filler. For example, the tablet core contains from about 1 mg to about 200 mg of filler. In some embodiments, the tablet core contains about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of filler. In other embodiments, the tablet core contains from about 1 mg to about 180 mg, from about 1 mg to about 160 mg, from about 1 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1 mg to about 100 mg, from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 2 mg to about 200 mg, from about 2 mg to about 180 mg, from about 2 mg to about 160 mg, from about 2 mg to about 140 mg, from about 2 mg to about 120 mg. mg, about 2 mg to about 100 mg, about 2 mg to about 80 mg, about 2 mg to about 60 mg, about 2 mg to about 40 mg, about 2 mg to about 20 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 5 mg to about 200 mg, about 5 mg to about 180 mg, about 5 mg to about 160 mg, about 5 mg to about 140 mg, about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, about 5 mg to about 60 mg, about 5 mg to about 40 mg, about 5 mg to about 20 mg g, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg,about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg In some embodiments, the tablet core contains about 88.5 mg of filler. In yet other embodiments, the tablet core contains about 177 mg of filler.

[0137] In some preferred embodiments, the oral tablet comprises a core of about 100 mg and includes about 5 mg of artikaplan, about 5 mg of a disintegrant, about 88.5 mg of a filler, about 1 mg of a glidant, and about 0.5 mg of a lubricant.

[0138] In other preferred embodiments, the oral tablet comprises an about 200 mg tablet core comprising about 10 mg artikaplan, about 10 mg disintegrant, about 177 mg filler, about 2 mg glidant, and about 1 mg lubricant.

[0139] As described above, the tablet core can be coated with a film coating. In some embodiments, the oral tablet comprises about 3 mg of film coating. In other embodiments, the oral tablet comprises about 6 mg of film coating.

[0140] In some aspects, the film-coated oral tablet comprises about 80 wt % to about 99.9 wt % of the tablet core, and about 0.1 wt % to about 20 wt % of the tablet core, based on the weight of the film-coated oral tablet. In some embodiments, the film-coated oral tablet comprises about 80 wt %, about 81 wt %, about 82 wt %, about 83 wt %, about 84 wt %, about 85 wt %, about 86 wt %, about 87 wt %, about 88 wt %, about 89 wt %, about 90 wt %, about 91 wt %, about 92 wt %, about 93 wt %, about 94 wt %, about 95 wt %, about 96 wt %, about 97 wt %, about 98 wt %, about 99 wt %, or 99.9 wt %. In other embodiments, the film-coated oral tablet comprises about 80 wt % to about 99 wt %, about 80 wt % to about 96 wt %, about 80 wt % to about 94 wt %, about 80 wt % to about 92 wt %, about 80 wt % to about 90 wt %, about 80 wt % to about 88 wt %, about 80 wt % to about 86 wt %, about 80 wt % to about 84 wt %, about 80 wt % to about 82 wt %, about 82 wt % to about 99 wt %, based on the weight of the film-coated oral tablet. about 82 wt % to about 96 wt %, about 82 wt % to about 94 wt %, about 82 wt % to about 92 wt %, about 82 wt % to about 90 wt %, about 82 wt % to about 88 wt %, about 82 wt % to about 86 wt %, about 82 wt % to about 84 wt %, about 84 wt % to about 99 wt %, about 84 wt % to about 99 wt %, about 84 wt % to about 96 wt %, about 84 wt % to about 94 wt %, about 84 wt % to about 92 wt %, about 84 wt % to about 88 wt %, about 82 wt % to about 86 wt %, about 82 wt % to about 84 wt %, about 84 wt % to about 99 wt %, about 84 wt % to about 96 wt %, about 84 wt % to about 94 wt %, about 84 wt % to about 92 wt %, about 84 wt % % to about 90 wt %, about 84 wt % to about 88 wt %, about 84 wt % to about 86 wt %, about 86 wt % to about 99 wt %, about 86 wt % to about 96 wt %, about 86 wt % to about 94 wt %, about 86 wt % to about 92 wt %, about 86 wt % to about 90 wt %, about 86 wt % to about 88 wt %, about 88 wt % to about 99 wt %, about 88 wt % to about 96 wt %, about 88 wt % to about 94 wt %, about 88 wt % to about 92 wt %. %, about 88 wt % to about 90 wt %, about 90 wt % to about 99 wt %, about 90 wt % to about 96 wt %, about 90 wt % to about 94 wt %, about 90 wt % to about 92 wt %, about 92 wt % to about 99 wt %, about 92 wt % to about 96 wt %, about 92 wt % to about 94 wt %, about 94 wt % to about 99 wt %, about 94 wt % to about 96 wt %, about 96 wt % to about 99 wt %, or about 98 wt % to about 99 wt % of the tablet core. In other embodiments, the film-coated oral tablet comprises about 97 wt % of the tablet core based on the weight of the film-coated oral tablet. In yet other embodiments, the film-coated oral tablet comprises about 0.1 wt % to about 20 wt % of the film coating based on the weight of the film-coated oral tablet. In yet other embodiments, the film-coated oral tablet comprises about 0.1 wt %, about 0.%, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, or about 20 wt % film coating. In other embodiments, the film-coated oral tablet comprises, based on the weight of the film-coated oral tablet, about 0.1 wt % to about 18 wt %, about 0.1 wt % to about 16 wt %, about 0.1 wt % to about 14 wt %, about 0.1 wt % to about 12 wt %, about 0.1 wt % to about 10 wt %, about 0.1 wt % to about 8 wt %, about 0.1 wt % to about 6 wt %, about 0.1 wt % to about 4 wt %, about 0.1 wt % to about 2 wt %, about 0.1 wt % to about 1 wt %, about 0.5 wt % to about 20 wt %, about 0.5 wt % to about 18 wt %, about 0.5 wt % to about 16 wt %, about 0.5 wt % to about 14 wt %, about 0.5 wt % to about 12 wt %, about 0.5 wt % to about 10 wt %, about 0.5 wt % to about 8 wt %, about 0.5 wt % to about 6 wt %, about 0.5 wt % to about 4 wt %, about 0.1 wt % to about 25 wt % to about 2 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 18 wt %, about 1 wt % to about 16 wt %, about 1 wt % to about 14 wt %, about 1 wt % to about 12 wt %, about 1 wt % to about 10 wt %, about 1 wt % to about 8 wt %, about 1 wt % to about 6 wt %, about 1 wt % to about 4 wt %, about 1 wt % to about 2 wt %, about 2 wt % to about 20 wt %, about 2 wt % to about 18 wt %, about 2 wt % to about 16 wt %, about 2 wt % to about 1 4 wt %, about 2 wt % to about 12 wt %, about 2 wt % to about 10 wt %, about 2 wt % to about 8 wt %, about 2 wt % to about 8 wt %, about 2 wt % to about 6 wt %, about 2 wt % to about 4 wt %, about 4 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 4 wt % to about 16 wt %, about 4 wt % to about 12 wt %, about 4 wt % to about 10 wt %, about 4 wt % to about 8 wt %, about 4 wt % to about 6 wt %, about 6 wt % to about 20 wt %, about 6 wt % to about % to about 18 wt %, about 6 wt % to about 16 wt %, about 6 wt % to about 14 wt %, about 6 wt % to about 12 wt %, about 6 wt % to about 10 wt %, about 6 wt % to about 8 wt %, about 8 wt % to about 20 wt %, about 8 wt % to about 18 wt %, about 8 wt % to about 16 wt %, about 8 wt % to about 14 wt %, about 8 wt % to about 12 wt %, about 8 wt % to about 10 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 18 wt %, about 10 ... %, about 12 wt % to about 16 wt %, about 10 wt % to about 14 wt %, about 10 wt % to about 12 wt %, about 12 wt % to about 20 wt %, about 12 wt % to about 18 wt %, about 12 wt % to about 16 wt %, about 12 wt % to about 14 wt %, about 14 wt % to about 20 wt %, about 14 wt % to about 18 wt %, about 14 wt % to about 16 wt %, about 16 wt % to about 20 wt %, about 16 wt % to about 18 wt %, or about 18 wt % to about 20 wt % of film coating. In further embodiments, the film-coated oral tablet comprises about 3 wt % of film coating based on the weight of the film-coated oral tablet. In yet other embodiments, the film-coated oral tablet comprises about 97 wt % of the tablet core and about 3 wt % of the film coating based on the weight of the film-coated oral tablet. .

[0141] In some embodiments, the present disclosure provides an oral tablet comprising about 5 mg of artikaplanam, wherein the oral tablet comprises about 100 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; 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 anhydrous colloidal silicon dioxide, and about 0.5 mg of magnesium stearate.

[0142] In other embodiments, the present disclosure provides an oral tablet comprising about 10 mg of artikaplanam, wherein the oral tablet comprises about 200 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silicon dioxide, and about 1 mg of magnesium stearate.

[0143] The solid composition may also have a desired dissolution profile that provides the desired release of artikaplan. In some embodiments, the solid composition contains about 2 mg and 20 mg of artikaplan and has a dissolution profile with a Q value between about 60% and 90% at 45 minutes under the following dissolution operating conditions: (i) Equipment: 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) Analytical Completion: UHPLC with UV detection at 247 nm. In some embodiments, the Q value at 45 minutes 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%. In other embodiments, the Q value at 45 minutes 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%. In other embodiments, the Q value at 45 minutes is between about 70% and 80%. In other aspects, the Q value at 45 minutes is about 75%.

[0144] Advantageously, artikaplank may be administered once daily, or the total daily dosage may be administered in divided doses of two, three, or four times daily. In some embodiments, the composition containing artikaplank is administered once daily. In other embodiments, the oral tablet containing artikaplank is administered once daily. In yet other embodiments, the solid pharmaceutical composition containing artikaplank is administered once daily.

[0145] As described herein, in particular, prior to treatment with artikaplanam, the patient had an inadequate response to other antidepressant therapies. Thus, in a specific embodiment, the present disclosure relates to artikaplanam for use as described herein, wherein prior to treatment with artikaplanam, the patient had an inadequate response to other antidepressant therapies. In another specific embodiment, the present disclosure also relates to the use of artikaplanam in the preparation of a medicament as described herein, wherein prior to treatment with artikaplanam, the patient had an inadequate response to other antidepressant therapies. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein prior to treatment with artikaplanam, the patient had an inadequate response to other antidepressant therapies. Such antidepressant therapies may be particularly selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0146] As described herein, artikaplanm can be used as an adjunctive therapy, or in other words, as an add-on or in combination with one or more antidepressants, for example, a patient may already be or is also taking one or more antidepressants. Thus, in another specific embodiment, the present disclosure relates to artikaplanm for use as described herein, the use comprising administering artikaplanm as an adjunctive therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to artikaplanm for use as described herein, the use comprising administering artikaplanm in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to artikaplanm for use as described herein, the use comprising administering artikaplanm in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of artikaplanm in the preparation of a medicament as described herein, wherein the treatment comprises administering an effective amount of artikaplanm as an adjunctive therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of artikaplanm as described herein, wherein the treatment comprises administering an effective amount of artikaplanm in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of artikaplan as described herein, wherein the treatment comprises administering an effective amount of artikaplan in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of artikaplan as an adjunct therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of artikaplan in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or medicament as described herein, wherein the treatment instructions direct the administration of an effective amount of artikaplan in combination with an effective amount of one or more antidepressants. The one or more antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0147] As already described, the present disclosure relates to artikaplank for use as described herein. In a specific embodiment, artikaplank is S-artikaplank. In another embodiment of the present disclosure, the amount of artikaplank (particularly S-artikaplank) used as described herein will be about 2 mg to about 35 mg, more particularly about 10 mg. In yet another embodiment, artikaplank (particularly S-artikaplank) used as described herein is administered orally. In addition, in another specific embodiment, the present disclosure relates to artikaplank (particularly S-artikaplank) used as described herein, which is administered once a day. The present disclosure also relates to the use of artikaplank in the preparation of a medicament as described herein. In a specific embodiment, artikaplank is S-artikaplank. In another embodiment of the use described herein, the amount of artikaplank administered should be about 2 mg to about 35 mg, more particularly about 10 mg. In yet another embodiment of the use, artikaplank should be administered orally. In addition, in another specific embodiment of the use, artikaplanm (particularly S-artikaplanm) will be administered once a day. In another specific embodiment, the present disclosure also relates to a package or a pharmaceutical product as described herein, wherein artikaplanm (particularly S-artikaplanm). In another embodiment of the package or the pharmaceutical product as described herein, the treatment instructions instruct the administration of about 2 mg to about 35 mg of artikaplanm, more particularly about 10 mg of artikaplanm. In yet another embodiment of the package or the pharmaceutical product as described herein, the treatment instructions instruct the oral administration of artikaplanm (particularly S-artikaplanm). In addition, in another specific embodiment of the package or the pharmaceutical product as described herein, the treatment instructions instruct the administration of artikaplanm (particularly S-artikaplanm) once a day.

[0148] Advantageously, administration of artikaplanam does not result in weight gain during treatment, including clinically relevant weight gain. Therefore, in another specific embodiment, the present disclosure relates to artikaplanam for use as described herein, wherein the patient does not experience weight gain during treatment with artikaplanam. In another specific embodiment, the present disclosure relates to the use as defined herein, wherein the patient does not experience weight gain during treatment with artikaplanam. In another specific embodiment, the present disclosure also relates to a package or a pharmaceutical product as described herein, wherein the patient does not experience weight gain during treatment with artikaplanam. In particular, the patient's weight can be assessed at the initial administration of artikaplanam.

[0149] It was also unexpectedly observed that, based on the assessment at the time of initial administration, the patient did not experience a decrease in sexual function during treatment with artikaplanm. Thus, in another specific embodiment, the present disclosure relates to artikaplanm for use as described herein, wherein the patient did not experience a decrease in sexual function during treatment with artikaplanm. In another specific embodiment, the present disclosure relates to the use as described herein, wherein the patient did not experience a decrease in sexual function during treatment with artikaplanm. In another specific embodiment, the present disclosure relates to a package or pharmaceutical product as described herein, wherein the patient did not experience a decrease in sexual function during treatment with artikaplanm. The term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, reaching orgasm, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to the skilled person, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[0150] As already described, the patient suffers from anhedonia. In certain aspects, the anhedonia is moderate. In other aspects, the anhedonia is severe. Anhedonia can be measured by an anhedonia scale, such as the Snaith-Hamilton Pleasure Rating Scale (SHAPS). Thus, in a specific embodiment, the disclosure relates to artikaplan for use as described herein, wherein after 6 weeks of treatment with artikaplan, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score of the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score of the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS). Thus, in one specific embodiment, the disclosure relates to a use as described herein, wherein after 6 weeks of treatment with artikaplan, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score of the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score of the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS). In another specific embodiment, the disclosure relates to a package or pharmaceutical product as described herein, wherein after 6 weeks of treatment with artikaplan, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score of the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score of the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS).

[0151] Treatment

[0152] In one aspect of the invention, methods are 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. Patients may also be experiencing anhedonia. MDD alone is difficult to treat, and the treatment of patients with anhedonia is even more problematic because their ability to measure pleasure is impaired. As a result, these patients often do not receive appropriate treatment due to ineffective medication, repeated and unnecessary medical appointments, lack of patient compliance, and overall frustration of the patient. In addition, antidepressants are known to have a variety of side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, and the like. Therefore, patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side effects.

[0153] The methods described herein are effective in controlling depression and anhedonia in patients using artikaplan. Ideally, these methods successfully allow patients to control their depression while reducing anhedonia. In certain embodiments, patients treated according to the methods suffer from moderate to severe anhedonia. As used herein, the term "anhedonia" refers to a lack or decrease in the ability to experience pleasure in daily activities. The term anhedonia includes sensory experiences (i.e., touch, taste, smell) and loss of pleasure in social interactions. In some embodiments, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia is also manifested as a defect in one or more components of reward-related behaviors (also known as the pleasure cycle, such as wanting, liking, and learning). The pleasure cycle can be divided into three stages: the desire stage (mainly wanting), the completion stage (mainly liking), and the satisfaction stage (mainly learning). The desire stage is characterized by the initial energy expenditure to obtain the reward; the completion stage is to enjoy the reward; and the satisfaction stage is characterized by learning and feedback integration.

[0154] In order to assess the potential impact on anhedonia, anhedonia scales can be used. For example, the Snaith-Hamilton Hedonia Scale (SHAPS) analysis is an effective scale for measuring anhedonia. SHAPS is a scale completed by subjects, in which subjects rate whether they experience pleasure when performing a series of activities or experiences. SHAPS is a self-reported 14-item tool developed to assess hedonic capacity. Subjects rate whether they experience pleasure when performing a series of activities or experiences. Subjects can rate answers as 1 to 4, with 1 indicating "totally agree", 2 indicating "agree", 3 indicating "disagree", and 4 indicating "totally disagree". The subject's answers are added together to provide a total score ranging from 14 to 56. A higher SHAPS total score indicates that the current level of anhedonia is higher. Doctor / clinical judgment can be used to assess anhedonia alone or together with anhedonia scales.

[0155] In some embodiments, the patient suffers from moderate anhedonia. In other embodiments, the patient suffers from severe anhedonia. The assessment of moderate or severe anhedonia is usually determined by a doctor / clinical judgment and / or by one or more tests that can provide a deep understanding of whether the patient suffers from anhedonia. For example, the SHAPS method can be used to determine the severity of anhedonia. In some embodiments, patients suffering from moderate or severe anhedonia are considered to suffer from high levels of anhedonia. For example, patients with a SHAPS score of 38 or higher are considered to suffer from moderate to severe anhedonia, which can be considered to be a high level of anhedonia. In some embodiments, a high level of anhedonia is reflected as 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 higher. Patients with mild or no anhedonia are considered to suffer from low levels of anhedonia, which are assessed by a doctor / clinical judgment and / or one or more tests. For example, patients with a SHAPS score lower than 38 are considered to suffer from low anhedonia. In certain embodiments, patients suffering from mild anhedonia may have a SHAPS score of 20 to less than 38, e.g., a SHAPS score of 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 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. Generally, a SHAPS score below 20 may be considered to correspond to normal hedonic functioning, and for purposes of this disclosure will be classified as a low category of anhedonia, e.g., a SHAPS score below 38.

