Polymorphic forms of articaram for treatment of major depressive disorder

Abstract

The present disclosure provides a crystalline form of atipram and an amorphous form of atipram. The present disclosure also provides a pharmaceutical composition comprising the amorphous form or the crystalline form, a method of treating major depressive disorder using the amorphous form of articaram or the crystalline form of articaram, and a pharmaceutical composition comprising the amorphous form of articaram or the crystalline form of articaram. Amorphous form of artepacram or crystalline form of artepacram for the treatment of major depressive disorder in a human patient suffering from pleasant sensation deficiency, the use of the amorphous form of artepacram or crystalline form of artepacram for the preparation of a medicament for the treatment of major depressive disorder, and a package or pharmaceutical product comprising (i) articaram in amorphous form or crystalline form and (ii) instructions for the treatment of major depressive disorder. In some aspects, a human patient as treated herein has a deficit of pleasure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 317,475, filed on March 7, 2022. Technical Field

[0003] The present disclosure relates to polymorphs of artikaplanam and methods of using these polymorphs. 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 crystalline Form I of artikaplanam.

[0008] In other aspects, the present disclosure provides artikaplanam in crystalline Form II.

[0009] In a further aspect, the present disclosure provides artikaplanam in crystalline Form III.

[0010] In yet other aspects, the present disclosure provides artikaplanam in an amorphous form.

[0011] In yet a further aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of artikaplanam or an amorphous form of artikaplanam as described herein. The crystalline form of artikaplanam may be Form I, Form II or Form III.

[0012] In other aspects, the present disclosure provides a method of treating major depressive disorder in a human patient, the method comprising administering to a human patient in need thereof an effective amount of a crystalline form of artikaplanm or an amorphous form of artikaplanm as described herein. The crystalline form of artikaplanm may be Form I, Form II, or Form III.

[0013] In a further aspect, the present disclosure provides a crystalline form of Artikaplanam as described herein for use in treating major depressive disorder in a human patient. The crystalline form of Artikaplanam may be Form I, Form II or Form III.

[0014] In still other aspects, the present disclosure provides an amorphous form of artikaplanam for use in treating major depressive disorder in a human patient.

[0015] In yet a further aspect, the present disclosure provides use of a crystalline form of artikaplanam or an amorphous form of artikaplanam as described herein in the preparation of a medicament for treating major depressive disorder in a human patient. The crystalline form of artikaplanam may be Form I, Form II or Form III.

[0016] In other aspects, the present disclosure provides a package or pharmaceutical product comprising (i) a crystalline form of artikaplanam, an amorphous form of artikaplanam, or a combination thereof as described herein, and (ii) instructions for use in treating major depressive disorder in a human patient. The crystalline form of artikaplanam can be Form I, Form II, or Form III. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the x-ray powder diffraction (XRPD) pattern of Artikaplan Form III (transmission mode).

[0018] Figure 2 is the XRPD pattern of amorphous artikaplanam. The top pattern was generated from 1,4-dioxane, the middle pattern was generated from tert-butyl alcohol, and the bottom pattern was generated from THF / H2O.

[0019] Figure 3 is a modulated differential scanning calorimetry (mDSC) thermogram of amorphous artikaplanam.

[0020] Figure 4 is a differential scanning calorimetry (DSC) thermogram of artikaplanam in Form III.

[0021] Figure 5 The temperature was heated from -40℃ to 131℃ at 10℃ / min. Figure 3 DSC thermogram of the sample.

[0022] Figure 6 is the XRPD pattern of Form I of Artikaplanam.

[0023] Figure 7 is the DSC thermogram of crystalline Form I of Atikaplan.

[0024] Figure 8 is the XRPD pattern of crystalline Form II of Atikaplan (1 g scale).

[0025] Fig. 9 is the mDSC thermogram of crystalline Form II of Atikaplan (1 g scale).

[0026] Fig.10 is a gravimetric vapour sorption (GVS) isotherm of artikaplanam (1 g scale) in crystalline Form II.

[0027] Fig.11 is a GVS kinetic diagram of crystalline Form II of Atikaplan (1 g scale).

[0028] Fig.12 is the mDSC thermogram of Artikaplan in crystalline Form III.

[0029] Fig.13 is a schematic diagram showing a decision tree for the treatment of gums / oils in a solubility screen.

[0030] Fig.14 This is the experimental design of Example 1.

[0031] Fig.15 is a line graph showing the MADRS (Montgomery-Asberg Depression Rating Scale) total score: least squares mean change from baseline during the treatment period (± SE) for the enriched intention-to-treat (eITT) analysis set.

[0032] Fig.16 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.

[0033] Fig.17 is a line graph showing the least squares mean change (± SE) from baseline during the treatment period for the SHAPS (Snaith-Hamilton Hedonic Feeling Scale) Total Score: eITT analysis set.

[0034] Fig.18Graphs 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.

[0035] Fig.19 is a line graph showing the MADRS total score: mean (± SE) over time for the eITT analysis set.

[0036] Figure 20-A is a line graph showing the MADRS total score: mean (± SE) over time for the full intention-to-treat (fITT) analysis set. Figure 20-B Is from Figure 20-A Excerpts from treatment weeks 0 to 6.

[0037] Fig.21 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.

[0038] Fig. 22 is a line graph showing the MADRS total score: percentage of subjects with remission of depressive symptoms (total score ≤ 10) during the treatment period for the fITT analysis set.

[0039] Fig.23 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.

[0040] Fig.24 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.

[0041] Fig.25 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.

[0042] Fig.26 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.

[0043] Fig. 27 is a line graph showing the SHAPS total score: mean (± SE) over time for the eITT analysis set.

[0044] Fig.28 is a line graph showing SHAPS total score: mean (± SE) over time for the fITT analysis set.

[0045] Fig.29 Shown are the changes from baseline in MADRS according to anhedonia severity.

[0046] Figure 30-A is a line graph showing the change from baseline in MADRS for patients with high anhedonia (ie, SHAPS ≥ 38). Figure 30-B is a line graph showing the change in MADRS from baseline for patients with low anhedonia (ie, SHAPS < 38).

[0047] Fig.31 is a bar graph showing a comparison of MADRS for patients with low anhedonia and high anhedonia.

[0048] Fig.32 is a line graph showing the mean change from baseline in ASEX total score.

[0049] Fig.33 is a bar graph showing the mean change from baseline in the ASEX item level change total score.

[0050] Fig.34 is a bar graph showing the SHAPS item: Change from baseline in the LS mean of the SHAPS total score at Week 6 for the fITT analysis set. In this graph, from top to bottom, the bars alternately represent placebo or artikaplan. For example, the first bar refers to artikaplan, the second bar refers to placebo, the third bar refers to artikaplan, and so on.

[0051] Fig.35 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

[0052] 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).

[0053] The present disclosure provides new crystalline and amorphous forms of artikaplanam. The crystalline forms (i.e., Form I, Form II, and Form III) are anhydrous and stable in solid form. In some embodiments, crystalline Form I is anhydrous. In other embodiments, crystalline Form II is anhydrous. In additional embodiments, crystalline Form III is anhydrous.

[0054] The term "crystal" refers to a solid form of a chemical moiety containing a highly ordered intermolecular structure.

[0055] 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.

[0056] The term "amorphous" refers to a solid form of a chemical part that exists in a non-crystalline state. Amorphous solids are crystals that do not have a characteristic shape or form. That is, amorphous forms lack long-range structural order. Characterization of amorphous forms can be performed by those skilled in the art, including but not limited to XRPD, TGA, infrared spectroscopy, Raman spectroscopy, solid-state NMR, DSC, scanning electron microscopy, dynamic solvent adsorption, laser diffraction, dissolution, MET analysis, densitometry, viscometry, high pressure liquid chromatography (HPLC), reversed-phase gas chromatography or a combination thereof. In some aspects, an amorphous sample does not contain other forms, i.e., the sample is 100% w / w amorphous. Amorphous samples may also contain solids that are crystalline. In certain aspects, an amorphous form may contain a solid such that the sample is at least about 99% w / w amorphous, at least about 95% w / w amorphous, at least about 90% w / w amorphous, at least about 85% w / w amorphous, at least about 80% w / w amorphous, etc.

[0057] 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.

[0058] As used herein, the term "anhydrous" or "anhydrate" refers to a crystalline or amorphous form that is substantially free of water 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.

[0059] 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°.

[0060] 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°.

[0061] 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.

[0062] The present disclosure also provides artikaplanam in crystalline Form I. Artikaplanam in crystalline Form I can be characterized by a variety of techniques, including, but not limited to, x-ray diffraction and differential scanning calorimetry. In some embodiments, artikaplanam in crystalline Form I is characterized by x-ray diffraction. Artikaplanam in crystalline Form I is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°. In some embodiments, artikaplanam in crystalline Form I is characterized by x-ray diffraction pattern peaks at 2θ (± 0.2) at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°. In further embodiments, the crystalline Form I of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.6°, 13.9°, 17.3°, 17.4°, 18.0°, and 24.0°, 2θ (± 0.2). In other embodiments, the crystalline Form I of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°, 2θ (± 0.2) and one or more additional peaks at 3.8°, 7.7°, 10.1°, 19.7°, 21.8°, 22.4°, 23.1°, and 25.3°, 2θ (± 0.2). In further embodiments, the crystalline Form I of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (± 0.2) and one or more additional peaks at 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 25.3°, 28.2°, and 29.5° 2θ (± 0.2). In yet other embodiments, the crystalline Form I of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° 2θ (± 0.2) and one or more additional peaks at 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 12.5°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 26.6°, 25.3°, 27.0°, 28.2°, 28.9°, 29.5°, and 30.3° 2θ (± 0.2).In yet other embodiments, the crystalline Form I of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0° and 24.0° and one or more additional peaks as shown in Table 1.

[0063]

[0064]

[0065] In yet further embodiments, the crystalline Form I of artikaplanam is characterized by the x-ray diffraction pattern peaks in Table 2.

[0066]

[0067] In other embodiments, the crystalline Form I of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 3.

[0068]

[0069] In another embodiment, the crystalline form I of artikaplanam is characterized by corresponding to Figure 6 X-ray powder diffraction pattern of .

[0070] Crystalline Form I of artikaplanam may also be characterized by differential scanning calorimetry. In some embodiments, crystalline Form I of artikaplanam is characterized by a differential scanning calorimetry thermogram comprising a T at about 92.9°C. 起始 In another embodiment, the crystalline Form I of artikaplanam is characterized by a differential scanning calorimetry thermogram comprising a peak temperature (T m In other embodiments, the crystalline form I of artikaplanam is characterized by corresponding to Figure 7 Differential scanning calorimetry thermogram of .

[0071] The present disclosure also provides artikaplankton in crystalline form II. Artikaplankton in crystalline form II can be characterized by a variety of techniques, including, but not limited to, x-ray diffraction and differential scanning calorimetry. In some embodiments, artikaplankton in crystalline form II is characterized by x-ray diffraction. In other embodiments, artikaplankton in crystalline form II is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 3.1°, 19.0°, 24.0°, 24.3°, or 26.2°. In additional embodiments, artikaplankton in crystalline form II is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 3.1°, 19.0°, 24.0°, 24.3°, or 26.2° and one or more additional peaks at 2θ (± 0.2) of 12.9°, 14.6°, 20.8°, 22.7°, and 23.5°. In yet other embodiments, the crystalline Form II 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 at 11.9°, 12.9°, 14.6°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5° and 28.4° 2θ (± 0.2). In yet further embodiments, the crystalline Form II of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 3.1°, 19.0°, 24.0°, 24.3° or 26.2° and one or more additional peaks at 2θ (± 0.2) of 6.2°, 9.3°, 11.9°, 12.9°, 14.6°, 16.7°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5°, 27.6°, 28.4° and 29.5°. In other embodiments, the crystalline Form II of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 3.1°, 19.0°, 24.0°, 24.3° or 26.2° and one or more additional peaks of Table 4.

