Pharmaceutical Composition and Use of Aticaprant

Description

Pharmaceutical Composition and Use of Aticaprant Separated from BR112024018001-8, filed on March 6, 2023. CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims the benefit of US provisional patent application No. 63 / 317,471, filed March 7, 2022. TECHNICAL FIELD

[002] The present invention relates to compositions, including oral compositions, comprising aticaprant and methods for using them. BACKGROUND

[003] Kappa opioid receptors (KORs) and their native ligand dynorphin are located in brain areas that affect 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, KOR activation, and subsequent downstream signaling pathways to inhibit the rise of mesolimbic dopamine, contributing to negative affective states. The behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety, and has been found to have significant effects that may translate into therapeutic benefit in humans. KOR antagonists may be effective for the treatment of patients with mood disorders, perhaps by modulating the negative affective state associated with the stress response.

[004] Anhedonia is one of the main symptoms of depression. At least moderate symptoms of anhedonia are present in about 90% of patients suffering from major depressive disorder (MDD). Only about 50% of patients with MDD show a significant response (>50% improvement to first-line antidepressant treatment), leaving many patients with impaired function. Petition 870260020670, dated 05 / 03 / 2026, page 15 / 525 2 / 225 persistent substantial. Therapeutic strategies such as switching antidepressants and the use of adjuvant drug treatments may improve the response, however almost 40% of patients remain symptomatic and fail to achieve complete remission.

[005] New compounds and treatments are needed for patients with depression and, optionally, anhedonia. SUMMARY

[006] In some respects, the invention provides pharmaceutical compositions comprising from about 2 mg to about 20 mg of aticaprant and a filler, the composition comprising from about 0.1% to about 90% aticaprant by weight.

[007] In other respects, the invention provides oral tablets comprising about 5 mg of aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg of microcrystalline cellulose, about 30 mg of lactose monohydrate, about 2.5 mg of croscarmellose sodium and about 0.5 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises about 28.5 mg of silicified microcrystalline cellulose, about 2.5 mg of croscarmellose sodium, about 0.5 mg of anhydrous colloidal silica and about 0.5 mg of magnesium stearate.

[008] In further aspects, the invention provides oral tablets comprising about 10 mg of aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and an extragranular phase, wherein the intragranular phase comprises about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium and about 1 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises Petition 870260020670, dated 05 / 03 / 2026, page 16 / 525 3 / 225 contains approximately 57 mg of silicified microcrystalline cellulose, approximately 5 mg of croscarmellose sodium, approximately 1 mg of anhydrous colloidal silica, and approximately 1 mg of magnesium stearate.

[009] In still other aspects, the invention provides pharmaceutical compositions comprising between about 2 mg and 20 mg of aticaprant, the composition having a pharmacokinetic profile (PK pharmacokinetic) comprising one or more of the following parameters after administration of the composition to a human after fasting for at least 10 hours (with dose normalization up to 10 mg): (a) a mean Cmax between about 20 and 45 ng / mL; (b) a mean AUCinfinite between about 250 and 450 h*ng / mL; (c) a mean AUC ultimate between about 250 and 450 h*ng / mL; and (d) a mean tmax between about 1 and 4 hours.

[0010] In still other aspects, the invention provides methods for treating major depressive disorder (MDD) in a human patient, wherein the method comprises administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of aticaprant, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant, and wherein the administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the following PK parameters (with dose normalization up to 10 mg) after administration of the composition to a human after fasting for at least 10 hours: (a) a mean Cmax between about 30 and 40 ng / mL; (b) a mean AUCinfinite between about 300 and 430 h*ng / mL; (c) a mean AUC ultimate between about 280 and 430 h*ng / mL; and (d) an average tmax between approximately 1 and 4 hours.

[0011] In other respects, the invention provides solid pharmaceutical compositions comprising between about 2 mg and 20 mg of aticaprant, the composition having a dissolution profile that Petition 870260020670, dated 05 / 03 / 2026, page 17 / 525 4 / 225 comprises a Q value between approximately 60% and 90% in 45 minutes, under the following dissolution operating conditions: Apparatus: Paddle (USP type 2, Ph. Eur., JP); Dissolution medium: 0.01 M hydrochloric acid; Volume: 900 ml; Temperature: 37 + / - 0.5 °C; Rotation speed: 50 rpm; and analytical finish: UHPLC with UV detection at 247 nm.

[0012] In other respects, the invention provides methods for treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition, the oral tablet or the solid pharmaceutical composition described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is the powder X-ray diffraction (PXRD) pattern of aticaprant polymorph III form (transmission mode).

[0014] Figure 2 is the differential scanning calorimetry (DSC) thermogram of the aticaprant polymorph III form.

[0015] Figure 3 is the mDSC thermogram of the polymorph shape. III of aticaprant.

[0016] Figure 4 is the test design for Example 1.

[0017] Figure 5 is a line graph showing the total score on the Montgomery-Asberg Depression Rating Scale (MADRS): changes in least squares mean from baseline (±SE) during the treatment period for the enriched intent-to-treat (eITT) analysis set.

[0018] Figure 6 is a graph showing the changes in the total MADRS score at treatment week 6 for an enriched and complete population: MMRM Results - Estimated LS Means and Comparison versus Placebo.

[0019] Figure 7 is a line graph showing the total score. Petition 870260020670, dated 05 / 03 / 2026, page 18 / 525 5 / 225 of the SHAPS (Snaith-Hamilton pleasure scale): changes in least squares mean from baseline (±SE) during the treatment period for the eITT analysis set.

[0020] Figure 8 is a graph showing the changes in the total SHAPS score at treatment week 6 for an enriched and complete population: MMRM (mixed-effects model for repeated measurements) results - estimated LS means and comparison versus placebo.

[0021] Figure 9 is a line graph showing the total score on the MADRS: mean values ​​(±SE) over time for the eITT analysis set.

[0022] Figure 10-A is a line graph showing the total score on the MADRS: mean values ​​(±SE) over time for the full intent-to-treat (fITT) analysis set. Figure 10-B is an excerpt from Figure 10-A for treatment weeks 0 to 6.

[0023] Figure 11 is a line graph showing the total score on the MADRS: percentage of individuals with remission of depressive symptoms (total score < 10) during the treatment period for the eITT analysis set.

[0024] Figure 12 is a line graph showing the total score on the MADRS: percentage of individuals with remission of depressive symptoms (total score < 10) during the treatment period for the fITT analysis set.

[0025] Figure 13 is a line graph showing the total score on the MADRS: percentage of responders (improvement >30% from baseline) during the treatment period for the eITT analysis set.

[0026] Figure 14 is a line graph showing the total score on the MADRS: percentage of responders (improvement > 30% at par Petition 870260020670, dated 05 / 03 / 2026, page 19 / 525 6 / 225 tir from baseline) during the treatment period for the fITT analysis set.

[0027] Figure 15 is a line graph showing the total score on the MADRS: percentage of responders (improvement >50% from baseline) during the treatment period for the eITT analysis set.

[0028] Figure 16 is a line graph showing the total score on the MADRS: percentage of responders (improvement > 50% from baseline) during the treatment period for the set of fITT analyses.

[0029] Figure 17 is a line graph showing the total score on the SHAPS: mean values ​​(±SE) over time for the eITT analysis set.

[0030] Figure 18 is a line graph showing the total score on the SHAPS: mean values ​​(±SE) over time for the set of fITT analyses.

[0031] Figure 19 illustrates the change in MADRS relative to baseline by severity of anhedonia.

[0032] Figure 20-A is a line graph showing the change in MADRS from baseline for patients with high anhedonia, i.e., SHAPS > 38. Figure 20-B is a line graph showing the change in MADRS from baseline for patients with low anhedonia, i.e., SHAPS < 38.

[0033] Figure 21 is a bar graph showing the comparison of MADRS in patients with low and high anhedonia.

[0034] Figure 22 is a line graph showing the average change in the total score on the ASEX relative to the baseline.

[0035] Figure 23 is a bar graph showing the average change in the total score of the item level change in the ASEX relative to the baseline. Petition 870260020670, dated 05 / 03 / 2026, page 20 / 525 7 / 225

[0036] Figure 24 is the flowchart for the process of preparing tablets containing aticaprant. In this figure, a refers to microfine, i.e., ground aticaprant.

[0037] Figure 25 is a schematic overview of part 1 of the study. In this figure, Treatment A = 2x5 mg capsules; Treatment B = 1x10 mg tablet concept; Treatment C = 1x5 mg tablet concept; Treatment D = 1x10 mg tablet concept with a high-fat diet.

[0038] Figure 26 is a schematic overview of part 2 of the study. In this figure, a) Day 1 of a treatment period is the first day of the pharmacological rest period. Treatment E: 2x5 mg oral capsule administered in the morning, after at least 10 hours of overnight fasting. Treatment F: formulation concept 2 1x10 mg administered in the morning, after at least 10 hours of overnight fasting. Treatment G: formulation concept 2 1x5 mg administered in the morning, after at least 10 hours of overnight fasting. Treatment H: formulation concept 2 1x10 mg administered in the morning, approximately 30 minutes after the start of a standardized high-fat breakfast after at least 10 hours of overnight fasting.

[0039] Figures 27 and 28 show the relative bioavailability results for PK profiles of aticaprant in relation to BA.

[0040] Figures 29 and 30 show the relative bioavailability results for the PK profile of aticaprant, dose proportionality.

[0041] Figures 31 to 33 show the relative bioavailability results for the PK profile of aticaprant, food effect.

[0042] Figure 34 is the study design for Example 7. All patients will continue to take their SSRI / SNRI oral antidepressants throughout the study. Approximately 34 more elderly participants will be randomized. Petition 870260020670, dated 05 / 03 / 2026, page 21 / 525 8 / 225

[0043] Figure 35 is the study design for Example 8. All patients will continue to take their SSRI / SNRI oral antidepressants throughout the study. Approximately 68 more elderly participants will be randomized.

[0044] Figure 36 is a bar graph showing the items of SHAPS: LS means the change from baseline at week 6 by the total baseline SHAPS score for the fITT analysis set. In this figure, and going from top to bottom, the bars refer alternately to placebo or aticaprant. For example, the first bar refers to aticaprant, the second bar refers to placebo, the third bar refers to aticaprant, etc.

[0045] Figure 37 is a graph showing the total n MADRS score: difference in mean LS (60%) at Weeks 6 by different subgroups for the fITT analysis set. In this graph, < 17 indicates mild severity; 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity. DETAILED DESCRIPTION OF ILLUSTRATIVE MODALITIES

[0046] All individual features (e.g., specific modalities or specific preferred features) mentioned herein may be considered individually or in combination with any other feature (including the specific modality or preferred feature) mentioned herein; therefore, preferred features may be taken together with other preferred features, or independently of them (and also with specific modalities).

[0047] The invention provides compositions comprising the pure crystalline form of aticaprant III that are anhydrous and stable in solid form.

[0048] The term crystalline refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure. Petition 870260020670, dated 05 / 03 / 2026, page 22 / 525 9 / 225

[0049] The term polymorph refers to a crystalline form of a molecule with a specific crystalline structure. A crystalline compound may have one crystalline form or may have two or more crystalline forms, i.e., polymorphs. As understood by those skilled in the art, the polymorphs of a chemical compound may be distinguished from one another by comparable physicochemical properties such as solubility, dissolution rate, stability, bioavailability, among others. Polymorphs may also have different spectra selected from, without limitation, powder X-ray diffraction (PXRD), single-crystal X-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid-state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot-stage microscopy, or dynamic solvent sorption.

[0050] The term crystalline refers to the solid-state form of a chemical moiety in which the atoms, molecules, or ions are assembled in a highly ordered structure extending in all directions. Thus, crystalline includes all crystalline forms of compound I, including salts thereof. Characterization of crystalline forms can be performed by those skilled in the art, including, without limitation, XRD or DSC. Typically, the XRD pattern contains sharp intensity peaks. This contrasts with the XRD pattern of an amorphous form which often contains a broad peak, without identifying peaks. A crystalline form can be completely crystalline or partially crystalline. In some respects, a crystalline sample can be 100% w / w crystalline. A crystalline sample can also contain solids that are amorphous.In certain respects, a crystalline form may contain solids such that the sample is at least about 99% w / w crystalline, or at least about... Petition 870260020670, dated 05 / 03 / 2026, p. 23 / 525 10 / 225% in amorphous w / w form, at least about 90% in crystalline w / w form, at least about 85% in crystalline w / w form, at least about 80% in crystalline w / w form, or similar.

[0051] The term anhydrous or anhydrate, as used herein, refers to a crystalline form as described herein which is substantially devoid of water. In some respects, an anhydrous form contains less than about 1% by w / w of water. In other respects, an 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% by w / w of water.

[0052] As provided herein, all temperature values ​​may vary. Such variations may depend on the type of instrument, instrument parameters, laboratory techniques and / or laboratory conditions. Unless otherwise defined, a quoted temperature may vary. In some respects, the temperatures observed in the present invention vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4° or about 5°.

[0053] Similarly, the 2Θ values ​​obtained from XRD standards may also vary. Such variations may depend on the instrument type, instrument parameters, laboratory techniques, sample (including particle size, impurities, etc.) and / or laboratory conditions. Unless otherwise defined, XRD standards and / or 2Θ peak values ​​may vary. In some respects, 2Θ peak values ​​vary (plus or minus) by about 0.05°, about 0.1°, about 0.15° or about 0.2°. In other respects, one or more of the 2Θ peak values ​​are higher by about 0.05°, about 0.1°, about 0.15° or about 0.2°. In other respects, one or more of the 2θ peak values ​​are lower by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.

[0054] As used here, the term corresponds to can be used Petition 870260020670, dated 05 / 03 / 2026, page 24 / 525 11 / 225 in reference to certain spectra. Thus, "corresponds to" includes a spectrum that is identical or substantially similar to another spectrum. One skilled in the art would be able to compare such spectra and determine whether one spectrum corresponds to another. Thus, the term "corresponds to" is used in the present invention to compare XRD patterns, DSC thermograms, among others. In some respects, an XRD pattern corresponds to another XRD pattern when their 2θ values ​​are within the margin of error, as described above. In other respects, an XRD pattern corresponds to another XRD pattern when the peaks have the same 2θ peak value, but one or more peaks have a different height (intensity). In other respects, an XRD pattern corresponds to another XRD pattern when the peaks have the same 2θ peak value, but one or more peaks have a different peak area.In yet another aspect, one XRD pattern corresponds to another XRD pattern when the peaks have the same peak value of 2θ, but one or more peaks are obscured. Such obscured peaks may be due to impurities, excipients, or the like. Such obscured peaks typically do not prevent the characterization of the crystalline form.

[0055] As used herein, except where otherwise specified, the term aticaprant refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, that is, the following compound: and is also known as JNJ-67953964, 67953964-AAA, CERC Petition 870260020670, dated 05 / 03 / 2026, p. 25 / 525 12 / 225 501 and LY-2456302. In some embodiments, aticaprant refers to the (S)-enantiomer of aticaprant, that is, the following compound: also known as (S)-aticaprant or (S)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide. In other embodiments, the aticaprant used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-aticaprant or (R)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, which has the following structure:

[0056] In other embodiments, aticaprant contains less than about 10% by weight, based on the weight of aticaprant, of the aticaprant (R)enantiomer. In other embodiments, aticaprant 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, based on the weight of aticaprant, of the aticaprant (R)-enantiomer. In still other embodiments, aticaprant contains from about 0.001% to about 10% by weight, based on the weight of aticaprant, of the aticaprant (R)enantiomer. In still other forms, aticaprant contains from about 0.001 to about 10%, from about 0.001 to about Petition 870260020670, dated 05 / 03 / 2026, page 26 / 525 13 / 225%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight, based on the weight of the aticaprant.

[0057] Pharmaceutically acceptable salts of aticaprant are also contemplated by the present invention, which can be readily selected by those skilled in the art. A pharmaceutically acceptable salt refers to an aticaprant salt that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to an individual. See, for a general reference, GS Paulekuhn, Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database, J. Med. Chem., 2007, 50:6665 to 6672, SM Berge, Pharmaceutical Salts, J. Pharm. Sci., 1977, 66:1 to 19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmacologically acceptable salts are those that are pharmacologically effective and suitable for administration to patients without causing undue toxicity, irritation, or allergic response.