[0156] 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 40% following treatment with artikaplanam, as measured by a change from baseline in the total score on the anhedonia scale. 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% following treatment with artikaplanam, as measured by a change from baseline in the total score on the anhedonia scale. In still further embodiments, in still other embodiments, following treatment with artikaplan, 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. In other embodiments, following treatment with artikaplan, 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.

[0157] After initiation of treatment with artikaplan, a reduction in anhedonia can be measured relative to the patient's anhedonia measured prior to treatment with artikaplan (i.e., a baseline anhedonia measure). Thus, the treating clinician can calculate the change in anhedonia from baseline to a real-time anhedonia measure at any time point after treatment with artikaplan. Thus, a standard method of measuring anhedonia can be used, such as an anhedonia scale, e.g., SHAPS.

[0158] Ideally, the baseline anhedonia measurement is obtained no more than about 1 week prior to initiating treatment with artikaplanam. In some embodiments, the baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to treatment with artikaplanam. In other embodiments, the baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiating treatment with artikaplanam.

[0159] The change in the patient's anhedonia will depend on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to artikaplank, other medications being administered, etc. In some embodiments, the patient's anhedonia decreases after about 3 weeks of treatment with artikaplank. In other embodiments, the patient's anhedonia decreases after about 3 weeks of treatment with artikaplank. In additional embodiments, the patient's anhedonia decreases after about 3 weeks to about 6 weeks of treatment with artikaplank, and in certain embodiments, decreases by the 6th week of treatment with artikaplank. In certain embodiments, after about 6 weeks of treatment with artikaplank, the patient's anhedonia decreases by at least 40%, as measured by the change from baseline in the total score of the anhedonia scale. In other embodiments, the patient's anhedonia decreases within about 3 weeks, and in some embodiments, within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score of the anhedonia scale and / or physician / clinical judgment.

[0160] The methods described herein have been found to improve not only the patient's depression and anhedonia symptoms, but also to reduce the side effects of antidepressants. This can result in fewer absences (i.e., more visits or interactions with the physician), better cognitive function, better health-related quality of life, more interest and participation in daily activities, better family and interpersonal relationships, better ability to function in the workplace, and fewer hospitalizations.

[0161] In some embodiments, the present disclosure provides a method of treating MDD in a human patient by administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplan, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with artikaplan. In some embodiments, administering the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile (dose normalized to 10 mg) comprising one or more of the above PK parameters following administration of the composition to a human after at least 10 hours of fasting.

[0162] As used herein, unless otherwise indicated, the terms "subject" and "patient" refer to a human being who has been the subject of treatment, observation or experiment. Preferably, the patient has experienced and / or exhibits 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, the term "adult" refers to a person who is about 18 years of age or older. In certain aspects, the patient is an elderly adult, i.e., greater than or equal to 65 years of age.

[0163] As used herein, unless otherwise indicated, the terms "treatment" and "treating" and the like shall 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 include the administration of the compounds described herein to prevent the onset of symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder.

[0164] 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, melancholy, midlife depression, geriatric depression, bipolar depression, depression caused by identifiable stressors, refractory depression, or a combination thereof. In certain embodiments, depression is major depressive disorder. In other embodiments, major depressive disorder is accompanied by melancholic features or anxious distress. In additional embodiments, depression is refractory depression. In other embodiments, depression is major depressive disorder with suicidal ideation.

[0165] As is known in the art, a patient is considered to have major depressive disorder if they exhibit five or more symptoms that are different from previous functioning during the same two-week period; depressed mood and / or loss of interest / pleasure must be present; excluding symptoms that are clearly attributable to another medical condition. See, e.g., Table 4.

[0166]

[0167] In some embodiments, to be diagnosed with MDD, the following criteria must also be met:

[0168]

[0169] Major depressive disorder can be classified as mild, moderate or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In other embodiments, MDD is severe. As used herein, "mild MDD" is applicable to patients with almost no symptoms (if any symptoms exceeding the symptoms required for diagnosis), the intensity of the symptoms is painful but controllable, and the symptoms cause slight obstacles in social or occupational function. Mild MDD may be a single attack (ICD-10F32.0) or repeated attacks (ICD-10F33.0). "Moderate MDD" is applicable to patients with multiple symptoms, symptom intensity and / or functional impairment between designated as "mild" and "severe" symptoms. Moderate MDD may be a single attack (ICD-10F32.1) or repeated attacks (ICD-10F33.1). "Severe MDD" is applicable to patients whose number of symptoms greatly exceeds the number required for diagnosis, the intensity of the symptoms is seriously painful and uncontrollable, and the symptoms obviously interfere with social and occupational function and need urgent symptom control. In some embodiments, severe MDD may be a single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition of Table 5.

[0170]

[0171] Several scales are known in the prior art that can be used to diagnose or monitor MDD patients. 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 Symptom Rating Scale for Major Depressive Disorder (SMDDS), the Self-Assessment of Treatment Experience (SATE) scale, and the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), i.e., the MGH-ATRQ.

[0172] In some embodiments, MADRS is utilized to diagnose and / or monitor patients.MADRS is a 10-item rating scale for antidepressant research. It is performed by a clinician, and is designed to be used for MDD patients, to measure the overall severity of depressive symptoms. The MADRS scale is a validated, reliable and is accepted by regulatory health authorities as the main scale for determining the efficacy in major depression. In some embodiments, the structured interview guide (SIGMA) of MADRS is used to perform MADRS. The scale is composed of 10 items, wherein each of the scores is from 0 (the item does not exist or is normal) to 6 (symptoms are severe or persist), and the total possible score is 60. Higher scoring represents a more serious illness. MADRS evaluates obvious sadness, reported sadness, inner tension, sleep, appetite, attention, fatigue, inability to feel (interest level), pessimistic thoughts and suicidal thoughts.

[0173] In other embodiments, CGI-S is used to diagnose and / or monitor depression in patients. CGI-S is a scale that rates the severity of a subject's illness at the time of assessment relative to a clinician's past experience with subjects with the same diagnosis and treatment improvements. CGI-S provides an overall summary measure of the severity of a subject's illness as determined by a clinician, taking into account all available information, including knowledge of the subject's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the subject's ability to work. CGI-S rates the severity of psychopathology on a scale of 0 to 7. The severity of a subject's mental illness is assessed according to the following during the assessment: 0 = not assessed; 1 = normal (not sick at all); 2 = borderline psychosis; 3 = mildly ill; 4 = moderately ill; 5 = significantly ill; 6 = severely ill; 7 = in the most severely ill patients.

[0174] In another embodiment, SMDDS is utilized to diagnose and / or monitor depression in patients. SMDDS is a subjective assessment of patients. SMDDS is a 16-item PRO measure. Each item is assessed by a subject according to a 5-point Likert scale. Subjects use a rating between 0 ("not at all" or "never") and 4 ("very" or "always") to answer each question. The total score ranges from 0 to 60. SMDDS uses a 7-day recall period and a verbal rating. Higher ratings indicate more severe depressive symptoms.

[0175] In yet other embodiments, SATE is used to diagnose and / or monitor depression in patients. SATE is one to three questionnaires performed when the subject is unable to complete other assessments (i.e., away from the clinical setting, such as at home). SATE helps to evaluate the improvement or deterioration of the subject's depressive symptoms in the short term. For the overall depression assessment, the subject selects an option from improved, no change, or worsened; for depression improvement, the subject selects an option from slightly improved, much improved, and greatly improved, and for depression worsening, the subject can choose slightly worsened, severely worsened, and very severely worsened. See Table 6.

[0176]

[0177] If the subject selected answer 3 (somewhat worse), the following questions were asked:

[0178]

[0179] The MGH-ATRQ is a self-rating scale for determining treatment resistance in patients with MDD. The questionnaire inquires about the history of antidepressant treatment, using specific anchor points to define the adequacy of the dose and duration of each antidepressant trial and the degree of symptom improvement. The MGH-ATRQ allows the determination of treatment resistance in depression and is known to those skilled in the art.

[0180] In certain embodiments, the patient is insufficiently responsive to other antidepressant therapies. As used herein, "insufficient response" refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is less than about 50%. Typically, insufficient response occurs during the current / active episode of depression. In some embodiments, insufficient response refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is about 26% to less than about 50%. In other embodiments, insufficient response refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is 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%. The patient's response can be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, insufficient response is measured by MGH-ATRQ, MADRS or SHAPS. In other embodiments, insufficient response is measured by MGH-ATRQ.

[0181] To the extent that a patient is said to have a partial response to treatment, this means that some mild to moderate symptoms have improved since the start of treatment, but some of the initial symptoms remain and bother the patient, and these persistent symptoms still affect behavior and function. For example, the patient's motivation, productivity, and interest in their usual activities may still be impaired.

[0182] As used herein, the term "other antidepressant therapy" refers to an antidepressant drug or non-pharmacological treatment used to treat a patient suffering from depression. In some aspects, the other antidepressant therapy is an antidepressant drug. 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 artikaplanam.

[0183] Antidepressants are any agents that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclic drugs, tetracyclic drugs, acyclic drugs, triazolopyridines, selective serotonin reuptake inhibitors (SSRIs), serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic agents, noradrenalin reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, etc. Examples of tricyclic drugs include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc. Examples of tetracyclic drugs include maprotiline, etc. Examples of acyclic drugs include nomifensine, etc. Examples of triazolopyridines include trazodone, etc. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, fluvoxamine, etc. Examples of serotonin receptor antagonists include nefazodone, etc. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levmilnacipran, etc. Examples of noradrenergic and specific serotonergic drugs include mirtazapine, etc. Examples of norepinephrine reuptake inhibitors include reboxetine, edivoxetine, etc. (a) Examples of typical antipsychotics include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), indolinones (e.g., molindone), substituted benzamides (e.g., sulpiride, amisulpride), etc. Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonapiprazole, aripiprazole, nemopride, SR-31742, CX-516, SC-111, NE-100, divalproex (mood stabilizer), etc. In other embodiments, the antidepressant includes natural products such as kava pepper, St. John's wort, etc., or dietary supplements such as s-adenosylmethionine, etc. In yet other embodiments, the antidepressant includes neuropeptides such as thyrotropin-releasing hormone, etc., or compounds targeting neuropeptide receptors, such as neurokinin receptor antagonists, etc. In yet other embodiments, the antidepressant is a hormone such as triiodothyronine, etc. In other embodiments, the antidepressant is an SSRI, SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI, i.e., escitalopram, sertraline, paroxetine, fluoxetine, or citalopram. In other embodiments, the antidepressant is an SNRI, i.e., venlafaxine, duloxetine, vortioxetine, or desvenlafaxine.

[0184] Non-pharmacological treatments for use herein can be selected by those skilled in the art. In some embodiments, the non-pharmacological treatment is psychotherapy, transcranial magnetic stimulation, and the like.

[0185] Therapeutically effective amounts / dosage levels and dosage regimens for other antidepressant drug therapies can be readily determined by one of ordinary skill in the art. For example, therapeutic dosages and dosing regimens for approved marketed pharmaceutical agents are publicly available and are listed, for example, in package labels, standard dosage guidelines, standard dosage references such as the Physician's Desk Reference (Medical Economics Company or website http: / / / www.pdrel.com), or other sources.

[0186] In some embodiments, the other antidepressant therapy may include one antidepressant. 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 will be able to select the appropriate antidepressant therapy for use as described herein.

[0187] In certain embodiments, the patient is being treated with other antidepressant therapies prior to receiving artikaplan. In some embodiments, the patient is being treated with other antidepressant therapies including SSRIs, SNRIs, or combinations thereof. In other embodiments, the patient has discontinued treatment with other antidepressant therapies prior to starting treatment with artikaplan.

[0188] Also contemplated are adjunctive treatments comprising the use of an effective amount of one or more antidepressants in the methods described herein. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" shall mean treatment of a patient in need thereof by administering a combination of artikaplan and one or more antidepressants, wherein artikaplan and the antidepressant are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation by any suitable means.

[0189] In some aspects, artikaplan is administered adjunctively with other antidepressants currently administered to the patient, including current antidepressants to which the patient has responded inadequately (i.e., the antidepressant fails to treat the patient's depression). In other embodiments, artikaplan is administered adjunctively with an antidepressant not previously administered to the patient (i.e., a new antidepressant). In still other embodiments, artikaplan is administered in a regimen with an antidepressant previously administered to the patient.

[0190] When artikaplan and the other antidepressant are administered in separate dosage forms, the number of doses of each active compound administered per day may be the same or different, and more usually may be different. The antidepressant may be administered as prescribed by the attending physician and / or in accordance with its label, and artikaplan is administered as described herein. Typically, the patient is treated with both the antidepressant and artikaplan simultaneously, with both being administered according to their prescribed dosing regimens. Artikaplan and the antidepressant may be administered according to a simultaneous or alternating regimen, at the same time or at different times during treatment, simultaneously in separate forms or in a single form.

[0191] Artikaplan and the antidepressant may be administered via the same or different routes of administration. Examples of suitable administration methods include, but are not limited to, oral administration, intravenous administration (iv), intranasal administration (in), intramuscular administration (im), subcutaneous administration (sc), transdermal administration, oral administration, and rectal administration. In some embodiments, artikaplan is administered orally.

[0192] Treatment with artikaplank as described herein has several advantages over prior art treatments. In some embodiments, the patient does not experience multiple of the side effects associated with other antidepressants (i.e., antidepressants other than artikaplank). In certain aspects, the patient does not experience weight gain during treatment with artikaplank. As used herein, the term "weight gain" refers to an increase in a patient's weight relative to the patient's weight before taking artikaplank or the patient's weight assessed at the time of initial administration of artikaplank. In certain embodiments, the patient may actually see a loss in overall weight relative to the patient's weight before taking artikaplank. In other embodiments, the patient's weight is stable, i.e., neither increasing nor decreasing. In certain embodiments, the patient does not experience clinically relevant weight gain, which is characterized by a weight gain of ≥7%.

[0193] This is in contrast to many other antidepressants, where weight gain (including clinically relevant weight gain) is a common but unfortunate side effect.

[0194] In a further aspect, the patient did not experience a decrease in sexual function during treatment with artikaplan. As used herein, the term "decreased sexual function" refers to a reduction or weakening of one or more components of human sexual drive (i.e., sexual function). In some embodiments, sexual function includes one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasm, or orgasm satisfaction. In other embodiments, sexual function includes sexual drive. In other embodiments, sexual function includes vaginal lubrication satisfaction. In other embodiments, sexual function includes orgasm. In yet other embodiments, sexual function includes orgasm satisfaction. Desirably, the patient's sexual function is assessed at the time of initial administration of artikaplan. Therefore, the patient's sexual function when taking artikaplan can be compared with the patient's sexual function before the administration of artikaplan. Sexual function can be assessed by using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). ASEX is used to study whether artikaplan has further positive or negative effects on sexual function. The ASEX is a 5-item rating scale administered to patients that quantifies sexual drive, arousal, vaginal lubrication or penile erection, ability to orgasm, and satisfaction. Scores range from 5 to 30, and there are two different versions of the scale (for men and women).

[0195] Other scales can be used to determine the effectiveness of the methods used in this article in treating patients. Examples include the Cognitive and Physical Function Questionnaire (CPFQ), the Karolinska Sleepiness Scale (KSS), and the Temporal Pleasurable Experience Scale (TEPS). The CPFQ is a brief self-report scale that provides additional information about the effects of adjunctive therapy on various aspects of cognitive and executive function (including attention, memory, and mental acuity). It has been reported that subjects with MDD often have difficulties in functioning in this regard. The KSS is an assessment reported by a subject that is used to rate sleepiness on a scale of 1 to 9, ranging from "extremely alert" (1) to "very sleepy, trying to stay awake, and struggling with sleep" (9). The TEPS includes 18 items, 2 subscales, and is designed to distinguish between anticipated pleasure and completed pleasure.

[0196] The methods described herein include administering to a patient an effective amount of artikaplan. As used herein, the term "effective amount" means an amount of an active compound or agent that elicits in a human body the biological or medicinal response that a researcher, physician, or other clinician is seeking, including relief of one or more of the symptoms of the disease or disorder being treated. In some embodiments, artikaplan is used in an effective amount determined by the attending physician. In other embodiments, other antidepressants are used in effective amounts alone or in combination with an antidepressant.

[0197] Implementation plan:

[0198] The present invention also provides the following non-limiting embodiments:

[0199] Embodiment 1 is a pharmaceutical composition comprising about 2 mg to about 20 mg of artikaplan and a filler, wherein the composition comprises between about 0.1% to about 90% by weight of artikaplan.

[0200] Embodiment 2 is a pharmaceutical composition according to embodiment 1, further comprising one or more of the following: a disintegrant, a glidant, a lubricant, a solvent, a colorant, and a binder.

[0201] Embodiment 3 is a pharmaceutical composition according to embodiment 1 or 2, wherein the composition comprises between about 10% to about 99.9% by weight of filler.

[0202] Embodiment 4 is a pharmaceutical composition according to any one of embodiments 1 to 3, wherein the composition comprises a disintegrant.

[0203] Embodiment 5 is a pharmaceutical composition according to embodiment 4, wherein the composition comprises between about 0.5 weight % and about 50 weight % of a disintegrant.

[0204] Embodiment 6 is a pharmaceutical composition according to any one of embodiments 1 to 5, wherein the composition comprises a glidant.

[0205] Embodiment 7 is a pharmaceutical composition according to embodiment 6, wherein the composition comprises between about 0.1 wt % and about 10 wt % of a glidant.