[0072]

[0073]

[0074] In further embodiments, the crystalline Form II of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 5.

[0075]

[0076] In yet other embodiments, the crystalline Form II of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 6.

[0077]

[0078] In yet another embodiment, the crystalline form II of artikaplanam is characterized by corresponding to Figure 8 X-ray powder diffraction pattern of .

[0079] Crystalline Form II of Artikaplanam can also be characterized by differential scanning calorimetry. In some embodiments, the crystalline Form II of Artikaplanam is characterized by a differential scanning calorimetry thermogram comprising one or two endothermic peaks at about 74.7°C and about 96.2°C. In other aspects, the crystalline Form II of Artikaplanam is characterized by a differential scanning calorimetry thermogram comprising a peak temperature (T m In another embodiment, the crystalline form II of artikaplanam is characterized by corresponding to Fig. 9 Differential scanning calorimetry thermogram of .

[0080] The present disclosure also provides artikaplanam in crystalline form III. Artikaplanam in crystalline form III can be characterized by a variety of techniques, including, but not limited to, x-ray diffraction and differential scanning calorimetry. In some embodiments, artikaplanam in crystalline form III is characterized by x-ray diffraction. In other embodiments, artikaplanam in crystalline form III is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°. In additional embodiments, artikaplanam in crystalline form III is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°. In yet other embodiments, crystalline Form III of 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 7.

[0081]

[0082]

[0083] In yet other embodiments, the crystalline Form III of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 8.

[0084]

[0085] In yet other embodiments, the crystalline Form III of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 9.

[0086]

[0087]

[0088] In another embodiment, the crystalline form III of artikaplanam is characterized by corresponding to Figure 1 X-ray powder diffraction pattern of .

[0089] 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 artikaplanam is characterized by corresponding to Figure 4 Differential scanning calorimetry thermogram of .

[0090] The present disclosure also provides an amorphous form of artikaplanam. In certain embodiments, the amorphous form is characterized by a differential scanning calorimetry thermogram comprising a glass transition temperature (T) of about 45.5°C. g In other embodiments, the amorphous form of artikaplanam is characterized by a Figure 3 In yet other embodiments, the amorphous form of artikaplanam is characterized by a differential scanning calorimetry thermogram comprising a T of about 43.8°C. 起始 In another embodiment, the amorphous form of artikaplanam is characterized by corresponding to Fig.12 mDSC thermogram.

[0091] Treatment

[0092] In one aspect of the invention, methods are provided for treating patients with more severe types of depression, i.e., major depressive disorder. In some embodiments, the patient is experiencing moderate to severe 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. Therefore, 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, etc. Therefore, patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side effects.

[0093] The methods described herein use artikaplan in crystalline form I, artikaplan in crystalline form II, artikaplan in crystalline form III, or amorphous artikaplan to effectively manage depression and anhedonia in patients. Ideally, these methods successfully allow patients to control their depression while reducing anhedonia. In a specific embodiment, the patient treated according to the method suffers from moderate to severe anhedonia. As used herein, the term "anhedonia" refers to the 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 (dominated by wanting), the completion stage (dominated by liking), and the satisfaction stage (dominated by learning). The desire phase is characterized by the initial energy expenditure to obtain the reward; the completion phase is the enjoyment of the reward; and the satisfaction phase is characterized by learning and feedback integration.

[0094] 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.

[0095] 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.

[0096] 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% after treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam, as measured by the 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% after treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam, as measured by the change from baseline in the total score on the anhedonia scale. In yet further embodiments, in yet other embodiments, following treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam, 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, the patient's anhedonia is improved (i.e., reduced) by 100% following treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam as measured by the change from baseline in the total score on the Anhedonia Scale.

[0097] The reduction in anhedonia after initiation of treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam can be measured relative to the patient's anhedonia measured prior to treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam (i.e., a baseline anhedonia measurement). In doing so, the treating clinician is able to calculate the change in anhedonia from baseline to a real-time anhedonia measurement at any point after treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam. Thus, standard methods of measuring anhedonia, such as anhedonia scales, e.g., SHAPS, can be used.

[0098] Desirably, the baseline anhedonia measurement is obtained no more than about 1 week prior to initiating treatment with crystalline Form I, crystalline Form II, crystalline Form III, or amorphous 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 crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. In further embodiments, the baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiating treatment with crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam.

[0099] The change in anhedonia in a patient will depend on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam, other agents administered, etc. In some embodiments, the patient's anhedonia is reduced after about 3 weeks of treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. In other embodiments, the patient's anhedonia is reduced after about 3 weeks of treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. In further embodiments, the patient's anhedonia is reduced after about 3 weeks to about 6 weeks of treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam, and in certain embodiments up to week 6. In certain embodiments, the patient's anhedonia is reduced by at least 40% after about 6 weeks of treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam, as measured by the change from baseline in the total score on the anhedonia scale. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on the anhedonia scale and / or physician / clinical judgment.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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 11.

[0105]

[0106] In some embodiments, to be diagnosed with MDD, the following criteria must also be met:

[0107]

[0108] 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 12.

[0109]

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 13.

[0115]

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] In certain embodiments, the patient is being treated with other antidepressant therapies prior to receiving crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. In some embodiments, the patient is being treated with other antidepressant therapies that include SSRIs, SNRIs, or combinations thereof. In other embodiments, the patient discontinues treatment with other antidepressant therapies prior to initiating treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam.

[0125] Also contemplated in the methods described herein are adjunctive treatments comprising the use of an effective amount of one or more antidepressants. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" mean treating a patient in need thereof by administering a combination of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam and one or more antidepressants, wherein the crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam and the antidepressant are administered simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means.

[0126] In some aspects, artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam 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, artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam is administered adjunctively with an antidepressant that has not been previously administered to the patient (i.e., a new antidepressant). In still other embodiments, artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam is administered on a regimen with an antidepressant previously administered to the patient.

[0127] Where crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam 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, more typically different. The antidepressant may be administered according to the prescription of the attending physician and / or its label, and crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam is administered as described herein. Typically, the patient is treated with both the antidepressant and crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam, wherein both are administered via their prescribed dosing regimens. Crystalline form I artikaplanam, crystalline form II artikaplanam, crystalline form III artikaplanam or amorphous artikaplanam and the antidepressant may be administered simultaneously according to simultaneous or alternating regimens, at the same or different times during the course of therapy, in divided or single forms.

[0128] Crystalline Form I artikaplanam, crystalline Form II artikaplanam, crystalline Form III artikaplanam, or amorphous artikaplanam and the antidepressant can be administered by 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, crystalline Form I artikaplanam, crystalline Form II artikaplanam, crystalline Form III artikaplanam, or amorphous artikaplanam is administered orally.

[0129] Treatment with crystalline Form I, Form II, Form III, or amorphous artikaplanam as described herein has several advantages over treatments in the art. In some embodiments, the patient does not experience many of the side effects associated with other antidepressants (i.e., antidepressants other than crystalline Form I, Form II, Form III, or amorphous artikaplanam). In certain aspects, the patient does not experience weight gain during treatment with crystalline Form I, Form II, Form III, or amorphous artikaplanam. As used herein, the term "weight gain" refers to an increase in a patient's weight relative to the patient's weight prior to taking crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam, or the patient's weight assessed at the time of initial administration of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. In certain embodiments, the patient actually sees a decrease in total body weight relative to the patient's weight prior to taking crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. 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 ≥ 7% increase in body weight.

[0130] This is in contrast to many other antidepressants, where weight gain (including clinically relevant weight gain) is a common but unfortunate side effect.

[0131] In other aspects, patients do not experience a decrease in sexual function during treatment with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. As used herein, the term "decreased sexual function" refers to a reduction or attenuation of one or more components of human sexual drive (i.e., sexual function). In some embodiments, sexual function comprises one or more of sexual drive, sexual arousal, vaginal lubrication, erection, reaching orgasm, or orgasmic satisfaction. In other embodiments, sexual function comprises sexual drive. In other embodiments, sexual function comprises vaginal lubrication satisfaction. In other embodiments, sexual function comprises reaching orgasm. In yet other embodiments, sexual function comprises orgasmic satisfaction. Ideally, the patient's sexual function is assessed when crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam is initially administered. Therefore, the sexual function of a patient while taking crystalline form I, crystalline form II, crystalline form III, or amorphous artikaplanam can be compared with the sexual function of the patient before administration of crystalline form I, crystalline form II, crystalline form III, or amorphous artikaplanam. Sexual function can be assessed using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). ASEX is used to investigate whether crystalline form I, crystalline form II, crystalline form III, or amorphous artikaplanam has further positive or negative effects on sexual function. ASEX is a 5-item rating scale administered to patients that quantifies sexual drive, sexual arousal, vaginal lubrication or penile erection, the ability to reach orgasm, and satisfaction. Scores range from 5 to 30, and there are two different versions of the scale (male and female).

[0132] 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.

[0133] 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:

[0134]

[0135] Also known as JNJ-67953964, CERC-501, and LY-2456302. In some embodiments, "artikaplan" refers to the (S)-enantiomer of artikaplan, i.e., the following compound:

[0136]

[0137] 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:

[0138]

[0139] In other embodiments, the crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam contains less than about 10 weight % of the (R)-enantiomer of artikaplanam based on the weight of the crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. In further embodiments, the crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanm contains less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.1%, about 0.005%, or about 0.001% by weight of the (R)-enantiomer of artikaplanm, based on the weight of the crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanm. In yet other embodiments, the crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam contains from about 0.001 wt % to about 10 wt % of the (R)-enantiomer of artikaplanam, based on the weight of the crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. In yet other embodiments, the crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanm contains from about 0.001% to about 10% by weight, from about 0.001% to about 5% by weight, from about 0.001% to about 1% by weight, from about 0.001% to about 0.5% by weight, from about 0.001% to about 0.1% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 1% by weight, from about 0.1% to about 5% by weight, or from about 0.5% to about 5% by weight of the (R)-enantiomer of artikaplanm, based on the weight of the crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanm.

[0140] The methods described herein include administering to a patient an effective amount of crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam. As used herein, the term "effective amount" means an amount of an active compound or agent that elicits in a human body a biological or pharmaceutical 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, crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam is used in an effective amount determined by the attending physician. In other embodiments, other antidepressants are used alone or in combination with crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam in an effective amount.