[0058] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfone Petition 870260020670, dated 05 / 03 / 2026, page 27 / 525 14 / 225 tos, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

[0059] In some embodiments, aticaprant is the crystalline form. Aticaprant crystal form III can be characterized by a number of techniques including, but not limited to, X-ray diffraction and differential scanning calorimetry. In some embodiments, aticaprant crystal form III is characterized by X-ray diffraction. In other embodiments, aticaprant crystal 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 other embodiments, the aticaprant crystal 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 still other embodiments, the aticaprant crystal 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 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2° and 28.8°. In still other embodiments, the aticaprant crystal 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 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 aticaprant crystal form III 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 from Table 1. Petition 870260020670, dated 05 / 03 / 2026, page 28 / 525 15 / 225 Table 1 Position (28) Table 1 Position (28) Table 1 Position (28) Table 1 Position (28) 4.1 18.6 26.23 33.0 8.2 19.4 26.4 33.2 9.0 19.7 27.1 33.6 9.7 20.1 28.4 33.9 10.7 20.3 28.6 34.4 12.0 20.6 28.8 35.4 12.3 21.4 20.0 36.0 13.5 22.2 30.2 36.4 15.1 24.1 30.5 37.0 16.4 24.4 31.2 38.2 16.& 25.0 31.8 38.5 17.6 25.2 32.2 39.5 18.0 25.7 32.5

[0060] In still other embodiments, the crystalline form III of aticaprant is characterized by the X-ray diffraction pattern peaks in Table 2. Table 2 Position (28) Table 2 Position (28) Table 2 Position (28) Table 2 Position (28) 4.1 15.1 20.1 26.3 8.2 16.4 20.3 28.4 9.0 17.6 21.4 28.8 97 18.0 24.1 30.0 12.0 19.4 25.0 13.5 19.7 25.7

[0061] In still other embodiments, the crystalline form III of aticaprant is characterized by the X-ray diffraction pattern peaks in Table 3. Petition 870260020670, dated 05 / 03 / 2026, page 29 / 525 16 / 225 Table 3 Table 3 Table 3 Table 3 Position (20) Position (20) Position (20) Position (20) 4.1 18.0 25.7 32.5 8.2 18.6 26.3 33.0 9.0 19.4 26.4 33.2 97 19.7 27.1 33.6 10.7 20.1 25.4 33.9 12.0 20.3 25.6 34.4 12.3 20.6 25.5 35.4 13.5 21.4 30.0 36.0 15.1 22.2 30.2 36.4 16.4 24.1 30.5 37.0 16.3 24.4 31.2 3&.2 17.6 25.0 31.S 3&.5 25.2 32.2 39.5

[0062] In additional embodiments, the crystalline form III of aticaprant is characterized by an X-ray powder diffraction pattern that corresponds to Figure 1.

[0063] The crystalline form III of aticaprant can also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram comprises a peak temperature (Tm) at about 121 °C. In other embodiments, the crystalline form III of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Figure 2. Pharmaceutical compositions

[0064] The invention also contemplates the pharmaceutical composition comprising aticaprant and one or more pharmaceutically acceptable excipients. As used herein, the term composition is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product, Petition 870260020670, dated 05 / 03 / 2026, page 30 / 525 17 / 225 resulting, directly or indirectly, from combinations of the specified ingredients in the specified quantities. The preferred pharmaceutical composition contains the crystalline form III of aticaprant as the active ingredient intimately mixed with a pharmaceutical vehicle according to conventional pharmaceutical composition techniques, the vehicle being able to assume a wide variety of forms depending on the desired mode of preparation for administration. Pharmaceutically acceptable vehicles are well known in the art. Descriptions of some of these pharmaceutically acceptable vehicles can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0065] The amount of aticaprant present in the compositions is from about 2 mg to about 60 mg. In some embodiments, the composition contains from about 2 mg to about 20 mg of aticaprant. In some embodiments, the composition contains about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19 or about 20 mg of aticaprant. In other embodiments, the composition contains approximately 5 to approximately 20 mg, approximately 10 to approximately 20 mg, approximately 15 to approximately 20 mg, approximately 1 to approximately 15 mg, approximately 2 to approximately 15 mg, approximately 5 to approximately 15 mg, approximately 10 to approximately 15 mg, approximately 1 to approximately 10 mg, approximately 2 to approximately 10 mg, or approximately 5 to approximately 10 mg of aticaprant. In still other embodiments, the effective amount of aticaprant is approximately 5 to approximately 15 mg.In other formulations, the amount of aticaprant is approximately 5 or 10 mg. In other formulations, the amount of aticaprant is approximately 5 mg. In still other formulations, the amount of aticaprant is... Petition 870260020670, dated 05 / 03 / 2026, page 31 / 525 18 / 225 approximately 10 mg. The composition contains approximately 0.1% to approximately 90% by weight of aticaprant. In some embodiments, the composition contains approximately 0.1, approximately 0.5, approximately 1.5, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, approximately 60, approximately 65, approximately 70, approximately 75, approximately 80, approximately 85, approximately 90% by weight, based on the weight of the composition, of aticaprant. In other embodiments, the composition contains approximately 0.1 to approximately 80, approximately 0.1 to approximately 70, approximately 0.1 to approximately 60, approximately 0.1 to approximately 50, approximately 0.1 to approximately 40, approximately 0.1 to approximately 30, approximately 0.1 to approximately 20, approximately 0.1 to approximately 10, approximately 0.1 to approximately 5, approximately 0.1 to approximately 1, approximately 0.1 to approximately 0.5, approximately 1 to approximately 90, approximately 1 to approximately 80, approximately 1 to approximately 70, approximately 1 to approximately 60, approximately 1 to approximately 50, approximately 1 to approximately 40, close to 1 to close to 30, close to 1 to close to 20, close to 1 to close to 10, close to 1 to close to 5, close to 5 to close to 90, close to 5 to close to 80, close to 5 to close to 70, close to 5 to close to 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about from 30, from about 30 to about 90, from about 30 to about 80, from about 30 to about 70, from about 30 to about 60, from about 30 to about 50, from about 30 to about 40, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, from about 40 to about 60, from about 40 to about 50, from about 50 to about 90, Petition 870260020670, dated 03 / 05 / 2026, page. 32 / 525 19 / 225 approximately 50 to approximately 80, approximately 50 to approximately 70, approximately 50 to approximately 60, approximately 60 to approximately 90, approximately 60 to approximately 80, approximately 60 to approximately 70, approximately 70 to approximately 90, approximately 70 to approximately 80 or approximately 80 to approximately 90% by weight, based on the weight of the composition, of aticaprant. In further embodiments, the composition contains approximately 5% by weight of aticaprant. In still other embodiments, the composition contains approximately 6% by weight of aticaprant. In still other embodiments, the composition contains approximately 7% by weight of aticaprant. In other embodiments, the composition contains approximately 8% by weight of aticaprant. In additional formulations, the composition contains approximately 9% by weight of aticaprant. In still other formulations, the composition contains approximately 10% by weight of aticaprant.The amount of aticaprant for administration according to the methods described herein can be determined by one skilled in the art and, except where otherwise specified, is defined based on the free base of aticaprant. That is, the amounts indicate the quantity of the aticaprant molecule administered, excluding, for example, solvent (as in solvates) or counterions (as in pharmaceutically acceptable salts).

[0066] In some embodiments, pharmaceutical compositions have a particular pharmacokinetic (PK) profile at a specific dose. In some embodiments, pharmaceutical compositions have a PK profile that is dose-proportional. In other embodiments, pharmaceutical compositions have a PK profile that comprises parameters, for example, exposure parameters such as Cmax or AUC, that are dose-proportional. In other embodiments, pharmaceutical compositions have a PK profile or PK parameter that is dose-proportional between about 1 mg and 60 mg of aticaprant, between about 2 mg and 60 mg of aticaprant, between about 2 mg and 40 mg of aticaprant, between about 2 mg and 20 mg of aticaprant, between about 2 mg and 15 mg of Petition 870260020670, dated 05 / 03 / 2026, p. 33 / 525 20 / 225 aticaprant, between about 2 mg to 10 mg of aticaprant and between about 5 mg to 10 mg of aticaprant.

[0067] Some embodiments include pharmaceutical compositions comprising aticaprant that are bioequivalent to any of the pharmaceutical compositions described herein. In some embodiments, the pharmaceutical composition comprises between about 2 mg and about 60 mg, between about 2 mg and about 20 mg of aticaprant, between about 5 mg and about 10 mg of aticaprant, or about 5 mg or about 10 mg of aticaprant, wherein the composition is bioequivalent to a pharmaceutical composition comprising aticaprant that, when administered to a human after fasting for at least 10 hours, produces a PK profile that includes one or more of: a mean Cmax between about 30 and 35 ng / mL, a mean AUCinfinite between about 300 and 320 ng / mL, and a mean tmax of about 1.5 hours (with dose normalization up to 10 mg).Bioequivalence can be demonstrated by any method known to one skilled in the art, for example, as described in Example 9 of the present invention, or as described in Chow, Bioavailability and Bioequivalence in Drug Development, Wiley Interdisciplinary Reviews, Computational Statistics, 6, 4 (2014): 304 to 312. doi:10.1002 / wics.1310.

[0100] In some embodiments, the pharmaceutical composition comprises between about 2 mg and about 20 mg of aticaprant, about 5 mg of aticaprant or about 10 mg of aticaprant, such that, when the pharmaceutical composition is compared with a reference composition, the 90% confidence interval of the geometric mean ratio of one or more PK parameters of the pharmaceutical composition and the reference composition is within the bioequivalence limits of 80% and 125%. In some embodiments, the reference composition is a composition comprising aticaprant which, when administered to a human after a period of fasting, Petition 870260020670, dated 05 / 03 / 2026, page 34 / 525 21 / 225 minus 10 hours produces a PK profile that includes one or more of the following: a mean Cmax between approximately 30 and 35 ng / mL, a mean AUCinfinite between approximately 300 and 320 ng / mL, and a mean tmax of approximately 1.5 hours (with dose normalization up to 10 mg). In some other modalities, the reference composition has a PK profile of any one of Treatment A, Treatment B, Treatment C, or Treatment D described in Table 69.

[0068] In some embodiments, the PK profile is based on administering the composition, containing about 2 mg to about 60 mg of aticaprant, to a human being after a fast of at least 10 hours. In some other embodiments, the PK profile is based on administering the composition, containing about 2 mg to about 60 mg of aticaprant, to a human being about 30 minutes after the start of a high-fat meal following a fast of at least 10 hours. As another example, the PK profile is based on administering the composition, containing about 2 mg to about 20 mg of aticaprant, to a human being after a fast of at least 10 hours.In some embodiments, the PK profile is based on the administration of a composition containing approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, or approximately 20 mg of aticaprant to a human being. In additional embodiments, the PK profile is based on the administration of a composition containing approximately 2 to approximately 19, approximately 2 to approximately 18, approximately 2 to approximately 16, approximately 2 to approximately 14, approximately 2 to approximately 12, approximately 2 to approximately 10, approximately 2 to approximately 8, approximately 2 to approximately 6, approximately 2 to approximately 4, approximately 4 to approximately 20, approximately 4 to approximately 18, approximately 4 to approximately 16, approximately 4 to approximately 14, approximately 4 to approximately 12, approximately 4 to approximately 10, approximately 4 to approximately 8, approximately 4 to approximately 6, approximately. Petition 870260020670, dated 05 / 03 / 2026, page 35 / 525 22 / 225 from 6 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18 or about 18 to about 20 mg of aticaprant in a human being.

[0069] In certain aspects, the PK profile is determined after a food fast of at least 10 hours. In some modalities, the food fast is at least about 1, about 2, about 4, about 5, about 10, about 12, about 15, about 18, about 20, about 22, 24, about 28 or about 32 hours.

[0070] For example, the PK profile may include a Cmax in the range between about 1 and about 100, about 5 and about 70, about 5 and about 65, about 5 and about 60, about 5 and about 55, about 5 and about 50, about 5 and about 45, about 10 and about 70, about 10 and about 65, about 10 and about 60, about 10 and about 55, about 10 and about 50, about 10 and about 45, about 13 and about 60, about 13 and about 55, about 13 and about 50, about 20 and about 70, about 20 and about 65 or about 20 and about 63 ng / mL (with dose normalization up to 10 mg). In some modalities, the PK profile includes a Cmax in the range between approximately 20 and approximately 45, approximately 22 and approximately 45, approximately 23 and approximately 45, or approximately 24 and approximately 44 ng / mL (with dose normalization up to 10 mg) when administered after a fasting period of at least 10 mg. Petition 870260020670, dated 05 / 03 / 2026, p. 36 / 525 23 / 225 minus 10 hours. In some modalities, the PK profile includes a Cmax in the range between approximately 25 and approximately 50, approximately 27 and approximately 38, approximately 25 and approximately 40, or approximately 28 and approximately 38 ng / mL (with dose normalization up to 10 mg) when administered approximately 30 minutes after the start of a high-fat meal following at least 10 hours of fasting.

[0071] In some modes, the PK profile includes an AUCinfinite in the range between approximately 50 and approximately 800, approximately 100 and approximately 500, approximately 100 and approximately 480, approximately 100 and approximately 450, approximately 100 and approximately 400, approximately 110 and approximately 500, approximately 110 and approximately 480, approximately 110 and approximately 450, approximately 110 and approximately 400, approximately 150 and approximately 700, approximately 200 and approximately 700, approximately 200 and approximately 650, approximately 250 and approximately 450, approximately 280 and approximately 420, approximately 290 and approximately 410, or approximately 210 and approximately 650 h*ng / mL (with dose normalization up to 10 mg). In some embodiments, the PK profile includes an infinite AUC in the range between approximately 200 and approximately 400, approximately 210 and approximately 400, approximately 210 and approximately 398, approximately 220 and approximately 400, or approximately 220 and approximately 398 h*ng / mL (with dose normalization up to 10 mg) when administered after a fasting period of at least 10 hours. In some modalities, the PK profile includes an AUC infinity in the range between approximately 300 and approximately 600, approximately 300 and 550, or approximately 320 and approximately 530 h*ng / mL (with dose normalization up to 10 mg) when administered approximately 30 minutes after the start of a high-fat meal following a fast of at least 10 hours.

[0072] In some modes, the PK profile includes an AUCultima in the range between about 50 and about 800, about 100 and about 500, approximately 100 and approximately 480, approximately 100 and approximately 450, approximately 100 and approximately 400, approximately 110 and approximately 500, approximately 110 and approximately 480, approximately 110 and approximately 450, approximately 110 and approximately Petition 870260020670, dated 05 / 03 / 2026, p. 37 / 525 24 / 225 400, approximately 150 and approximately 700, approximately 200 and approximately 700, approximately 200 and approximately 650, approximately 250 and approximately 450, approximately 280 and approximately 420, approximately 290 and approximately 410, or approximately 210 and approximately 650 h*ng / mL (with dose normalization up to 10 mg). In some embodiments, the PK profile includes an AUCultima in the range between approximately 300 and approximately 400 (with dose normalization up to 10 mg).

[0073] In some modalities, the PK profile includes a tmax in the range between about 0.5 and about 5, between about 1 and about 4.5, about 1 and about 4, about 1 and about 3, about 1 and about 2.5, or about 1 and about 2 hours. In some modalities, the PK profile includes a tmax ranging from about 1 to about 2.5, about 1 and about 2, or about 1 and about 3 hours when administered after a fast of at least 10 hours. In some modalities, the PK profile includes a tmax that is in the range between about 1 and about 4 hours when administered about 30 minutes after the start of a high-fat meal after a fast of at least 10 hours.

[0074] In some modes, the PK profile includes a t1 / 2 in the range between approximately 5 and approximately 60, approximately 5 and approximately 55, approximately 5 and approximately 50, approximately 5 and approximately 45, approximately 5 and approximately 40, approximately 9 and approximately 60, approximately 9 and approximately 55, approximately 9 and approximately 50, approximately 9 and approximately 45 or approximately 9 and approximately 40 hours.

[0075] In some modes, the PK profile includes an Az in the range between approximately 0.010 and approximately 0.080, approximately 0.010 and approximately 0.075, approximately 0.010 and approximately 0.070, approximately 0.015 and approximately 0.080, approximately 0.015 and approximately 0.075, approximately 0.015 and approximately 0.070, approximately 0.015 and approximately 0.065, approximately 0.015 and approximately 0.060, approximately 0.015 and approximately 0.055 or approximately 0.015 and approximately 0.050 l / hour.