[0206] Embodiment 8 is a pharmaceutical composition according to any one of embodiments 1 to 7, wherein the composition comprises a lubricant.

[0207] Embodiment 9 is a pharmaceutical composition according to embodiment 8, wherein the composition comprises between about 0.05 wt % and about 5 wt % of a lubricant.

[0208] Embodiment 10 is a pharmaceutical composition according to any one of embodiments 1 to 9, wherein the composition comprises one or more of the following: a weight ratio of artikaplank to filler between 0.005 and 9; a weight ratio of artikaplank to disintegrant between 0.1 and 10; a weight ratio of artikaplank to glidant between 0.5 and 50; and a weight ratio of artikaplank to lubricant between 1 and 100.

[0209] Embodiment 11 is a pharmaceutical composition according to any one of embodiments 1 to 10, wherein the composition comprises about 5 weight % of artikaplanam, about 88.5 weight % of filler, about 5 weight % of disintegrant, about 1 weight % of glidant and about 0.5 weight % of lubricant.

[0210] Embodiment 12 is a pharmaceutical composition according to any one of embodiments 1 to 11, wherein the composition is an oral tablet.

[0211] Embodiment 13 is a pharmaceutical composition according to embodiment 12, wherein the oral tablet is a film-coated oral tablet comprising (a) a tablet core and (b) a film coating.

[0212] Embodiment 14 is a pharmaceutical composition according to embodiment 13, wherein the weight ratio of the film coating to the core tablet is between about 0.03 and 10.

[0213] Embodiment 15 is a pharmaceutical composition according to embodiment 13 or 14, wherein the film coating comprises a coating powder.

[0214] Embodiment 16 is a pharmaceutical composition according to any one of embodiments 13 to 15, wherein the core comprises an intragranular phase and an extragranular phase.

[0215] Embodiment 17 is a pharmaceutical composition according to embodiment 16, wherein the ratio of intragranular phase to extragranular phase in the tablet core is between about 1.5 and 3.

[0216] Embodiment 18 is a pharmaceutical composition according to embodiment 16, wherein the intragranular phase comprises artikaplanam, a filler, a disintegrant, and a glidant.

[0217] Embodiment 19 is a pharmaceutical composition according to embodiment 18, wherein the intragranular phase comprises one or more of: a weight ratio of artikaplanam to filler between about 0.008 and 0.8; a weight ratio of artikaplanam to disintegrant between about 0.2 and 20; and a weight ratio of artikaplanam to glidant between about 1 and 100.

[0218] 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.

[0219] Embodiment 21 is a pharmaceutical composition according to embodiment 20, wherein the extragranular phase comprises one or more of the following: a weight ratio of filler to disintegrant between about 1 and 100; a weight ratio of filler to glidant between about 5 and 500; and a weight ratio of filler to lubricant between about 5 and 500.

[0220] Embodiment 22 is a pharmaceutical composition according to any one of embodiments 13 to 21, wherein the film-coated oral tablet comprises about 97 weight % of the tablet core and about 3 weight % of the film coating, and wherein the tablet core comprises about 5 weight % of artikaplanam, about 88.5 weight % of the filler, about 5 weight % of the disintegrant, about 1 weight % of the glidant, and about 0.5 weight % of the lubricant.

[0221] 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 tablet core, the tablet core comprising about 5 mg of artikaplan, about 5 mg of a disintegrant, about 88.5 mg of a filler, about 1 mg of a glidant, and about 0.5 mg of a lubricant.

[0222] Embodiment 24 is a pharmaceutical composition according to embodiment 23, further comprising about 3 mg of film coating.

[0223] 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 tablet core, the tablet core comprising about 10 mg of artikaplan, 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.

[0224] Embodiment 26 is a pharmaceutical composition according to embodiment 25, further comprising about 6 mg of film coating.

[0225] Embodiment 27 is a pharmaceutical composition according to any one of embodiments 1 to 26, wherein the filler is selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose.

[0226] Embodiment 28 is a pharmaceutical composition according to any one of embodiments 2 to 27, wherein the disintegrant is croscarmellose sodium.

[0227] Embodiment 29 is a pharmaceutical composition according to any one of embodiments 2 to 28, wherein the glidant is anhydrous colloidal silicon dioxide.

[0228] Embodiment 30 is a pharmaceutical composition according to any one of embodiments 2 to 29, wherein the lubricant is magnesium stearate.

[0229] Embodiment 31 is a pharmaceutical composition according to any one of embodiments 15 to 30, wherein the coating powder is Opadry II Orange.

[0230] Embodiment 32 is an oral tablet comprising about 5 mg of artikaplanam, wherein the oral tablet comprises about 100 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; 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 anhydrous colloidal silicon dioxide, and about 0.5 mg of magnesium stearate.

[0231] Embodiment 33 is an oral tablet according to embodiment 32, further comprising about 3 mg of film coating.

[0232] Embodiment 34 is an oral tablet according to embodiment 33, wherein the film coating comprises Opadry II Orange.

[0233] Embodiment 35 is an oral tablet comprising about 10 mg of artikaplanam, wherein the oral tablet comprises about 200 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silicon dioxide, and about 1 mg of magnesium stearate.

[0234] Embodiment 36 is an oral tablet according to embodiment 35, further comprising a 3 mg film coating.

[0235] Embodiment 37 is an oral tablet according to embodiment 36, wherein the film coating comprises Opadry II Orange.

[0236] Embodiment 38 is a pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplanam, wherein the composition has a pharmacokinetic (PK) profile comprising one or more of the following parameters after administration of the composition to a human after at least 10 hours of fasting (dose normalized to 10 mg):

[0237] a. Average C between about 30 ng / mL and 40 ng / mL max ;

[0238] b. Mean AUC between approximately 300 h*ng / mL and 430 h*ng / mL infinity ;

[0239] c. Mean AUC between approximately 280 h*ng / mL and 430 h*ng / mL last ;

[0240] d. Median t between about 1 hour and 4 hours max .

[0241] Embodiment 39 is a pharmaceutical composition according to embodiment 38, wherein the mean Cmax is between about 30 ng / mL and 35 ng / mL.

[0242] Embodiment 40 is a pharmaceutical composition according to embodiment 38 or 39, wherein the mean AUCinfinity is between about 300 h*ng / mL and 320 h*ng / mL.

[0243] Embodiment 41 is a pharmaceutical composition according to any one of embodiments 38 to 40, wherein the mean AUClast is between about 280 h*ng / mL and 310 h*ng / mL.

[0244] Embodiment 42 is a pharmaceutical composition according to any one of Embodiments 38 to 41, wherein the median t max For about 1.5 hours.

[0245] Embodiment 43 is a pharmaceutical composition according to any one of embodiments 38 to 42, wherein the composition is an oral tablet.

[0246] Embodiment 44 is a pharmaceutical composition according to any one of embodiments 38 to 43, wherein the composition further comprises one or more of the following: a filler, a disintegrant, a glidant, a lubricant, a binder, and a colorant.

[0247] Embodiment 45 is a pharmaceutical composition according to any one of embodiments 38 to 44, wherein the composition comprises between about 0.1% and 90% by weight of artikaplan.

[0248] Embodiment 46 is a pharmaceutical composition according to any one of embodiments 38 to 45, wherein the composition comprises about 5 mg of artikaplanam or about 10 mg of artikaplanam.

[0249] Embodiment 47 is a pharmaceutical composition according to any one of embodiments 38 to 46, wherein the composition comprises one or more of the following: a weight ratio of artikaplank to filler between 0.005 and 9; a weight ratio of artikaplank to disintegrant between 0.1 and 10; a weight ratio of artikaplank to glidant between 0.5 and 50; and a weight ratio of artikaplank to lubricant between 1 and 100.

[0250] Embodiment 48 is a pharmaceutical composition according to any one of embodiments 38 to 47, wherein the composition comprises about 5 weight % artikaplanam, about 88.5 weight % filler, about 5 weight % disintegrant, about 1 weight % glidant and about 0.5 weight % lubricant.

[0251] Embodiment 49 is a method for treating major depressive disorder (MDD) in a human patient, the method comprising administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplan, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with artikaplan, and wherein administering the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the following PK parameters (dose normalized to 10 mg) after administration of the composition to the human after at least 10 hours of fasting:

[0252] e. Average C between about 30 ng / mL and 40 ng / mL max ;

[0253] f. Mean AUC between approximately 300 h*ng / mL and 430 h*ng / mL infinity ;

[0254] g. Mean AUC between approximately 280 h*ng / mL and 430 h*ng / mL last ;

[0255] h. A median t between about 1 hour and 4 hours max .

[0256] Embodiment 50 is a method according to embodiment 49, wherein the average C max Between about 30 ng / mL and 35 ng / mL.

[0257] Embodiment 51 is a method according to embodiment 49 or 50, wherein the mean AUC infinity Between about 300 h*ng / mL and 320 h*ng / mL.

[0258] Embodiment 52 is a method according to any one of embodiments 49 to 51, wherein the mean AUC last Between approximately 280 h*ng / mL and 310 h*ng / mL.

[0259] Embodiment 53 is a method according to any one of embodiments 49 to 52, wherein the median t max For about 1.5 hours.

[0260] Embodiment 54 is a method according to any one of embodiments 49 to 53, wherein the composition is an oral tablet.

[0261] Embodiment 55 is a method according to any one of embodiments 49 to 54, wherein the composition further comprises one or more of the following: a filler, a disintegrant, a glidant, a lubricant, a binder, and a colorant.

[0262] Embodiment 56 is a method according to any one of embodiments 49 to 55, wherein the composition comprises between about 0.1% and 90% by weight artikaplan.

[0263] Embodiment 57 is a method according to any one of embodiments 49 to 56, wherein the composition comprises between about 10% and 99.9% by weight filler.

[0264] Embodiment 58 is a method according to any one of embodiments 49 to 57, wherein the composition comprises one or more of the following: a weight ratio of artikaplank to filler between 0.005 and 9; a weight ratio of artikaplank to disintegrant between 0.1 and 10; a weight ratio of artikaplank to glidant between 0.5 and 50; and a weight ratio of artikaplank to lubricant between 1 and 100.

[0265] Embodiment 59 is a method according to any one of embodiments 49 to 58, wherein the composition comprises about 5 weight % artikaplanam, about 88.5 weight % filler, about 5 weight % disintegrant, about 1 weight % glidant and about 0.5 weight % lubricant.

[0266] Embodiment 60 is a method according to any one of embodiments 49 to 59, wherein the patient suffers from anhedonia.

[0267] Embodiment 61 is a method according to any one of embodiments 49 to 60, wherein the pharmaceutical composition comprises about 5 mg of artikaplan.

[0268] Embodiment 62 is a method according to any one of embodiments 49 to 60, wherein the pharmaceutical composition comprises about 10 mg of artikaplan.

[0269] Embodiment 63 is a method according to any one of embodiments 49 to 60, wherein the additional antidepressant drug therapy comprises one or more antidepressants.

[0270] Embodiment 64 is a method according to embodiment 63, wherein the one or more antidepressants include an SSRI, a SNRI, or a combination thereof.

[0271] Embodiment 65 is a method according to any one of embodiments 49 to 64, wherein the artikaplanam is S-artikaplanam.

[0272] Embodiment 66 is a method according to any one of embodiments 49 to 65, further comprising treating with an effective amount of one or more antidepressants.

[0273] Embodiment 67 is a method according to embodiment 66, wherein the one or more antidepressants are SSRIs, SNRIs, or a combination thereof.

[0274] Embodiment 68 is a method according to any one of embodiments 49 to 67, wherein the pharmaceutical composition comprising artikaplanam is administered once a day.

[0275] Embodiment 69 is a solid pharmaceutical composition comprising between about 2 mg and 20 mg of artikaplan, wherein the composition has a dissolution profile comprising a Q value between about 60% and 90% at 45 minutes under the following dissolution operating conditions:

[0276] Equipment: Paddle (USP Type 2, Ph.Eur., JP)

[0277] Dissolution medium: 0.01M hydrochloric acid

[0278] Volume: 900mL

[0279] Temperature: 37+ / -0.5 degrees Celsius

[0280] Speed: 50rpm

[0281] Analysis completed: UHPLC with UV detection at 247 nm

[0282] Embodiment 70 is a solid pharmaceutical composition according to embodiment 69, wherein the composition comprises about 5 mg or about 10 mg of artikaplan.

[0283] Embodiment 71 is a solid pharmaceutical composition according to embodiment 69 or 70, wherein the Q value at 45 minutes is between about 70% and 80%.

[0284] Embodiment 72 is a solid pharmaceutical composition according to embodiment 71, wherein the Q value is about 75% at 45 minutes.

[0285] Embodiment 73 is a solid pharmaceutical composition according to any one of embodiments 69 to 72, wherein the composition is an oral tablet.

[0286] 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 the following: a filler, a disintegrant, a glidant, a lubricant, a binder, and a colorant.

[0287] Embodiment 75 is a solid pharmaceutical composition according to any one of embodiments 69 to 74, wherein the composition comprises between about 0.1 wt % and 90 wt % of artikaplan.

[0288] Embodiment 76 is a solid pharmaceutical composition according to any one of embodiments 69 to 75, wherein the composition comprises between about 10% and 99.9% by weight of filler.

[0289] Embodiment 77 is a solid pharmaceutical composition according to any one of embodiments 69 to 76, wherein the composition comprises one or more of the following: a weight ratio of artikaplank to filler between 0.005 and 9; a weight ratio of artikaplank to disintegrant between 0.1 and 10; a weight ratio of artikaplank to glidant between 0.5 and 50; and a weight ratio of artikaplank to lubricant between 1 and 100.

[0290] Embodiment 78 is a solid pharmaceutical composition according to any one of embodiments 69 to 77, wherein the composition comprises about 5 weight % artikaplanam, about 88.5 weight % filler, about 5 weight % disintegrant, about 1 weight % glidant and about 0.5 weight % lubricant.

[0291] Embodiment 79 is a method of treating major depressive disorder (MDD) in a human patient, the method 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.

[0292] Embodiment 80 is a method according to embodiment 79, wherein the patient suffers from anhedonia.

[0293] Embodiment 81 is a method according to any one of embodiments 79 to 80, wherein the pharmaceutical composition, the oral tablet or the solid pharmaceutical composition comprises about 5 mg of artikaplan.

[0294] Embodiment 82 is a method according to any one of embodiments 79 to 81, wherein the pharmaceutical composition, the oral tablet or the solid pharmaceutical composition comprises about 10 mg of artikaplan.

[0295] Embodiment 83 is a method according to any one of embodiments 79 to 82, wherein prior to treatment with artikaplanam, the patient has had an inadequate response to other antidepressant therapies.

[0296] Embodiment 84 is a method according to embodiment 83, wherein the other antidepressant therapy comprises one or more antidepressants.

[0297] Embodiment 85 is a method according to embodiment 84, wherein the one or more antidepressants comprise an SSRI, a SNRI, or a combination thereof.

[0298] Embodiment 86 is a method according to any one of embodiments 79 to 85, wherein the artikaplanam is S-artikaplanam.

[0299] Embodiment 87 is a method according to any one of embodiments 79 to 86, further comprising treating with an effective amount of one or more antidepressants.

[0300] Embodiment 88 is a method according to embodiment 87, wherein the one or more antidepressants are SSRIs, SNRIs, or a combination thereof.

[0301] Embodiment 89 is a method according to any one of embodiments 79 to 88, wherein the pharmaceutical composition, the oral tablet, or the solid pharmaceutical composition comprising artikaplanam is administered once a day.

[0302] Embodiment 90 is a method of treating major depressive disorder in a human patient, the method comprising administering to the human patient a pharmaceutical composition comprising artikaplan and one or more pharmaceutically acceptable excipients, wherein the patient has previously had an inadequate response to other antidepressant therapies, and wherein the pharmaceutical composition is administered orally once daily with or without food.

[0303] Embodiment 91 is a method according to embodiment 90, wherein the pharmaceutical composition is an oral tablet.

[0304] Embodiment 92 is a method according to embodiment 90 or 91, wherein the pharmaceutical composition comprises about 5 mg to 10 mg of artikaplanam, about 5 mg of artikaplanam, or about 10 mg of artikaplanam.

[0305] Embodiment 93 is a method according to any one of embodiments 90 to 92, wherein the additional antidepressant therapy comprises one or more antidepressants.

[0306] Embodiment 94 is a method according to embodiment 93, wherein the one or more antidepressants comprise an SSRI, a SNRI, or a combination thereof.

[0307] Embodiment 95 is a method according to any one of embodiments 90 to 94, wherein the artikaplanm is S-artikaplanm or the artikaplanm is crystalline artikaplanm.

[0308] Embodiment 96 is a method according to any one of embodiments 90 to 95, further comprising treating with an effective amount of one or more antidepressants.

[0309] Embodiment 97 is a method according to embodiment 96, wherein the one or more antidepressants are SSRIs, SNRIs, or a combination thereof.

[0310] Embodiment 98 is a method according to any one of embodiments 90 to 97, wherein the patient suffers from anhedonia, optionally moderate to severe anhedonia.

[0311] Embodiment 99 is a method according to any one of embodiments 90 to 98, wherein the pharmaceutical composition comprises one or more of the following: a filler, a disintegrant, a glidant, a lubricant, a binder, and a colorant.

[0312] Embodiment 100 is a method according to embodiment 99, wherein the filler is selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is anhydrous colloidal silicon dioxide; and the lubricant is magnesium stearate.

[0313] Embodiment 101 is a method according to any one of embodiments 90 to 100, wherein the pharmaceutical composition comprises between about 0.1% and 90% by weight of artikaplan.

[0314] Embodiment 102 is a method according to any one of embodiments 90 to 101, wherein the pharmaceutical composition comprises between about 10% and 99.9% by weight of filler.