[0141] The amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam for administration according to the methods described herein can be determined by one of skill in the art, and unless otherwise indicated, is described on a crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam free base basis. That is, the amount represents the amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam molecules administered, excluding, for example, solvent (such as in a solvate) or counterions (such as in a pharmaceutically acceptable salt). In some embodiments, the effective amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam is less than about 60 mg. In other embodiments, the effective amount of crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.In further embodiments, an effective amount of crystalline Form I artikaplanam, crystalline Form II artikaplanam, crystalline Form III artikaplanam, or amorphous artikaplanam is from about 1 mg to about 50 mg, from about 5 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 50 mg, from about 30 mg to about 50 mg, from about 40 mg to about 50 mg, from about 1 mg to about 45 mg, from about 2 mg to about 45 mg, from about 5 mg to about 45 mg, from about 10 mg to about 45 mg, from about 20 mg to about 45 mg, from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 1 mg to about 40 mg, from about 5 mg to about 40 mg, from about 20 mg to about 40 mg, from about 30 mg to about 40 mg, from about 1 mg to about 35 mg, about 2 mg to about 35 mg, about 5 mg to about 35 mg, about 10 mg to about 35 mg, about 20 mg to about 35 mg, about 25 mg to about 35 mg, about 30 mg to about 35 mg, about 1 mg to about 30 mg, about 2 mg to about 30 mg, about 5 mg to about 30 mg, about 10 mg to about 30 mg, about 20 mg to about 30 mg, about 25 mg to about 30 mg, about 1 mg to about 20 mg, about 2 mg to about 20 mg, 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. In yet other embodiments, the effective amount of crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam is about 5 mg to about 15 mg. In yet other embodiments, the effective amount of crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam is about 10 mg.

[0142] Pharmaceutical composition

[0143] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product obtained directly or indirectly by combining the specified ingredients in the specified amounts. Preferred pharmaceutical compositions contain, as the active ingredient, crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam, intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier can take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0144] Methods of formulating pharmaceutical compositions are described in multiple publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; all of which are published by Marcel Dekker, Inc.

[0145] In certain embodiments, the pharmaceutical compositions used herein further comprise one or more buffers, preservatives, osmotic agents, wetting agents, surfactants, solubilizers, thickeners, colorants, antioxidants, emulsifiers, isotonic agents, suspending agents and / or viscosity increasing agents.

[0146] In some embodiments, the pharmaceutical composition further comprises one or more buffers and / or buffer systems (i.e., conjugate acid-base pairs). As used herein, the term "buffer" shall refer to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts the pH of the preparation when added to an aqueous preparation. Those skilled in the art will recognize that buffers can adjust the pH of aqueous preparations from any direction (towards a more acidic, more alkaline or more neutral pH). Preferably, buffers are pharmaceutically acceptable. Suitable examples of buffers that can be used in aqueous preparations described herein include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, etc.

[0147] Optionally, the pharmaceutical composition herein may contain a preservative. As used herein, unless otherwise indicated, the terms "antimicrobial preservative" and "preservative" refer to any substance added to a pharmaceutical composition to protect it from microbial degradation or microbial growth. In this regard, microbial growth generally plays a vital role, i.e., the main purpose of preservatives for avoiding microbial contamination. It may also be desirable to avoid any effects of microorganisms on active ingredients and excipients, i.e., to avoid microbial degradation, respectively. Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0148] As used herein, the terms "permeabilizer," "permeation enhancer," and "saturating agent" refer to any substance that increases or promotes the absorption rate and / or bioavailability of crystalline form I, crystalline form II, crystalline form III, or amorphous form of artikaplanam. Preferably, the permeabilizer increases or promotes the absorption and / or bioavailability of crystalline form I, crystalline form II, crystalline form III, or amorphous form of artikaplanam after administration. Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid, lecithin, and the like; and chitosan (and salts), as well as surface active ingredients such as benzalkonium chloride, sodium lauryl sulfate, sodium docusate, polysorbate, laureth-9, oxtoxynol, sodium deoxycholate, polyarginine, and the like. Preferably, the permeabilizer is selected to meet one or more of the following general requirements:

[0149]

[0150] The pharmaceutical compositions used herein may also contain one or more additional excipients, such as a wetting agent, a surfactant component, a solubilizer, a thickening agent, a colorant, an antioxidant component, and the like.

[0151] Examples of suitable antioxidant components, if used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbate salts, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid or its sodium or calcium salt; tocopherol; gallic acid esters, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long-term stability to the liquid composition.

[0152] Solubilizers and emulsifiers may be included to facilitate more uniform dispersion of the active ingredient or other excipients that are generally insoluble in the liquid carrier. If used, examples of suitable emulsifiers include, but are not limited to, for example, gelatin, cholesterol, gum arabic, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof. Examples of suitable solubilizers include polyethylene glycol, glycerol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof. The solubilizer or emulsifier may be present in an amount sufficient to dissolve or disperse the active ingredient (i.e., artikaplanam in crystalline form I, artikaplanam in crystalline form II, artikaplanam in crystalline form III, or amorphous artikaplanam) in the carrier.

[0153] If used, suitable isotonic agents may include sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

[0154] Suspending agents or viscosity increasing agents may also be added to the pharmaceutical composition. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and the like.

[0155] Advantageously, crystalline Form I artikaplanam, crystalline Form II artikaplanam, crystalline Form III artikaplanam or amorphous artikaplanam may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0156] As described herein, in particular, prior to treatment with crystalline Form I, Form II, Form III, or amorphous artikaplanam, the patient had an inadequate response to other antidepressant therapies. Thus, in certain embodiments, the present disclosure relates to crystalline Form I, Form II, Form III, or amorphous artikaplanam for use as described herein, wherein prior to treatment with crystalline Form I, Form II, Form III, or amorphous artikaplanam, the patient had an inadequate response to other antidepressant therapies. In another specific embodiment, the present disclosure also relates to the use of crystalline form I, crystalline form II, crystalline form III or amorphous artikaplanam in the preparation of a medicament as described herein, wherein prior to treatment with crystalline form I, crystalline form II, crystalline form III or amorphous 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 crystalline form I, crystalline form II, crystalline form III or amorphous artikaplanam, the patient had an inadequate response to other antidepressant therapies. Such antidepressant therapies may in particular be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI) or a combination thereof.

[0157] As described herein, crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam can be used as an adjunctive therapy, or in other words in conjunction with, as an adjunct to, or in combination with one or more antidepressants, for example, a patient may already be taking or may also be taking one or more antidepressants. Thus, in another specific embodiment, the present disclosure relates to crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam for use as described herein, the use comprising administering crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam as an adjunctive therapy with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to artikaplanam for use as described herein, the use comprising administering artikaplanam in conjunction with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam for use as described herein, the use comprising administering crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam in the preparation of a medicament as described herein, wherein the treatment comprises administering an effective amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam as an adjunct therapy to an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam as described herein, wherein the treatment comprises administering an effective amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam as described herein, wherein the treatment comprises administering an effective amount of crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam 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 crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam as an adjunct therapy 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 crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam 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 crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam, or amorphous artikaplanam 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.

[0158] As already described, the present disclosure relates to crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam for the use as described herein. In a specific embodiment, the crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam is S-artikaplanam. In another embodiment of the present disclosure, the crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) for the use as described herein will be administered in an amount of about 2 mg to about 35 mg, more particularly about 10 mg. In yet another embodiment, crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) for the use as described herein is administered orally. Furthermore, in another specific embodiment, the present disclosure relates to crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) for the use as described herein, which is administered once a day. The present disclosure also relates to the use of artikaplanam in the preparation of a medicament as described herein. In a specific embodiment, crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam is S-artikaplanam. In another embodiment of the use as described herein, about 2 mg to about 35 mg of crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam will be administered, more particularly about 10 mg. In yet another embodiment of the use, crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam will be administered orally. Furthermore, in another specific embodiment of the use, crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) will be administered once a day. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam is particularly S-artikaplanam. In another embodiment of the package or pharmaceutical product as described herein, the treatment instructions direct the administration of about 2 mg to about 35 mg of crystalline Form I artikaplanam, crystalline Form II artikaplanam, crystalline Form III artikaplanam or amorphous artikaplanam, more particularly about 10 mg.In yet another embodiment of the package or pharmaceutical product as described herein, the therapeutic instructions direct that crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) is for oral administration. Furthermore, in another specific embodiment of the package or pharmaceutical product as described herein, the therapeutic instructions direct that crystalline Form I of artikaplanam, crystalline Form II of artikaplanam, crystalline Form III of artikaplanam or amorphous artikaplanam (particularly S-artikaplanam) is for once daily administration.

[0159] Advantageously, administration of crystalline Form I, Form II, Form III or amorphous Artikaplanam does not result in weight gain, including clinically relevant weight gain, during treatment. Thus, in another specific embodiment, the present disclosure relates to crystalline Form I, Form II, Form III or amorphous Artikaplanam for use as described herein, wherein during treatment with crystalline Form I, Form II, Form III or amorphous Artikaplanam, the patient does not experience weight gain. In another specific embodiment, the present disclosure relates to the use as defined herein, wherein during treatment with crystalline Form I, Form II, Form III or amorphous Artikaplanam, the patient does not experience weight gain. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam. In particular, the patient's weight can be assessed upon initial administration of artikaplanam.

[0160] It was also unexpectedly observed that, based on the assessment at the time of initial administration, patients do not experience a decrease in sexual function during treatment with crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. Thus, in another specific embodiment, the present disclosure relates to crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam for use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. In another specific embodiment, the present disclosure relates to the use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with crystalline Form I, crystalline Form II, crystalline Form III, or amorphous artikaplanam. In another specific embodiment, the present disclosure relates to a package or a pharmaceutical product as described herein, wherein during treatment with artikaplanam in crystalline form I, artikaplanam in crystalline form II, artikaplanam in crystalline form III, or amorphous artikaplanam, the patient does not experience a decrease in sexual function. The term "sexual function" encompasses sexual drive, sexual arousal, vaginal lubrication, erection, achieving 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).

[0161] 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 anhedonia scale, such as the Snaith-Hamilton Pleasure Scale (SHAPS). Therefore, in a specific embodiment, the present disclosure relates to crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam for use as described herein, wherein after 6 weeks of treatment with crystalline form I of artikaplanam, crystalline form II of artikaplanam, crystalline form III of artikaplanam or amorphous artikaplanam, the patient's anhedonia is reduced by at least 40%, as measured by the change in the total score relative to baseline in the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change in the total score relative to baseline in the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in a specific embodiment, the present disclosure relates to the use as described herein, wherein after 6 weeks of treatment with artikaplanam in crystalline form I, artikaplanam in crystalline form II, artikaplanam in crystalline form III, or amorphous artikaplanam, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS). In another specific embodiment, the present disclosure relates to a package or a pharmaceutical product as described herein, wherein after 6 weeks of treatment with artikaplanam in crystalline Form I, artikaplanam in crystalline Form II, artikaplanam in crystalline Form III, or amorphous artikaplanam, the patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on the anhedonia scale, more particularly, the patient's anhedonia is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS).

[0162] Implementation

[0163] The present invention also provides the following non-limiting embodiments:

[0164] Embodiment 1 is a crystalline Form I of Atikaplanam characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) at 4.6°, 17.3°, 17.4°, 18.0° and 24.0°, wherein Atikaplanam has the following structure:

[0165]

[0166] Embodiment 2 is crystalline form I of atikaplan, characterized in that it corresponds to Figure 6 X-ray powder diffraction pattern of .

[0167] Embodiment 3 is crystalline Form I of Atikaplan according to embodiment 1 or 2, characterized in that the differential scanning calorimetry thermogram comprises an endothermic peak at about 92.9°C.

[0168] Embodiment 4 is crystalline form I of atikaplan according to any one of embodiments 1-3, characterized in that it corresponds to Figure 7 Differential scanning calorimetry thermogram of .

[0169] Embodiment 5 is crystalline Form I of Artikaplanam according to any one of embodiments 1-4, which is anhydrous.

[0170] Embodiment 6 is crystalline Form II of Atikaplanam characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3° or 26.2°, wherein Atikaplanam has the following structure:

[0171]

[0172] Embodiment 7 is the crystalline form II of Atikaplan according to embodiment 6, characterized in that it corresponds to Figure 8 X-ray powder diffraction pattern of .