[0076] In some other modes, the PK profile includes a Petition 870260020670, dated 05 / 03 / 2026, p. 38 / 525 25 / 225 CL / F in the range between about 10 and about 90, about 10 and about 85, about 10 and about 80, about 10 and about 75, about 10 and about 70, about 10 and about 60, about 10 and about 50, about 15 and about 90, about 15 and about 80, about 15 and about 70, about 15 and about 60, about 15 and about 50, about 20 and about 90, about 20 and about 80, about 20 and about 75, about 20 and about 70, about 20 and about 60 or about 20 and about 50 L / h.

[0077] In some other modes, the PK profile includes a Vd / F in the range between approximately 400 and approximately 6000, approximately 400 and approximately 5500, approximately 400 and approximately 5000, approximately 400 and approximately 4000, approximately 400 and approximately 3500, approximately 400 and approximately 3400, approximately 450 and approximately 3500, approximately 450 and approximately 3000, approximately 500 and approximately 3500, approximately 500 and approximately 3000, approximately 400 and approximately 2000, approximately 400 and approximately 1500, approximately 400 and approximately 1200, approximately 550 and approximately 3500, approximately 550 and approximately 3000, about 600 and about 3500, about 600 and about 3000, about 600 and about 2500 or about 450 and about 1200 L.

[0078] For example, the PK profile may include a mean Cmax between approximately 20 and 45 ng / mL when dose normalized to 10 mg. In some embodiments, the mean Cmax is approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, approximately 30, approximately 31, approximately 32, approximately 33, approximately 34, approximately 35, approximately 36, approximately 37, approximately 38, approximately 39, approximately 40, approximately 41, approximately 42, approximately 43, approximately 44, or approximately 55 ng / mL (with dose normalization to 10 mg). In other embodiments, the average Cmax is about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about Petition 870260020670, dated 05 / 03 / 2026, page 39 / 525 26 / 225 30, approximately 30 to approximately 45, approximately 30 to approximately 40, approximately 30 to approximately 35, approximately 35 to approximately 45, approximately 35 to approximately 40, or approximately 40 to approximately 45 ng / mL (with dose normalization up to 10 mg). In other modalities, the mean Cmax is between approximately 30 and 35 ng / mL, approximately 31 and 35 ng / mL, or approximately 31 and 34 ng / mL (with dose normalization up to 10 mg) when administered after a fasting period of at least 10 hours. In other modalities, the average Cmax is between approximately 35 and 40, approximately 36 and 39, or approximately 37 and 38 ng / mL (with dose normalization up to 10 mg) when administered approximately 30 minutes after the start of a high-fat meal following a fast of at least 10 hours.

[0079] The PK profile may also have an average AUCinfinite between approximately 250 and 450 h*ng / mL (with dose normalization up to 10 mg). In some modalities, the AUCinfinite is approximately 250, approximately 260, approximately 270, approximately 280, approximately 290, approximately 300, approximately 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, approximately 420, approximately 430, approximately 440 or approximately 450 h*ng / mL (with dose normalization up to 10 mg). In other embodiments, the average AUCinfinite is about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about of 400, about 300 to about from 390, about 300 to about 380, about 300 to about 370, about 300 to about 360, about 300 to about 350, about 300 to about 340, about 300 to about 330, about 300 to about 320, about 300 to about Petition 870260020670, dated 05 / 03 / 2026, page 40 / 525 27 / 225 310, approximately 325 to approximately 450, approximately 325 to approximately 425, approximately 325 to approximately 400, approximately 325 to approximately 375, approximately 325 to approximately 350, approximately 350 to approximately 450, approximately 350 to approximately 425, approximately 350 to approximately 400, approximately 350 to approximately 375, approximately 375 to approximately 450, approximately 375 to approximately 425, approximately 375 to approximately 400, approximately 400 to approximately 450, approximately 400 to approximately 425 or approximately 425 to approximately 450 h * ng / mL (with dose normalization up to 10 mg). In other modalities, the mean AUCinfinite is between approximately 300 and 320 h*ng / mL (with dose normalization up to 10 mg) when administered after a fast of at least 10 hours. In other modalities, the mean AUCinfinite is between approximately 320 and 530 h*ng / mL (with dose normalization up to 10 mg) when administered approximately 30 minutes after the start of a high-fat meal following a fast of at least 10 hours.

[0080] In other respects, the pharmaceutical composition has a PK profile comprising an average AUCultima between about 250 and 450 h*ng / mL (with dose normalization up to 10 mg). In some embodiments, the AUCultima is about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440 or about 450 h*ng / mL. In other embodiments, the average AUC is about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about 400, about 300 to about 390, about 300 to Petition 870260020670, dated 03 / 05 / 2026, page. 41 / 525 28 / 225 near 380, near 300 to near 370, near 300 to near 360, near 300 to near 350, near 300 to near 340, near 300 to near 330, near 300 to near 320, near 300 to near 310, near 325 to near 450, near 325 to near 425, from about 325 to about 400, from about 325 to about 375, from about 325 to about 350, from about 350 to about 450, from about 350 to about 425, from about 350 to about 400, from about 350 to about 375, approximately 375 to approximately 450, approximately 375 to approximately 425, approximately 375 to approximately 400, approximately 400 to approximately 450, approximately 400 to approximately 425, or approximately 425 to approximately 450 h*ng / mL (with dose normalization up to 10 mg). In other modalities, the PK profile has a mean AUCultima between approximately 280 and 310 h*ng / mL (with dose normalization up to 10 mg).

[0081] In still other aspects, the pharmaceutical composition has a PK profile that comprises an average tmax between approximately 1 to 4 hours. In some disciplines, the average tmax is approximately 1, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 1.7, approximately 1.8, approximately 1.9, approximately 2, approximately 2.1, approximately 2.2, approximately 2.3, approximately 2.4, approximately 2.5, approximately 2.6, approximately 2.7, approximately 2.8, approximately 2.9, approximately 3, approximately 3.1, approximately 3.2, approximately 3.3, approximately 3.4, approximately 3.5, approximately 3.6, approximately 3.7, approximately 3.8, approximately 3.9, or approximately 4 hours.In other embodiments, the average tmax is from about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 4, about 3 to about 3.5 or about 3.5 to about 4 hours. In other modes. Petition 870260020670, dated 05 / 03 / 2026, p. 42 / 525 29 / 225 des, the average tmax is about 1.5 hours.

[0082] In some embodiments, the pharmaceutical composition comprises a PK profile of Treatment A, Treatment B, Treatment C or Treatment D, as shown in Table 69.

[0083] In some embodiments, the pharmaceutical composition has a PK profile including a mean Cmax of about 30, about 31, about 32, about 33, about 34, or about 35 ng / mL when administered after fasting for at least 10 hours (with dose normalization up to 10 mg). In some embodiments, the pharmaceutical composition comprises a PK profile including a mean Cmax of about 31.2 ng / mL with a standard deviation of about 6.9 ng / mL (with dose normalization up to 10 mg). In some embodiments, the pharmaceutical composition comprises about 10 mg of aticaprant and has a PK profile including a mean Cmax of about 34.1 ng / mL with a standard deviation of about 10.0 ng / mL when administered after fasting for at least 10 hours. In some embodiments, the pharmaceutical composition comprises approximately 5 mg of aticaprant and has a PK profile including a mean Cmax of approximately 17.0 ng / mL with a standard deviation of approximately 4.48 ng / mL when administered after a fasting period of at least 10 hours.

[0084] In some embodiments, the pharmaceutical composition has a PK profile including a mean Cmax of about 36, about 37, about 38, about 39, or about 35 ng / mL when administered about 30 minutes after the start of a high-fat meal after at least 10 hours of fasting (with dose normalization up to 10 mg). In some embodiments, the pharmaceutical composition comprises about 10 mg of aticaprant and has a PK profile including a mean Cmax of about 37.7 ng / mL with a standard deviation of about 9.18 ng / mL when administered about 30 minutes after the start of a high-fat meal after at least 10 hours of fasting. Petition 870260020670, dated 05 / 03 / 2026, page 43 / 525 30 / 225 minus 10 hours.

[0085] In some embodiments, the pharmaceutical composition has a PK profile comprising a mean AUCinfinite of approximately 300, approximately 305, approximately 310, approximately 315 or approximately 320 h*ng / mL when administered after fasting for at least 10 hours (with dose normalization up to 10 mg).

[0086] In some embodiments, the pharmaceutical composition has a PK profile comprising an average AUCinfinite of approximately 400, approximately 420, approximately 425, approximately 430, approximately 440 or approximately 450 h*ng / mL when administered approximately 30 minutes after the start of a high-fat meal following a fasting period of at least 10 hours (with dose normalization up to 10 mg).

[0087] In some embodiments, the pharmaceutical composition has a PK profile comprising a mean tmax of about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9 or about 2.0 hours when administered after a fast of at least 10 hours. In some embodiments, the pharmaceutical composition has a PK profile comprising a mean tmax of about 1.5 hours when administered after a fast of at least 10 hours.

[0088] In some embodiments, the pharmaceutical composition has a PK profile comprising a mean tmax of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3.0 hours when administered about 30 minutes after the start of a high-fat meal after at least 10 hours of fasting. In some embodiments, the pharmaceutical composition has a PK profile comprising a mean tmax of about 2.75 hours when administered about 30 minutes after the start of a high-fat meal after at least 10 hours of fasting.

[0089] As mentioned, the compositions contain an excipient. Petition 870260020670, dated 05 / 03 / 2026, page 44 / 525 31 / 225 pharmaceutically acceptable filler, one of which may be a filler. In some embodiments, the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose, or a combination thereof. In other embodiments, the filler is microcrystalline cellulose. In other embodiments, the filler is lactose monohydrate. In still other embodiments, the filler is silicified microcrystalline cellulose. The composition comprises between about 10% and about 99.9% filler by weight, based on the weight of the composition.In some embodiments, the composition contains approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, approximately 60, approximately 65, approximately 70, approximately 75, approximately 80, approximately 81, approximately 82, approximately 83, approximately 84, approximately 85, approximately 86, approximately 87, approximately 88, approximately 89, approximately 90, approximately 91, approximately 92, approximately 93, approximately 94, approximately 95, approximately 96, approximately 97, approximately 98, approximately 99 or approximately 99.9% by weight, based on the weight of the composition, of a load.In other ways, the composition includes about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 99.9, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 99.9, about 30 to about 90, about 30 to about 80, close to close to 70, close to 30 to close to 60, close to 30 to close to 50, close to 30 to close to 40, close to 40 to close to 99.9, close to 40 to close to 90, close to 40 to close to 80, close to 40 to close to 70, close to 40 to close to 60, close to 40 to close to 50, close to 50 to close to 99.9, close to 50 to close to 90, close to 50 to close to 80, close to close to 70, close to 50 to close to 60, close to 60 to close to. Petition 870260020670, dated 05 / 03 / 2026, p. 45 / 525 32 / 225 99.9, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 99.9, about 70 to about 90, about 70 to about 80, about 80 to about 99.9, about 80 to about 90 or about 90 to about 99.9% by weight, based on the weight of the composition, of a load. In other embodiments, the composition comprises about 90% by weight, based on the weight of the composition, of the load. In other embodiments, the composition comprises about 88.5% by weight, based on the weight of the composition, of the load.

[0090] The ratio of aticaprant to load is between about 0.005 and about 9 by weight. In some modalities, the ratio between aticaprant and load is approximately 0.008 and approximately 0.8 by weight. In other modalities, the ratio between aticaprant and load is approximately 0.005 to approximately 8, approximately 0.005 to approximately 7, approximately 0.005 to approximately 6, approximately 0.005 to approximately 5, approximately 0.005 to approximately 4, approximately 0.005 to approximately 3, approximately 0.005 to approximately 2,near 0.005 to near 1, near 0.005 to near 0.5, near 0.005 to near 0.1, near 0.005 to near 0.05, near 0.005 to near 0.01, near 0.01 to near 9, near 0.01 to near 8, near 0.01 to near 7, near 0.01 to near 6, near 0.01 to near 5, near 0.01 to near 4, near 0.01 to near 3, near 0.01 to near 2, near 0.01 to near 1, near 0.01 to near 0.5, near 0.01 to near 0.1, near 0.01 to near 0.05, near 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3about 0.1 to about 2, about 0.1 to about 1, about 0.1 to, Petition 870260020670, dated 05 / 03 / 2026, p. 46 / 525 33 / 225 about 0.5, about 1 to about 9, about 1 to about 8, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 4, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 9, about 7 to about 8 or about 8 to about 9 by weight. In other embodiments, the ratio between aticaprant and load is about 0.056 by weight.

[0091] The composition may additionally comprise one or more of the following: a filler, a disintegrant, a flow agent, a lubricant, a solvent, a dyeing agent, a binder, buffers, preservatives, penetrating agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorants, antioxidants, emulsifying agents, isotonic agents, suspending agents and / or viscosity-increasing agents.

[0092] In some embodiments, the composition further comprises one or more disintegrants. Examples of disintegrants useful in compositions include, for example, croscarmellose sodium. The composition comprises between about 0.5% and about 50% by weight, based on the weight of the composition, of the disintegrant. In some embodiments, the composition comprises about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about Petition 870260020670, dated 05 / 03 / 2026, p. 47 / 525 34 / 225 40, approximately 45, or approximately 50% by weight, based on the weight of the composition of the disintegrator. In other modalities, the composition comprises approximately 0.5 to approximately 40%, approximately 0.5 to approximately 30%, approximately 0.5 to approximately 20%, approximately 0.5 to approximately 10%, approximately 0.5 to approximately 5%, approximately 0.5 to approximately 4%, approximately 0.5 to approximately 3%, approximately 0.5 to approximately 2%, approximately 0.5 to approximately 1%, approximately 5 to approximately 50%, approximately 5 to approximately 40%, approximately 5 to approximately 30%, approximately 5 to approximately 20%, approximately 5 to approximately 10%, approximately 10 to approximately 50%, approximately 10 to approximately 40%, approximately 10 to approximately 30%, approximately from 10 to about 20%, from about 20 to about 50%, from about 20 to about 40%, from about 20 to about 30%, from about 30 to about 50%, from about 30 to about 40% or from about 40 to about 50% by weight, based on the weight of the composition, of the disintegrator.In other embodiments, the composition comprises approximately 5% by weight, based on the weight of the composition, of the disintegrant. The ratio between aticaprant and disintegrant is between approximately 0.1 and 10 by weight. In some embodiments, the ratio between aticaprant and disintegrant is approximately 0.1, approximately 0.5, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10 by weight.In other embodiments, the ratio between aticaprant and disintegrant is from about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about from 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about. Petition 870260020670, dated 05 / 03 / 2026, page 48 / 525 35 / 225 5, near 1 to near 4, near 1 to near 3, near 1 to near 2, near 2 to near 10, near 2 to near 9, near 2 to near 8, near 2 to near 7, near 2 to near 6, near 2 to near 5, near 2 to near 4, near 2 to near 3, near 3 to near 10, near 3 to near 9, near 3 to near 8, near 3 to near 7, near 3 to near 6, near 3 to near 5, near 3 to near 4, near 4 to near 10, near 4 to near 9, near 4 to near 8, near 4 to near 7, near 4 to near 6, near 4 to near 5, near 5 to near 10, near to near 9, near 5 to near 8, near 5 to near 7, near 5 to near 6, near 6 to near 10, near 6 to near 9, near 6 to near 8, near 6 to near 7, near 7 to near 10, approximately 7 to approximately 9, approximately 7 to approximately 8, approximately 8 to approximately 10, approximately 8 to approximately 9, approximately 9 to approximately 10 by weight. In other embodiments, the ratio between aticaprant and disintegrant is approximately 5 by weight. In other embodiments, the ratio between aticaprant and disintegrant is approximately 1 by weight.