[0315] Embodiment 103 is a method according to any one of embodiments 90 to 102, wherein the pharmaceutical composition is a film-coated oral tablet comprising (i) a film coating and (ii) a tablet core, wherein the tablet core comprises about 5 weight % artikaplanam, about 88.5 weight % filler, about 5 weight % disintegrant, about 1 weight % glidant, and about 0.5 weight % lubricant.

[0316] Embodiment 104 is a method wherein the film-coated oral tablet comprises about 97% by weight of the tablet core and about 3% by weight of the film coating.

[0317] Embodiment 105 is a method according to any one of embodiments 90 to 104, wherein the pharmaceutical composition is an oral tablet comprising about 10 mg of artikaplanam, wherein the oral tablet comprises about 200 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silicon dioxide, and about 1 mg of magnesium stearate.

[0318] The following examples are presented to aid in understanding the present invention and are not intended to, and should not be construed to, limit in any way the present invention set forth in the claims that follow the examples.

[0319]

[0320]

[0321]

[0322] Example 1: Instrument and method details

[0323] AX-ray powder diffraction (XRPD)

[0324] Bruker AXSD8 Advance

[0325] XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit followed by a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac PlusEVA, respectively.

[0326] The samples were run in flat specimen format under ambient conditions using powder as received. The samples were prepared on polished zero background (510) silicon wafers by gently pressing onto a flat surface or loading into a cutting chamber. The samples were rotated on their own plane.

[0327] Details of the standard Pharmorphix data collection method are:

[0328] · Angular range: 2° to 42° 2θ

[0329] Step size: 0.05°2θ

[0330] Collection time: 0.5 sec / step (total collection time: 6.40 min)

[0331] When necessary, other data collection methods were used, the details of which are shown in Table 7.

[0332]

[0333] PANalyticalEmpyrean

[0334] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer in transmission geometry using Cu Ka radiation (45 kV, 40 mA). A 0.5° slit, a 4 mm mask and a 0.04 rad Soller slit and focusing mirror were used on the incident beam. A PIXcel placed on the diffracted beam 3D The detector was equipped 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. Diffrac Plus EVA or HighScore Plus was used to analyze and present the data.

[0335] Samples were prepared and analyzed in transmission mode in metal or microporous 96-well plates. X-ray transparent film was used between metal sheets on metal well plates and powders (approximately 1 mg-2 mg) were used as received. Solids were separated and analyzed from suspensions using microporous plates by adding a small amount of suspension directly to the plate and then filtering under a slight vacuum.

[0336] The scanning mode for metal plates uses the gonio scanning axis, whereas 2θ scanning is used for microplates.

[0337] Details of standard screening data collection methods:

[0338] · Angular range: 2.5° to 32.0° 2θ

[0339] Step size: 0.0130°2θ

[0340] Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0341] The software used for data collection was X'Pert Data Collector, and the data were analyzed and presented using Diffrac Plus EVA.

[0342] B. Differential Scanning Calorimetry (DSC)

[0343] TA Instruments Q2000

[0344] DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Typically, 0.5 mg to 3 mg of each sample in a pinhole aluminum pan was heated from 25° C. to 275° C. at 10° C. / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0345] 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.

[0346] The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Universal Analysis or TRIOS.

[0347] TA Instruments Discovery DSC

[0348] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position autosampler. Typically, 0.5 mg to 3 mg of each sample in a pinhole aluminum pan was heated from 25° C. to 275° C. at 10° C. / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0349] The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0350] C. Chemical purity determination by HPLC

[0351] Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full method details are provided in Table 8.

[0352]

[0353] Example 2 - Preparation of Artikaplan THF Solvate

[0354]

[0355] Aqueous sodium hydroxide solution is added to the compound 1 in 2-methyltetrahydrofuran. After phase separation, the compound 2 (i.e. the free alkali of compound 1) in 2-MeTHF is subjected to solvent conversion to tetrahydrofuran (THF). By adding sodium triacetoxyborohydride and THF, compound 2 is used to carry out the reductive amination of compound 3. After the reaction is completed, the reaction mixture is washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 is concentrated, and ethanol and water are added. THF, ethanol and water are used to make the product crystallize to produce compound 4 in solid.

[0356] 7.3 L / kg water was charged to the reactor. 6.6 L / kg 2-MeTHF was charged to the reactor. 1.15 mol / mol of compound 1 was charged to the reactor. 2.3 mol / mol 50% aqueous NaOH solution was placed in the reactor at 22°C for a minimum of 20 minutes while stirring. Rinse into the reactor with 1.0 L / kg water. Stir at 22°C for a minimum of 30 minutes. Settle for a minimum of 30 minutes. Separate and discard the lower aqueous layer. Vacuum concentrate to a minimum volume at a maximum of 45°C. Several portions of THF were charged to the reactor and distilled back to a minimum volume to complete the solvent conversion. The reactor was adjusted to 20°C. 5.0 L / kg THF was charged to the reactor. 1.00 mole of compound 3 was charged to the reactor. 10.0 L / kg THF was charged to the reactor. R1 was adjusted to 32°C and stirred for a minimum of 1 hour. The reactor was adjusted to 15°C. 1.50 mol / mol NaBH(OAc) was added at 15°C 3 Load into the reactor in batches. Stir for at least 1 hour at 15°C. Put 5.0L / kg water into the reactor at 15°C. Put 3.05 mol / mol 50% NaOH aqueous solution into the reactor at 15°C and stir for at least 2 hours. Rinse with 0.5L / kg water. Settle for at least 30 minutes. Separate and discard the lower aqueous layer. Load 6.2L / kg 20% ​​NaCl aqueous solution into the reactor at 15°C and stir for at least 30 minutes. Settle for at least 30 minutes. Separate and discard the lower aqueous layer. Vacuum concentrate to 8.0L / kg at a maximum of 45°C. The reactor is adjusted to 25°C. 8.0L / kg EtOH (2% MeOH) and 8.0L / kg water are loaded into the reactor at 25°C. 2.0L / kg water is put into the reactor at least 2.5 hours at 25°C. 0.03kg / kg of crude compound 4 seeds are loaded into the reactor at 25°C. Stir at 25°C for a minimum of 2 hours. Charge the reactor with 6.0 L / kg of water 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.

[0357] Example 3 - Preparation of pure artikaplan

[0358]

[0359] 1.0 mol of crude compound 4 was charged into a dissolution reactor. 1.91 L / mol of 2-MeTHF was added. 2.39 L / mol of n-heptane was added. The contents of the reactor were stirred. The temperature was adjusted to 42°C and stirred for at least 10 minutes until completely dissolved. The solution was filtered through a luster filter into a crystallization reactor to remove any insoluble matter that may be present. The luster filter was rinsed. Stir at 40°C for at least 10 minutes. Cool to 20°C within at least 1 hour. Stir at 20°C for at least 10 minutes. Add 1.23 L / mol of n-heptane at 20°C within at least 30 minutes. Stir at 20°C for at least 10 minutes. Seed with 0.02 mol / mol of JNJ 67953964 AAA at 20°C. Stir at least 8 hours at 20°C. Add 3.68 L / mol of n-heptane at 20°C within at least 12 hours. Stir at 20°C for at least 2 hours. Cool to 10°C within at least 3 hours. Stir at 10°C for minimum 4 hours. Isolate Compound 5. Wash the wet cake with 2-MeTHF / n-heptane (25 / 75 w / w%). Dry Compound 5 at 50°C.

[0360] Compound 5 was characterized and the results are shown in Table 9.

[0361]

[0362] Form III of artikaplanam was found to be crystalline by XRPD. 1 H NMR showed the material was consistent with the proposed structure, with residual ethyl acetate present. Ion chromatography showed the absence of cations / anions, and HPLC showed 99.8% purity. DSC (heated from 20°C to 131°C at 10°C / min) showed a peak temperature of 121°C. See Figure 3 .

[0363] Example 4 - Tablet containing Artikaplan

[0364] according to Fig.24 Tablets containing artikaplanam were prepared according to the protocol described herein, which contained the components in Table 10.

[0365]

[0366] Tablets were prepared according to the following steps:

[0367] 1. Mix the following sieved ingredients in a blend using a suitable blender:

[0368] a. Artikaplan or Artikaplan Micropowder

[0369] b. Microcrystalline cellulose

[0370] c. Anhydrous colloidal silica

[0371] d. Lactose monohydrate

[0372] 2. Sieve the blend using a suitable sieve.

[0373] 3. Add the following sieved ingredients to the blend. Mix further using a suitable blender:

[0374] a. Microcrystalline cellulose

[0375] b. Lactose monohydrate

[0376] 4. Sieve the blend using a suitable sieve.

[0377] 5. Add the following sieved ingredients to the blend. Mix further using a suitable blender.

[0378] a. Microcrystalline cellulose

[0379] b. Lactose monohydrate

[0380] 6. Sieve the blend using a suitable sieve.

[0381] 7. Add the following sieved ingredients to the blend. Mix further using a suitable blender:

[0382] Microcrystalline Cellulose

[0383] Lactose monohydrate

[0384] Croscarmellose Sodium

[0385] 8. Prepare dry granules by using suitable compression techniques.

[0386] 9. Add the following sieved ingredients to the dry granules and mix using a suitable blender:

[0387] a.Siliconized microcrystalline cellulose

[0388] b. Cross-linked carboxymethyl cellulose sodium

[0389] c. Anhydrous colloidal silica

[0390] 10. Add the following sieved ingredients to the blend and mix using a suitable blender:

[0391] a. Magnesium stearate

[0392] 11. Compress the blend into tablet cores using a suitable tablet press.

[0393] 12. Use a suitable container to suspend the coating powder in purified water.

[0394] 13. Spray the coating suspension onto the tablet cores using a suitable coating machine.

[0395] 14. Collect the film-coated tablets and pack them in suitable containers.

[0396] Example 5 - Testing of Tablets Containing Artikaplan

[0397] The tablets of Example 3 were tested to determine dissolution characteristics and chemical stability. See Table 11 for dissolution conditions and Table 12-13 for results.

[0398]

[0399]

[0400] The chemical stability of the tablets was evaluated over a 28-day period using a Risk-Based Predictive Stability (RiBPS) study. The stability protocols for these studies are provided in Tables 14-15.

[0401]

[0402] The ICH stability protocol is presented in Table 16.

[0403]

[0404] During the RiBPS study, 3 major degradation products (RRT 0.399, RRT 0.466, and RRT 0.874) showed an increasing trend over the storage period. The degradation levels ranged from 0.06% to 0.98% for RRT 0.399, <0.05% to 0.39% for RRT 0.466, and <0.05% to 0.99% for RRT 0.874.

[0405] The results of the RiBPS study showed that the degradant RRT 0.466 was a shelf-life limiting attribute of the drug product.

[0406] The results showed that for the specification limit of 0.30%, the probability was 99% over 12 months for the drug product stored in open dishes when stored at 25°C / 60% RH and 30°C / 75% RH.

[0407] Example 6

[0408] This is a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who have an inadequate response to SSRI / SNRI therapy. Atikaplan was evaluated as an adjunctive therapy; therefore, eligible subjects maintained their SSRI / SNRI therapy without any changes throughout the study. At least 50% of the enrolled subjects had to suffer from anhedonia (as measured by a SHAPS total score ≥ 20).

[0409] A. Purpose

[0410] The primary objective was to evaluate the efficacy of artikaplanam compared with placebo in reducing depressive symptoms when administered as adjunctive treatment to subjects with MDD who have a partial response to SSRI / SNRI treatment, as assessed by the change from baseline in the MADRS in non-responders during a placebo run-in period.

[0411] Secondary objectives are:

[0412] i. To evaluate the efficacy of artikaplanam compared to placebo in reducing depressive symptoms when administered as adjunctive treatment to subjects with MDD who have partially responded to SSRI / SNRI treatment, as assessed by the change from baseline in the MADRS in responders and non-responders during a placebo run-in period.

[0413] ii. To investigate the overall safety and tolerability of adjunctive artikaplan treatment in subjects with MDD when used in combination with an SSRI or SNRI.

[0414] iii. To investigate the effect of artikaplan versus placebo on depression-related anhedonia as assessed by SHAPS.

[0415] iv. The effect of artikaplanam on depressive symptoms was investigated using the Clinical Global Impression-Severity (CGI-S), the Patient-Reported Major Depressive Disorder Symptom Scale (SMDDS), and the Self-Assessment of Treatment Experience (SATE).

[0416] v. Use HAM-A to study the effect of artikaplanam on anxiety symptoms and use HAM-A 6 The subscale investigated the effect of artikaplanam on core symptoms of anxiety.

[0417] vi. To evaluate the plasma PK of artikaplanam in MDD subjects and explore its relationship with efficacy and safety parameters.

[0418] Secondary exploratory objectives include:

[0419] i. The CPFQ was used to explore the effects of artikaplanam on various aspects of cognitive and executive function.

[0420] ii. 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 artikaplanam.

[0421] B. Research Design

[0422] 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. Figure 4 .

[0423] Subjects with MDD who had been treated with licensed SSRI / SNRI and had an inadequate or partial response to treatment were screened. Assessments included the MINI, the Antidepressant Treatment History Questionnaire (TRQ), and the MADRS.

[0424] The treatment phase consisted of 3 periods. A placebo run-in period of undisclosed duration followed by a double-blind treatment period during which they were randomized to either 10 mg of artikaplan (two 5 mg capsules) or to continue taking placebo for 6 weeks. Each capsule contained artikaplan (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 for each subject was approximately 16 weeks. Including screening, a total of 11 visits were scheduled. Figure 4 The overall flow chart is shown in FIG.

[0425] Subjects were screened within 35 to 2 days prior to Day 1 to determine whether they met the inclusion and exclusion criteria. Symptoms of depression were assessed using the structured interview guide of the MADRS.

[0426] Double-blind treatment phase

[0427] The duration of the double-blind treatment phase was 11 weeks, divided into 3 time periods. Subjects received medication after completing the visit on Day 1. The first dose was taken at home on Day 2. All medications were taken in the fasting state. At the 3rd, 4th, and 5th visits, subjects were re-randomized to blind the subjects during the placebo run-in period. During the double-blind phase, subjects visited the outpatient center once every 1 to 2 weeks. See Table 17.

[0428] Table 17: Time and Event Schedule

[0429]

[0430]

[0431] EW = Early Withdrawal; a. The visit should be conducted on the scheduled day ± 3 days (based on the second visit, not the previous visit). b. If the subject discontinues treatment before the end of the double-blind treatment period, an EW visit should be completed. d. At home:

[0432] Fasting state. On clinic visit days: use the blister dispensed at the previous visit. Fasting state after completing pre-dose assessments. e. Continue medication when visit 11 is scheduled 3 days later. j. During the first screening visit and up to 4 days before visit 2, by phone if 2 weeks or more have passed between the MADRS assessment at screening and visit 2. k. Use the Q1.6-app on the subject's smartphone.

[0433] l. Eat breakfast, lunch or dinner on the spot after taking the medicine.

[0434] Run-in Period: Subjects who successfully complete the baseline examination visit at the clinical site / unit are treated with placebo for the duration of the run-in period.

[0435] Treatment Period: At the end of the run-in period, placebo run-in responders and placebo run-in non-responders were randomized to receive placebo or 10 mg of artikaplan in a 1:1 ratio for 6 weeks. Subjects remained blinded to the exact time of randomization, response criteria, and drug treatment assignment for each subject.

[0436] Withdrawal Period: Subjects who completed the double-blind treatment period before the end of Week 11 entered a withdrawal period during which they were treated with placebo for the remainder of the treatment phase.

[0437] C. Dosage and Administration

[0438] Artikaplanam was provided as 5 mg capsules. Placebo was provided as matching capsules. All subjects took 2 capsules, QD. From Day 2 to Day 78, capsules were taken daily with some water on an empty stomach (fasting for at least 4 hours before dosing). Take the medication before breakfast. If the subject forgets to take the medication before breakfast, the medication should be taken before the next meal, and at the latest with dinner that day. If the subject remembers after dinner, the dose for that day is waived and the subject takes the dose before breakfast the next day.

[0439] When Visit 11 was scheduled 3 days later, subjects continued taking medication until Visit 11.

[0440] The capsules were swallowed whole and did not need to be chewed, split, dissolved, or crushed. After taking the drug, the subjects did not eat or drink for at least 30 minutes.

[0441] The first dose was taken on an empty stomach on day 2 of the double-blind phase. The doses were:

[0442] 10 mg of Artikaplan: 2 5 mg Artikaplan capsules

[0443] Placebo: 2 placebo capsules.

[0444] Based on the results of the blinded review of safety data, the drug dose was adjusted to 5 mg QD as needed. When the decision was made to reduce the dose, this was only for new subjects, and the drug was dosed at:

[0445] 5mg Artikaplan: 1 5mg Artikaplan capsule

[0446] Placebo: 1 placebo capsule.

[0447] As used herein, the enriched ITT analysis set (eITT) is defined as all participating import placebo non-responders who are randomized into the treatment period, receive at least one dose of study drug during the treatment period, and perform at least one post-baseline MADRS assessment during the treatment period. Similarly, the full ITT analysis set (fITT) is defined as all participating subjects who are randomized into the treatment period, receive at least one dose of study drug during the treatment period, and perform at least one post-treatment baseline assessment of MADRS during the treatment period.

[0448] D. Clinical evaluation

[0449] (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Symptom Scale for Major Depressive Disorder (SMDDS)

[0450] Self-Assessment of Treatment Experience (SATE)

[0451] (ii) Anhedonia: Snaith-Hamilton Hedonic Feeling Scale (SHAPS)

[0452] (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and HAM-A6

[0453] (iv) Effects on cognition: Cognitive and Physical Function Questionnaire (CPFQ)

[0454] (v) Safety assessment

[0455] Standard safety assessments were performed, including physical and neurological examinations, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI disease in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical laboratory test panel to monitor gastric mucosal status.