[0173] Embodiment 8 is crystalline Form II of Atikaplan according to embodiment 6 or 7, characterized in that the differential scanning calorimetry thermogram comprises one or two endothermic peaks at about 74.7°C and about 96.2°C.

[0174] Embodiment 9 is crystalline form II of Atikaplan according to any one of embodiments 6-8, characterized in that it corresponds to Fig. 9 Differential scanning calorimetry thermogram of .

[0175] Embodiment 10 is crystalline Form II of Artikaplanam according to any one of embodiments 6-9, which is anhydrous.

[0176] Embodiment 11 is a crystalline Form III of Atikaplanam 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°, wherein Atikaplanam has the following structure:

[0177]

[0178] Embodiment 12 Artikaplanam in crystalline form III according to embodiment 11, characterized in that it corresponds to Figure 1 X-ray powder diffraction pattern of .

[0179] Embodiment 13 is crystalline form III of artikaplanam according to embodiment 11 or 12, characterized in that the peak temperature (T m ).

[0180] Embodiment 14 is crystalline form III of Atikaplan according to any one of embodiments 11-13, characterized in that it corresponds to Figure 4 Differential scanning calorimetry thermogram of .

[0181] Embodiment 15 is crystalline Form III of Artikaplanam according to any one of embodiments 11-14, which is anhydrous.

[0182] Embodiment 16 is an amorphous form of Artikaplan, wherein Artikaplan has the following structure:

[0183]

[0184] Embodiment 17 is the amorphous form of embodiment 16, characterized in that the differential scanning calorimetry thermogram comprises a T of about 45.5°C. g .

[0185] Embodiment 18 is an amorphous form of artikaplanam according to embodiment 16 or 17, characterized in that it corresponds to Figure 3 Differential scanning calorimetry thermogram of .

[0186] Embodiment 19 is a pharmaceutical composition comprising the crystalline form of Atikaplanam according to any one of Embodiments 1-15 or the amorphous form of Atikaplanam according to any one of Embodiments 16-18.

[0187] Embodiment 20 is a method of treating major depressive disorder in a human patient with crystalline artikaplanam.

[0188] Embodiment 21 is a method of treating major depressive disorder in a human patient, the method comprising administering crystalline artikaplanam to the human patient, wherein the patient has previously responded inadequately to other antidepressant therapies.

[0189] Embodiment 22 is a method of treating major depressive disorder in a human patient, the method comprising administering to the human patient in need thereof an effective amount of the crystalline form of atikaplanam according to any one of embodiments 1-15 or the amorphous form of atikaplanam according to any one of embodiments 16-18.

[0190] Embodiment 23 is a method according to embodiment 22, wherein said treatment comprises administering an effective amount of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0191] Embodiment 24 is a method according to embodiment 22 or 23, wherein prior to treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0192] Embodiment 25 is a method according to any one of embodiments 21, 23 or 24, wherein the additional antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0193] Embodiment 26 is a method according to any one of embodiments 20-25, further comprising adjunctive treatment with an effective amount of one or more antidepressant drugs.

[0194] Embodiment 27 is a method according to any one of embodiments 20-26, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0195] Embodiment 28 is a method according to any one of embodiments 20-27, wherein the crystalline form of Artikaplan is a crystalline form of S-Artikaplan and the amorphous form of Artikaplan is an amorphous form of S-Artikaplan.

[0196] Embodiment 29 is a method according to any one of embodiments 20-28, wherein the effective amount of the crystalline form of artikaplanam or the amorphous form of artikaplanam is from about 2 mg to about 35 mg.

[0197] Embodiment 30 is a method according to embodiment 29, wherein the effective amount of the crystalline form of artikaplanam or the amorphous form of artikaplanam is about 10 mg.

[0198] Embodiment 31 is a method according to any one of embodiments 20-30, wherein the crystalline form of artikaplanam or the amorphous form of artikaplanam is administered orally.

[0199] Embodiment 32 is a method according to any one of embodiments 20-31, wherein the crystalline form of artikaplanam or the amorphous form of artikaplanam is administered once a day.

[0200] Embodiment 33 is a method according to any one of embodiments 20-32, wherein the patient suffers from anhedonia.

[0201] Embodiment 34 is a method according to any one of embodiments 20-33, wherein the patient suffers from moderate anhedonia.

[0202] Embodiment 35 is a method according to any one of embodiments 20-33, wherein the patient suffers from severe anhedonia.

[0203] Embodiment 36 is a method according to any one of embodiments 22-35, wherein said patient does not experience weight gain during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0204] Embodiment 37 is a method according to embodiment 36, wherein the patient's weight is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0205] Embodiment 38 is a method according to any one of embodiments 20-37, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0206] Embodiment 39 is a method according to embodiment 38, wherein the patient's sexual function is assessed upon initial administration of the crystalline form of artikaplanam or the amorphous form of artikaplanam.

[0207] Embodiment 40 is a method according to embodiment 38 or 39, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm, or satisfying orgasm.

[0208] Embodiment 41 is a method according to any one of embodiments 38-40, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0209] Embodiment 42 is a method according to any one of embodiments 33-35, wherein said patient's anhedonia is reduced by at least 40% after 6 weeks of said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam as measured by the change from baseline in the total score on an anhedonia scale.

[0210] Embodiment 43 is a method according to any one of embodiments 33-35 and 42, wherein the anhedonia of the patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0211] Embodiment 44 is a method according to embodiment 42 or 43, wherein the anhedonia scale is the Snaith-Hamilton Anhedonia Scale.

[0212] Embodiment 45 is a crystalline form of Atikaplan for use in treating major depressive disorder in a human patient.

[0213] Embodiment 46 is a crystalline form of artikaplanam according to any one of embodiments 1-15 for use in treating major depressive disorder in a human patient, wherein the patient has previously had an inadequate response to other antidepressant drug therapies.

[0214] Embodiment 47 is a crystalline form of Atikaplan according to any one of embodiments 1-15 for use in treating major depressive disorder in a human patient.

[0215] Embodiment 48 is a crystalline form of Artikaplanam according to embodiment 47, wherein said treatment comprises administering an effective amount of said crystalline form of Artikaplanam or said amorphous form of Artikaplanam.

[0216] Embodiment 49 is a crystalline form of artikaplanam according to embodiment 47 or 48, wherein prior to treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0217] Embodiment 50 is a crystalline form of artikaplanam according to any one of embodiments 46 or 49, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0218] Embodiment 51 is a crystalline form of artikaplanam according to any one of embodiments 45-50, wherein the method further comprises adjunctive treatment with an effective amount of one or more antidepressants.

[0219] Embodiment 52 is a crystalline form of artikaplanam according to any one of embodiments 45-51, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0220] Embodiment 53 is a crystalline form of Artikaplanam according to any one of embodiments 45-52, wherein the crystalline form of Artikaplanam is a crystalline form of S-Artikaplanam and the amorphous form of Artikaplanam is an amorphous form of S-Artikaplanam.

[0221] Embodiment 54 is a crystalline form of Artikaplanam according to any one of embodiments 45-53, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is from about 2 mg to about 35 mg.

[0222] Embodiment 55 is a crystalline form of Artikaplanam according to embodiment 54, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is about 10 mg.

[0223] Embodiment 56 is a crystalline form of Artikaplanam according to any one of embodiments 45-55, wherein the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is administered orally.

[0224] Embodiment 57 is a crystalline form of Artikaplanam according to any one of embodiments 45-56, wherein said crystalline form of Artikaplanam or said amorphous form of Artikaplanam is administered once daily.

[0225] Embodiment 58 is a crystalline form of artikaplanam according to any one of embodiments 45-57, wherein the patient suffers from anhedonia.

[0226] Embodiment 59 is a crystalline form of artikaplanam according to any one of embodiments 45-58, wherein the patient suffers from moderate anhedonia.

[0227] Embodiment 60 is a crystalline form of artikaplanam according to any one of embodiments 45-58, wherein the patient suffers from severe anhedonia.

[0228] Embodiment 61 is a crystalline form of artikaplanam according to any one of embodiments 47-60, wherein said patient does not experience weight gain during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0229] Embodiment 62 is a crystalline form of artikaplanam according to embodiment 61, wherein the patient's weight is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0230] Embodiment 63 is a crystalline form of artikaplanam according to any one of embodiments 45-62, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0231] Embodiment 64 is a crystalline form of artikaplanam according to embodiment 63, wherein said patient's sexual function is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0232] Embodiment 65 is a crystalline form of artikaplanam according to embodiment 63 or 64, wherein the sexual function comprises sexual drive, arousal, vaginal lubrication, erection, orgasm, or orgasm satisfaction.

[0233] Embodiment 66 is a crystalline form of artikaplanam according to any one of embodiments 63-65, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0234] Embodiment 67 is a crystalline form of artikaplanam according to any one of embodiments 58-60, wherein after 6 weeks of said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on an anhedonia scale.

[0235] Embodiment 68 is a crystalline form of artikaplanam according to any one of embodiments 58-60 and 67, wherein the anhedonia of the patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0236] Embodiment 69 is a crystalline form of artikaplanam according to embodiment 67 or 68, wherein the anhedonia rating scale is the Snaith-Hamilton Hedonic Rating Scale.

[0237] Embodiment 70 is an amorphous form of artikaplanam for use in treating major depressive disorder in a human patient.

[0238] Embodiment 71 is an amorphous form of artikaplanam according to any one of embodiments 16-18 for use in treating major depressive disorder in a human patient, wherein the patient has previously had an inadequate response to other antidepressant drug therapies.

[0239] Embodiment 72 is the amorphous form of artikaplanam according to any one of embodiments 16-18 for use in treating major depressive disorder in a human patient.

[0240] Embodiment 73 is the amorphous form of Artikaplanam according to embodiment 72, wherein the treatment comprises administering an effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam.

[0241] Embodiment 74 is the amorphous form of artikaplanam according to embodiment 72 or 73, wherein prior to treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0242] Embodiment 75 is an amorphous form of artikaplanam according to any one of embodiments 71 or 74, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0243] Embodiment 76 is the amorphous form of artikaplanam according to any one of embodiments 70-75, wherein the method further comprises adjunctive treatment with an effective amount of one or more antidepressants.

[0244] Embodiment 77 is an amorphous form of artikaplanam according to any one of embodiments 70-76, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0245] Embodiment 78 is an amorphous form of Artikaplanam according to any one of embodiments 70-77, wherein the crystalline form of Artikaplanam is a crystalline form of S-Artikaplanam and the amorphous form of Artikaplanam is an amorphous form of S-Artikaplanam.

[0246] Embodiment 79 is the amorphous form of Artikaplanam according to any one of embodiments 70-78, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is from about 2 mg to about 35 mg.

[0247] Embodiment 80 is the amorphous form of Artikaplanam according to embodiment 79, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is about 10 mg.

[0248] Embodiment 81 is the amorphous form of Artikaplanam according to any one of embodiments 70-80, wherein the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is administered orally.

[0249] Embodiment 82 is the amorphous form of Artikaplanam according to any one of embodiments 70-81, wherein the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is administered once a day.

[0250] Embodiment 83 is the amorphous form of artikaplanam according to any one of embodiments 70-82, wherein the patient suffers from anhedonia.

[0251] Embodiment 84 is the amorphous form of artikaplanam according to any one of embodiments 70-83, wherein the patient suffers from moderate anhedonia.

[0252] Embodiment 85 is the amorphous form of artikaplanam according to any one of embodiments 70-84, wherein the patient suffers from severe anhedonia.