[0093] In other embodiments, the composition additionally comprises one or more of a flow agent. Examples of useful flow agents in compositions include, for example, anhydrous colloidal silica. The composition comprises between about 0.1% and about 10% of flow agent by weight, based on the weight of the composition. In some embodiments, the composition contains about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the weight of the composition, of the flow agent. In other embodiments, the composition contains approximately 0.1 to approximately 9, approximately 0.1 to approximately 8, approximately 0.1 to approximately 7, approximately 0.1 to approximately 6, approximately 0.1 to approximately 5, approximately 0.1 to approximately 4, approximately 0.1 to approximately 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to Petition 870260020670, dated 05 / 03 / 2026, p. 49 / 525 36 / 225 near 0.5, near 0.5 to near 10, near 0.5 to near 9, near 0.5 to near 8, near 0.5 to near 7, near 0.5 to near 6, near 0.5 to near 5, near 0.5 to near 4, near 0.5 to near 3, near 0.5 to near 2, near 0.5 to near 1, near 1 to near 10, near 1 to near 9, near 1 to near 8, near 1 to near 7, near 1 to near 6, near 1 to near 5, near 1 to near 4, near 1 to near 3, near 1 to near 2, near 2 to near 10, near 2 to near 9, near 2 to near 8, near 2 to near 7, near 2 to near 6, near 2 to near 5, near 2 to near 4, near 2 to near 3, near 3 to near 10, near 3 to near 9, near 3 to near 8, near 3 to near 7, near 3 to near 6, near 3 to near 5, near 3 to near 4, near 4 to near 10, near 4 to near 9, near 4 to near 8, near 4 to near 7,about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10% by weight, based on the weight of the composition, of the flow agent. In other embodiments, the composition contains about 1% by weight, based on the weight of the composition, of the flow agent. The ratio of aticaprant to flow agent is between 0.5 and 50 by weight. In some embodiments, the ratio of aticaprant to flow agent is approximately 0.5, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40,about 45 or about 50 by weight. In other embodiments, the ratio between aticaprant and flow agent is about 0.5 to about 50, about 0.5 to about 45, about, Petition 870260020670, dated 05 / 03 / 2026, p. 50 / 525 37 / 225 from 0.5 to about 40, about 0.5 to about 35, about 0.5 to about 30, about 0.5 to about 25, about 0.5 to about 20, about 0.5 to about 15, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 50, about 5 to near 45, near 5 to near 40, near 5 to near 35, near 5 to near 30, near 5 to near 25, near 5 to near 20, near 5 to near 15, near 5 to near 10, near 10 to near 50, near 10 to near 45, near 10 to near 40, near 10 to near 35, near 10 to near 30, near 10 to near 25, near 10 to near 20, near 10 to near 15, near 20 to near 50,approximately 20 to approximately 40, approximately 20 to approximately 30, approximately 30 to approximately 50, approximately 23 to approximately 40, approximately 40 to approximately 50, or approximately 45 to approximately 50 by weight. In other embodiments, the ratio between aticaprant and flow agent is approximately 5 by weight.

[0094] In additional embodiments, the composition further comprises one or more of a lubricant. Examples of lubricants useful in compositions include, for example, the lubricant being magnesium stearate. The composition comprises between about 0.05% and about 5% of lubricant by weight, based on the weight of the composition. In some embodiments, the composition comprises about 0.05, about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5% by weight, based on the weight of the composition, of lubricant. In other modalities, the composition comprises approximately 0.05 to approximately 4.5, approximately 0.05 to approximately 4, approximately 0.05 to approximately 3, approximately 0.05 to approximately 2, approximately 0.05 to approximately 1, Petition 870260020670, dated 05 / 03 / 2026, p. 51 / 525 38 / 225 about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5% by weight, based on the weight of the composition, of lubricant. In other embodiments, the composition comprises about 0.5% by weight, based on the weight of the composition, of lubricant. The ratio of aticaprant to lubricant is between about 1 and about 100 by weight.In some embodiments, the ratio of aticaprant to lubricant is about 1, about 5, 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 by weight. In other embodiments, the ratio of aticaprant to lubricant is about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about . 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, close to 1 to close to 50, close to 1 to close to 40, close to 1 to close to 30, close to 1 to close to 20, close to 1 to close to 10, close to 1 to close to 5, close to 5 to close to 100, close to 5 to close to 90, close to 5 to close to 80, close to 5 to close to 70, close to 5 to close to 60, close to 5 to close to 50, close to 5 to close to 40, close to 5 to close to 30, close to 5 to close to 20, close to 5 to close to Petition 870260020670, dated 03 / 05 / 2026, page. 52 / 525 39 / 225 10, close to 10 to close to 100, close to 10 to close to 90, close to 10 to close to 80, close to 10 to close to 70, close to 10 to close to 60, close to 10 to close to 50, close to 10 to close to 40, close to 10 to close to 30, close to 10 to close to 20, close to 20 to close to 100, close to 20 to close to 90, close to 20 to close to 80, close to 20 to close to 70, close to 20 to close to 60, close to 20 to close to 50, close to 20 to close to 40, close to 20 to close to 30, close to 30 to close to 100, close to 30 to close to 90, close to 30 to close to 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40, about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 100,approximately 60 to approximately 90, approximately 60 to approximately 80, approximately 60 to approximately 70, approximately 70 to approximately 100, approximately 70 to approximately 90, approximately 70 to approximately 80, approximately 80 to approximately 100, approximately 80 to approximately 90, or approximately 90 to approximately 100 by weight. In other embodiments, the ratio between aticaprant and lubricant is approximately 10 by weight.

[0095] In some respects, the composition comprises one or more of the following: a ratio of aticaprant to filler between 0.005 and 9 by weight; a ratio of aticaprant to disintegrant between 0.1 and 10 by weight; a ratio of aticaprant to flow agent between 0.5 and 50 by weight; and a ratio of aticaprant to lubricant between 1 and 100 by weight.

[0096] In other respects, the composition comprises one or more of the following: a ratio of aticaprant to filler of about 0.06 by weight; a ratio of aticaprant to disintegrant of about 1 by weight; a ratio of aticaprant to flow agent of about 5 by weight; and a ratio of aticaprant to lubricant of about 10 by weight. Petition 870260020670, dated 05 / 03 / 2026, page 53 / 525 40 / 225 weight.

[0097] In other respects, the composition comprises about 5% by weight of aticaprant, about 88.5% by weight of filler, about 5% by weight of disintegrant, about 1% by weight of flow agent and about 0.5% by weight of lubricant, based on the weight of the composition.

[0098] Preferably, the composition is formulated as a solid composition. In some embodiments, the solid composition is a tablet, capsule, or caplet. In other embodiments, the solid composition is a tablet, such as an oral tablet. In other embodiments, the solid composition is a capsule, such as an oral capsule. In still other embodiments, the solid composition is a capsule, such as an oral caplet. Optionally, the solid compositions are coated. For example, the coating is an enteric coating. In doing so, the coating provides a film coating on the solid composition. In some embodiments, the film coating comprises a powder coating. In other embodiments, the film coating comprises Opadry II Orange. In other embodiments, the powder coating is Opadry II Orange.

[0099] The tablet may comprise one or more layers. In some embodiments, the tablet comprises a core tablet and a film coating to provide a film-coated tablet. The ratio of the film coating to the core tablet is between about 0.03 and 10 by weight. In some embodiments, the ratio of the film coating to the core tablet is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 by weight, based on the weight of the composition. In other embodiments, the ratio of the film coating to the core tablet is about 0.03 to about 9, about 0.03 to about 8, about 0.03 to about 7, about 0.03 to about 6, about 0.03 to about 6, Petition 870260020670, dated 05 / 03 / 2026, p. 54 / 525 41 / 225 near 0.03 to near 5, near 0.03 to near 4, near 0.03 to near 3, near 0.03 to near 2, near 0.03 to near 1, near 0.03 to near 0.5, near 0.03 to near 0.1, near 0.05 to near 10, 0.05 to near 9, near 0.05 to near 8, near 0.05 to near 7, near 0.05 to near 6, near 0.05 to near 6, near 0.05 to near 5, near 0.05 to near 4, near 0.05 to near 3, near 0.05 to near 2, near 0.05 to near 1, near 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 10, 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0,5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 6, about 2 to about 5, about 2 to about 4, near 2 to near 3, near 3 to near 10, near 3 to near 9, near 3 to near 8, near 3 to near 7, near 3 to near 6, near 3 to near 6, near 3 to near 5, near 3 to near 4, near 4 to near 10, near 4 to near 9, near 4 to near 8, near 4 to near 7, near 4 to near 6, near 4 to near 5, near 5 to near 10,about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about, Petition 870260020670, dated 05 / 03 / 2026, p. 55 / 525 42 / 225 ca from 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9 or about 9 to about 10.

[00100] The nuclear tablet may contain one or more phases. In some embodiments, the nuclear tablet comprises a first phase, such as an intragranular phase. In other embodiments, the nuclear tablet comprises a second phase, such as an extragranular phase. In other embodiments, the nuclear tablet comprises both intragranular and extragranular phases.

[00101] The ratio between the intragranular phase and the extragranular phase in the nuclear tablet is between about 1.5 and about 3 by weight. In some embodiments, the ratio between the intragranular phase and the extragranular phase in the nuclear tablet is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3 by weight.In other embodiments, the ratio of the intragranular phase to the extragranular phase in the core tablet is about 1.5 to about 2.8, about 1.5 to about 2.5, about 1.5 to about 2.3, about 1.5 to about 2, about 1.5 to about 1.8, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.5, about 1.8 to about 2.3, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.5, about 2 to about 2.3, about 2 to about 2.1, about 2.1 to about 3, about 2.1 to about 2.8, about from 2.1 to about 2.5, about 2.1 to about 2.3, about 2.3 to about 3, about 2.3 to about 2.8, about 2.3 to about 2.5, about 2.5 to about 3, about 2.5 to about 2.8, and about 2.8 to about 3 by weight. In other embodiments, the ratio between the intragranular phase and the extragranular phase in the nuclear tablet is about 2.1 by weight. Petition 870260020670, dated 05 / 03 / 2026, page 56 / 525 43 / 225

[00102] Regarding the composition, the solid composition contains aticaprant and one or more pharmaceutically acceptable excipients. In some respects, the intragranular phase comprises an aticaprant, a filler, a disintegrant, and a flow agent. In other respects, the intragranular phase comprises a filler. In other respects, the intragranular phase comprises two fillers.

[00103] The intragranular phase comprises approximately 10 to approximately 120 mg of the load. In some embodiments, the intragranular phase comprises approximately 10, approximately 20, approximately 30, approximately 40, approximately 50, approximately 60, approximately 70, approximately 80, approximately 90, approximately 100, approximately 110, or approximately 120 mg of the load. In other embodiments, the intragranular phase comprises from about 10 to about 110, from about 10 to about 100, from about 10 to about 90, from about 10 to about 80, from about 10 to about 70, from about 10 to about 60, from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, from about 10 to about 20, from about 20 to about 120, from about 20 to about 110, from about 20 to about 100, from about 20 to about 90, from about 20 to about 80, from about 20 to about 70, from about 20 to about 60, from about 20 to about 50, from about 20 to about 40, from about 20 to about 30, from about 30 to about 120,from about 30 to about 110, from about 30 to about 100, from about 30 to about 90, from about 30 to about 80, from about 30 to about 70, from about 30 to about 60, from about 30 to about 50, from about 30 to about 40, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, from about 40 to about 60, from about 40 to about 50, from about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, of cer, Petition 870260020670, dated 03 / 05 / 2026, page. 57 / 525 44 / 225 ca from 50 to about 70, from about 50 to about 60, from about 60 to about 120, from about 60 to about 110, from about 60 to about 100, from about 60 to about 90, from about 60 to about 80, from about 60 to about 70, from about 70 to about 120, from about 70 to about 110, from about 70 to about 100, from about 70 to about 90, from about 70 to about 80, from about 80 to about 120, from about 80 to about 110, from about 80 to about 100, from about 80 to about 90, from about 90 to about 120, from about 90 to about 110, from about 90 to about 100, from about 100 to about 120, from about 100 to about 110, or from about 110 to about 120. In additional embodiments, the intragranular phase contains about 60 mg of filler. In still other embodiments, the intragranular phase contains about 30 mg of microcrystalline cellulose. In still other embodiments, the intragranular phase contains about 30 mg of lactose monohydrate.In other embodiments, the intragranular phase contains approximately 60 mg of microcrystalline cellulose. In other embodiments, the intragranular phase contains approximately 60 mg of lactose monohydrate.

[00104] The intragranular phase comprises an aticaprant-to-filler ratio of between about 0.008 and 0.8 by weight. In some embodiments, the intragranular phase contains an aticaprant-to-filler ratio of about 0.008, about 0.005, about 0.001, about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7 or about 0.8 by weight. In other embodiments, the intragranular phase comprises a ratio between aticaprant and filler of about 0.008 to about 0.7, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.6, about 0.008 to about 0.4, about 0.008 to about 0.2, about 0.008 to about 0.5, about 0.008 to about 0.3, about 0.008 to about 0.1, about 0.008 to Petition 870260020670, dated 05 / 03 / 2026, page 58 / 525 45 / 225 near 0.05, from near 0.008 to near 0.01, from near 0.01 to near 0.8, from near 0.01 to near 0.7, from 0.01 to near 0.6, from near 0.01 to near 0.5, from near 0.01 to near 0.4, from near 0.01 to near 0.5, from near 0.01 to near 0.4, from near 0.01 to near 0.3, from near 0.01 to near 0.2, from near 0.01 to near 0.1, from near 0.01 to near 0.05, from near 0.05 to near 0.8, from near 0.05 to near 0.9, from near 0.05 to about 0.8, from about 0.05 to about 0.7, from about 0.05 to about 0.6, from about 0.05 to about 0.6, from about 0.05 to about 0.5, from about 0.05 to about 0.4, from about 0.05 to about 0.3, from about 0.05 to about 0.2, from about 0.05 to about 0.1, from about 0.1 to about 0.8, from about 0.1 to about 0.7, from about 0.1 to about 0.6, from about 0.1 to about 0.5, from about 0.1 to about 0.4, from about 0.1 to about 0.3, from about 0.1 to about 0.2from about 0.2 to about 0.8, from about 0.2 to about 0.7, from about 0.2 to about 0.6, from about 0.2 to about 0.5, from about 0.2 to about 0.4, from about 0.2 to about 0.3, from about 0.3 to about 0.8, from about 0.3 to about 0.7, from about 0.3 to about 0.6, from about 0.3 to about 0.5, from about 0.3 to about 0.4, from about 0.4 to about 0.8, from about 0.4 to about 0.7, from about 0.4 to about 0.6, from about 0.4 to about 0.5, from about 0.5 to about 0.8, from about 0.5 to about 0.7, from about 0.5 to about 0.6, from about 0.6 to about 0.8, from about 0.6 to about 0.7, or from about 0.7 to about 0.8 by weight. In other embodiments, the intragranular phase comprises an aticaprant-to-filler ratio of about 0.08 by weight.

[00105] The intragranular phase may also contain a disintegrant. In some embodiments, the intragranular phase contains about 1 to about 10 mg of the disintegrant. In other embodiments, the intragranular phase contains about 1, about 1.5, about 2, about 2.5, about Petition 870260020670, dated 05 / 03 / 2026, p. 59 / 525 46 / 225 of 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 mg of the disintegrator. In additional modalities, the intragranular phase contains approximately 1 to approximately 9, approximately 1 to approximately 8, approximately 1 to approximately 7, approximately 1 to approximately 6, approximately 1 to approximately 5, approximately 1 to approximately 4, approximately 1 to approximately 3, approximately 1 to approximately 2, approximately 2 to approximately 10, approximately 2 to approximately 9, approximately 2 to approximately 8, approximately 2 to approximately 7, approximately 2 to approximately 6, approximately 2 to approximately 5, approximately 2 to approximately 4, approximately 2 to approximately 3, approximately 2.5 to approximately 10, approximately 2.5 to approximately 9, approximately 2.5 to approximately 8, approximately 2.5 to approximately 7, from about 2.5 to about 6, from about 2.5 to about 5, from about 2.5 to about 4, from about 2.5 to about 3, from about 3 to about 10,from about 3 to about 9, from about 3 to about 8, from about 3 to about 7, from about 3 to about 6, from about 3 to about 5, from about 3 to about 4, from about 4 to about 10, from about 4 to about 9, from about 4 to about 8, from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 10, from about 5 to about 9, from about 5 to about 8, from about 5 to about 7, from about 5 to about 6, from about 6 to about 10, from about 6 to about 9, from about 6 to about 8, from about 6 to about 7, from about 7 to about 10, from about 7 to about 9, from about 7 to about 8, from about 8 to about 10, from about 8 to about 9, or from about 0 to about 10. In still other embodiments, the intragranular phase contains about 2.5 mg of the disintegrant. In still other embodiments, the intragranular phase contains about 5 mg of the disintegrant. In other embodiments,The intragranular phase contains approximately 2.5 mg of croscarmellose sodium. In other embodiments, the intragranular phase contains approximately 5 mg of croscarmellose only. Petition 870260020670, dated 05 / 03 / 2026, page 60 / 525 47 / 225 tip.