[0456] (vi) Suicidal ideation: C-SSRS

[0457] (vii) Exploratory: CPFQ

[0458] (viii) Central nervous system sedation: Karolinska Sleepiness Scale

[0459] (ix) Sexual dysfunction: ASEX

[0460] E. Patient Groups

[0461] Of the 184 subjects, 169 subjects were randomized into the treatment period and included in the safety population, while 166 subjects were considered the full ITT population. Of the 166 subjects in the full ITT population, 121 subjects (73%) were non-responders to the introduction of placebo (enriched ITT population), and the remaining 45 subjects (27%) were responders to the introduction of placebo. Of the 121 subjects in the enriched population, 112 subjects (92.6%) were white and 84 subjects (69.4%) were female. The average age was 41.6 years, ranging from 19 to 64 years. All subjects suffered from anhedonia (defined as a SHAPS total score ≥ 20) at treatment baseline. High levels of anhedonia (defined as a SHAPS total score ≥ 38) were observed in 43.8% of the subjects. In general, the treatment groups were similar in terms of baseline characteristics. The demographic characteristics and safety analysis of the subjects of eITT are provided in Tables 18 and 19.

[0462] Table 18: Summary of Demographics and Baseline Characteristics; Overall Safety Analysis

[0463]

[0464]

[0465] Table 19: Summary of demographic and baseline characteristics; eITT

[0466]

[0467]

[0468] E. Efficacy evaluation

[0469] At the end of the run-in period, subjects were assessed for response status according to double-blind response criteria based on MADRS reduction from run-in baseline. During the treatment period, run-in placebo responders and run-in placebo non-responders were randomized in a 1:1 ratio to either artikaplan- am or placebo. Randomization was stratified according to run-in response status (non-responders had a <30% reduction from baseline in MADRS total score at the end of the run-in period, while responders had a ≥30% reduction from baseline at the end of the run-in period) and presence / absence of anhedonia (presence defined as a SHAPS total score ≥20).

[0470] Treatment Duration: 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 trial consisted of 3 periods. The first period was a 3-week placebo run-in, after which subjects entered the treatment period, during which they were randomly assigned to either artikaplan or continue taking placebo for 6 weeks. Subjects who successfully completed the treatment period were treated with placebo during a 2-week rest period (i.e., Period 3). The total duration for each subject was approximately 16 weeks.

[0471] Primary analysis set for efficacy: Efficacy analyses were based on the eITT set, which was defined as all participating run-in placebo nonresponders who were randomized into the treatment period, received at least one dose of drug, and had at least one post-baseline MADRS assessment during the treatment period. The primary analysis set was used for all efficacy endpoints.

[0472] Secondary analysis sets for efficacy: The secondary analysis set was the fITT set, which was defined as all participating subjects who were randomized into the treatment period, received at least one dose of drug, and had at least one post-baseline MADRS assessment during the treatment period. The secondary analysis set was used for all efficacy endpoints to examine effects in the general population, which may help design subsequent studies in the development program.

[0473] Security analysis set: Safety analyses were based on the full safety analysis set, which was defined as all participating subjects who received at least one dose of drug during the treatment period.

[0474] Efficacy endpoints of eITT and fITT are presented.

[0475] Significance level: The analysis of the primary efficacy endpoint was performed at a significance level of 0.20 (one-sided). The analysis of the secondary efficacy endpoints was performed at a significance level of 0.20 (two-sided). No adjustment was made for multiple comparisons.

[0476] F. Results

[0477] (i) Primary endpoint: Change in MADRS total score from baseline at week 6 in non-responders during the placebo run-in period

[0478] Enrichment ITT analysis set

[0479] The mean (SD) MADRS total score at baseline was 29.0 (4.61), with a range of 19 to 41. Figure 5 The mean change (SD) in MADRS total score from baseline at week 6 was -10.2 (8.44) for artikaplan and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 20 to 22 and Figure 8 .

[0480] Table 20: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; eITT Analysis Set

[0481]

[0482]

[0483] Table 21: MADRS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0484]

[0485] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of atikaplan. Negative effect sizes favor atikaplan; positive effect sizes favor placebo.

[0486] Table 22: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0487]

[0488]

[0489] a In the case of no difference between treatments, a one-sided test was performed using an MMRM model with subject as a random effect; country, treatment, time, and time / treatment interaction as factors; and baseline MADRS total score as a continuous covariate. The AR(1) variance-covariance matrix was used

[0490] Based on the results of the MMRM model with subject as a random effect; country, treatment, time, and time / treatment interaction as factors; and baseline MADRS total score as a continuous covariate, a significant positive efficacy signal for artikaplank relative to placebo was detected at a one-sided 0.20 significance level. The estimated LS mean difference between artikaplank and placebo at week 6 of treatment was -2.1, with an upper limit of the 80% one-sided CI of -1.09. The corresponding p-value was 0.044. The treatment effect in the fITT population was greater than that in the eITT population: -3.1, with an upper limit of the 80% one-sided CI of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figure 2 and Figure 3 .

[0491] Full ITT Analysis Set

[0492] The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), with a range of 0 to 41. Figure 7 A and Figure 7 B. The mean change from treatment baseline in the MADRS total score at week 6 for artikaplan and placebo was less for the fITT than for the eITT, at -9.7 (8.02) and -6.6 (8.57), respectively. The observed effect size was 0.36. These results demonstrate statistical superiority over placebo, with the greatest difference in effect durability observed at week 6. See Table 23.

[0493] Table 23: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; fITT Analysis Set

[0494]

[0495] A significant effect of artikaplan versus placebo was also detected in the fITT population. The estimated LS mean difference between artikaplan and placebo at treatment week 6 was -3.1, with an upper limit of the 80% one-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 24 to 25 and Figure 6 .

[0496] Table 24: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0497]

[0498]

[0499] aIn the case of no difference between treatments, a one-sided test was performed using an MMRM model with subject as a random effect; country, treatment, time, and time / treatment interaction as factors; and baseline MADRS total score as a continuous covariate. The AR(1) variance-covariance matrix was used

[0500] Table 25: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0501]

[0502] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of atikaplan. Negative effect sizes favor atikaplan; positive effect sizes favor placebo.

[0503] Impact of COVID-19 on primary efficacy assessments

[0504] Supplementary analyses were performed using the same MMRM model as described for the primary analysis for all data collected before March 15, 2020 (the estimated date of COVID-19 lockdown in most countries participating in the trial). Due to the impact of COVID-19, 17% of the subjects in the fITT population and 19% of the subjects in the eITT population had at least one MADRS assessment excluded from the model. The results of the analysis confirmed the results of the primary efficacy analysis in the eITT and fITT populations. The estimates of the LS mean difference for the eITT and fITT were -3.0 (upper limit of the 80% one-sided CI, -1.88) and -3.4 (upper limit of the 80% one-sided CI, -2.51), respectively.

[0505] (ii) Secondary endpoints

[0506] MADRS remission rate during the treatment period

[0507] At treatment week 6, the percentages of subjects in MADRS remission (MADRS total score ≤ 10) were 16.9% and 16.9% for artikaplan and placebo, respectively, in the eITT population. The remission rates at treatment week 6 were 31.2% and 22.2% for artikaplan and placebo, respectively, in the fITT population. No significant treatment differences were detected at treatment week 6 for both populations (eITT and fITT) using the chi-square test (two-sided p = 0.999 and p = 0.203, respectively). See Fig.11 and Fig.12 .

[0508] MADRS response rate during treatment period (at least 30% improvement)

[0509] In the eITT population, the percentage of subjects with a ≥30% improvement in the MADRS total score at Week 6 was 57.6% for artikaplan and 45.8% for placebo, respectively. In the fITT population, the response rates at Week 6 were 61.8% for artikaplan and 44.4% for placebo, respectively. 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).

[0510] MADRS response rate (at least 50% improvement) during the treatment period

[0511] In the eITT population, the percentage of subjects with a ≥50% improvement in the MADRS total score at Week 6 was 35.6% for artikaplan and 22.0% for placebo. In the fITT population, the response rates at Week 6 were 38.2% for artikaplan and 23.5% for placebo. For both populations, the treatment difference at Week 6 was significant at the 20% two-sided significance level (Chi-square test: p=0.104 for eITT and p=0.046 for fITT). See Tables 26 and Figures 13 to 16 .

[0512] Table 26: Change from Treatment Baseline in MADRS Total Score at Treatment Week 6 in Responders and Non-Responders During the Placebo Run-in Period

[0513]

[0514] Change in SHAPS total score from baseline to treatment week 6

[0515] Enrichment ITT analysis set

[0516] In the eITT population, a greater difference between artikaplan and placebo at treatment week 6 was observed in the subgroup of subjects with high anhedonia levels (baseline SHAPS total score ≥38) compared with subjects with low anhedonia levels (20≤baseline SHAPS total score <38). The effect sizes were 0.38 and 0.11, respectively.

[0517] The mean (SD) SHAPS total score at treatment baseline was 36.6 (5.45), with a range of 20 to 50. The mean change (SD) in the SHAPS total score from treatment baseline at Week 6 was -4.6 (6.23) for artikaplan and -4.2 (5.04) for placebo, respectively. The observed effect size was 0.07. See Table 27 and Fig.17 and Fig.37 .

[0518] Table 27: SHAPS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0519]

[0520]

[0521] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of atikaplan. Negative effect sizes favor atikaplan; positive effect sizes favor placebo.

[0522] The change in SHAPS total score was analyzed using the same MMRM model as for the MADRS total score. The estimated LS mean difference with 80% two-sided CI between artikaplan and placebo at treatment week 6 was -0.7 [-1.81, 0.41]. Figure 7 and Table 28 and Table 29 and Fig.18 The corresponding p-value is 0.419.

[0523] Table 28: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0524]

[0525]

[0526] a In the case of no difference between treatments, two-sided tests were performed using an MMRM model with subject as a random effect, country, treatment, time, and time / treatment interaction as factors, and baseline SHAPS total score as a continuous covariate. The AR(1) variance-covariance matrix was used.

[0527] Table 29: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0528]

[0529]

[0530] a In the absence of differences between treatments, random effects were used with subject as the random effect; country, treatment, time, time /

[0531] Treatment interaction was used as a factor; the MMRM model was tested two-sidedly with baseline SHAPS total score as a continuous covariate. The AR(1) variance-covariance matrix was used

[0532] The estimated LS mean difference with 80% two-sided CI between artikaplan and placebo at treatment week 6 was -0.8 [-1.79, 0.10]. The corresponding p value was 0.250. Figure 7 and Figure 8 .

[0533] Full ITT Analysis Set

[0534] Similar trends were observed in the fITT population, and the magnitude of the difference was greater 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), ranging from 14 to 50. The mean change in the SHAPS total score at treatment baseline for artikaplan and placebo at week 6 of the fITT population was similar to that in the eITT, at -4.7 (5.91) and -4.2 (4.98), respectively. The observed effect size was 0.08. See Table 30.

[0535] Table 30: SHAPS Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0536]

[0537]

[0538] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of atikaplan. Negative effect sizes favor atikaplan; positive effect sizes favor placebo.

[0539] Change in MADRS total score from treatment baseline to treatment week 6 according to the level of anhedonia at baseline

[0540] Enrichment ITT analysis set

[0541] In the subgroup of subjects with high anhedonia levels (SHAPS total score ≥ 38) at treatment baseline (n = 53), a greater difference between artikaplan and placebo was observed at treatment week 6 compared to subjects with low anhedonia levels (20 ≤ baseline SHAPS total score < 38) (n = 65): -3.4 at [-7.5, 0.7] 90% bilateral CI and -0.9 at [-4.2, 2.5] 90% bilateral CI, respectively (Table 31). The observed effect sizes were 0.38 and 0.11, respectively.

[0542] Table 31: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period According to Anhedonia Level at Treatment Baseline; eITT Analysis Set

[0543]

[0544]

[0545] Low anhedonia level (SHAPS total score at treatment baseline>=20 and <38), high anhedonia level (SHAPS total score at treatment baseline>=38). MADRS total scores range from 0 to 60, with higher scores indicating greater severity of depression.

[0546] Full ITT Analysis Set

[0547] Similar trends were observed in the fITT population. The magnitude of the differences was larger than in the eITT population: -4.6 at [-8.4, -0.8] 90% bilateral CI for high anhedonia subjects (n = 63) and -2.3 at [-5.0, 0.4] 90% bilateral CI for low anhedonia subjects (n = 94). See Table 32. The observed effect sizes were 0.51 and 0.29, respectively.

[0548] Table 32: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period According to Anhedonia Level at Treatment Baseline; fITT Analysis Set

[0549]

[0550]

[0551] Low anhedonia level (SHAPS total score at treatment baseline>=20 and <38), high anhedonia level (SHAPS total score at treatment baseline>=38). MADRS total scores range from 0 to 60, with higher scores indicating greater severity of depression.

[0552] These data suggest that stratification into high and low anhedonia may be beneficial in the treatment of MDD: artikaplan had a higher treatment effect. In addition, patients with high anhedonia had a lower placebo response than those with low anhedonia.

[0553] Change in CGI-S total score during treatment from treatment baseline

[0554] Table 33: Changes in CGI-S Total Score During Treatment from Treatment Baseline

[0555]

[0556] Changes in SMDDS total score at week 6 compared with baseline

[0557] Table 34: Changes in SMDDS Total Score at Treatment Weeks from Treatment Baseline

[0558]

[0559] Number of subjects with SATE scores at treatment week 6

[0560] Table 35: Number of subjects with SATE scores at treatment week 6

[0561]

[0562] Change in HAM-A6 total score at week 6 compared with baseline

[0563] Table 36: Changes in HAM-A6 Total Score at Week 6 Compared to Treatment Baseline

[0564]

[0565] These data suggest that patients treated with artikaplan-treated patients experienced greater improvements in HAMA6 scores compared with placebo.

[0566] Changes in SIGH-A structured interview guide scores at week 6 from treatment baseline

[0567] Table 37: Changes in SIGH-A Structured Interview Guide Scores at Week 6 from Treatment Baseline

[0568]

[0569] The maximum plasma concentration of artikaplan max )

[0570] C max Defined as the maximum plasma concentration of artikaplanam. The eITT population includes all participating run-in placebo nonresponders who were randomized into the treatment period, received at least 1 dose of study drug, and had at least 1 post-baseline MADRS assessment during the treatment period. "N" (number of subjects analyzed) here includes the number of subjects evaluable for this endpoint. "n" (number of analyses) here includes all subjects evaluable for the specified time point category.

[0571]

[0572] (iii) Safety endpoints

[0573] Overall, in the full safety analysis set, 40 / 85 (47.1%) subjects in the artikaplanam group and 30 / 84 (35.7%) subjects in the placebo group experienced at least one TEAE during the treatment period. See Table 39.

[0574] Table 39: Overall Summary of Treatment-Emergent Adverse Events During the Treatment Period; Full Safety Analysis Set

[0575]

[0576]

[0577] a Included in this category were possible, probable, and very likely drug relationships. Subjects were represented by the treatments received during the treatment period.

[0578] The most common TEAEs during the treatment period were headache (experienced by 10 / 85 (i.e., 11.8%) subjects in the artikaplan group and 6 / 84 (i.e., 7.1%) subjects in the placebo group) and diarrhea (experienced by 7 / 85 (i.e., 8.2%) subjects in the artikaplan group and 2 / 84 (i.e., 2.4%) subjects in the placebo group). See Table 40.

[0579] Table 40: Based on the Body System or Organ Class and Dictionary

[0580] Treatment-emergent adverse events that occurred in >= 5% of subjects in any treatment group during the treatment period of terms derived from the Dictionary of Clinical Trials; Full safety analysis set

[0581]

[0582] Percentages were calculated using the number of subjects in each group as the denominator. Dictionary version reported: MedDRA 22.1. Subjects were represented by the treatment received during the treatment period.

[0583] A total of 2 subjects discontinued treatment during the treatment period due to treatment-emergent adverse events: 1 subject in the artikaplan-10 group discontinued treatment due to diarrhea, nausea, vomiting, and headache, and another subject in the placebo group discontinued treatment due to acute calculous cholecystitis.

[0584] Overall, 17 / 169 subjects experienced TEAEs of special interest during the treatment period: 13 / 85 (15.3%) subjects in the artikaplanm group and 4 / 84 (4.8%) subjects in the placebo group. The most common treatment-emergent adverse events during the treatment period were headache and diarrhea. The most common TEAEs of special interest during the treatment period were diarrhea and pruritus (experienced by 5 / 85 (5.9%) subjects in the artikaplanm group and 0 / 84 subjects in the placebo group). One patient (1.19%) in the placebo group also experienced acute cholecystitis, compared to 0 patients receiving artikaplanm. See Table 41.

[0585] Table 41: Treatment-Emergent Adverse Events of Special Interest During the Treatment Period; Full Safety Analysis Set

[0586]

[0587] Percentages were calculated using the number of subjects in each group as the denominator. Dictionary version reported: MedDRA 22.1. Subjects were represented by the treatment received during the treatment period.

[0588] Two serious adverse events occurred. One subject in the placebo group experienced acute calculous cholecystitis during the treatment period, and another subject developed suicidal ideation during the run-in period. Two subjects discontinued treatment due to these AEs.

[0589] No deaths were reported.

[0590] (iv) Anhedonia Analysis

[0591] Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 42 to 44.

[0592] Table 42: Frequency of Anhedonia in Subjects at Treatment Baseline; fITT Analysis Set

[0593]

[0594] Anhedonia classification based on SHAPS total score calculated at the Day 22 visit

[0595] The results suggest that the more anhedonia patients had at baseline, the greater the treatment response. Fig.19 Table 432: Frequency of subjects experiencing different levels of anhedonia at baseline and at week 6 of treatment; eITT analysis set

[0596]

[0597] The classification of anhedonia was based on the recalculated SHAPS total score at the baseline and week 6 analysis visits. Table 44: Frequency of different levels of anhedonia experienced by subjects at baseline and week 6; fITT analysis set

[0598]

[0599] The classification of anhedonia was based on the recalculated SHAPS total score at the treatment baseline and treatment week 6 analysis visits.