[0253] Embodiment 86 is an amorphous form of artikaplanam according to any one of embodiments 72-85, wherein said patient does not experience weight gain during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0254] Embodiment 87 is the amorphous form of artikaplanam according to embodiment 86, wherein the patient's weight is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0255] Embodiment 88 is an amorphous form of artikaplanam according to any one of embodiments 70-87, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0256] Embodiment 89 is the amorphous form of artikaplanam according to embodiment 88, wherein the patient's sexual function is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0257] Embodiment 90 is the amorphous form of artikaplanam according to embodiment 88 or 89, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm, or orgasmic satisfaction.

[0258] Embodiment 91 is the amorphous form of artikaplanam according to any one of embodiments 88-90, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0259] Embodiment 92 is an amorphous form of artikaplanam according to any one of embodiments 83-85, wherein after 6 weeks of said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on an anhedonia scale.

[0260] Embodiment 93 is an amorphous form of artikaplanam according to any one of embodiments 83-85 and 92, wherein said patient's anhedonia is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0261] Embodiment 94 is the amorphous form of artikaplanam according to embodiment 92 or 93, wherein the anhedonia rating scale is the Snaith-Hamilton Hedonia Rating Scale.

[0262] Embodiment 95 is the use of Atikaplan in crystalline form or Atikaplan in amorphous form for the preparation of a medicament for treating major depressive disorder in a human patient.

[0263] Embodiment 96 is the use of atikaplan in crystalline form according to any one of embodiments 1-15 or atikaplan in amorphous form according to any one of embodiments 16-18 for the preparation of a medicament for treating major depressive disorder in a human patient, wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0264] Embodiment 97 is the use of the crystalline form of Atikaplanam according to any one of embodiments 1-15 or the amorphous form of Atikaplanam according to any one of embodiments 16-18 for the preparation of a medicament for treating major depressive disorder in a human patient.

[0265] Embodiment 98 is the use according to embodiment 97, wherein the treatment comprises administering an effective amount of a crystalline form of artikaplanam or an amorphous form of artikaplanam.

[0266] Embodiment 99 is the use according to embodiment 97 or 98, wherein prior to treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0267] Embodiment 100 is the use according to any one of embodiments 96 or 99, wherein the other antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0268] Embodiment 101 is the use according to any one of embodiments 95-100, wherein the method further comprises adjunctive treatment with an effective amount of one or more antidepressants.

[0269] Embodiment 102 is the use according to any one of embodiments 95-101, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0270] Embodiment 103 is an amorphous form of Artikaplanam according to any one of embodiments 95-102, wherein the crystalline form of Artikaplanam is a crystalline form of S-Artikaplanam and the amorphous form of Artikaplanam is an amorphous form of S-Artikaplanam.

[0271] Embodiment 104 is the amorphous form of Artikaplanam according to any one of embodiments 95-103, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is from about 2 mg to about 35 mg.

[0272] Embodiment 105 is the amorphous form of Artikaplanam according to embodiment 104, wherein the effective amount of the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is about 10 mg.

[0273] Embodiment 106 is the amorphous form of Artikaplanam according to any one of embodiments 95-105, wherein the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is administered orally.

[0274] Embodiment 107 is the amorphous form of Artikaplanam according to any one of embodiments 95-106, wherein the crystalline form of Artikaplanam or the amorphous form of Artikaplanam is administered once a day.

[0275] Embodiment 108 is the amorphous form of artikaplanam according to any one of embodiments 95-107, wherein the patient suffers from anhedonia.

[0276] Embodiment 109 is the amorphous form of artikaplanam according to any one of embodiments 95-83, wherein the patient suffers from moderate anhedonia.

[0277] Embodiment 110 is the amorphous form of artikaplanam according to any one of embodiments 95-84, wherein the patient suffers from severe anhedonia.

[0278] Embodiment 111 is an amorphous form of artikaplanam according to any one of embodiments 77-85, wherein said patient does not experience weight gain during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0279] Embodiment 112 is the amorphous form of artikaplanam according to embodiment 111, wherein the patient's weight is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0280] Embodiment 113 is an amorphous form of artikaplanam according to any one of embodiments 95-112, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0281] Embodiment 114 is the amorphous form of artikaplanam according to embodiment 113, wherein the patient's sexual function is assessed upon initial administration of said crystalline form of artikaplanam or said amorphous form of artikaplanam.

[0282] Embodiment 115 is the amorphous form of artikaplanam according to embodiment 113 or 114, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm, or orgasmic satisfaction.

[0283] Embodiment 116 is the amorphous form of artikaplanam according to any one of embodiments 113-114, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0284] Embodiment 117 is an amorphous form of artikaplanam according to any one of embodiments 108-110, wherein after 6 weeks of said treatment with said crystalline form of artikaplanam or said amorphous form of artikaplanam, said patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on an anhedonia scale.

[0285] Embodiment 118 is an amorphous form of artikaplanam according to any one of embodiments 108-110 and 117, wherein said anhedonia of said patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0286] Embodiment 119 is the amorphous form of artikaplanam according to embodiment 117 or 118, wherein the anhedonia rating scale is the Snaith-Hamilton Hedonia Rating Scale.

[0287] Embodiment 120 is a package or pharmaceutical product comprising: (i) the crystalline form of atikaplan according to any one of embodiments 1-15, the amorphous form of atikaplan according to any one of embodiments 16-18, or a combination thereof, and (ii) instructions for use in treating major depressive disorder in a human patient suffering from anhedonia.

[0288] 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.

[0289]

[0290]

[0291] Example 1: Instrument and method details

[0292] AX-ray powder diffraction (XRPD)

[0293] Bruker AXSD8 Advance

[0294] 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.

[0295] 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.

[0296] Details of the standard Pharmorphix data collection method are:

[0297] · Angular range: 2° to 42° 2θ

[0298] Step size: 0.05°2θ

[0299] Collection time: 0.5 sec / step (total collection time: 6.40 min)

[0300] When necessary, other data collection methods were used, the details of which are shown in Table 14.

[0301]

[0302] PANalyticalEmpyrean

[0303] 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.

[0304] 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.

[0305] The scanning mode for metal plates uses the gonio scanning axis, whereas 2θ scanning is used for microplates.

[0306] Details of standard screening data collection methods:

[0307] · Angular range: 2.5° to 32.0° 2θ

[0308] Step size: 0.0130°2θ

[0309] Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0310] The software used for data collection was X'Pert Data Collector, and the data were analyzed and presented using Diffrac Plus EVA.

[0311] B. Nuclear Magnetic Resonance (NMR)

[0312] 1 H NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Samples were prepared in DMSO-d6 solvent unless otherwise stated. Standard Bruker loading experiments ( 1 H) Acquisition of automated experiments. Offline analysis was performed using an ACD Spectrus processor.

[0313] C. Differential Scanning Calorimetry (DSC)

[0314] TA Instruments Q2000

[0315] 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.

[0316] 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.

[0317] The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Universal Analysis or TRIOS.

[0318] TA Instruments DiscoveryDSC

[0319] 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.

[0320] The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0321] D. Thermogravimetric analysis (TGA)

[0322] TAInstrumentsQ500

[0323] TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 1 mg-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10°C / min from ambient temperature to 350°C. A nitrogen purge of 60 mL / min was maintained over the sample.

[0324] The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Universal Analysis or TRIOS.

[0325] TAInstruments DiscoveryTGA

[0326] TGA data were collected on a TA Instruments Discovery TGA equipped with a 25 position autosampler. Typically, 1 mg-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10°C / min from ambient temperature to 350°C. A nitrogen purge of 25 mL / min was maintained over the sample.

[0327] The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0328] E. Polarized Light Microscopy (PLM)

[0329] Leica LM / DM polarized light microscope

[0330] Samples were analyzed on a Leica LM / DM polarized light microscope with a digital camera for image capture. A small amount of each sample was placed on a slide with or without immersion oil and covered with a coverslip. Samples were observed with appropriate magnification and partially polarized light coupled to a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0331] Nikon LM / DM Polarized Light Microscope

[0332] The samples were studied on a Nikon SMZ1500 polarized light microscope with a digital camera for image capture connected to a DS Camera control unit DS-L2. The samples were observed with appropriate magnification and partially polarized light coupled to a lambda false color filter.

[0333] F. Scanning Electron Microscopy (SEM)

[0334] Data were collected on a Phenom Pro SEM. Small samples were mounted on aluminum stubs using conductive double-sided tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 s).

[0335] G. Gravimetric Vapor Sorption (GVS)

[0336] Adsorption isotherms were obtained using the SMSDVS intrinsic moisture adsorption analyzer controlled by the DVS intrinsic control software. The sample temperature was maintained at 25°C by instrument control. Humidity was controlled by mixing dry nitrogen flow and wet nitrogen flow, with a total flow rate of 200 mL / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0%-100% RH) located near the sample. The weight change (mass relaxation) of the sample as a function of %RH was continuously monitored by a microbalance (accuracy ± 0.005 mg).

[0337] Typically, 5 mg-30 mg of sample was placed in a tared stainless steel basket under ambient conditions. Samples were loaded and unloaded at 40% RH and 25°C (typical room conditions). Moisture adsorption isotherms were performed as outlined below (2 scans per complete cycle). Standard isotherms were performed at 25°C in the range of 0-90% RH at 10% RH intervals. Typically, two cycles (4 scans) were performed. Data analysis was performed in Microsoft Excel using the DVS analysis suite. See Table 15.

[0338]

[0339]

[0340] Samples were recovered after completion of the isotherm and reanalyzed by XRPD.

[0341] H. Chemical purity determination by HPLC

[0342] 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 16.

[0343]

[0344] I. Ion Chromatography (IC)

[0345] Data were collected on a Metrohm 930 Compact IC Flex with an 858 Professional autosampler and an 800 Dosino dosage unit monitor using IC MagicNet software. Accurately weighed samples were prepared as stock solutions in suitable solvents. Quantification was achieved by comparison with standard solutions of known concentrations of the ions to be analyzed. The analysis was performed in duplicate, and the average value of the values ​​was given unless otherwise stated. See Table 17A and Table 17B.

[0346]

[0347]

[0348]

[0349] J. Single Crystal X-ray Diffraction (SCXRD)

[0350] Data were collected on a Rigaku Oxford Diffraction Supernova Dual Source, Cu at Zero, Atlas CCD diffractometer equipped with an Oxford Cryosystems Cobra cooling device. Data were collected using Cu Kα or Mo Kα radiation as described in the experimental table. The structure was resolved and refined using the Bruker AXS SHELXTL suite or OLEX crystallography software. More details can be found in CIF. Unless otherwise stated, hydrogen atoms attached to carbon are geometrically placed and allowed to be refined with riding isotropic displacement parameters. Hydrogen atoms attached to heteroatoms are located in the differential Fourier synthesis and are allowed to be freely refined with isotropic displacement parameters. Reference diffraction patterns for crystal structures were generated as described in Macrae, "Mercury: Visualization and analysis of crystal structures," 2006, J. Appl. Cryst., Vol. 39, pp. 453-457.

[0351] K. Raman spectroscopy

[0352] Data were collected on a Renishaw inVia Qontor. Instrument control, data analysis and display software was WiRE.

[0353] Method: Excitation source, λ 激发 = 633nm or 785nm laser, appropriately attenuated to avoid sample degradation.

[0354] Raman shift range: 100cm -1 –5000cm -1 ; Exposure time: 0.02s-10s; Accumulation: 1–3.