[00106] The intragranular phase may additionally contain a flow agent. In some embodiments, the intragranular phase contains from about 0.1 to about 5 mg of a flow agent. In other embodiments, the intragranular phase contains about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg of a flow agent.In other embodiments, the intragranular phase contains from about 0.1 to about 4, from about 0.1 to about 3, from about 0.1 to about 2, from about 0.1 to about 1, from about 0.1 to about 0.5, from about 0.5 to about 5, from about 0.5 to about 4, from about 0.5 to about 3, from about 0.5 to about 2, from about 0.5 to about 1, from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, from about 2 to about 5, from about 2 to about 4, from about 2 to about 3, from about 3 to about 5, from about 3 to about 4 or from about 4 to approximately 5 mg of a flow agent. In still other embodiments, the intragranular phase contains approximately 0.5 mg of the flow agent. In still other embodiments, the intragranular phase contains approximately 1 mg of the flow agent. In other embodiments, the intragranular phase contains approximately 0.5 mg of anhydrous colloidal silica.In other formulations, the intragranular phase contains approximately 1 mg of anhydrous colloidal silica.

[00107] The intragranular phase has an aticaprant to disintegrant ratio of about 0.2 to 20 by weight; In some embodiments, the intragranular phase has an aticaprant to disintegrant ratio of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about Petition 870260020670, dated 05 / 03 / 2026, page 61 / 525 48 / 225 of 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19 or approximately 20 by weight. In other embodiments, the intragranular phase comprises a ratio between aticaprant and disintegrant of about 0.2 to about 18, about 0.2 to about 16, about 0.2 to about 14, about 0.2 to about 12, about 0.2 to about 10, about 0.2 to about 8, about 0.2 to about 6, about 0.2 to about 4, about 0.2 to about 3, about 0.2 to about 2, about 0.2 to about 1, about 0.2 to about 0.5, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14,near 1 to near 12, near 1 to near 10, near 1 to near 8, near 1 to near 6, near 1 to near 4, near 1 to near 3, near 1 to near 2, near 1 to near 1.5, near 2 to near 20, near 2 to near 18, near 2 to near 16, near 2 to near 14, near 2 to near 12, near 2 to near 10, near 2 to near 8, near 2 to near 6, near 2 to near 4, near 4 to near 20, near 4 to near 18, near 4 to near 16, near 4 to near 14, near 4 to near 12, near 4 to near 10, near 4 to near 6, near 4 to near 8, near 4 to near 6, near 5 to near 20, near 6 to near 18, near 6 to near 16, near 6 to near 14, near 6 to near 12, near 6 to near 10, near 6 to near 8, near 8 to near 20, near 8 to near 18, near 8 to near 16, near 8 to near 14, near 8 to near 12,about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about, Petition 870260020670, dated 05 / 03 / 2026, page 62 / 525 49 / 225 14, approximately 10 to approximately 12, approximately 12 to approximately 20, approximately 12 to approximately 18, approximately 12 to approximately 16, approximately 12 to approximately 14, approximately 14 to approximately 20, approximately 14 to approximately 18, approximately 14 to approximately 16, approximately 16 to approximately 20, approximately 16 to approximately 18 or approximately 18 to approximately 20 by weight. In other embodiments, the intragranular phase comprises a ratio between aticaprant and disintegrant of approximately 2 by weight.

[00108] The intragranular phase comprises an aticaprant to flow agent ratio of about 1 to 100 by weight. In some embodiments, the intragranular phase comprises an aticaprant to flow agent ratio of about 1, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 by weight. In other embodiments, the intragranular phase comprises an aticaprant to flow agent ratio of about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 15, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 80, about 40 to about 60 or about 60 to about 80 by weight. In other embodiments, the intragranular phase comprises a ratio of aticaprant to flow agent of 10 by weight.

[00109] The extragranular phase comprises one or more of a filler, a disintegrant, a flow agent, and a lubricant. In Petition 870260020670, dated 05 / 03 / 2026, page 63 / 525 50 / 225 In some embodiments, the extragranular phase comprises a filler. In other embodiments, the extragranular phase comprises a disintegrator. In other embodiments, the extragranular phase comprises a flow agent. In still other embodiments, the extragranular phase comprises a lubricant.

[00110] The extragranular phase may comprise a filler. In some embodiments, the extragranular phase contains a filler. In another embodiment, the extragranular phase contains about 10 to about 80 mg of a filler. In further embodiments, the extragranular phase contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, or about 80 mg of a filler. In still other embodiments, the extragranular phase contains approximately 10 to approximately 70, approximately 10 to approximately 60, approximately 10 to approximately 50, approximately 10 to approximately 40, approximately 10 to approximately 30, approximately 10 to approximately 20, approximately 10 to approximately 15, approximately 15 to approximately 80, approximately 15 to approximately 70, approximately 15 to approximately 60, approximately 15 to approximately 50, approximately 15 to approximately 40, approximately 15 to approximately 30, approximately 15 to approximately 20, approximately 20 to approximately 80, approximately 20 to approximately 70, approximately 20 to approximately 60, approximately 20 to approximately 50,about 20 to about 40, about 20 to about 30, about 25 to about 80, about 25 to about 70, about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 30, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 35 to about 80, about 35 to about 70, about 35 to about 60, about 35 to about 50, about 35 to about 40, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 40 to about 80, about 40 to about 70, about 45 to about 80, about 45 to, Petition 870260020670, dated 03 / 05 / 2026, page. 64 / 525 51 / 225 approximately 70, approximately 45 to approximately 60, approximately 45 to approximately 50, approximately 50 to approximately 80, approximately 50 to approximately 70, approximately 50 to approximately 60, approximately 50 to approximately 55, approximately 55 to approximately 80, approximately 55 to approximately 70, approximately 55 to approximately 60, approximately 60 to approximately 80, approximately 60 to approximately 70, approximately 65 to approximately 80, approximately 65 to approximately 80, approximately 70 to approximately 80 or approximately 75 to approximately 80 mg of a load. In still other embodiments, the extragranular phase contains approximately 28.5 mg of the load. In other embodiments, the extragranular phase contains approximately 28.5 mg of silicified microcrystalline cellulose. In other embodiments, the extragranular phase contains approximately 57 mg of the filler. In still other embodiments, the extragranular phase contains approximately 57 mg of silicified microcrystalline cellulose.

[00111] The extragranular phase may additionally contain a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In other embodiments, the extragranular phase contains from about 1 to about 10 mg of a disintegrant. In further embodiments, the extragranular phase contains about 1, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 7.5, about 8, about 9 or about 10 mg of a disintegrant.In still other embodiments, the extragranular phase contains about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about from 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about. Petition 870260020670, dated 05 / 03 / 2026, page 65 / 525 52 / 225 from 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about from 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 7.5 to about 10, about 7.5 to about 9, about 7.5 to about 8, about 8 to about 10, about 8 to about 9 or about 9 to about 10 mg of a disintegrant. In still other embodiments, the extragranular phase contains about 2.5 mg of a disintegrant.In other embodiments, the extragranular phase contains approximately 5 mg of a disintegrant. In other embodiments, the extragranular phase contains approximately 2.5 mg of croscarmellose sodium. In still other embodiments, the extragranular phase contains approximately 5 mg of croscarmellose sodium.

[00112] The extragranular phase comprises a feed-to-disintegrant ratio of between about 1 and 100 by weight. In some embodiments, the extragranular phase comprises a feed-to-disintegrant ratio of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 by weight. In other embodiments, the extragranular phase comprises a charge-to-disintegrant ratio of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 10 to about 80, about 10 to about Petition 870260020670, dated 05 / 03 / 2026, p. 66 / 525 53 / 225 60, approximately 10 to approximately 40, approximately 10 to approximately 20, approximately 10 to approximately 15, approximately 20 to approximately 100, approximately 20 to approximately 80, approximately 20 to approximately 60, approximately 20 to approximately 40, approximately 40 to approximately 100, approximately 40 to approximately 80, approximately 40 to approximately 60, approximately 60 to approximately 100, approximately 60 to approximately 80 or approximately 80 to approximately 100 by weight. In still other embodiments, the extragranular phase comprises a feed to disintegrant ratio of approximately 11.4.

[00113] The extragranular phase may additionally contain a flow agent. In some embodiments, the flow agent is anhydrous colloidal silica. In other embodiments, the extragranular phase contains from about 0.1 to about 5 mg of the flow agent. In other embodiments, the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 mg of a flow agent. In still other embodiments, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a flow agent.In still other embodiments, the extragranular phase contains approximately 0.5 mg of a flow agent. In other embodiments, the extragranular phase contains approximately 1 mg of a flow agent. In other embodiments, the extragranular phase contains approximately 0.5 mg of anhydrous colloidal silica. In still other embodiments, the extragranular phase contains approximately 1 mg of anhydrous colloidal silica.

[00114] The extragranular phase comprises a feedstock-to-flow ratio of approximately 5 to 500 by weight. In other modalities, Petition 870260020670, dated 05 / 03 / 2026, page 67 / 525 54 / 225 embodiments, the extragranular phase comprises a feeder-to-flow ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In other embodiments, the extragranular phase comprises a feeder-to-flow ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about to about from 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400 or about 400 to about 500 by weight. In still other embodiments, the extragranular phase comprises a feeder-to-flow ratio of about 57.

[00115] The extragranular phase may also contain a lubricant. In some embodiments, the lubricant is magnesium stearate. In other embodiments, the extragranular phase contains about 0.1 to about 5 mg of the lubricant. In other embodiments, the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4 or 5 mg of a lubricant. In still other embodiments, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about Petition 870260020670, dated 05 / 03 / 2026, p. 68 / 525 55 / 225 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a lubricant. In still other embodiments, the extragranular phase contains about 0.5 mg of a lubricant. In other embodiments, the extragranular phase contains about 1 mg of a lubricant. In other embodiments, the extragranular phase contains about 0.5 mg of magnesium stearate. In still other formulations, the extragranular phase contains approximately 1 mg of magnesium stearate.

[00116] The extragranular phase comprises a load-to-lubricant ratio of between approximately 5 and 500 by weight. In other embodiments, the extragranular phase comprises a feed-to-lubricant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In other embodiments, the extragranular phase comprises a feed-to-lubricant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about to about from 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about of of 300, about 100 to Petition 870260020670, dated 05 / 03 / 2026, p. 69 / 525 56 / 225 approximately 200, approximately 200 to approximately 500, approximately 200 to approximately 400, approximately 200 to approximately 300, approximately 300 to approximately 500, approximately 300 to approximately 400 or approximately 400 to approximately 500 by weight. In still other embodiments, the extragranular phase comprises a load-to-lubricant ratio of approximately 57.

[00117] In some embodiments, the intragranular phase comprises one or more of the following: an aticaprant-to-feed ratio of between about 0.008 and 0.8 by weight; an aticaprant-to-disintegrant ratio of between about 0.2 and 20 by weight; and an aticaprant-to-flow ratio of between about 1 and 100 by weight.

[00118] In some embodiments, the extragranular phase comprises one or more of the following: a feed-to-disintegrant ratio of about 1 to 100 by weight; a feed-to-flow ratio of about 5 to 500 by weight; and a feed-to-lubricant ratio of about 5 to 500 by weight. In other embodiments, the extragranular phase comprises a feed-to-disintegrant ratio of about 11.4 by weight. In other embodiments, the extragranular phase comprises a feed-to-flow ratio of about 57 by weight. In still other embodiments, the extragranular phase comprises a feed-to-lubricant ratio of about 57 by weight.

[00119] In other respects, the nuclear tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00120] The oral tablet may have a weight suitable for administration by one patient. In some embodiments, the oral tablet has a core tablet of about 10 to about 1000 mg. In other embodiments, the core tablet is about 10, about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about Petition 870260020670, dated 05 / 03 / 2026, p. 70 / 525 57 / 225 of 900 or about 1000 mg. In other forms, the nuclear tablet is approximately 10 to approximately 900, approximately 10 to approximately 800, approximately 10 to approximately 700, approximately 10 to approximately 600, approximately 10 to approximately 500, approximately 10 to approximately 400, approximately 10 to approximately 300, approximately 10 to approximately 200, approximately 10 to approximately 100, approximately 10 to approximately 50, approximately 25 to approximately 1000, approximately 25 to approximately 900, approximately 25 to approximately 800, approximately 25 to approximately 700, approximately 25 to approximately 600, approximately 25 to approximately 500, approximately 25 to approximately 400, approximately 25 to approximately 300, approximately 25 to approximately 200, approximately 25 to approximately 100, approximately 25 to approximately 75, approximately 50 to approximately 1000, approximately 50 to approximately 900, approximately 50 to approximately 800, approximately 50 to approximately 700, approximately 50 to approximately 600, approximately 50 to approximately 500, approximately 50 to approximately 400, approximately 50 to approximately 300, approximately 50 to approximately 200, approximately 50 to approximately 100, approximately 100 to approximately 1000,approximately 100 to approximately 900, approximately 100 to approximately 800, approximately 100 to approximately 700, approximately 100 to approximately 600, approximately 100 to approximately 500, approximately 100 to approximately 400, approximately 100 to approximately 300, approximately 100 to approximately 200, approximately 200 to approximately 1000, approximately 200 to approximately 900, approximately 200 to approximately 800, approximately 200 to approximately 700, approximately 200 to approximately 600, approximately 200 to approximately 500, approximately 200 to approximately 400, approximately 200 to approximately 300, approximately 500 to approximately 1000, approximately 500 to about 800, about 500 to about 600, about 800 to about 1000 or about 800 to about 900 mg. In other forms, the nuclear tablet is about 100 mg. In other ways, the oral tablet comprises a nuclear tablet of about 200 mg.

[00121] In some aspects, the nuclear tablet contains a disintegrator. For example, the nuclear tablet contains about 5 to about 100 mg of a disintegrator. In some embodiments, the nuclear tablet contains about 5, about 10, about 20, about Petition 870260020670, dated 05 / 03 / 2026, page 71 / 525 58 / 225 about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 mg of a disintegrator. In other embodiments, the core tablet contains about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80 or about 80 to about 100 mg of a disintegrant. In other embodiments, the nuclear tablet contains about 5 mg of the disintegrant. In still other embodiments, the nuclear tablet contains about 10 mg of the disintegrant.

[00122] In other respects, the nuclear tablet contains a flow agent. For example, the nuclear tablet contains from about 1 to about 100 mg of a flow agent. In some embodiments, the nuclear tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 mg of a flow agent.In other forms, the nuclear tablet contains approximately 1 to approximately 100, approximately 1 to approximately 80, approximately 1 to approximately 60, approximately 1 to approximately 40, approximately 1 to approximately 20, approximately 1 to approximately 10, approximately 1 to approximately 5, approximately 2 to approximately 100, approximately 2 to approximately 80, approximately 2 to approximately 60, approximately 2 to approximately 40, approximately 2 to approximately 20, approximately 2 to approximately 10, approximately 2 to approximately 5, approximately 5 to approximately 80, approximately 5 to approximately 60, approximately 5 to approximately 40, approximately 5 to approximately 20, approximately 5 to approximately 15, approximately 5 to approximately 10, approximately 10 to approximately 100, approximately from 10 to about 80, about 10 to about 60. Petition 870260020670, dated 03 / 05 / 2026, page. 72 / 525 59 / 225 approximately 10 to approximately 40, approximately 10 to approximately 20, approximately 20 to approximately 100, approximately 20 to approximately 80, approximately 20 to approximately 60, approximately 20 to approximately 40, approximately 40 to approximately 100, approximately 40 to approximately 80, approximately 40 to approximately 60, approximately 60 to approximately 100, approximately 60 to approximately 80, or approximately 80 to approximately 100 mg of a flow agent. In other embodiments, the nuclear tablet contains approximately 1 mg of the flow agent. In still other embodiments, the nuclear tablet contains approximately 2 mg of the flow agent.