[0600] The results show that the more anhedonia patients have at baseline, the better the treatment effect. See Figure 20-A and Figure 20-B. In Figure 20-A (i.e., the high anhedonia group), the placebo + oral antidepressant group showed the same Figures 7 and 8 Similarly, the treatment effect of artikaplanam + oral antidepressant was greater in the high anhedonia group compared with the low anhedonia group. Overall, the effect size at each single time point (starting from week 1) was larger in the high anhedonia group. At week 6, the LSMD in the high anhedonia group was more than twice that in the low anhedonia group. Furthermore, when looking at symptom levels, improvements in items related to anhedonia and anxiety were greater in the high anhedonia subgroup compared with the low anhedonia subgroup. See Fig.21 .

[0601] (v) Weight changes

[0602] At the run-in baseline time point, the mean weight of the placebo group was 76.17 kg, while the mean weight of the artikaplanm group was 78.66 kg. After 6 weeks of the double-blind treatment phase, the mean weight of the placebo group was 75.75 kg, while the mean weight of the artikaplanm group was 78.57 kg. This suggests that weight remained relatively stable in both groups during the 6-week double-blind treatment period. This was unexpected because other adjunctive treatments for MDD can result in an increase in mean weight. See 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, AZ, December 7-11, 2008). Nashville, TN, ACNP, 2008; Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Scottsdale, AZ, December 7-11, 2008). Nashville, TN, ACNP, 2008; Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Scottsdale, AZ, December 7-11, 2008). Meeting Abstracts (Boca Raton, FL, December 9-13, 2007). Nashville, TN, ACNP, 2007. See Table 45.

[0603] Table 45: Mean body weight according to treatment group (kg)

[0604]

[0605]

[0606] (vi) Completion rate

[0607] Patients who passed the screening phase entered the run-in phase and subsequently the double-blind phase. Patients who responded to the placebo during the run-in phase were labeled as non-responders. Patients who did not respond to the placebo were labeled as non-responders. The double-blind treatment phase lasted for an additional 6 weeks, after which patients entered a drug-free period.

[0608] Of the 121 subjects in the enriched population (60 in the artikaplan-treated group and 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate for the full ITT analysis set was 95%. In comparison, the completion rate for adjuvant aripiprazole studies was approximately 85% (Pae, CNS Drugs, 2011; 25, 109-127) and the completion rate for adjuvant quetiapine was 45% to 62% (El Khalili cited above). A total of 4 subjects (3.3%) discontinued the study: 2 placebo-treated subjects and 2 artikaplan-treated subjects. See Tables 46 and 47.

[0609] Table 46: Completion / early withdrawal information; eITT analysis set

[0610]

[0611] Percentages were calculated using the number of subjects in each group as the denominator.

[0612] Table 47: Completion / Early Exit Information; Full Safety Analysis Set

[0613]

[0614]

[0615] Percentages were calculated using the number of subjects in each group as the denominator.

[0616] (vii) Sexual function

[0617] Sexual dysfunction is a common side effect of antidepressant therapy and can be very upsetting to patients and their sexual partners. Major depressive disorder itself is associated with an increase in sexual dysfunction, and multiple medications in pharmacotherapy are known to further worsen sexual function. In a large survey of nearly 5,000 patients in France, the prevalence of sexual dysfunction was estimated to be 65% in untreated MDD patients. In patients treated with antidepressant therapy, the prevalence of sexual dysfunction increased to 71%.

[0618] Sexual pleasure is an important component of hedonic mood. The brain reward circuit is controlled by several areas: the nucleus accumbens, ventral tegmental area, and amygdala. It is hypothesized that treatment with kappa opioid receptors may restore normal homeostatic balance in patients with overactivation. Treatment with artikaplanam may improve symptoms of anhedonia. Other symptoms related to the reward circuit include: sexual pleasure, lack of interest, and lack of enjoyment.

[0619] The patient's sexual function was measured using the standard, widely accepted rating scale, ASEX. See Table 48.

[0620] Table 48: ASEX scores according to treatment groups

[0621]

[0622] The mean change (SD) from treatment baseline in the ASEX total score at week 6 was -1.5 (4.02) points for artikaplan and -0.7 (2.98) points for placebo. Lower scores on the ASEX indicate improvement. The decrease in scores at week 6 was greater in the artikaplan group compared with placebo. This was unexpected because adjunctive treatment with other agents would be expected to worsen sexual function, i.e., ASEX scores would increase over time. See Fig. 22 .

[0623] Patients treated with artikaplan-treated patients experienced significant improvements in sexual function. Changes at the individual item level were also examined, and the greatest changes were found in items related to complete pleasure: orgasmic satisfaction, reaching orgasm, and vaginal lubrication / erection. Most improvements were seen in Fig.23 Items 3, 4 and 5 of the.

[0624] (viii) Onset of Effect

[0625] The onset of effect of artikaplanam was estimated from the study. Figure 10-B depicts the least square mean change from baseline. A significant treatment effect favoring artikaplanam was observed as early as Week 3. At this point, artikaplanam showed a statistically superior effect to placebo.

[0626] Example 7 - Single Dose of Artikaplan as Adjunctive Antidepressant Therapy

[0627] Study Design: A 6-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of artikaplanam in adult and elderly subjects (18 to 74 years) with MDD and marked anhedonia (MDD ANH+) who had an inadequate response to SSRIs or serotonin and SNRIs in their current depressive episode. Fig.34 .

[0628] For all subjects, this study will consist of 3 phases: a screening phase (up to 4 weeks before the first dose), a 6-week double-blind treatment phase, and a 1- to 2-week follow-up. Subjects who complete the double-blind phase may participate in an open-label long-term safety study.

[0629] Sample Size and Randomization: Approximately 544 MDD subjects with significant anhedonia (MDD ANH+) and without significant anhedonia (MDD ANH-) will be randomized in a 1:1 ratio to adjunctive placebo or artikaplan to obtain at least 314 adult subjects who meet the predefined criteria for MDD ANH+ to be eligible for inclusion in the primary analysis. Randomization will be stratified by study site, age group (adults [<65 years], elderly [≥65 years]), baseline anhedonia, and baseline MADRS total score. All subjects will continue to take baseline antidepressant medication (SSRI / SNRI) throughout the study.

[0630] Dosing and Administration All eligible subjects will receive artikaplan or placebo in addition to their baseline SSRI / SNRI, which will continue throughout the study. Study medication will be taken daily.

[0631] Inclusion criteria:

[0632]

[0633]

[0634]

[0635] Exclusion criteria:

[0636]

[0637]

[0638]

[0639] A. Efficacy Objectives and End Points

[0640] Primary and secondary (critical and other) endpoints will be assessed on a FAS that includes MDD ANH+ adult (non-elderly) subjects who have taken at least 1 dose of study drug.

[0641] Primary endpoint: To evaluate the efficacy of artikaplan as adjunctive therapy to an antidepressant (SSRI or SNRI) compared with placebo in improving depressive symptoms in adult subjects with MDD ANH+ who have an inadequate response to current antidepressants as assessed by the change from baseline in the MADRS total score from Day 1 (pre-randomization) to the end of the 6-week double-blind treatment phase (Day 43):

[0642] Change in MADRS total score from baseline to day 43

[0643] Key secondary endpoints: To evaluate the efficacy of artikaplanam compared with placebo as adjunctive therapy to antidepressants in adult subjects with MDD ANH+ based on the following patient-reported assessments of anhedonia:

[0644] Change from baseline to Day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0645] Other secondary endpoints: To assess the efficacy of artikaplan as adjunctive therapy compared with placebo in adult subjects with MDD ANH+ based on:

[0646] The proportion of responders (reduction in MADRS total score ≥50%) at day 43.

[0647] The proportion of subjects with remission of depressive symptoms (defined as MADRS total score ≤ 12 at Day 43).

[0648] Change from baseline to day 43 in MADRS 6.

[0649] Change from baseline to day 43 in PHQ-9 total score.

[0650] Change from baseline to day 43 in the SHAPS total score.

[0651] Change from baseline to day 43 in anxiety symptoms using the GAD-7.

[0652] Exploratory endpoints: The efficacy of artikaplan as adjunctive therapy compared with placebo in adult subjects with MDD ANH+ and in all MDD subjects (adult subjects with MDD ANH+ and MDD ANH- and elderly subjects) was evaluated based on:

[0653] Change in MADRS total score over time from baseline.

[0654] Changes in MADRS anhedonia factor scores over time from baseline.

[0655] Changes over time from baseline in patient-reported anhedonia outcomes (SHAPS, DARS).

[0656] Change from baseline in PHQ-9 total score over time.

[0657] Change from baseline to day 43 in health-related quality of life and health status, as assessed by the EQ-5D-5L questionnaire.

[0658] Change in SDS total score from baseline to day 43

[0659] Changes in CGI-S scores over time from baseline.

[0660] Changes in anxiety symptoms over time relative to baseline using the GAD-7.

[0661] Changes in depressive symptoms over time from baseline using the PGI-S.

[0662] Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0663] To assess the efficacy of artikaplan-am as adjunctive therapy compared with placebo in adult subjects with MDD ANH-oncology based on:

[0664] Change in MADRS total score over time from baseline.

[0665] Change in DARS total score from baseline over time.

[0666] Security Purpose (All) : The following safety endpoints will be evaluated separately for adult and elderly subjects; the safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug:

[0667] AEs, including AESI. AEs may be related to the use of drugs (investigational or non-investigational)

[0668] Any unfavorable and unanticipated sign (including unusual findings), symptom, or disease temporally associated with the product, whether or not related to the drug (investigational or non-investigational) product.

[0669] TEAEs were AEs occurring during the treatment period that worsened from baseline. The full safety analysis set included all participating subjects who received at least 1 dose of study drug during the treatment period.

[0670] Vital signs

[0671] ECG, laboratory values

[0672] Weight / BMI

[0673] Suicidal tendencies assessment using C-SSRS

[0674] Withdrawal symptom assessment using the PWC-20

[0675] B. Concomitant and Contraindicated Therapies

[0676] Background therapy:All subjects will continue to take baseline antidepressants (SSRI / SNRI) throughout the study. The following antidepressants are allowed: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. During the study, subjects will continue to take only one of these allowed antidepressants at an adequate tolerated dose (i.e., monotherapy). No changes in antidepressants or doses are allowed from screening until the end of the study.

[0677] Prohibited therapies: Subjects were not to use the following medications or food supplements prior to or during the study, unless indicated for the treatment of AEs or breakthrough symptoms, preferably after the EOT visit:

[0678] MAOI within 4 weeks before screening and until the first follow-up visit.

[0679] Antipsychotic medications from at least 14 days before Day 1 until the first follow-up visit.

[0680] Hypnotic medications or food supplements (from at least 7 days before Day 1 until the first follow-up visit), including but not limited to benzodiazepines, nonbenzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suorexin, and lamivudine), sedating antihistamines, including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin / agomelatine.

[0681] Subjects who were taking benzodiazepines and / or permitted non-benzodiazepine sleep medications during the screening phase were allowed to continue taking these medications (at a dose equal to or less than 6 mg / day lorazepam equivalents) during the double-blind treatment phase. No dose increases above 6 mg / day lorazepam equivalents and no new benzodiazepines were allowed during the double-blind treatment phase.

[0682] Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days before Day 1 until the first follow-up visit.

[0683] During the screening and double-blind phases, any new psychotherapy or change in current psychotherapy was prohibited.

[0684] Opioids and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days before Day 1 until the first follow-up visit.

[0685] • Stimulants (e.g., dextroamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine) and isoxeprine from at least 7 days before Day 1 until before EOT.

[0686] Magnetic and electrical stimulation therapies: electroconvulsive therapy, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening to the end-of-study visit.

[0687] The use of TMS or DCS or electrical stimulation before screening was not excluded.

[0688] T3, thyroid hormone, or other thyroid supplements used to treat depression.

[0689] These medications are permitted when used to manage pre-existing thyroid disease / disorder.

[0690] Ketamine or esketamine within 5 years before and during the study (up to 2 doses allowed in lifetime before screening).

[0691] Psychedelic drugs (eg, psilocybin).

[0692] · Memantine.

[0693] Other study medications within 30 days before and during the study.

[0694] Example 8 - A randomized, double-blind, multicenter, placebo-controlled study designed to evaluate Fixed doses of artikaplan 5 mg and 10 mg were used in patients with MDD and significant anhedonia who were resistant to current antidepressant therapy. Efficacy, safety, and tolerability in adult and elderly subjects who had an inadequate response to

[0695] Study Design: An 8-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of artikaplanam in adult and elderly subjects (18 to 74 years) with MDD and significant anhedonia who have an inadequate response to an SSRI or SNRI in a current depressive episode. Fig.35 .

[0696] For all subjects, this study will consist of 3 phases:

[0697] Eligibility screening phase (up to 4 weeks before first dose administration),

[0698] An 8-week double-blind treatment phase,

[0699] and a 1- to 2-week follow-up phase.

[0700] Approximately 624 subjects (randomized 2:1:1 to placebo, atikaplan 5 mg, and atikaplan 10 mg) will participate in this study. The recruitment goal is to reach at least 556 adult subjects with MDD and significant anhedonia and approximately 68 elderly subjects (≥65 years) with MDD and significant anhedonia.

[0701] Subjects who completed the double-blind treatment phase were eligible to participate in an open-label long-term safety study.

[0702] Sample Size and Randomization: Approximately 624 adult subjects (<65 years) and elderly subjects (≥65 years) with MDD and marked anhedonia will be randomized in a 2:1:1 ratio to adjunctive placebo, 5 mg artikaplan, or 10 mg artikaplan to obtain a minimum of 556 adult subjects who meet the predefined criteria for MDD and marked anhedonia to be eligible for inclusion in the primary efficacy analysis set. Randomization will be stratified by study site, age group (adult, elderly), and baseline MADRS total score. All subjects will continue to take their baseline antidepressant (SSRI / SNRI) throughout the study.

[0703] Dosage and Administration: All eligible subjects will receive artikaplan 5 mg, artikaplan 10 mg, or placebo in addition to their baseline SSRI / SNRI, which will continue throughout the study. Study medication will be taken daily.

[0704] Inclusion criteria:

[0705]

[0706]

[0707] Exclusion criteria:

[0708]

[0709]

[0710]

[0711]

[0712] A. Efficacy Objectives and End Points

[0713] Primary and secondary (key and other) endpoints will be assessed on the full analysis set (FAS), which includes adult (non-elderly) subjects with MDD and significant anhedonia who have taken at least 1 dose of study medication.

[0714] Primary endpoint: To evaluate the efficacy of 2 fixed doses of artikaplan (5 mg and 10 mg) compared with placebo as adjunctive therapy to an antidepressant (SSRI or SNRI) in improving depressive symptoms in adult participants (18 to 64 years) with MDD and significant anhedonia who have an inadequate response to current antidepressants

[0715] Change in MADRS total score from baseline to day 43

[0716] Key secondary endpoints: To evaluate the efficacy of artikaplan 10 mg as adjunctive therapy to antidepressants compared with placebo in adult subjects with MDD and significant anhedonia based on the following patient-reported assessments of anhedonia:

[0717] Change from baseline to Day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0718] Other secondary endpoints: To evaluate the efficacy of atikaplan as adjunctive therapy to an antidepressant (SSRI or SNRI) compared with placebo in adult subjects with MDD and significant anhedonia:

[0719] The proportion of responders (reduction in MADRS total score ≥50%) at Day 43 and Day 57.

[0720] The proportion of subjects with remission of depressive symptoms (defined as MADRS total score ≤ 12 at Day 43 and Day 57).

[0721] Change from baseline to Day 43 and Day 57 in MADRS-6.

[0722] Change from baseline to Day 43 and Day 57 in the 9-item Patient Health Questionnaire (PHQ-9) total score.

[0723] Exploratory endpoints: To assess the efficacy of artikaplanam compared with placebo as adjunctive therapy in adult subjects with MDD and significant anhedonia based on:

[0724] Change in MADRS total score over time from baseline.

[0725] Changes in MADRS anhedonia factor scores over time from baseline.

[0726] Changes over time from baseline in patient-reported anhedonia outcomes (SHAPS, DARS).

[0727] Change from baseline in PHQ-9 total score over time.

[0728] Change from baseline to day 43 in health-related quality of life and health status, as assessed by the EQ-5D-5L questionnaire.

[0729] Change from baseline to day 43 in the Sheehan Disability Scale (SDS) total score.

[0730] Changes in CGI-S scores over time from baseline.

[0731] Changes in anxiety symptoms over time relative to baseline using the GAD-7.

[0732] Changes in depressive symptoms over time from baseline using the PGI-S.

[0733] Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0734] Security Purpose (All) : The following safety endpoints will be evaluated separately for adult and elderly subjects; the safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug:

[0735] AE including AESI

[0736] Vital signs

[0737] ECG

[0738] Laboratory values

[0739] Weight / BMI

[0740] Suicidal tendencies assessment using C-SSRS

[0741] Withdrawal symptom assessment using the PWC-20

[0742] Other purposes (exploratory):

[0743] To identify diagnostic biomarkers and investigate changes in MDD-related biomarkers associated with clinical response to artikaplan monotherapy in terms of depressive symptoms and anhedonia.

[0744] Identify genetic and other factors that may affect the pharmacokinetics (PK), safety, or tolerability of artikaplanam.