[0355] L. Fourier Transform Infrared (FTIR)

[0356] The spectral range was 4000 cm on a Perkin-Elmer Spectrum One equipped with a universal attenuated total reflectance (ATR) sampling accessory. -1 –650cm-1 Data were collected over 16 scans. Data were collected using Spectrum software and processed using an ACDSpectrus processor.

[0357] Example 2 - Technology

[0358] A. Crystallization Technology

[0359] To investigate the crystalline form, ripening experiments (or slurry ripening) were carried out in various solvents or solvent mixtures and subjected to heating-cooling cycles.

[0360] Curing room procedures

[0361] The suspension for maturation was placed in a platform shaking incubator (Heidolph Titramax / Incubator 1000) and subjected to a series of heating-cooling cycles from ambient temperature to approximately 50° C. This was achieved by switching the heating on or off every 4 hours. Shaking was maintained throughout.

[0362] Polar Bear Program

[0363] The suspension was stirred in a Polar Bear (Cambridge Reactor Design) at 50°C. The sample was then cooled to 25°C and stirred for a further 4 hours. After this time, the sample was heated back to 50°C. The cycle was then repeated.

[0364] Cooling crystallization

[0365] Crystallization is obtained by lowering the temperature of the clear solution.

[0366] Controlled evaporation

[0367] Crystallization is produced by controlled evaporation of a clear, particle-free solution. At approximately constant temperature, solvent is removed from the system, thereby increasing the solute concentration. When a certain maximum supersaturation is reached, crystal nucleation and growth are obtained.

[0368] Precipitation / crystallization by adding antisolvent

[0369] Antisolvent crystallization (or sedimentation crystallization) is used to precipitate a substance from a solution. Crystallization involves adding a miscible antisolvent to a solution of a solute, reducing the initial solubility of the solute, increasing the supersaturation and thereby causing it to precipitate.

[0370] Crystallization by solvent deposition or solvent layer diffusion

[0371] Solvent diffusion crystallization is used to slowly precipitate a substance from a solution. The substance is dissolved in an appropriate solvent in a vial, and a miscible antisolvent is added very slowly to settle on the solvent layer. The vial is then sealed.

[0372] The antisolvent is selected to be miscible with the solvent in all proportions and the solute is relatively insoluble in it. In addition, a density gradient is required to allow the antisolvent to gradually diffuse into the solvent layer, thereby reducing the overall solubility and ultimately leading to crystallization of the substance.

[0373] B. Thermal Technology

[0374] Desolvation of solvates / hydrates (after drying)

[0375] Various environmental conditions, such as temperature and pressure, are used to desolvate artikaplanam in the solid hydrated or solvated phase.

[0376] C. Grinding Technology

[0377] Grinding is used herein both alone and via polymer-assisted grinding (POLAG). As an alternative to liquid-assisted grinding, POLAG is a mechanochemical process that uses polymers associated with grinding to promote and / or accelerate the mechanochemical reaction.

[0378] Planetary milling procedure: Artikaplan and related polymers were placed in a sample bottle and two stainless steel grinding beads (3 mm diameter) were added. The mixture was milled at 500 rpm for 2 hours using a planetary Fritsch Mill (Pulverisette 6) with an Automaxion adapter. After milling, all samples were initially analyzed by XRPD.

[0379] Example 3 - Generation and Characterization of Amorphous Artikaplan .

[0380] Both freeze drying and flash evaporation techniques were used to produce amorphous artikaplanam.

[0381] A. Freeze drying

[0382] Artikaplanam (20 mg) of Form III was weighed into 3 HPLC vials. Each vial was treated with 10 volumes (250 μL) of the relevant solvent at 25°C and shaken. The sample in t-BuOH was placed at 90°C for a few seconds, where a solution was obtained. The solution was filtered using a 0.45 μm PTFE membrane Acrodisc filter and then flash frozen in an acetone / dry ice bath for 5 minutes. The sample was then freeze-dried overnight. The resulting solid was characterized by XRPD.

[0383] Form III was shown to be soluble in 70% THF / H2O at room temperature (biphasic) and in t-BuOH at 90°C. The results are shown in Table 18.

[0384]

[0385] XRPD analysis showed that the freeze drying method successfully produced amorphous material from t-BuOH and 70% THF / H2O. Figure 2 For samples from THF / water 1 H NMR showed the presence of residual THF (peak too small to integrate), and the glass transition temperature was found to be 56.8°C. See mDSC of amorphous artikaplanam ( Figure 3 ).

[0386] After static storage of amorphous artikaplanam at 40°C / 75% RH for 1 week, Form II was obtained.

[0387] B. Blow-down Evaporation (BDE) Procedure

[0388] THF and acetone were used as solvents to probe BDE as a technique to generate amorphous artikaplanam. Form III artikaplanam (30 mg) was dissolved in 5 volumes (150 μL) of acetone at room temperature and shaken to obtain a clear solution. The solvent was removed by BDE using 60°C N2 at a flow rate of 30 L / min for 40 minutes. The material was then used for polymorph screening at 5°C and 50°C.

[0389] Fresh amorphous artikaplanam was prepared for static storage at 40°C / 75% RH for 1 week. Both solvents produced amorphous artikaplanam. T was determined by mDSC. g The temperature was 45.5° C. See Table 19 for the characterization of amorphous artikaplanam.

[0390]

[0391] Example 4 - Polymorph Screening

[0392] A. Solubility Assessment

[0393] Artikaplanam (20 mg) of Form III was dispensed into amber HPLC vials with a magnetic stirring bar. Each vial was treated with the relevant solvent (5 volumes) at room temperature and stirred at 300 rpm for 10 minutes. If suspension was still observed, Artikaplanam (20 mg) of Form III was dispensed into amber HPLC vials (x 49) with a magnetic stirring bar. Each vial was treated with the relevant solvent (5 volumes) at room temperature and stirred at 300 rpm for 10 minutes. If suspension was still observed, the solvent of increasing volume was added until the material was completely dissolved or until a maximum of 80 volumes was used (Table 20). All samples were heated to 50 ° C and kept for 1 hour. The samples were then cooled to 5 ° C at a rate of 0.1 ° C / min, and stirred overnight. Any suspension remaining at this time was matured for 2 weeks at room temperature / 50 ° C.

[0394] The solution remaining after 24 h was evaporated to dryness, the suspension was isolated by filtration under positive pressure and all solids were analyzed by XRPD. Fig.13 Schematic diagram of further processing of the jelly or oil.

[0395] The results of the solubility evaluation are shown in Table 20. Form III of artikaplanam was obtained from water, DMSO (after aging the formed gum at 25°C / 50°C for 8 days), ether (crystallization), DCM (crystallization), heptane, 3-methyl-1-butanol, water / methanol (20%), nitromethane, chloroform (crystallization) and cyclohexane.

[0396]

[0397] B. Low temperature polymorph screening

[0398] A low temperature polymorph screen was performed using amorphous artikaplan at 5°C. Amorphous artikaplan (30 mg) was generated by BDE in the "Blowdown Evaporation (BDE) Method" section above. Each vial was treated with a given volume of the solvent described in Table 21 to produce a slurry at 5°C and stirred at 500 rpm for 10 minutes. For clear solutions that converted to slurries at 10 minutes, a small aliquot was removed and analyzed by XRPD. Any samples that were still clear solutions were set aside and cooled to room temperature overnight and then treated with an anti-solvent. The results of the low temperature polymorph screen can be seen in Table 21.

[0399]

[0400]

[0401] Most samples produced clear solutions within 10 minutes and remained in solution after 24 hours. Samples that formed turbid solutions after 10 minutes formed suspensions within 1 hour. Form III was obtained from 1-propanol, 2-propanol, acetone, MEK, NBP, DMF, DMI, DMPU, 10% water / methanol, 5% water / EtOH, 20% water / methanol, 10% water / IPA, 10% water / ACN, pyridine, 1-methylpyrrolidine, and DMAc.

[0402] Samples that were still in solution after 14 days were equilibrated at room temperature and treated with water as antisolvent to induce precipitation. See Table 21. Samples were treated with antisolvent / solvent ratios starting at 1:1 and increasing to 2:1, 3:1, or 5:1 until precipitation occurred. After 3 hours, any solid / suspension was isolated by filtration on a Millipore plate and analyzed by XRPD.

[0403] In samples treated with antisolvents, Form III was obtained with 1- and 2-propanol, acetone, MEK, NBP, DMF, DMI, DMPU, 10% water / methanol, 10% water / ACN, pyridine, 1-methylpyrrolidine, and DMAc.

[0404] C. High Temperature Polymorph Screening

[0405] A high temperature polymorph screen was performed at 50°C using amorphous artikaplanam. The procedure was performed as described in the low temperature screen, except that the sample was initially shaken at 50°C for 10 minutes. The initial observations were recorded and again at the 1 hour and 24 hour time points. If the clear solution converted to a slurry at 10 minutes, an aliquot was removed and analyzed by XRPD. After 7 days, the suspension was analyzed again by XRPD. Any sample that was still a clear solution after 24 hours was cooled to room temperature overnight and then treated with an antisolvent. The results of the high temperature polymorph screen can be seen in Table 22.

[0406]

[0407]

[0408]

[0409] The sample that was still in solution after 7 days at 50°C was cooled to room temperature and treated with n-heptane. The sample was initially treated with a 1:1 antisolvent / solvent ratio, observed and observed again after stirring for 10 minutes (300rpm / 10min). An additional volume of antisolvent was added until a precipitate was formed. If a dilute white suspension was obtained, or the recovery after filtration was estimated to be poor, additional antisolvent was added. Further observations were recorded after 3 hours and 16 hours, and an aliquot of the suspension was taken out and analyzed by XRPD. The crystallization of the formed jelly was performed by further treatment as detailed in Table 22. The results of antisolvent addition can also be seen in Table 22. Form III was obtained by adding heptane antisolvent to many solvent systems.

[0410] D. Temperature Cycling Polymorph Screening

[0411] Temperature cycling screening (25°C / 50°C) was performed on amorphous Artikaplan. Samples were treated with the solvents in Table 23 (2.5-5 volumes, depending on solubility). Initial observations were made before placing the samples on a platform shaking incubator programmed at 25°C / 50°C with a 4 hour cycle. Observations were made after 1 day and 7 days, and any solids were analyzed by XRPD. Samples that were still in solution were treated with cold anti-solvent (n-heptane or water) and then returned to the maturation chamber.

[0412] Similar to the previous two screens, most samples produced solutions upon addition of solvent and were still in solution after 7 days. Suspensions were observed in samples with heptane and 20% water / methanol, and jelly was formed in samples with water and 10% water / acetone. The suspension in heptane showed Form III after 24 hours and was still Form III after 7 days. The remaining samples formed solutions and were treated with antisolvents.

[0413] Samples that formed solutions in the temperature cycling screen were treated with antisolvent (water or heptane) in the reverse antisolvent screen.

[0414] Depending on the solvent miscibility, solutions were treated with water or n-heptane as the antisolvent at a 5:1 antisolvent:solvent ratio. Vials containing a given amount of the relevant antisolvent were prepared and placed in a refrigerator for approximately 2 hours. Solutions from the maturation screen were kept at room temperature for approximately 4 hours and then added to the antisolvent sample. Aliquots of the solids were taken out and analyzed by XRPD. See Table 23.

[0415]

[0416] E. Solvent deposition (solvent layer diffusion) screening

[0417] Prepare a stock solution of Form III. See Table 24.