[00123] In other respects, the nuclear tablet contains a lubricant. For example, the nuclear tablet contains from about 0.5 to about 100 mg of a lubricant. In some embodiments, the nuclear tablet contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 mg of a lubricant.In other forms, the nuclear tablet contains approximately 0.5 to approximately 80, approximately 0.5 to approximately 60, approximately 0.5 to approximately 40, approximately 0.5 to approximately 20, approximately 0.5 to approximately 10, approximately 0.5 to approximately 5, approximately 0.5 to approximately 1, approximately 1 to approximately 100, approximately 1 to approximately 80, approximately 1 to approximately 60, approximately 1 to approximately 40, approximately 1 to approximately 20, approximately 1 to approximately 10, approximately 1 to approximately 5, approximately 2 to approximately 100, approximately 2 to approximately 80, approximately 2 to approximately 60, approximately 2 to approximately 40, approximately 2 to approximately 20, approximately 2 to approximately 10, approximately from 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about. 40, about 10 to about 20, about 20 to about 100, about about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about Petition 870260020670, dated 05 / 03 / 2026, page 73 / 525 60 / 225 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a lubricant. In other embodiments, the nuclear tablet contains about 0.5 mg of the lubricant. In still other embodiments, the nuclear tablet contains about 1 mg of the lubricant.

[00124] In other respects, the nuclear tablet contains a load. For example, the nuclear tablet contains from about 1 to about 200 mg of a load. In some embodiments, the nuclear tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190 or about 200 mg of a load. In other embodiments, the core tablet contains about 1 to about 180, about 1 to about 160, about 1 to about 140, about 1 to about 120, 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about about 10, about 1 to about 5, about 2 to about 200, about 2 to about 180, about 2 to about 160, about 2 to about 140,near 2 to near 120, near 2 to near 100, near 2 to near 80, near 2 to near 60, near 2 to near 40, near 2 to near 20, near 2 to near 10, near 2 to near 5, near 5 to near 200, near 5 to near 180, near 5 to near 160, near 5 to near 140, near 5 to near 120, near 5 to near 100, near 5 to near 80, near 5 to near 60, near 5 to near 40, near 5 to near 20, near 5 to near 15, near 5 to near 10, near 10 to near 200, near 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about, Petition 870260020670, dated 03 / 05 / 2026, page. 74 / 525 61 / 225 of 80, about 10 to about 60, about 10 to about 40, about to about 20, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 200, about to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about to about 80, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 to about 120, about 80 to about 100 mg, about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about from 140 to about 200, about 140 to about 180, about 140 to about 160, about 160 to about 200, about 160 to about 180 or about 180 to about 200 mg of a load. In other embodiments, the nuclear tablet contains about 88.5 mg of charge. In other forms, the nuclear tablet contains about 177 mg of charge.

[00125] In some preferred embodiments, the oral tablet comprises a core tablet of approximately 100 mg containing approximately 5 mg of aticaprant, approximately 5 mg of disintegrant, approximately 88.5 mg of filler, approximately 1 mg of flow agent and approximately 0.5 mg of lubricant. Petition 870260020670, dated 05 / 03 / 2026, page 75 / 525 62 / 225

[00126] In other preferred embodiments, an oral tablet comprising a core tablet of about 200 mg, wherein the core tablet comprises about 10 mg of aticaprant, about 10 mg of disintegrant, about 177 mg of filler, about 2 mg of flow agent and about 1 mg of lubricant.

[00127] As mentioned above, the nuclear tablet may be coated with a film coating. In some embodiments, the oral tablet comprises approximately 3 mg of film coating. In other embodiments, the oral tablet comprises approximately 6 mg of film coating.

[00128] In some aspects, the film-coated oral tablet comprises about 80 to about 99.9% by weight of the core tablet and about 0.1 to about 20% by weight, based on the weight of the film-coated oral tablet, of the core tablet. In some embodiments, the film-coated oral tablet comprises about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99 or 99.9% by weight, based on the weight of the film-coated oral tablet.In other embodiments, the film-coated oral tablet comprises approximately 80 to approximately 99, approximately 80 to approximately 96, approximately 80 to approximately 94, approximately 80 to approximately 92, approximately 80 to approximately 90, approximately 80 to approximately 88, approximately 80 to approximately 86, approximately 80 to approximately 84, approximately 80 to approximately 82, approximately 82 to approximately 99, approximately 82 to approximately 96, approximately 82 to approximately 94, approximately 82 to approximately 92, approximately 82 to approximately 90, approximately 82 to approximately 88, approximately 82 to approximately 86, approximately 82 to approximately 84, approximately 84 to approximately 99, approximately 84 to approximately 99, approximately 84 to about 96, about 84 to about 94, about 84 to about 92, about 84 to. Petition 870260020670, dated 05 / 03 / 2026, page 76 / 525 63 / 225 near 90, near 84 to near 88, near 84 to near 86, near 86 to near 99, near 86 to near 96, near 86 to near 94, near 86 to near 92, near 86 to near 90, near 86 to near 88, near 88 to near 99, near 88 to near 96, near 88 to near 94, near 88 to near 92, near 88 to near 90, near 90 to near 99, near 90 to near 96, near 90 to near 94, near 90 to near 92, near 92 to near 99, near 92 to near 96, near 92 about 94, about 94 to about 99, about 94 to about 96, about 96 to about 99, or about 98 to about 99% by weight, based on the weight of the film-coated oral tablet, the nuclear tablet. In other embodiments, the film-coated oral tablet comprises about 97% nuclear tablet by weight, based on the weight of the film-coated oral tablet.In still other embodiments, the film-coated oral tablet comprises from about 0.1 to about 20% by weight, based on the weight of the film-coated oral tablet, of film coating. In still other embodiments, the film-coated oral tablet comprises from about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19 or about 20% by weight, based on the weight of the film-coated oral tablet, of film coating.In other embodiments, the film-coated oral tablet comprises approximately 0.1 to approximately 18, approximately 0.1 to approximately 16, approximately 0.1 to approximately 14, approximately 0.1 to approximately 12, approximately 0.1 to approximately 10, approximately 0.1 to approximately 8, approximately 0.1 to approximately 6, approximately 0.1 to approximately 4, approximately 0.1 to approximately 2, approximately 0.1 to approximately 1, approximately 0.5 to approximately 20, approximately 0.5 to approximately 18, approximately 0.5 to approximately 16, approximately 0.5 to approximately 14. Petition 870260020670, dated 05 / 03 / 2026, page 77 / 525 64 / 225 near 0.5 to near 12, near 0.5 to near 10, near 0.5 to near 8, near 0.5 to near 6, near 0.5 to near 4, near 0.5 to near 2, near 1 to near 20, near 1 to near 18, near 1 to near 16, near 1 to near 14, near 1 to near 12, near 1 to near 10, near 1 to near 8, near 1 to near 6, near 1 to near 4, near 1 to near 2, near 2 to near 20, near 2 to near 18, near 2 to near 16, near 2 to near 14, near 2 to near 12, near 2 about 10, about 2 to about 8, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 12, about 4 to about 10, about 4 to about 8, about 4 to about 6, about 6 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12,about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18,m about 14 to about 16, about from 16 to about 20, about 16 to about 18, or about 18 to about 20% by weight, based on the weight of the film-coated oral tablet, of the film coating. In other embodiments, the film-coated oral tablet comprises about 3% by weight, based on the weight of the film-coated oral tablet, of the film coating. In still other embodiments,The film-coated oral tablet comprises approximately 97% tablet core by weight and approximately 3% film coating by weight, based on, Petition 870260020670, dated 05 / 03 / 2026, page 78 / 525 65 / 225 by weight of the film-coated oral tablet.

[00129] In some embodiments, the invention provides oral tablets comprising about 5 mg of aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg of microcrystalline cellulose, about 30 mg of lactose monohydrate, about 2.5 mg of croscarmellose sodium and about 0.5 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises about 28.5 mg of silicified microcrystalline cellulose, about 2.5 mg of croscarmellose sodium, about 0.5 mg of anhydrous colloidal silica and about 0.5 mg of magnesium stearate.

[00130] In other embodiments, the invention provides oral tablets comprising about 10 mg of aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium and about 1 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silica and about 1 mg of magnesium stearate.

[00131] Solid compositions may also have a desirable dissolution profile that provides the desired release of aticaprant. In some embodiments, the solid composition contains about 2 mg and 20 mg of aticaprant and has a dissolution profile comprising a Q value between about 60% and 90% in 45 minutes, under the following dissolution operating conditions: (i) apparatus: Paddle (USP type 2, Ph. Eur., JP), (ii) dissolution medium: 0.01 M hydrochloric acid, (iii) volume: Petition 870260020670, dated 05 / 03 / 2026, p. 79 / 525 66 / 225 900 ml, (iv) temperature: 37 ± 0.5 °C, (v) rotation speed: 50 rpm and (vi) analytical finish: UHPLC with UV detection at 247 nm. In some embodiments, the Q value is about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, near 73, near 74, near 75, near 75, near 76, near 77, near 78, near 79, near 80, near 81, near 82, near 83, near 84, near 85, near 86, near 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94 or about 95% in 45 minutes. In other modes, the Q value is about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85 or about 85 to about 90% in 45 minutes. In other embodiments, the Q value is between about 70% and 80% at 45 minutes. In other respects, the Q value is about 75% in 45 minutes.

[00132] Advantageously, aticaprant can be administered once daily, or the total daily dosage can be administered in divided doses two, three, or four times a day. In some embodiments, the composition containing aticaprant is administered once daily. In other embodiments, the oral tablet containing aticaprant is administered once daily. In other embodiments, the solid pharmaceutical composition containing aticaprant is administered once daily.

[00133] In some embodiments, the patient had an inadequate response to other antidepressant therapy before treatment with aticaprant. Thus, in a specific embodiment, the invention is Petition 870260020670, dated 05 / 03 / 2026, page 80 / 525 67 / 225 refers to aticaprant, for use as described herein, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. In another specific embodiment, the invention also relates to the use of aticaprant in the manufacture of a medicament, as described herein, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. In a further specific embodiment, the invention further relates to a pharmaceutical packaging or product, as described herein, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. Such antidepressant therapy may, in particular, be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[00134] As described herein, aticaprant can be used as adjunctive treatment or, in other words, in conjunction with, as a complement to, or in combination with one or more antidepressants, for example, the patient may already be, or may also be administered with, one or more antidepressants. Thus, in a further specific embodiment, the invention relates to aticaprant, for use as described herein, comprising the administration of aticaprant as adjunctive treatment with an effective amount of one or more antidepressants. In a further specific embodiment, the invention relates to aticaprant, for use as described herein, comprising the administration of aticaprant in conjunction with an effective amount of one or more antidepressants. In a further specific embodiment, the invention relates to aticaprant, for use as described herein, comprising the administration of aticaprant in combination with an effective amount of one or more antidepressants.In a further specific embodiment, the invention also relates to the use. Petition 870260020670, dated 05 / 03 / 2026, p. 81 / 525 68 / 225 of aticaprant in the manufacture of a medicament, as described herein, wherein the treatment comprises administering an effective amount of aticaprant as adjunctive therapy with an effective amount of one or more antidepressants. In a further specific embodiment, the invention also relates to the use of aticaprant, as described herein, wherein the treatment comprises administering an effective amount of aticaprant in conjunction with an effective amount of one or more antidepressants. In a further specific embodiment, the invention also relates to the use of aticaprant, as described herein, wherein the treatment comprises administering an effective amount of aticaprant in combination with an effective amount of one or more antidepressants.In a further specific embodiment, the invention also relates to a pharmaceutical packaging or product, as described herein, wherein the treatment instructions direct the administration of an effective amount of aticaprant as adjunctive treatment with an effective amount of one or more antidepressants. In a further specific embodiment, the invention also relates to a pharmaceutical packaging or product as described herein, wherein the treatment instructions direct the administration of an effective amount of aticaprant in conjunction with an effective amount of one or more antidepressants. In a further specific embodiment, the invention also relates to a pharmaceutical packaging or product as described herein, wherein the treatment instructions direct the administration of an effective amount of aticaprant in combination with an effective amount of one or more antidepressants.One or more such antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), or a combination thereof. Petition 870260020670, dated 05 / 03 / 2026, page 82 / 525 69 / 225

[00135] As already described, the invention relates to aticaprant for use as described herein. In one specific embodiment, aticaprant is S-aticaprant. In a further embodiment of the invention, aticaprant, in particular S-aticaprant, for use as described herein, is to be administered in an amount of about 2 to about 35 mg, more particularly, about 10 mg. In yet another embodiment, aticaprant, in particular S-aticaprant, for use as described herein, is administered orally. Furthermore, in a further specific embodiment, the invention relates to aticaprant, in particular S-aticaprant, for use as described herein, administered once daily. The invention also relates to the use of aticaprant in the manufacture of a medicament, as described herein. In one specific embodiment, aticaprant is S-aticaprant.In a further embodiment of use, as described herein, approximately 2 to approximately 35 mg of aticaprant should be administered, more particularly, approximately 10 mg. In yet another embodiment of use, aticaprant should be administered orally. Furthermore, in a specific additional embodiment of the use of aticaprant, in particular S-aticaprant, it should be administered once daily. In a specific additional embodiment, the invention further relates to a pharmaceutical package or product, as described herein, wherein the aticaprant is, in particular, S-aticaprant. In a further embodiment of the pharmaceutical package or product as described herein, the treatment instructions direct the administration of approximately 2 to approximately 35 mg of aticaprant, more particularly, approximately 10 mg.In yet another embodiment of the pharmaceutical packaging or product, as described herein, the treatment instructions referring to aticaprant, in particular S-aticaprant, are for oral administration. Furthermore, in a specific additional embodiment of the pharmaceutical packaging or product, as described herein, the treatment instructions refer to... Petition 870260020670, dated 05 / 03 / 2026, page 83 / 525 70 / 225 aticaprant, in particular S-aticaprant, is for once-daily administration.

[00136] Advantageously, the administration of aticaprant does not result in weight gain during treatment, including clinically relevant weight gain. Thus, in a further specific embodiment, the invention relates to aticaprant, for use as described herein, wherein the patient does not experience weight gain during treatment with aticaprant. In a further specific embodiment, the invention relates to a use, as defined herein, wherein the patient does not experience weight gain during treatment with aticaprant. In a further specific embodiment, the invention further relates to a pharmaceutical packaging or product, as described herein, wherein the patient does not experience weight gain during treatment with aticaprant. The patient's body weight can, in particular, be assessed at the time of initial administration of aticaprant.

[00137] It was also unexpectedly observed that, based on the assessment at the time of initial administration, the patient does not experience a decrease in sexual function during treatment with aticaprant. Thus, in a further specific embodiment, the invention relates to aticaprant, for use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with aticaprant. In a further specific embodiment, the invention relates to a use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with aticaprant. In a further specific embodiment, the invention relates to a pharmaceutical packaging or product, as described herein, wherein the patient does not experience a decrease in sexual function during treatment with aticaprant. This term sexual function includes sexual drive, sexual arousal, vaginal lubrication, Petition 870260020670, dated 05 / 03 / 2026, page 84 / 525 71 / 225 erection, orgasm attainment, or orgasm satisfaction. Sexual satisfaction can be assessed by methods known to those skilled in the art, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[00138] As already described, the patient has anhedonia. In some respects, the anhedonia is moderate. In other respects, the anhedonia is severe. Anhedonia can be measured using an anhedonia scale, such as the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in a specific embodiment, the invention relates to aticaprant, for use as described herein, wherein the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on an anhedonia scale after 6 weeks of treatment with aticaprant, and 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 an anhedonia scale. In a further specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS).Thus, in a specific embodiment, the invention relates to the use as described herein, wherein the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on an anhedonia scale after 6 weeks of treatment with aticaprant, and 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 an anhedonia scale. In a further specific embodiment, the invention relates to the pharmaceutical packaging or product, as described herein, wherein the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on an anhedonia scale. Petition 870260020670, dated 05 / 03 / 2026, page 85 / 525 72 / 225 baseline in the total score on an anhedonia scale after 6 weeks of treatment with aticaprant, and more specifically, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on an anhedonia scale. In a specific additional modality, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Treatment methods

[00139] In one aspect of the present invention, methods are provided for treating patients with a more severe type of depression, namely major depressive disorder, using the compounds, compositions, for example, tablets and solid compositions, for example, oral tablets, described herein. The patient may also be suffering from anhedonia. As isolated MDD is difficult to treat, patients with anhedonia are even more problematic, since their ability to measure pleasure is impaired. Thus, such patients often receive inadequate treatment due to ineffective medications, repeated and unnecessary medical consultations, lack of patient adherence or general patient frustration, among others. Furthermore, antidepressants are known to have a variety of side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia and cognitive impairment, among others.Therefore, patients can choose to avoid or stop taking antidepressants to avoid or prevent any side effects.