[0745] B. Concomitant and Contraindicated Therapies

[0746] Background therapy:All subjects will continue to take baseline antidepressants (SSRI / SNRI) throughout the study. The following antidepressants are allowed: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. During the study, subjects will continue to take only one of these allowed antidepressants at an adequate tolerated dose (i.e., monotherapy). No changes in antidepressants or doses are allowed from screening until the end of the study.

[0747] Prohibited therapies:

[0748] Subjects were not to use the following medications or food supplements prior to or during the study, unless indicated for the treatment of AEs or breakthrough symptoms, preferably after the EOT visit:

[0749] MAOI within 4 weeks before screening and until the first follow-up visit.

[0750] Antipsychotic medications from at least 14 days before Day 1 until the first follow-up visit.

[0751] Hypnotic medications or food supplements (from at least 7 days before Day 1 until the first follow-up visit), including but not limited to benzodiazepines, nonbenzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suorexin, and lamivudine), sedating antihistamines (including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine)), and melatonin. Subjects who took benzodiazepines and / or permitted nonbenzodiazepine sleep medications during the Screening Phase may continue to take these medications (at a dose equal to or less than the equivalent of 6 mg / day of lorazepam) during the Double-Blind Treatment Phase. Dose increases of more than 6 mg / day of lorazepam were not permitted during the Double-Blind Treatment Phase.

[0752] days of lorazepam equivalents, and no new benzodiazepines were allowed.

[0753] Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days before Day 1 until the first follow-up visit.

[0754] During the screening and double-blind phases of this study, any form of new psychotherapy or change in current psychotherapy was prohibited.

[0755] Opioids and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days before Day 1 until the first follow-up visit.

[0756] • Stimulants (e.g., dextroamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine) and isoxeprine from at least 7 days before Day 1 until before EOT.

[0757] Magnetic and electrical stimulation therapies: electroconvulsive therapy, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening to the end-of-study visit.

[0758] The use of TMS or DCS or electrical stimulation before screening was not excluded.

[0759] T3, thyroid hormone, or other thyroid function supplements used to treat depression. These medications are allowed when used to control pre-existing thyroid disease / disorder.

[0760] Ketamine or esketamine within 5 years before and during the study (up to 2 doses allowed in lifetime before screening).

[0761] Psychedelic drugs (eg, psilocybin).

[0762] · Memantine.

[0763] Other study medications within 30 days before and during the study.

[0764] Example 9

[0765] This was a phase 1, open-label, single-dose, multicenter, 4-part study in healthy adult participants.

[0766] A total of approximately 80 eligible healthy adult participants are planned to be enrolled in the study: 24 participants will be enrolled in each part to ensure that at least 20 participants complete all required PK assessments in each part. Eligible participants may be enrolled in more than one part of the study if participants complete an adequate washout period between time periods.

[0767] Potential participants will be screened from Day -28 to Day -2 to determine eligibility for the study. For Part 1, eligible participants will be admitted on Day -1 of each treatment period and will remain inside for the total duration of treatment (Day -1 until Day 5, single dose treatment on Day 1, and PK for 96 hours), whereas for Part 2, PK sampling will be performed for up to 120 hours (Day 6). After the last dose of study intervention, each dosed participant will have a safety follow-up on Days 10 to 14.

[0768] Part 1

[0769] Part 1 of the study involved determining the relative bioavailability of the tablet formulation (Formulation Concept 1, i.e., unmilled artikaplanam formulation, see Table 10) and capsule formulation (for a description of the capsule formulation, see Example 6, Study Design) as well as the dose proportionality and food effect of the tablet formulation (Formulation Concept 1) in healthy adult participants ( Fig.25 ). Part 1 will consist of Subpart 1A and Subpart 1B, consisting of a total of 4 time periods. Subpart 1A is a randomized, open-label, three-way crossover, 3-time period study to be conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg artikaplanam administered as 1×10 mg oral tablet (Formulation Concept 1) under fasting conditions (Treatment B) compared to 10 mg artikaplanam administered as 2×5 mg oral capsules under fasting conditions (Treatment A) and to evaluate the dose proportionality of a single dose of 5 mg artikaplanam administered as 1×5 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 (1×10 mg, Treatment B; Table 49). Participants will be assigned to 1 of 6 treatment sequences (Table 51) and will be administered to the 3 treatments in a 3-way crossover. The same 24 participants who complete Subpart 1A will be recruited into Subpart 1B. Subpart 1B consists of a fourth time period evaluating the food effect of a single dose of 10 mg artikaplanam (Treatment D; Tables 50 and 52) administered as 1 x 10 mg oral tablets (Formulation Concept 1) under fed conditions. A preliminary PK analysis of all time periods from Part 1 will be performed at the end of the food effect portion (Subpart 1B) and the food effect data will be included.

[0770]

[0771]

[0772] Main objectives:

[0773] - To evaluate the relative oral bioavailability of a potential Phase 3 tablet concept formulation of artikaplanm (unmilled API formulation concept; 1 x 10 mg) compared to an oral capsule formulation (2 x 5 mg) when administered as a single oral dose of 10 mg artikaplanm in healthy adult participants under fasting conditions.

[0774] - To evaluate the dose proportionality of a potential Phase 3 tablet concept formulation of artikaplanam (unmilled API formulation concept; 1 x 5 mg) relative to a potential Phase 3 tablet concept formulation (unmilled API formulation concept; 1 x 10 mg) when administered in healthy adult participants under fasting conditions.

[0775] - To evaluate the PK of a potential Phase 3 tablet concept formulation (unmilled API formulation concept; 1 x 10 mg) of an oral single dose of artikaplanam in healthy adult participants under fasting and fed (high fat meal) conditions.

[0776] Secondary objectives:

[0777] -To evaluate the safety and tolerability of oral doses of artikaplanam in healthy adult participants.

[0778] Part 2

[0779] Part 2 of the study addressed the relative bioavailability of the tablet formulation (Formulation Concept 2, i.e., milled (micronized) artikaplanam formulation; see Table 10) and capsule formulation (see Example 6, Study Design for a description of the capsule formulation) in healthy adult participants, as well as the dose proportionality and food effect of the tablet formulation (Formulation Concept 2). Fig.26 ) determination. Part 2 will consist of Subpart 2A and Subpart 2B, consisting of a total of 4 time periods. Subpart 2A is a randomized, open-label, three-way crossover, 3-time period study to be conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg artikaplanam administered as a 1×10 mg oral tablet (Formulation Concept 2) under fasting conditions (Treatment F) compared to 10 mg artikaplanam administered as 2×5 mg oral capsules under fasting conditions (Treatment E) and to evaluate a single dose of 5 mg artikaplanam administered as a 1×5 mg oral tablet (Formulation Concept 2) under fasting conditions (Treatment G) compared to a potential Phase 3 oral tablet (Formulation Concept 2) under fasting conditions (1×10 mg, Treatment F; Table 53). Participants will be assigned to 1 of 6 treatment sequences (Table 55) and will be administered to the 3 treatments in a 3-way crossover. The same 24 participants who complete Subpart 2A will be recruited into Subpart 2B. Subpart 2B consisted of evaluating a single dose of 10 mg artikaplanam (Treatment H; Table 54 and Table 56) administered as 1 x 10 mg oral tablet (Formulation Concept 2) under fed conditions. A preliminary PK analysis of all time periods from Part 2 was performed at the end of the food effect part (Subpart 2B) and food effect data will be included.

[0780]

[0781]

[0782] Main objectives:

[0783] - To evaluate the relative oral bioavailability of a potential Phase 3 tablet concept formulation of artikaplanm (milled artikaplanm formulation concept; 1 x 10 mg) compared to an oral capsule formulation (2 x 5 mg) when administered as a single oral dose of 10 mg artikaplanm in healthy adult participants under fasting conditions.

[0784] - To evaluate the dose proportionality of a potential Phase 3 tablet concept formulation of artikaplan (milled API formulation concept; 1 x 5 mg) relative to a potential Phase 3 tablet concept formulation (milled artikaplan formulation concept; 1 x 10 mg) when administered in healthy adult participants under fasting conditions.

[0785] - To evaluate the PK of a potential Phase 3 tablet concept formulation (milled artikaplan formulation concept; 1 x 10 mg) of an oral single dose of artikaplan in healthy adult participants under fasting and fed (high fat meal) conditions.

[0786] Additional points

[0787] For each individual participant, there will be a washout period of at least 7 days for Part 1 and at least 8 days for Part 2 between subsequent study intervention intakes. Day 1 of the treatment period (the day of study intervention intake) is the first day of the washout period (also between study parts, if applicable).

[0788] Participants will fast in Part 1A and Part 2A. Participants will eat in Part 1B and Part 2B. For fasting conditions, participants will fast (not eating or drinking except non-carbonated water) overnight at least 10 hours before the study intervention is used during each fasting treatment period, and until 4 hours after the study intervention is used. About 4 hours after administration and after 4 hours of PK sampling, a standard lunch will be provided at the research site. Allow water intake until 2 hours before the intake study intervention. After this, only water intake is allowed for the study intervention intake and for breakfast, if applicable. Allow water ad libitum about 2 hours after administration. For feeding conditions, after overnight fasting (at least 10 hours), participants will eat standardized high-fat breakfast in a 20-minute time period. A high-fat (approximately 50% of the total calories in the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended for food-effect bioavailability studies (e.g., 2 strips of fried bacon, 2 eggs fried in butter, 4 ounces [120 grams] of chopped brown potatoes fried in butter, 2 pieces of buttered whole-wheat bread, and 240 mL of whole milk). The study intervention will be administered approximately 30 minutes after the start of breakfast.

[0789] In Part 1 and Part 2, the plasma concentration of artikaplanam will be determined. Beginning on Day 1, blood samples for determination of the plasma concentration of artikaplanam were collected at pre-dose and post-dose time points as shown in Tables 57-58.

[0790] Part 1 and Part 2 of the study will start at any time regardless of the other parts of the study.

[0791] For Part 1 and Part 2, the study will consist of a screening phase (within 28 days prior to administration of the study intervention), an open-label treatment phase (Day -1 through Day 5, with a single dose on Day 1, and at least 96 hours of PK for Part 1 and 120 hours of PK for Part 2 (Day 6)).

[0792]

[0793]

[0794]

[0795]

[0796]

[0797] For Table 57 to Table 58:

[0798] (a) When scheduled procedures overlap, they should preferably be performed in the following order: 12-lead ECG, vital signs (supine BP, pulse / heart rate), blood / CSF draw for PK or laboratory measurements, and C-SSRS.

[0799] (b) For all female participants.

[0800] (c) Time period 1 only.

[0801] (d) During the period of administration under fed conditions only: The standardized high-fat breakfast should be consumed within a 20-minute period.

[0802] (e) Under fasting conditions where dosing was done under fasting conditions, the study intervention was administered in the morning after at least a 10-hour overnight fast, and for periods where dosing was done under fed conditions, the study intervention was administered 30 minutes after breakfast.

[0803] (f) For all postmenopausal women, perform FSH to confirm the postmenopausal status of women who have no alternative medical reason.

[0804] (g) After collecting 4-hour PK blood samples and / or CSF samples.

[0805] (h) An additional 6 mL of blood was collected from each participant prior to dosing for experimental work related to protein binding of the parent and metabolites.

[0806] (i) Additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing may be performed based on site-specific guidance or practices.

[0807] (j) There are 2 versions of the C-SSRS. Complete the Baseline / Screening version of the C-SSRS at Screening, and then complete the C-SSRS from your last visit before dosing on Day -1, before leaving on Day 5 of each treatment period (for Part 1), before leaving on Day 6 of each treatment period (for Part 2), and at the end of the study or early withdrawal.

[0808] (k) After leaving the clinic, participants may be contacted by telephone to assess adverse events.

[0809] (l) Determination of free and total plasma concentrations of artikaplanam.

[0810] (m)

[0811] (n) Blood pressure and pulse / heart and respiratory rates will be measured in the supine position after 5 minutes of rest.

[0812] (o) Urine alcohol testing or alcohol breath testing will be used for alcohol screening per site-specific guidelines or practices.

[0813] (p) Before spinal catheter insertion.

[0814] (q) Whenever a catheter remains in place for more than 24 hours, the catheter tip will be used for culture analysis.

[0815] A. Research Group

[0816] A total of approximately 80 eligible healthy adult participants are planned to be enrolled in the study: In the 24 participants were enrolled in each of Parts 1 and 2 to ensure that at least 20 participants in each part completed all required PK assessments. Eligible participants could be enrolled in more than one part of the study if they completed an adequate washout period between time periods.

[0817] Screening of eligible participants will be performed within 28 days prior to administration of the study intervention.

[0818] (i) Inclusion criteria

[0819] Each potential participant must meet all of the following study recruitment criteria:

[0820] For all participants

[0821]

[0822]

[0823] Other inclusion criteria

[0824]

[0825] (ii) Exclusion criteria

[0826] Any potential participant who meets any of the following criteria will be excluded from participating in the study: For all participants:

[0827]

[0828]

[0829]

[0830] Other exclusion criteria

[0831] Have donated blood or blood products or plasma within 3 months before the first administration of study intervention or have had a massive blood loss (more than 500 mL) or intend to donate blood or blood products during the study.

[0832] Inability to swallow solid, oral dosage forms whole with water (participants may not be able to chew, split, dissolve, or crush the study intervention).

[0833] A history of smoking or using nicotine-containing substances within the previous 3 months before screening, as determined by medical history or verbal report by the participant.

[0834] Vulnerable participants (e.g., those who remain stagnant).

[0835] Drinking more than 8 cups of tea / coffee / cocoa / cola or other caffeinated beverages on average per day.

[0836] Clinically significant acute illness within 7 days prior to administration of study intervention.

[0837] · History of clinically significant drug and / or food allergies.

[0838] (iii) Meals and dietary restrictions

[0839] 1. Participants should not consume any food or beverages containing grapefruit juice, Seville oranges (including any orange marmalade), or quinine (e.g., tonic water) from 48 hours before the first dose of the study intervention (72 hours in the case of grapefruit juice and Seville oranges) until the last dose of the study intervention.

[0840] 2. No water was allowed within 2 hours before the study intervention, except for 240 mL of non-carbonated water taken with the oral study intervention and water given with the high-fat breakfast. Water was not allowed until 2 hours after dosing, after which water was allowed ad libitum.

[0841] 3. No food or beverages (including additional salt or sugar) may be consumed except those provided by study site personnel during the inpatient stay.

[0842] 4. For the entire study period (including the screening period and follow-up), subjects must abstain from the use of any methylxanthine-containing products (i.e., chocolate bars or drinks, energy drinks (if they contain methylxanthines), coffee, tea, or cola) starting 48 hours before the administration of the study intervention and during the restraint period, and must also avoid excessive caffeine use (i.e., not exceeding approximately 500 mg / day, as contained in 5 cups of tea or coffee or 8 cans of cola).

[0843] 5. No consumption of foods containing poppy seeds during the study period starting 72 hours prior to Screening or 72 hours prior to entering the study site for each treatment period (to avoid false-positive urine drug tests for codeine).

[0844] Caffeine, alcohol, tobacco, and drug abuse

[0845] 1. No smoking of cigarettes (or equivalent) and / or use of nicotine-based products were allowed from 3 months before screening until completion of follow-up.

[0846] 2. Alcohol use should be limited to an absolute minimum. It is best not to use alcohol from the first screening visit until follow-up. If any alcohol is taken, up to 2 standard drinks per day will be allowed. One standard drink is defined as: 5% ABV beer in a 350mL glass, 12% ABV wine in a 150mL glass, or 40% ABV (80 proof) alcohol in a 45mL glass.

[0847] active

[0848] 1. Strenuous exercise can affect study-specified assessments and safety laboratory results; therefore, strenuous exercise should be avoided within 48 hours prior to all planned study visits and during stay in the CRC. Prior exercise was allowed if the participant's serum creatinine concentration was within the normal range. Minor abnormalities that were not considered clinically relevant were acceptable.

[0849] 2. Participants will be advised not to donate blood for at least 3 months after completion of the study or not to participate in study drug research for at least 1 month after completion of the study.

[0850] B. Study Intervention

[0851] All study interventions will be taken with 240 mL of non-carbonated water in the morning on Day 1 of each treatment period. Study interventions must be swallowed whole and not chewed, split, dissolved, or crushed.

[0852] All doses must be administered at approximately the same time for each participant.

[0853] Participants receiving the study intervention under fasting conditions will fast overnight for at least 10 hours.

[0854] Participants receiving the study intervention under fed conditions will fast overnight (at least 10 hours) and then consume a high-fat breakfast within a 20-minute period. The high-fat breakfast will be the same on the dosing day during the fed period (Part 1 and Period 4 of Part 2). The study intervention will be administered approximately 30 minutes after the start of breakfast.

[0855] Non-carbonated water will be allowed until 2 hours before the study intervention is administered. Participants will continue to fast until at least 4 hours after the study intervention is administered. Approximately 2 hours after dosing (but not earlier), water will be allowed ad libitum. After collecting the 4-hour PK blood samples, a standardized lunch will be provided to all participants on Day 1. Participants can resume their normal diet after 4 hours.

[0856] The exact composition of breakfast and lunch will be recorded. Lunch will be the same in all intervention periods. The exact start and end times of breakfast and the start time of lunch will be recorded, along with any deviations regarding meal times.

[0857] Artikaplanam was provided in this study as 5 mg capsules and 5 mg and 10 mg tablet formulations.

[0858] Concomitant therapy

[0859] Pre-study therapy administered up to 30 days prior to the first dose of study intervention will be recorded at Screening.

[0860] All therapies other than study medication (prescription or over-the-counter medications, including vaccines, vitamins, herbal supplements; nonpharmacological therapies that are different from the study intervention (such as electrical stimulation, acupuncture, special diets, exercise regimens, or other specific categories of interest) must be recorded. The information recorded will include a description of the type of therapy, duration of administration, dosing regimen, route of administration, and indication. Effective pre-existing therapies should not be modified for the express purpose of enrolling the participant in the study.