[0418]

[0419] The solution was then dispensed into the relevant number of vials to give 30 mg per HPLC vial. The samples in DMSO and t-BuOH were placed in a freezer for approximately 1 hour, after which they were removed and treated with the relevant antisolvent at a 5:1 antisolvent / solvent ratio. The antisolvent was slowly added to the frozen solution. The samples were then left standing at room temperature. The results of the solvent deposition screen can be seen in Table 25.

[0420]

[0421] The solution that did not produce solid after 6 days was taken out of the refrigerator and the lid was removed to evaporate the solvent. After 6 days of evaporation, solids were also produced in the sample in t-BuOH / cyclohexane, which was shown as Form II by XRPD. The t-BuOH sample was separated by vacuum filtration and dried under vacuum for 2 hours. Thereafter, it was covered and left overnight.

[0422] F. Solvent Interface Crystallization Screening

[0423] Solvent interface screening was performed using immiscible solvent / antisolvent combinations. A stock solution of Form III of Artikaplan was initially prepared. See Table 26. The solution was then dispensed into vials to give 30 mg per vial. The samples were treated with the relevant antisolvent at a 5:1 antisolvent / solvent ratio. The samples were then left to stand at room temperature. The samples that were still solutions were placed in a refrigerator and those that produced solids were analyzed by XRPD.

[0424]

[0425] The results of the solvent interface crystallization screen are shown in Table 27. In the t-BuOH / water system, a white suspension consisting of a gummy solid formed shortly after the antisolvent was added to the frozen t-BuOH. Ripening of the gum at room temperature / 50°C produced a white solid that was found to be Form II after analysis by XRPD. Form II was also produced by systems in MEK / water and 2-methylTHF, initially producing a gum and producing Form II after aging.

[0426]

[0427]

[0428] K. Characterization of Forms I, II, and III

[0429] Form I

[0430] Form I was obtained in the screen from ethyl acetate and MEK (both by solvent evaporation). It was also obtained by adding heptane antisolvent to solutions of ethyl acetate and ether. Samples from the solubility assessment in ethyl acetate were separated and analyzed by XRPD, 1 H NMR and DSC characterization ( Figure 7 ), and static storage at elevated temperature and humidity. The results are shown in Table 30.

[0431]

[0432] DSC showed a broad endothermic peak at 92.9°C (57.4 J / g). After static storage, the sample was shown to remain in Form I. These findings suggest that Form I may be an anhydrous form that remains stable after storage at elevated temperature and humidity.

[0433] Form II

[0434] As described above, Form II was obtained from amorphous artikaplanam after static storage for 1 week at 40°C / 75% RH and was also observed several times in the amorphous screen. Form II is anhydrous and exhibits low hygroscopicity and remains stable by GVS analysis and static storage under elevated temperature and humidity conditions (40°C / 75% RH and 25°C / 97% RH).

[0435] Form III

[0436] Form III exhibits desirable solid state characteristics and appears to be the most stable form. In addition, it is readily obtained from a number of solvents, including solutions of methanol, 20% methanol / water, 10% water / IPA, and 5% water / ethanol, crystallizing at 5°C. Form III was characterized and the results are shown in Table 31.

[0437]

[0438]

[0439] 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 Fig.12 Cycling the amorphous form through two cycles (cycle 1 = cooling from 131°C to -40°C; cycle 2 = heating from -40°C to 131°C at 10°C / min) produced annealed glass. Figure 5 .

[0440] Example 5 - Thermodynamic Stability Relationship

[0441] A. Competitive slurry

[0442] Competitive slurry experiments were performed with Form I, Form II, and Form III to determine the relative stability order. Slurry experiments were performed in six different solvent systems at 5°C and 50°C.

[0443] B. Preparation of Saturated Solution

[0444] Saturated solutions of Form III were prepared in different solvent systems. See Table 32. Each vial was filled with the relevant solvent (1.5 mL each) and placed to equilibrate at the relevant temperature. Thereafter, a small spoonful of solid was added until the solid no longer dissolved. As described, the samples were stirred at 5°C and 50°C for approximately 2 weeks or more.

[0445]

[0446]

[0447] C. Preparation of a mixture of Form I and Form II

[0448] Form III (180 mg) and Form II (180 mg) are merged into 4 mL bottles. Sample is placed on turbula blender for 30 minutes, then a small amount of sample is taken out and analyzed by XRPD to confirm the mixture. Weigh 10 mg of the mixture, and use the mixture of Form I and Form II as the seed in competitive slurries. Add a mixture of Form I and Form II (7 mg) to each bottle. Refer to Table 33.

[0449]

[0450] After 15 hours, several samples converted to Form III. After 15 days, most samples converted to Form III, and after 56 days all samples had converted to Form III (samples in 20% MeOH / H2O and cyclohexane (both at 5°C) took longer to convert). This indicates that Form III is the most stable form under these conditions.

[0451] Example 6 - Scale-up of Form I

[0452] A. Route 1 - Precipitation from ethyl acetate / n-heptane (0.5 g) solution

[0453] Artikaplanam (0.5 g) of Form III was weighed into a large bottle. The solid was dissolved in ethyl acetate (2.5 mL / 5 volumes). The solution was allowed to evaporate (cap loosened) overnight. The next morning, the solution was preserved. The sample was placed in a vacuum oven for approximately 1 hour to further concentrate the solution. Thereafter, a white precipitate had begun to form. The suspension was left at room temperature overnight, after which a white solid was obtained. Prior to reanalysis by XRPD, the solid was placed in a vacuum oven at 50° C. to remove any residual ethyl acetate for approximately 2.5 hours. The initial suspension was found to be Form I. After drying in a vacuum oven, it was converted to Form III.

[0454] B. Route 2 - Evaporation of ethyl acetate (0.5 g) solution

[0455] The sample from route 1 was redissolved in ethyl acetate (volume reduced to 2 mL). The sample was uncapped and a white precipitate was observed the next day. The sample was placed in a vacuum oven and dried for 3 days. The solid was determined to be Form III.

[0456] C. Route 3 - Add heptane antisolvent to ether (0.5 g) solution

[0457] Form III (0.5 g) was dissolved in ethyl acetate (2.5 mL / 5 volume) in a large bottle. The solution was evaporated (removing the vial cap) overnight. In the morning of the second day, a jelly was formed in which a small amount of white solid grew in the jelly. An aliquot of the solid was taken and analyzed by XRPD. After 24 hours, the sample became solid completely and grew very thin needles. It was found that the solid was a mixture of Form II and Form III.

[0458] D. Route 4-8 - Add heptane antisolvent to ether (100 mg) solution

[0459] Smaller scale experiments were performed to re-prepare Form I. Different sized vials were used at different temperatures. Form III (100 mg) was added to five vials, and ethyl acetate (500 μL) was added thereto, whereby the solid dissolved. Each vial was placed under the relevant conditions, and the vial cap was removed, unless otherwise noted in Table 34. Once solids were observed, a small sample was taken out and analyzed by XRPD.

[0460]

[0461] Example 7 - Scale-up of Form II (1 g scale)

[0462] Form III (1 g) was weighed into a 50 mL Duran bottle. The solid was dissolved in DMSO (13.3 mL / 13.3 volume), and the solution was placed in a freezer for approximately 30 minutes. Water was slowly added to the frozen solution (10 mL aliquots were added around the side of the bottle under rotation to minimize the interference of the solid), until a total of 50 mL of water had been added. A white suspension was formed almost immediately on the frozen solvent layer. The suspension was left to stand for four days. After this time, the sample looked more uniform (no longer two layers), with a slight white precipitate on the top of the container and a colloidal solid at the bottom of the container. The sample was placed for aging overnight (25 ° C / 50 ° C-4 hour cycle). The next morning, it was observed that the solid adhered to the sides of the container and was loosened / broken with a spatula. A small amount of sample was taken out and analyzed by XRPD. The amorphous content was still obvious by XRPD, so the sample was returned to the aging chamber for another day. Thereafter, improved crystallinity was observed, and the sample was separated by vacuum filtration / drying. The above method successfully prepared Form II on a large scale. See Table 35.

[0463]

[0464] Form II was successfully scaled up (1 g) from a water / DMSO solvent layer diffusion and was found to be anhydrous and exhibit low hygroscopicity. After GVS analysis, the sample remained Form II. Fig.10 and Fig.11 There were large agglomerates consisting of smaller particles (size <10 μm) as well as flakes (length approximately 60 μm) and larger ridged particles (length approximately 120 μm) present within the agglomerates. Form II remained stable after 1 week of static storage under elevated temperature and humidity conditions.

[0465] Separated solid 1 H NMR showed the presence of residual DMSO (0.08 mol eq.). TGA showed a small mass loss at -108 °C (0.95% / about 0.05 mol eq. DMSO) and additional mass loss from 108 °C to 255 °C, which was attributed to the onset of decomposition. XRPD was shown at Figure 8 DSC analysis showed an endothermic peak at 74.7°C (4.7 J / g), overlapping with a second sharper endothermic peak at 96.2°C (onset, 51.3 J / g). Fig. 9 GVS analysis showed Form II to be slightly hygroscopic. A mass uptake of 0.26% was observed from 40%-90% RH in the first cycle, with a mass loss of 0.57%. A similar mass water uptake (0.25%) was observed in the second adsorption cycle, and all the water was lost again in the second desorption cycle, with slight hysteresis observed. Figure 10 to Figure 11. XRPD analysis after GVS showed that the sample was still Form II. HPLC analysis showed a purity of 99.7%. Microscopy analysis by SEM / PLM showed the presence of irregular particles. The particle size range was <10 μm to about 200 μm. There were large agglomerates, which consisted of smaller particles (size <10 μm), flakes (length about 60 μm) also present in the agglomerates, and larger ridged particles (length about 120 μm). Static storage under elevated temperature and humidity conditions (40°C / 75% RH and 25°C / 97% RH) showed that the sample was still Form II. See Table 36.

[0466]

[0467] Example 8

[0468] 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).

[0469] A. Purpose

[0470] 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.

[0471] The secondary goal is :

[0472] 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.

[0473] 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.

[0474] iii. To investigate the effect of artikaplan versus placebo on depression-related anhedonia as assessed by SHAPS.

[0475] 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).

[0476] v. The effect of artikaplankton on anxiety symptoms was investigated using the HAM-A, and the effect of artikaplankton on core symptoms of anxiety was investigated using the HAM-A6 subscale.

[0477] vi. To evaluate the plasma PK of artikaplanam in MDD subjects and explore its relationship with efficacy and safety parameters.

[0478] Secondary exploratory objectives include :

[0479] i. The CPFQ was used to explore the effects of artikaplanam on various aspects of cognitive and executive function.

[0480] 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.

[0481] B. Research Design

[0482] 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. Fig.14 .

[0483] 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.

[0484] 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. Fig.14 The overall flow chart is shown in FIG.

[0485] 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.

[0486] Double-blind treatment phase

[0487] 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 37.

[0488] Table 37: Time and Event Schedule (TES)

[0489]

[0490]

[0491] 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.

[0492] 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.

[0493] 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.

[0494] C. Dosage and Administration

[0495] 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.

[0496] When Visit 11 was scheduled 3 days later, subjects continued taking medication until Visit 11.

[0497] 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.

[0498] The first dose was taken on an empty stomach on day 2 of the double-blind phase. The doses were:

[0499] 10 mg of Artikaplan: 2 5 mg Artikaplan capsules

[0500] Placebo: 2 placebo capsules.

[0501] 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:

[0502] 5mg Artikaplan: 1 5mg Artikaplan capsule

[0503] Placebo: 1 placebo capsule.

[0504] 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.