[00140] The methods described here are effective in managing the patient's depression and anhedonia with the use of aticaprant. Ideally, the methods successfully allow the patient to manage their depression while simultaneously reducing anhedonia. In particular modalities, patients treated according to the methods Petition 870260020670, dated 05 / 03 / 2026, page 86 / 525 73 / 225 all described have moderate to severe anhedonia. The term anhedonia, as used herein, refers to the lack or diminished ability to experience pleasure in everyday activities. The term anhedonia includes loss of pleasure in sensory experiences (e.g., touch, taste, smell) as well as in social interactions. In some modalities, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia also describes deficits in one or more components of reward-related behavior, also known as the pleasure cycle, such as wanting, liking, and learning. The pleasure cycle can be divided into three phases: the appetitive phase (dominated by wanting), the consummatory phase (dominated by liking), and the satiety phase (dominated by learning).The appetitive phase is characterized by the initial energy expenditure to achieve a reward; the consummatory phase is the pleasure of the reward; and the satiety phase is characterized by an integration of learning and feedback.

[00141] To assess a potential effect on anhedonia, an anhedonia scale can be used. For example, the Snaith-Hamilton Pleasure Scale (SHAPS) is a validated scale for measuring anhedonia. SHAPS is a complete individual scale where individuals rate whether or not they experience pleasure in performing a list of activities or experiences. SHAPS is a 14-item self-report instrument developed for assessing hedonic capacity. Individuals rate whether they experience pleasure in performing a list of activities or experiences. Individuals can rate responses from 1 to 4, where 1 indicates Strongly Agree, 2 indicates Agree, 3 indicates Disagree, and 4 indicates Strongly Disagree. The individual's item responses are summed to provide a total score ranging from 14 to 56. A higher total SHAPS score indicates higher levels of anhedonia. Petition 870260020670, dated 05 / 03 / 2026, page 87 / 525 74 / 225 current. Medical / clinical judgment can be used to assess anhedonia separately or in conjunction with an anhedonia scale.

[00142] In some modalities, the patient has moderate anhedonia. In some modalities, the patient has severe anhedonia. An assessment of moderate or severe anhedonia is typically determined by the physician / clinician's judgment and / or by one or more tests that provide information about whether a patient has anhedonia. For example, the severity of anhedonia can be determined using the SHAPS method. In some modalities, a patient with moderate or severe anhedonia is considered to have a high level of anhedonia. For example, a patient with a SHAPS score of 38 or more is considered to have moderate to severe anhedonia, which may be considered a high level of anhedonia. In some sports, a high level of anhedonia is reflected by a SHAPS score of at least around 40, around 42, around 44, around 46, around 48, around 50, around 52, around 54, around 56, around 58 or higher.A patient with mild or absent anhedonia would be considered to have a low level of anhedonia, as assessed by the physician / clinician's judgment and / or one or more tests. For example, a patient with a SHAPS score of less than 38 is considered to have mild anhedonia. In certain modalities, a patient with moderate anhedonia may have a SHAPS score of 20 to less than 38, for example, 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,. Petition 870260020670, dated 05 / 03 / 2026, p. 88 / 525 75 / 225 approximately 28 to approximately 36, approximately 28 to approximately 34, approximately 28 to approximately 32, approximately 28 to approximately 30, approximately 30 to approximately 36, approximately 30 to approximately 34, approximately 30 to approximately 32, approximately 32 to approximately 36, approximately 32 to approximately 34, or approximately 34 to approximately 36. Typically, a SHAPS score of less than 20 can be considered to correspond to normal hedonic functioning, and for the purposes of this invention, for example, a SHAPS score of less than 38 would be in the low anhedonia category.

[00143] In some modalities, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In still other modalities, the patient's anhedonia is reduced by at least about 40%, as measured by the change from baseline in the total score on an anhedonia scale after treatment with aticaprant. In still other modalities, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, as measured by the change from baseline in the total score on an anhedonia scale after treatment with aticaprant.In still additional modalities, in still other modalities, the patient's anhedonia is reduced by approximately 40 to approximately 90%, approximately 50 to approximately 90%, approximately 60 to approximately 90%, approximately 70 to approximately 90%, approximately 80 to approximately 90%, approximately 40 to approximately 80%, approximately 50 to approximately 60%, approximately 60 to approximately 80%, approximately 70 to approximately 80%, approximately 40 to approximately 70%, approximately 50 to approximately 70%, approximately 60 to approximately 70%, approximately 40 to approximately 60%, approximately 50 to approximately 60%, or approximately 50 to approximately 60%, as appropriate. measured by the change from baseline in the total score on an anhedonia scale after treatment with aticaprant. In other modalities, the patient's anhedonia is improved, that is, reduced. Petition 870260020670, dated 05 / 03 / 2026, p. 89 / 525 76 / 225 zida in 100% by weight, as measured by the change from baseline in the total score on an anhedonia scale after treatment with aticaprant.

[00144] The reduction in anhedonia after starting treatment with aticaprant can be measured relative to the patient's anhedonia as measured before treatment with aticaprant, i.e., a baseline measurement of anhedonia. By doing this, the treating physician is able to calculate the change in anhedonia from baseline to the real-time anhedonia measurement at any point after treatment with aticaprant. Thus, standard methods for measuring anhedonia can be used, such as an anhedonia scale, for example, the SHAPS scale.

[00145] Ideally, a baseline anhedonia measurement is obtained no more than about 1 week before initiating treatment with aticaprant. In some embodiments, a 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 before treatment with aticaprant. In other embodiments, a 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 before initiating treatment with aticaprant.

[00146] The change in a patient's anhedonia will depend on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to aticaprant, the administration of other pharmaceutical agents, among others. In some embodiments, the patient's anhedonia is reduced after approximately 3 weeks of treatment with aticaprant. In other embodiments, the patient's anhedonia is reduced after approximately 3 weeks of treatment with aticaprant. In additional embodiments, the patient's anhedonia is reduced after approximately 3 Petition 870260020670, dated 05 / 03 / 2026, page 90 / 525 77 / 225 weeks to approximately 6 weeks and, in certain modalities, up to week 6 of treatment with aticaprant. In certain modalities, the patient's anhedonia is reduced by at least approximately 40%, as measured by the change from baseline in the total score on an anhedonia scale after approximately 6 weeks of treatment with aticaprant. In additional modalities, the patient's anhedonia is reduced within approximately 3 weeks and, in some modalities, within approximately 3 weeks to approximately 6 weeks, as measured by the change from baseline in the total score on an anhedonia scale and / or by the physician's / clinician's judgment.

[00147] It has been found that the methods described herein not only improve the patient's symptoms of depression and anhedonia, but also resulted in fewer antidepressant side effects. This resulted in less absenteeism (i.e., more visits or interactions with doctors), greater cognitive functioning, improvements in health-related quality of life, more interest and involvement in daily activities, improved family and interpersonal relationships, ability to perform functions in the workplace, fewer hospitalizations, among others.

[00148] In some embodiments, the invention provides methods for treating MDD in a human patient by administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of aticaprant, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. In some embodiments, administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the PK parameters observed above (with dose normalization up to 10 mg) after administration of the composition to a human after fasting for at least 10 hours.

[00149] As used herein, except where otherwise specified, Petition 870260020670, dated 05 / 03 / 2026, page 91 / 525 78 / 225 The terms individual and patient refer to a human being who has been the object of treatment, observation, or experimentation. Preferably, the patient has experienced and / or presented at least one symptom of the disease or disorder to be treated and / or prevented. In some modalities, the patient is an adult. As used herein, the term adult refers to a human being who is approximately 18 years of age or older. In certain aspects, the patient is an elderly adult, that is, 65 years of age or older.

[00150] As used herein, except where otherwise specified, the terms treating, treatment and the like shall include the management and care of an individual or patient (preferably a mammal and, more preferably, a human being) for the purpose of combating a disease, condition or disorder, and include the administration of a compound 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.

[00151] As used herein, the term depression (also called depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, elderly depression, bipolar depression, depression due to identifiable stressors, treatment-resistant depression, or combinations thereof. In certain modalities, depression is a major depressive disorder. In other modalities, major depressive disorder has melancholic or anxiety-related distress. In another modality, depression is treatment-resistant depression. In other modalities, depression is major depressive disorder with suicidal ideation.

[00152] As is known in the technique, a patient is considered Petition 870260020670, dated 05 / 03 / 2026, page 92 / 525 79 / 225 as having major depressive disorder if exhibiting five or more symptoms during the same two-week period that are an alteration from previous functioning; depressed mood and / or loss of interest / pleasure must be present; excluding symptoms clearly attributable to another medical condition. See, for example, Table 4. Table 4 1. Depressed mood: Most of the day, almost every day; may be subjective (e.g., feels sad, empty, hopeless) or observed by others (e.g., appears tearful); in children and adolescents, it may be irritable mood. 2. Loss of interest / pleasure: Noticeably diminished interest or pleasure in all, or almost all, activities during most of the day, nearly every day; may be subjective or observed by others. 3. Weight loss or gain: Significant weight loss (without dieting) or gain (change of >5% of body weight in one month), or decrease or increase in appetite almost every day; in children, there may be a failure to gain weight as expected. 4. Insomnia or hypersomnia: Almost every day 5. Psychomotor agitation or retardation; almost every day and observable by others (not just subjectively restless or slow). 6. Fatigue: Or loss of energy, almost every day. 7. Feelings of worthlessness or excessive / inappropriate guilt: Almost every day; the guilt may be an illusion; not just self-blame or guilt about being sick. 8. Reduced concentration: Almost every day; may be indecisiveness; may be subjective or observed by others. 9. Thoughts of death / suicide: recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt, or a specific plan for suicide.

[00153] In some modalities, to be diagnosed with MDD, the following criteria must also be met: Petition 870260020670, dated 05 / 03 / 2026, page 93 / 525 80 / 225 1. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. 2. An episode not attributable to the physiological effects of a substance or another medical condition. 3. Episode not better explained by schizoaffective disorder, schizophrenia, schizophrenic disorder, delusional disorder, or other specified and unspecified spectrum of schizophrenia and other psychotic disorders. 4. No history of manic or hypomanic episodes.

[00154] Major depressive disorder can be classified as mild, moderate, or severe. In some modalities, MDD is mild. In other modalities, MDD is moderate. In additional modalities, MDD is severe. As used herein, mild MDD applies to a patient who has few, if any, excess symptoms relative to those required to produce the diagnosis, the intensity of the symptoms is concerning but manageable, and the symptoms result in minor dysfunction in social or occupational functioning. Mild MDD may be a single episode (ICD-10 F32.0) or a recurrent episode (ICD-10 F33.0). Moderate MDD applies to a patient who has a number of symptoms, symptom intensity, and / or functional dysfunction between those specified as mild and severe. Moderate MDD may be a single episode (ICD-10 F32.1) or a recurrent episode (ICD-10 F33.1).Severe MDD applies to a patient in whom the number of symptoms is substantially excessive in relation to those necessary to make the diagnosis, the intensity of the symptoms is seriously concerning and unmanageable, and the symptoms markedly interfere with social and occupational functioning, and urgent symptom control is necessary. In some modalities, severe MDD may be a single episode (ICD-10 F32.2) or a recurrent episode (ICD-10 F33.2). In other modalities, MDD is classified... Petition 870260020670, dated 05 / 03 / 2026, page 94 / 525 81 / 225 cado according to the DSM-5 definition in Table 5. Table 5: DSM-5 Criteria for MDD 1. Depressed mood At least 1 2. Loss of interest / pleasure (anhedonia) 1. Weight loss or gain At least 5 2. Sleep problems 3. Psychomotor agitation or retardation 4. Guilt or feelings of worthlessness 5. Decreased concentration 6. Suicidal behavior 7. Fatigue 1. The symptoms cause significant distress or impairment. (Must have all 4) 2. Not attributable to a medical condition. 3. Rule out schizophrenia disorders. 4. No history of mania or hypomania.

[00155] Several scales are known in the art, which can be used to diagnose or monitor patients with MDD. Examples of such scales include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression - Severity (CGI-S), Symptoms of Major Depressive Disorder Scale (SMDDS), Self-Assessment of Treatment Experience (SATE), and Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), i.e., MGH-ATRQ.

[00156] In some modalities, the MADRS is used to diagnose and / or monitor the patient. The MADRS is a classification scale. Petition 870260020670, dated 05 / 03 / 2026, page 95 / 525 The MADRS scale is a 10-item scale used in antidepressant studies. It is administered by a physician and designed for use in individuals with MDD to measure the overall severity of depressive symptoms. The MADRS scale is validated, reliable, and acceptable by health regulatory authorities as a primary scale for determining efficacy in major depression. In some modalities, the MADRS is administered using the Structured Interview Guide for the MADRS (SIGMA). The scale consists of 10 items, each scored from 0 (item not present or normal) to 6 (severe or persistent presence of symptoms), for a possible total score of 60. Higher scores represent a more severe clinical picture. The MADRS scale assesses apparent sadness, reported sadness, internal tension, sleep, appetite, concentration, tiredness, callousness (level of interest), pessimistic thoughts, and suicidal thoughts.

[00157] In other modalities, the CGI-S is used to diagnose and / or monitor a patient's depression. The CGI-S is a scale that classifies the severity of an individual's illness at the time of assessment, in relation to the clinician's previous experience with individuals who have the same diagnosis and improvement with treatment. The CGI-S provides a summary measurement of the severity of the individual's overall illness as determined by the physician, taking into account all available information, including knowledge of the individual's history, psychosocial circumstances, symptoms, behavior, and the impact of symptoms on the individual's functional capacity. The CGI-S assesses the severity of psychopathology on a scale of 0 to 7.The individual is assessed for the severity of their mental illness at the time of classification, according to: 0 = not assessed; 1 = normal (not ill); 2 = mentally ill - borderline; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill. Petition 870260020670, dated 05 / 03 / 2026, page 96 / 525 83 / 225

[00158] In additional modalities, the SMDDS is used to diagnose and / or monitor patient depression. The SMDDS is a subjective patient rating. The SMDDS is a 16-item PRO measure. Each item is rated by the individual according to a 5-point Likert scale. Individuals respond to each question using a rating scale between 0 (Never or Not at all) and 4 (Extremely or Always). The total score ranges from 0 to 60. The SMDDS uses a 7-day recall period and verbal rating scales. A higher score indicates more severe depressive symptomatology.

[00159] In other modalities, the SATE is used to diagnose and / or monitor a patient's depression. SATE is a one-to-three-point questionnaire administered when the individual is unable to complete other assessments, i.e., away from a clinical setting, such as at home. SATE is useful for assessing the improvement or deterioration of individuals' depressive symptoms over a short period of time. To assess general depression, the individual selected an option from Improved, No change, or Worsened; for improvement in depression, the individual selected an option from Improved slightly, Improved considerably, and Improved significantly; and for worsening of depression, the individual selected Worsened slightly, Worsened considerably, and Worsened significantly. See Table 6. Table 6: SATE Questionnaire Question 1: Since starting this study medication, overall, would you say your depression: It improved, it worsened, it didn't change. If the individual selects answer 1 (improved), the following question will be asked: Question 2: How much has your depression improved? Petition 870260020670, dated 05 / 03 / 2026, page 97 / 525 84 / 225 Improved a little Improved a lot Improved significantly If the individual selects answer 3 (worsened), the following question will be asked: Question 3: How much worse has your depression gotten? It got a little worse. It got quite a bit worse. It got much worse.

[00160] The MGH-ATRQ is a self-assessment scale used to determine treatment resistance in patients with MDD. This questionnaire examines the history of antidepressant treatment, using specific anchor points to define the adequacy of both the dose and duration of each antidepressant trial, and the degree of symptomatic improvement. The MGH-ATRQ allows for the determination of treatment resistance in depression and is known to those skilled in the art.