[0861] All concomitant therapies considered to be CYP inhibitors or inducers or transporter inhibitors or inducers were not permitted during the study and were not permitted for at least 1 month prior to the first intake of the study intervention.

[0862] Prescription or over-the-counter medications other than study intervention (including vitamins and herbal supplements) will be prohibited throughout the study, except for acetaminophen. A maximum of 3 doses of 500 mg acetaminophen per day, not to exceed 3 g per week, will be allowed throughout the study for the treatment of headache or other pain.

[0863] Women who use hormonal birth control as a means of birth control must continue to use the same hormonal birth control throughout the study. Women who use hormone replacement therapy must continue to use the same hormone replacement therapy throughout the study.

[0864] C. Research Evaluation

[0865] Tables 59 to 60 summarize the frequency and timing of PK measurements applicable to this study.

[0866] 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 draw for PK or laboratory measurements, and C-SSRS. Blood collection for PK assessments should be kept as close to the designated time as possible. Other measurements may be performed earlier than the designated time point if necessary.

[0867] For each participant, the maximum amount of blood drawn from each participant will not exceed 500mL.

[0868] Taking into account the daily CSF production rate, the total CSF volume collected per participant enrolled in the CSF PK will not exceed 52.3 mL, which is considered acceptable.

[0869]

[0870] (i) Vital signs

[0871] Temperature, pulse / heart rate, respiratory rate, blood pressure will be assessed.

[0872] Blood pressure and pulse / heart rate measurements will be assessed with a fully automated device consisting of an inflatable cuff and an oscillation detection system. All values ​​will be registered on a built-in recorder, making the measurements observer independent. Blood pressure and pulse / heart rate measurements will be recorded after 5 minutes of rest in a supine position in a quiet environment without distractions (e.g., television, cell phones).

[0873] (ii) Electrocardiogram

[0874] During the collection of ECG, participants should be in a quiet environment without distractions (e.g., television, mobile phones). Participants should rest in a supine position for at least 5 minutes before ECG collection, and should avoid talking or moving arms or legs. If blood sampling or vital sign measurements are scheduled at the same time point as the ECG recording, they should preferably be performed in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse / heart rate), blood / CSF extraction for PK or laboratory measurements, and C-SSRS.

[0875] (iii) Columbia-Suicide Severity Rating Scale (C-SSRS)

[0876] The C-SSRS is a measure of the suicidal ideation and behavior spectrum that was developed to assess severity and track suicidal events through any treatment. It is a clinical interview to assess the risk of treatment-induced suicidal ideation / behavior.

[0877] There are 2 versions of the C-SSRS. Complete the Baseline / Screening version of the C-SSRS at Screening and then complete the version from your last visit before dosing on Day -1, before leaving on Day 5 of each treatment period (for Part 1) and before leaving on Day 6 of each treatment period (for Part 2), at the end of the study or at early withdrawal.

[0878] (iv) Fundus ophthalmoscopy

[0879] Funduscopy is a form of examination of the fundus of the eye. Use according to internal standard operating procedures PanOptic TM Fundus ophthalmoscope (model 11810).

[0880] (v) Pharmacokinetics

[0881] Plasma and CSF samples will be used to evaluate the PK of artikaplanam.

[0882] evaluate

[0883] Blood samples (4 mL each) for determination of artikaplan plasma concentrations will be collected at the time points indicated in Tables 59-60.

[0884] Analytical procedures

[0885] During the study, serial blood samples (4 mL each) for determination of artikaplan plasma concentrations will be collected at the time points shown in Tables 59-60.

[0886] Plasma samples were analyzed using a validated, specific, and sensitive liquid chromatography coupled to tandem mass spectrometry (LC-MS / MS) method to determine the concentration of artikaplanam.

[0887] parameter

[0888] The following plasma PK parameters of artikaplanam will be determined. A non-compartmental model with extravascular input will be used for pharmacokinetic analysis.

[0889] Based on the individual concentration-time data, using the actual sampling times, the following PK parameters will be derived for artikaplanam:

[0890]

[0891] For t 1 / 2 , z and AUC ∞ The acceptable calculation should meet the following requirements:

[0892] A) Use at least 3 data points in the calculation, otherwise t 1 / 2 , z and AUC ∞ Not assessable.

[0893] B) Determination coefficient (r 2 adj) is at least 0.90.

[0894] If requirement (B) is not met, then t 1 / 2 , z and AUC ∞ Will be reported as approximate.

[0895] Significant deviations in the actual sampling times will be checked. If a significant deviation occurs for an actual sampling time that deviates by >20.00% from the scheduled time, that plasma concentration will be excluded from the descriptive statistics in the plasma concentration table.

[0896] Sample volume determination

[0897] PK parameters (AUC ∞ and C max) within-participant coefficient of variation (CV) for AUC ∞ It is estimated to be between 8.3% and 10.4%, and for C max Estimates ranged from 14.4% to 24.3%. Therefore, a within-participant CV of 25% was used for this sample size adjustment.

[0898] With a selected intra-participant CV of 25% and N = 20 or 24 completers, the PK parameters (AUC ∞ and C max The limits to which the point estimates of the ratio of the geometric means of ) will fall are given in Table 61.

[0899]

[0900]

[0901] 24 participants were recruited to ensure that 20 participants completed the study. If 20 participants did not complete the study, additional participants could be recruited.

[0902] Analysis set population

[0903] For the purpose of analysis, the following groups were defined:

[0904]

[0905] Statistical analysis

[0906] The statistical analysis plan will be completed prior to the DBL and it will include more technical and detailed descriptions of the statistical analyses described in this section.This section is an overview of the planned statistical analyses for the most important endpoints.

[0907] Initial participant characteristics

[0908] Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be presented for age, BMI, weight, and height for all participants who received at least one dose of the study intervention. Gender and race will be listed and tabulated.

[0909] Pharmacokinetic analysis

[0910] Data for all participants with available serum concentrations for each intervention will be listed. All concentrations below the limit of quantitation or with missing data will be marked as such in the concentration data list display. Concentrations below LOQ will be considered as 0 in the summary statistics and used to calculate pharmacokinetic parameters. All participants and samples excluded from the analysis will be clearly recorded in the clinical study report.

[0911] Factors that may affect plasma concentrations (e.g., vomiting, high predose concentrations) will be examined.

[0912] Reasons for excluding participants or samples from the analysis include, but are not limited to, the following:

[0913] Higher than 5% C max Pre-dose artikaplan plasma concentration

[0914] For immediate-release products, vomiting after administration of the study intervention (within 3 hours after dosing under fasting conditions and within 8 hours after dosing under fed conditions). (Considering a median T of 1.5 hours under fasting conditions max and the median T at 4 h under fed conditions max )

[0915] If for a given participant, %AUC ∞,ex If the AUC is greater than 20%, the participant will be excluded from the statistical analysis of AUC∞.

[0916] Too little data (greater than 10% missing values ​​per participant)

[0917] Failure to comply with study procedures that affect pharmacokinetics (e.g., co-administration)

[0918] All participants and samples excluded from the analysis will be clearly documented in the study report.

[0919] For each intervention, descriptive statistics including arithmetic mean, standard deviation (SD), coefficient of variation (CV), geometric mean, median, minimum and maximum will be calculated for the plasma concentration of artikaplanam at each sampling time and for all PK parameters of artikaplanam.

[0920] For relative bioavailability, graphical representations of the results for Artikaplan will include (but not be limited to) the following graphs:

[0921] For each individual log-linear and linear-linear plasma concentration-time curve

[0922] Log-linear and linear-linear plasma concentration-time curves for the mean values ​​of each intervention

[0923] Log-linear and linear-linear plasma concentration-time curves for the median values ​​of each intervention

[0924] Log-linear and linear-linear overlays of the individual plasma concentration-time curves for each intervention

[0925] Graphical comparison of individual and mean (±SD) values ​​of the key PK parameters of artikaplan for each intervention

[0926] For dose proportionality, graphical representations of the results for Artikaplan will include (but not be limited to) the following graphs:

[0927] • Log-linear and linear-linear plasma concentration-time curves for each individual for all dose levels.

[0928] Overlay of mean plasma concentration-time curves observed on log-linear and linear-linear scales for all dose levels Overlay of mean dose-normalized plasma concentration-time curves on log-linear and linear-linear scales.

[0929] ·With C max , AUC∞, AUC last and / or a plot of the observed individual values ​​of AUC truncated to a common time point relative to dose;

[0930] ·With C max , AUC∞, AUC last and / or a plot of the observed dose-normalized individual values ​​relative to the AUC truncated to a common time point;

[0931] The primary objectives of the statistical analysis were to estimate the relative bioavailability of the test atikaplank formulation relative to the reference atikaplank formulation, the dose proportionality of the test atikaplank formulation, and the effect of food on the PK of the test atikaplank formulation.

[0932] The main parameters of interest for the statistical analysis will be the log-transformed estimated AUC, AUC last , AUC ∞ and C max If more than half of the participants do not have reliable values, the AUC ∞ will be rejected as a primary parameter for a group. If one of the PK parameters of interest is not estimable for a given participant in one or more time periods, the participant's data will not be included in the statistical analysis for that particular PK parameter.

[0933] For relative bioavailability and dose proportionality in Subsection 1A (i.e., only the first 3 time periods will be included in this analysis), the dose-normalized AUClast , AUC ∞ and C max The least squares means and within-participant variation will then be estimated using a mixed effects model that includes treatment, time period, and treatment sequence as fixed effects and participant as a random effect. Using these estimated least squares means and within-participant variation, point estimates and 90% confidence intervals for the mean differences on a logarithmic scale between treatment B (test) and treatment A (reference) and between treatment C (test) and treatment B (reference) will be constructed. The bounds of the confidence intervals will be inversely transformed using the inverse logarithm to obtain the mean AUC and C for the test formulations versus the reference formulations (treatment B / treatment A and treatment C / treatment B). max 90% confidence interval for the ratio. Similar analyses will be performed for Treatment E, Treatment F, and Treatment G for relative bioavailability and dose proportionality in Subsection 2A.

[0934] For food effects in both Subpart 1B (Treatment D vs. Treatment B) and Subpart 2B (Treatment H vs. Treatment F), a mixed effects model will fit the data with the logarithm of the PK parameter as the dependent variable, treatment (fed vs. fasted) as a fixed effect, and participant as a random effect. Using the least squares means of these estimates from the mixed effects model and the within-participant variation, point estimates and 90% confidence intervals for the mean differences on the logarithmic scale between Treatment D (fed) and Treatment B (fasted) and between Treatment H (fed) and Treatment F (fasted) will be constructed. The bounds of the confidence intervals will be inversely transformed using the inverse logarithm to obtain mean AUC and C under fed conditions compared to fasted conditions. max 90% confidence intervals for the corresponding ratios.

[0935] D. Results

[0936] This study included two parts with similar study designs, Part 1 (unground API tablets) and Part 2 (ground API tablets) for investigating two different tablet formulation concepts. Within each part, evaluations included relative bioavailability of API (2×5 mg) in immediate release tablet formulations (1×10 mg) and capsule formulations, dose proportionality between 10 mg and 5 mg tablet strengths, and food effect assessment at 10 mg tablet strength. Each part consisted of subpart A and subpart B, for a total of 4 time periods. Subpart A was a randomized, open-label, three-way crossover, 3-period study conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg artikaplanm administered as a 1×10 mg oral tablet under fasting conditions compared to 10 mg artikaplanm administered as 2×5 mg oral capsules under fasting conditions and to evaluate the dose proportionality of a single dose of 5 mg artikaplanm administered as a 1×5 mg oral tablet under fasting conditions compared to 1×10 mg oral tablet under fasting conditions. The same 24 participants who completed Subpart A were recruited into Subpart B, which consisted of a fourth period to evaluate the food effect of a single dose of 10 mg artikaplanm administered as a 1×10 mg oral tablet under fed conditions.

[0937] Tables 62 to 65 show the results of the PK analysis of Part 1 (unground API tablet formulation), including PK parameters between treatments and statistical comparisons between treatments of interest. Table 62 summarizes the PK parameters between treatments in Part 1. Table 63 shows the statistical comparison results of the relative bioavailability of 1×10 mg unground API tablets and 2×5 mg API in capsule formulations. Table 64 shows the statistical comparison results of the dose proportionality between 1×10 mg unground API tablets and 1×5 mg unground API tablet formulations. Table 65 shows the statistical comparison results of the food effect evaluation using 1×10 mg unground API tablets when administered in the presence of a high-fat diet and when administered under fasting conditions. The results of the PK parameters are comparable between the API in the unground API tablet (1×10 mg) and capsule (2×5 mg) formulations, and the statistical evaluation using the calculated geometric mean ratio shows that the two formulations are comparable and within the standard BE limits. Based on the dose-dependent increase in PK parameters, dose proportionality was established between the 10 mg unmilled API tablet formulation strength and the 5 mg unmilled API tablet formulation strength, and comparisons of dose-normalized PK parameters and statistical evaluation of calculated geometric mean ratios were within the BE limits of 0.8 to 1.25. Finally, the unmilled API tablet formulation showed an approximately 40% increase in AUC when given at 10 mg in the presence of a high-fat meal compared to administration under fasting conditions, as demonstrated from the geometric mean ratios calculated for AUC.

[0938] Tables 66 to 73 show the results of the PK analysis of Part 2 (milled API tablet formulations), including PK parameters between treatments and statistical comparisons between treatments of interest. Table 70 summarizes the PK parameters between treatments in Part 2. Table 71 shows the statistical comparison results of the relative bioavailability of 1×10 mg milled API tablets and 2×5 mg API in capsule formulations. Table 72 shows the statistical comparison results of the dose proportionality between 1×10 mg milled API tablets and 1×5 mg milled API tablet formulations. Table 73 shows the statistical comparison results of the food effect evaluation using 1×10 mg milled API tablets when administered in the presence of a high-fat diet and when administered under fasting conditions. The results of the PK parameters are comparable between the API in the milled API tablet (1×10 mg) and capsule (2×5 mg) formulations, and the statistical evaluation using the calculated geometric mean ratio shows that the two formulations are comparable and within the standard BE limits. Based on the dose-dependent increase in PK parameters, dose proportionality was established between the 10 mg milled API tablet formulation strength and the 5 mg milled API tablet formulation strength, and comparison of dose-normalized PK parameters and statistical evaluation of calculated geometric mean ratios were within the BE limits of 0.8 to 1.25. Finally, the milled API tablet formulation showed an approximately 30% increase in AUC when given at 10 mg in the presence of a high-fat diet compared to administration under fasting conditions, as demonstrated from the geometric mean ratios calculated for AUC.

[0939] In summary, both 1×10 mg milled and unmilled API tablet formulations showed comparable artikaplanam exposures similar to those observed with 10 mg reference API in capsule formulation (2×5 mg API in capsules) and were bioequivalent. Dose proportionality was observed between the 10 mg tablet formulation strength and the 5 mg tablet formulation strength for each tablet formulation concept for both unmilled and milled API. A modest food effect of approximately 30% (milled API tablet) and approximately 40% (unmilled API tablet) increase in AUC was observed at 10 mg, with slightly delayed median T values ​​of 2.00 hours (milled API tablet) and 2.75 hours (unmilled API tablet) in the presence of a high-fat meal. max , while it is 1.5 hours when administered under fasting conditions. A 40% food effect is not considered clinically relevant for many drugs because it is part of the PK variability and there is no safety issue at the higher artikaplankton exposure. Therefore, artikaplankton can be administered with or without food.

[0940] (i) PK parameters

[0941]

[0942]

[0943] (ii) Relative BA assessment

[0944] The 1 x 10 mg unmilled API tablet concept may show artikaplanam exposures similar to those observed with 10 mg reference API in a capsule formulation (2 x 5 mg API in capsules).

[0945]

[0946]

[0947] (iii) Dose proportionality

[0948] Dose proportionality was observed between 1 x 10 mg unmilled API tablets and 1 x 5 mg unmilled API tablets.

[0949]

[0950] (iv) Food effects

[0951] A food effect (high fat diet) was observed for the 10 mg unmilled API tablet (AUC increased by approximately 44%), with T max The delay was to about 3 hours, whereas in the absence of a high-fat meal it was delayed to 1.5 hours.

[0952]

[0953]

[0954]

[0955]

Claims

1. A pharmaceutical composition comprising about 2 mg to about 20 mg of artikaplan and a filler, wherein the composition comprises between about 0.1% to about 90% by weight of artikaplan.

2. The pharmaceutical composition according to claim 1, further comprising one or more of the following: a disintegrant, a glidant, a lubricant, a solvent, a colorant and a binder.

3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises between about 10% to about 99.9% by weight of 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 between about 0.5% to about 50% by weight of a disintegrant.

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

7. The pharmaceutical composition of claim 6, wherein the composition comprises between about 0.1 wt % to about 10 wt % of the glidant.

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

9. The pharmaceutical composition of claim 8, wherein the composition comprises between about 0.05 wt % to about 5 wt % of a lubricant.

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

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

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition is an oral tablet comprising about 200 mg of a tablet core comprising about 10 mg of artikaplanam, 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. The pharmaceutical composition of claim 12, further comprising about 6 mg of a film coating.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the filler is selected from the group consisting of 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 anhydrous colloidal silicon dioxide.

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

18. A pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition is an oral tablet comprising about 10 mg of artikaplanam, wherein the oral tablet comprises about 200 mg of a tablet core, wherein the tablet core 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 anhydrous colloidal silicon dioxide; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silicon dioxide, and about 1 mg of magnesium stearate.

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

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

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

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

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

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

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

26. The method of any one of claims 19 to 25, wherein the artikaplanam is crystalline artikaplanam.

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

28. The method of claim 27, wherein the one or more antidepressants are SSRIs, SNRIs, or a combination thereof.

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

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

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