[0505] D. Clinical evaluation

[0506] (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Symptom Scale for Major Depressive Disorder (SMDDS)

[0507] Self-Assessment of Treatment Experience (SATE)

[0508] (ii) Anhedonia: Snaith-Hamilton Hedonic Feeling Scale (SHAPS)

[0509] (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A) and HAM-

[0510] A6

[0511] (iv) Effects on cognition: Cognitive and Physical Function Questionnaire (CPFQ)

[0512] (v) Safety assessment

[0513] 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.

[0514] (vi) Suicidal ideation: C-SSRS

[0515] (vii) Exploratory: CPFQ

[0516] (viii) Central nervous system sedation: Karolinska Sleepiness Scale

[0517] (ix) Sexual dysfunction: ASEX

[0518] E. Patient Groups

[0519] 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 old, ranging from 19 to 64 years old. All subjects suffered from anhedonia (defined as a SHAPS total score ≥ 20) at the baseline of treatment. 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 38 and 39.

[0520] Table 38: Summary of Demographics and Baseline Characteristics; Overall Safety Analysis

[0521]

[0522]

[0523] Table 39: Summary of demographic and baseline characteristics; eITT

[0524]

[0525]

[0526]

[0527] E. Efficacy evaluation

[0528] 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).

[0529] Duration of treatment : The study consists of two time 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 consists of 3 time periods. The first time period is a 3-week placebo lead-in, after which the subjects enter the treatment period, during which they are randomly assigned to artikaplan or continue to take placebo for 6 weeks. Subjects who successfully complete the treatment period are treated with placebo during a 2-week withdrawal period (i.e., the third time period). The total duration for each subject is approximately 16 weeks.

[0530] 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.

[0531] Secondary analysis set for efficacy : The secondary analysis set is the fITT set, which is 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.

[0532] 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.

[0533] Efficacy endpoints of eITT and fITT are presented.

[0534] 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.

[0535] F. Results

[0536] (i) Primary endpoint: The MADRS total score of non-responders in the placebo run-in period at week 6 compared with the treatment baseline. Line changes

[0537] Enrichment ITT analysis set

[0538] The mean (SD) MADRS total score at baseline was 29.0 (4.61), with a range of 19 to 41. Fig.15 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, respectively. The observed effect size was 0.23. See Tables 40 to 42 and Fig.18 .

[0539] Table 40: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; eITT Analysis Set

[0540]

[0541] Table 41: MADRS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0542]

[0543] Table 42: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0544]

[0545]

[0546] 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 Fig.15 and Fig.16 .

[0547] Full ITT Analysis Set

[0548] The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), with a range of 0 to 41. Figure 20-A and Figure 20-B The mean change from treatment baseline in the MADRS total score at week 6 for artikaplan and placebo was smaller 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 43.

[0549] Table 43: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; fITT Analysis Set

[0550]

[0551]

[0552] 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 80% 1-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 44 to 45 and Fig.16 .

[0553] Table 44: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0554]

[0555]

[0556] Table 45: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0557]

[0558] Impact of COVID-19 on primary efficacy assessments

[0559] 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.

[0560] (ii) Secondary endpoints

[0561] MADRS remission rate during the treatment period

[0562] 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.21 and Fig. 22 .

[0563] MADRS response rate during treatment period (at least 30% improvement)

[0564] 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).

[0565] MADRS response rate (at least 50% improvement) during the treatment period

[0566] 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 differences at Week 6 were significant at the 20% two-sided significance level (Chi-square test: p=0.104 for eITT and p=0.046 for fITT). See Table 46 and Figure 23 to Figure 26 .

[0567] Table 46: MADRS Total Scores at Treatment Week 6 in Responders and Non-Responders During the Placebo Run-in Period

[0568]

[0569]

[0570] Change in SHAPS total score from baseline to treatment week 6

[0571] Enrichment ITT analysis set

[0572] 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.

[0573] 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 47 and Fig. 27 and Fig.34 .

[0574] Table 47: SHAPS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0575]

[0576]

[0577] 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]. Fig.17 and Table 48 and Table 49 and Fig.28 The corresponding p-value is 0.419.

[0578] Table 48: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0579]

[0580]

[0581] Table 49: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0582]

[0583]

[0584] 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. Fig.17 and Fig.18 .

[0585] Full ITT Analysis Set

[0586] 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 week 6 for artikaplan and placebo in the fITT population relative to the treatment baseline 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 50.

[0587] Table 50: SHAPS Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0588]

[0589] Change in MADRS total score from treatment baseline to treatment week 6 according to the level of anhedonia at baseline

[0590] Enrichment ITT analysis set

[0591] 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 51). The observed effect sizes were 0.38 and 0.11, respectively.

[0592] Table 51: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Changes from Placebo During the Treatment Period According to Anhedonia Levels at Treatment Baseline; eITT Analysis Set

[0593]

[0594]

[0595] Full ITT Analysis Set

[0596] Similar trends were observed in the fITT population. The magnitude of the differences was greater 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 52. The observed effect sizes were 0.51 and 0.29, respectively.

[0597] Table 52: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Changes from Placebo During the Treatment Period According to Anhedonia Levels at Treatment Baseline; fITT Analysis Set

[0598]

[0599]

[0600] 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.

[0601] Change in CGI-S total score during treatment from treatment baseline

[0602] Table 53: Changes in CGI-S Total Score During Treatment from Treatment Baseline

[0603]

[0604] Changes in SMDDS total score at week 6 compared with baseline

[0605] Table 54: Changes in SMDDS Total Score at Treatment Week from Treatment Baseline

[0606]

[0607] Number of subjects with SATE scores at treatment week 6

[0608] Table 55: Number of subjects with SATE scores at treatment week 6

[0609]

[0610] Change in HAM-A6 total score at week 6 compared with baseline

[0611] Table 56: Changes in HAM-A6 Total Score at Week 6 Relative to Treatment Baseline

[0612]

[0613] These data suggest that patients treated with artikaplan-treated patients experienced greater improvements in HAMA6 scores compared with placebo.

[0614] Changes in SIGH-A structured interview guide scores at week 6 from treatment baseline

[0615] Table 57: Changes in SIGH-A Structured Interview Guide Scores at Week 6 from Treatment Baseline

[0616]

[0617] The maximum plasma concentration of artikaplan max )

[0618] 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.

[0619]

[0620] (iii) Safety endpoints

[0621] 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 59.

[0622] Table 59: Overall Summary of Treatment-Emergent Adverse Events During the Treatment Period; Full Safety Analysis Set

[0623]

[0624]

[0625] 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 60.

[0626] Table 60: Based on the Body System or Organ Class and Dictionary

[0627] 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

[0628]

[0629] 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.

[0630] 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 treated with artikaplanm. See Table 61.

[0631] Table 61: Treatment-Emergent Adverse Events of Special Interest During the Treatment Period; Full Safety Analysis Set

[0632]

[0633] 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.

[0634] No deaths were reported.

[0635] (iv) Anhedonia Analysis

[0636] Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 62 to 64.

[0637] Table 62: Frequency of Anhedonia in Subjects at Treatment Baseline; fITT Analysis Set

[0638]

[0639]

[0640] The results suggest that the more anhedonia patients had at baseline, the greater the treatment response. Fig.29 Table 63: Frequency of subjects experiencing different levels of anhedonia at baseline and at week 6 of treatment; eITT analysis set

[0641]

[0642] Table 64: Frequency of Subjects Experiencing Different Levels of Anhedonia at Treatment Baseline and Treatment Week 6; fITT Analysis Set

[0643]

[0644]

[0645] The results suggest that the more anhedonia patients had at baseline, the greater the treatment response. Figure 30-A and Figure 30-B .and Figure 30-B Compared with the low anhedonia group, Figure 30-A In the high anhedonia group (i.e., high anhedonia group), the placebo + oral antidepressant group showed less placebo response. Similarly, the treatment effect of artikaplan + oral antidepressant group 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. In addition, 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.31 .

[0646] (v) Weight changes

[0647] 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 65.

[0648] Table 65: Mean body weight according to treatment group (kg)

[0649]

[0650]

[0651] (vi) Completion rate

[0652] 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.

[0653] 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 66 and 67.

[0654] Table 66: Completion / early withdrawal information; eITT analysis set

[0655]

[0656] Table 67: Completion / Early Exit Information; Full Safety Analysis Set

[0657]

[0658]

[0659] (vii) Sexual function

[0660] 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%.

[0661] 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.

[0662] The patient's sexual function was measured using the standard, widely accepted rating scale, ASEX. See Table 68.

[0663] Table 68: ASEX scores according to treatment groups

[0664]

[0665] 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.32 .

[0666] 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.33 Items 3, 4 and 5 of the.

[0667] (viii) Onset of Effect

[0668] The onset of action of artikaplanam can be estimated from the studies. Figure 20-B The least square mean changes from baseline are depicted. A significant treatment effect favoring artikaplanam was observed as early as Week 3. At this point, artikaplanam demonstrated a statistically superior effect to placebo.

Claims

1. A method of treating major depressive disorder in a human patient, the method comprising administering crystalline artikaplanam to the human patient, wherein the patient has previously responded inadequately to other antidepressant therapies.

2. The method according to claim 1, wherein the crystalline artikaplanam is crystalline form I of artikaplanam characterized in that Four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0° and 24.0°, wherein artikaplanam has the following structure:

3. The method of claim 2, wherein the crystalline artikaplanam is crystalline form I of artikaplanam characterized in that Corresponds to the X-ray powder diffraction pattern of FIG6 .

4. The method of claim 2, wherein the crystalline Form I of artikaplanam is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at about 92.9°C.

5. The method of claim 2, wherein the crystalline Form I of artikaplanam is characterized by a differential scanning calorimetry thermogram corresponding to FIG. 7 .

6. The method of claim 2, wherein the crystalline artikaplanam is crystalline form II of artikaplanam characterized in that Four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3° or 26.2°, wherein artikaplanam has the following structure:

7. The method of claim 6, wherein the crystalline Form II of artikaplanam is characterized by an x-ray powder diffraction pattern corresponding to Figure 8.

8. The method of claim 6, wherein the crystalline Form II of artikaplanam is characterized by a differential scanning calorimetry thermogram comprising one or two endothermic peaks at about 74.7°C and about 96.2°C.

9. The method of claim 6, wherein the crystalline Form II of artikaplanam is characterized by a differential scanning calorimetry thermogram corresponding to FIG.

9.

10. The method of claim 1, wherein the crystalline artikaplanam is crystalline form III of artikaplanam characterized in that Four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0° or 21.4°, wherein artikaplanam has the following structure:

11. The method of claim 10, wherein the crystalline form III of artikaplanam is characterized by an x-ray powder diffraction pattern corresponding to Figure 1.

12. The method of claim 10, wherein the crystalline form III of artikaplanam is characterized by a peak temperature (T m ).

13. The method of claim 10, wherein the crystalline Form III of artikaplanam is characterized by a differential scanning calorimetry thermogram corresponding to Figure 4.

14. The method of claim 1, wherein the crystalline artikaplanam is anhydrous.

15. The method of claim 1, wherein the other antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

16. The method of claim 1, further comprising adjunctive treatment with an effective amount of one or more antidepressant drugs.

17. The method of claim 1, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or combinations thereof.

18. The method of claim 1, wherein the effective amount of the crystalline form of artikaplanam is between about 2 mg and about 35 mg, between about 5 mg and about 10 mg, about 5 mg, or about 10 mg.

19. The method of claim 1, wherein the crystalline form of artikaplanam is administered orally once daily.

20. The method of any claim 1, wherein the patient suffers from anhedonia.

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