[00161] In certain modalities, the patient has had an inadequate response to other antidepressant therapy. Inadequate response, as used herein, refers to a patient who has a reduction of less than about 50% in the severity of depressive symptoms since the beginning of treatment. Typically, the inadequate response occurs during a current / active episode of depression. In some modalities, an inadequate response refers to a patient who experiences a reduction of about 26 to less than about 50% in the severity of depressive symptoms since the beginning of treatment. In other modalities, an inadequate response refers to a patient who experiences 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 Petition 870260020670, dated 05 / 03 / 2026, p. 98 / 525 85 / 225 approximately 49, approximately 30 to approximately 45, approximately 30 to approximately 40, approximately 30 to approximately 35, approximately 35 to approximately 49, approximately 35 to approximately 45, approximately 35 to approximately 40, approximately 40 to approximately 49, or approximately 40 to approximately 45% reduction in the severity of depression symptoms since the beginning of treatment. A patient's response may be measured by one or more scales described herein and / or by the physician / clinician's judgment. In some modalities, an inadequate response is measured by the MGHATRQ, MADRS, or SHAPS. In other modalities, an inadequate response is measured by the MGH-ATRQ.

[00162] To the extent that a patient is said to have a partial response to treatment, this refers to some minor to moderate symptomatic improvement since the start of treatment, but some of the initial symptoms are still present and cause discomfort to 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.

[00163] The term "other antidepressant therapy," as used herein, refers to an antidepressant medication or non-pharmacological treatment that is used to treat patients with depression. In some respects, the other antidepressant therapy is an antidepressant medication. In other respects, the other antidepressant therapy is a non-pharmacological treatment. In other respects, the other antidepressant therapy is an antidepressant medication other than aticaprant.

[00164] Antidepressant medication refers to any pharmaceutical agent that can be used to treat depression. Suitable examples include, without limitation, monoamine oxidase inhibitors, tricyclic, tetracyclic, noncyclic, triazolopyridines, selective serotonin reuptake inhibitors (SSRIs), serotonin receptor antagonists Petition 870260020670, dated 05 / 03 / 2026, page 99 / 525 86 / 225 serotonin, serotonin noradrenergic reuptake inhibitors (SNRIs), specific noradrenergic and serotonergic agents, norepinephrine reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, mocleobide, and similar drugs. Examples of tricyclic antidepressants include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, and similar drugs. Examples of tetracyclic antidepressants include maprotiline and similar drugs. Examples of noncyclic antidepressants include nomifensine and similar drugs. Examples of triazolopyridines include trazodone and similar drugs. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, and similar drugs. Examples of serotonin receptor antagonists include nefazadone and similar drugs. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levomilnacipran, and similar drugs.Examples of specific noradrenergic and serotonergic agents include mirtazapine and similar drugs. Examples of norepinephrine reuptake inhibitors include reboxetine, edivoxetine, and similar drugs. 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), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and similar drugs. Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonepiprazole, aripiprazole, nemonapride, SR-31742, CX-516, SC-111, NE-100, divalproate (mood stabilizer), and similar drugs.In additional forms, antidepressant medication includes natural products such as Kava-Kava, St. John's Wort and similar remedies, or dietary supplements such as... Petition 870260020670, dated 05 / 03 / 2026, page 100 / 525 87 / 225 adenosylmethionine and similar drugs. In still other modalities, antidepressant medication includes neuropeptides such as thyrotropin-releasing hormone and similar drugs, or compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and similar drugs. In still other modalities, the antidepressant medication is a hormone, such as triiodothyronine and similar drugs. In other modalities, the antidepressant medication is an SSRI, SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI such as escitalopram, sertraline, paroxetine, fluoxetine, or citalopram. In other modalities, the antidepressant medication is an SNRI such as venlafaxine, duloxetine, vortioxetine, or desvenlafaxine.

[00165] The non-pharmacological treatment for use in the present invention document may be selected by one skilled in the art. In some modalities, the non-pharmacological treatment is psychotherapy, transcranial magnetic stimulation or similar.

[00166] Therapeutically effective dosage amounts / levels and dosage regimens for other antidepressant therapy can be readily determined by those skilled in the art. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example, as shown on package labels, in standard dosage guidelines, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / / www.pdrel.com) or other sources.

[00167] In some modalities, alternative antidepressant therapy may include one antidepressant medication. In other modalities, alternative antidepressant therapy includes two or more antidepressant medications. In additional modalities, alternative antidepressant therapy includes two antidepressant medications. In still other modalities, alternative antidepressant therapy includes three medications. Petition 870260020670, dated 05 / 03 / 2026, page 101 / 525 88 / 225 antidepressants. The attending clinician would be able to select appropriate antidepressant therapies for use as described herein.

[00168] In certain modalities, the patient was receiving treatment with another antidepressant therapy before receiving aticaprant. In some modalities, the patient was receiving treatment with another antidepressant therapy that comprised an SSRI, SNRI, or a combination thereof. In other modalities, the patient discontinued treatment with another antidepressant therapy before initiating treatment with aticaprant.

[00169] Also covered by the methods described here is adjunctive treatment with an effective amount of one or more antidepressants. As used herein, the term adjunctive treatment and adjunctive therapy shall mean the treatment of a patient in need thereof by administering aticaprant in combination with one or more antidepressants, wherein the aticaprant and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation.

[00170] In some ways, aticaprant is administered as an adjunct to other antidepressant(s) currently being administered to the patient, including current antidepressants to which the patient has had an inadequate response, i.e., the antidepressant has failed to treat the patient's depression. In other ways, aticaprant is administered as an adjunct to antidepressant(s) not previously administered to the patient, i.e., a new antidepressant. In still other ways, aticaprant is administered in a regimen with antidepressant(s) previously administered to the patient.

[00171] When aticaprant and other antidepressant(s) are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different, Petition 870260020670, dated 05 / 03 / 2026, page 102 / 525 89 / 225 and, more typically, different. The antidepressant may be dosed as prescribed by the attending physician and / or its label, and aticaprant is dosed as described here. Typically, a patient is under concomitant treatment with an antidepressant and aticaprant, where both are administered according to their prescribed dosage regimens. Aticaprant and the antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same time or at different times during the course of therapy, concomitantly in divided or single forms.

[00172] Aticaprant and the antidepressant(s) may be administered by the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (IV), intranasal (IN), intramuscular (IM), subcutaneous (SC), transdermal, buccal, or rectal. In some dosage forms, aticaprant is administered orally.

[00173] Treatment with aticaprant, as described herein, has several advantages over treatments in the technique. In some modalities, the patient does not experience many of the side effects that are associated with other antidepressants, i.e., antidepressants other than aticaprant. In certain modalities, the patient does not experience weight gain during treatment with aticaprant. As used herein, the term weight gain refers to an increase in the patient's weight relative to the patient's weight before taking aticaprant or the patient's weight as assessed at the time of initial administration of aticaprant. In certain modalities, the patient may actually observe a decrease in overall weight relative to the patient's weight before taking aticaprant. In additional modalities, the patient's weight is stable, i.e., it neither increases nor decreases. In certain modalities, the patient does not experience a clinically relevant weight gain that is distinguished as a weight increase > 7%. Petition 870260020670, dated 05 / 03 / 2026, page 103 / 525 90 / 225

[00174] This is contrary to many other antidepressants where weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[00175] In additional aspects, the patient does not experience a decrease in sexual function during treatment with aticaprant. As used herein, the term decrease in sexual function refers to the reduction or diminution of one or more components of the human sexual drive, that is, of sexual function. In some modalities, sexual function comprises one or more of the following: sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm, or orgasm satisfaction. In other modalities, sexual function comprises sexual drive. In additional modalities, sexual function comprises vaginal lubrication satisfaction. In other modalities, sexual function comprises attainment of orgasm. In still other modalities, sexual function comprises orgasm satisfaction. Ideally, the patient's sexual function is assessed at the time of initial administration of aticaprant.Thus, the patient's sexual function while taking aticaprant can be compared to the patient's sexual function before aticaprant administration. Sexual function can be assessed using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). The ASEX is used to investigate whether aticaprant has an additional positive or negative effect on sexual function. The ASEX is a 5-item rating scale administered to patients that quantifies sexual desire, sexual arousal, vaginal lubrication or penile erection, the ability to achieve orgasm, and satisfaction. Scores range from 5 to 30, and two different versions of the scale are available (men and women).

[00176] Other scales may be used to determine the effectiveness of the methods used here to treat the patient. Examples include the Cognitive and Physical Functioning Questionnaire (CPFQ), the Petition 870260020670, dated 05 / 03 / 2026, page 104 / 525 91 / 225 The Karolinska Sleepiness Scale (KSS) and the Temporal Scale of Pleasure (TEPS) are used in the assessment of cognitive function. The CPFQ is a brief self-report scale that provides additional information on the impact of adjunctive treatment on aspects of cognitive and executive function, including attention, memory, and mental acuity. Individuals with MDD are frequently reported to have difficulties functioning in this area. The KSS is an individual-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from extremely alert (1) to very sleepy, much effort to stay awake, struggling to stay awake (9). The TEPS includes 18 items, 2 subscales designed to distinguish between anticipatory and consummatory pleasure.

[00177] The methods described herein involve administering an effective amount of aticaprant to the patient. The term effective amount, as used herein, means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human being sought by a researcher, physician, or other healthcare professional, which includes relief of one or more of the symptoms of the disease or disorder being treated. In some embodiments, aticaprant is used in an effective amount as determined by the attending physician. In other embodiments, other antidepressant(s) is / are used in an effective amount separately or in combination with aticaprant.

[00178] Modalities:

[00179] The invention also provides the following non-limiting embodiments:

[00180] Embodiment 1 is a pharmaceutical composition comprising from about 2 mg to about 20 mg of aticaprant and a filler, the composition comprising from about 0.1% to about Petition 870260020670, dated 05 / 03 / 2026, page 105 / 525 92 / 225% aticaprant by weight.

[00181] Embodiment 2 is the pharmaceutical composition of embodiment 1 that additionally comprises one or more of: a disintegrant, a flow agent, a lubricant, a solvent, a dyeing agent and a binder.

[00182] Modality 3 is the pharmaceutical composition of modality 1 or 2, the composition comprising between about 10% and about 99.9% filler by weight.

[00183] Modality 4 is the pharmaceutical composition of any of the modalities 1 to 3, wherein the composition comprises a disintegrant.

[00184] Embodiment 5 is the pharmaceutical composition of embodiment 4, the composition comprising between about 0.5% and about 50% disintegrant by weight.

[00185] Embodiment 6 is the pharmaceutical composition of any of the embodiments 1 to 5, wherein the composition comprises a flow agent.

[00186] Embodiment 7 is the pharmaceutical composition of embodiment 6, the composition comprising between about 0.1% and about 10% flow agent by weight.

[00187] Embodiment 8 is the pharmaceutical composition of any of the embodiments 1 to 7, wherein the composition comprises a lubricant.

[00188] Embodiment 9 is the pharmaceutical composition of embodiment 8, the composition comprising between about 0.05% and about 5% lubricant by weight.

[00189] Embodiment 10 is the pharmaceutical composition of any of the embodiments 1 to 9, wherein the composition comprises one or more of the following: a ratio of aticaprant to filler between 0.005 and 9 by weight; a ratio of aticaprant to disintegrant between 0.1 and 10 Petition 870260020670, dated 05 / 03 / 2026, page 106 / 525 93 / 225 by weight; a ratio of aticaprant to flow agent between 0.5 and 50 by weight; and a ratio of aticaprant to lubricant between 1 and 100 by weight.

[00190] Embodiment 11 is the pharmaceutical composition of any of the embodiments 1 to 10, the composition comprising about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00191] Modality 12 is the pharmaceutical composition of any of the modalities 1 to 11, wherein the composition is an oral tablet.

[00192] Embodiment 13 is the pharmaceutical composition of embodiment 12, wherein the oral tablet is a film-coated oral tablet comprising (a) a core tablet and (b) a film coating.

[00193] Embodiment 14 is the pharmaceutical composition of embodiment 13, wherein the ratio of film coating to nuclear tablet is between about 0.03 to 10 by weight.

[00194] Embodiment 15 is the pharmaceutical composition of embodiment 13 or 14, wherein the film coating comprises a powder coating.

[00195] Embodiment 16 is the pharmaceutical composition of any of the embodiments 13 to 15, wherein the core tablet comprises an intragranular and an extragranular phase.

[00196] Modality 17 is the pharmaceutical composition of modality 16, wherein the ratio between the intragranular and extragranular phases in the nuclear tablet is between approximately 1.5 and 3.

[00197] Embodiment 18 is the pharmaceutical composition of embodiment 16, wherein the intragranular phase comprises an aticaprant, a filler, a disintegrant and a flow agent. Petition 870260020670, dated 05 / 03 / 2026, page 107 / 525 94 / 225

[00198] Embodiment 19 is the pharmaceutical composition of embodiment 18, wherein the intragranular phase comprises one or more of: an aticaprant-to-filler ratio of between about 0.008 and 0.8 by weight; an aticaprant-to-disintegrant ratio of between about 0.2 and 20 by weight; and an aticaprant-to-flow agent ratio of between about 1 and 100 by weight.

[00199] Modality 20 is the pharmaceutical composition of embodiment 16 or 17, wherein the extragranular phase comprises a filler, a disintegrant, a flow agent and a lubricant.

[00200] Embodiment 21 is the pharmaceutical composition of embodiment 20, wherein the extragranular phase comprises one or more of: a ratio of filler to disintegrant between about 1 and 100 by weight; a ratio of filler to flow agent between about 5 and 500 by weight; and a ratio of filler to lubricant between about 5 and 500 by weight.

[00201] Embodiment 22 is the pharmaceutical composition of any of the embodiments 13 to 21, wherein the film-coated oral tablet comprises about 97% core tablet by weight and about 3% film coating by weight, and wherein the core tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00202] Embodiment 23 is the pharmaceutical composition of any of the embodiments 1 to 22, wherein the composition is an oral tablet comprising a core tablet of about 100 mg, wherein the core tablet comprises about 5 mg of aticaprant, about 5 mg of disintegrant, about 88.5 mg of filler, about 1 mg of flow agent and about 0.5 mg of lubricant. Petition 870260020670, dated 05 / 03 / 2026, page 108 / 525 95 / 225

[00203] Embodiment 24 is the pharmaceutical composition of embodiment 23 that additionally comprises 3 mg of film coating.

[00204] Embodiment 25 is the pharmaceutical composition of any of the embodiments 1 to 24, wherein the composition is an oral tablet comprising a core tablet of about 200 mg, wherein the core tablet comprises about 10 mg of aticaprant, about 10 mg of disintegrant, about 177 mg of filler, about 2 mg of flow agent and about 1 mg of lubricant.

[00205] Embodiment 26 is the pharmaceutical composition of embodiment 25 which additionally comprises 6 mg of film coating.

[00206] Modality 27 is the pharmaceutical composition of any of the modalities 1 to 26, wherein the filler is selected from: microcrystalline cellulose, lactose monohydrate and silicified microcrystalline cellulose.

[00207] Modality 28 is the pharmaceutical composition of any of the modalities 2 to 27, wherein the disintegrant is croscarmellose sodium.

[00208] Embodiment 29 is the pharmaceutical composition of any of the embodiments 2 to 28, where the flow agent is anhydrous colloidal silica.

[00209] Modality 30 is the pharmaceutical composition of any of the modalities 2 to 29, the lubricant is magnesium stearate.

[00210] Embodiment 31 is the pharmaceutical composition of any of the embodiments 15 to 30, wherein the powder coating is Opadry II Orange.

[00211] Modality 32 is an oral tablet comprising approximately 5 mg of aticaprant, wherein the oral tablet comprises a core tablet of approximately 100 mg, wherein Petition 870260020670, dated 05 / 03 / 2026, page 109 / 525 96 / 225 nuclear oil comprises an intragranular and an extragranular phase, the intragranular phase comprising approximately 30 mg of microcrystalline cellulose, approximately 30 mg of lactose monohydrate, approximately 2.5 mg of croscarmellose sodium and approximately 0.5 mg of anhydrous colloidal silica; and the extragranular phase comprising approximately 28.5 mg of silicified microcrystalline cellulose, approximately 2.5 mg of croscarmellose sodium, approximately 0.5 mg of anhydrous colloidal silica and approximately 0.5 mg of magnesium stearate.

[00212] Embodiment 33 is the oral tablet of embodiment 32 which additionally comprises approximately 3 mg of film coating.

[00213] Embodiment 34 is the oral tablet of embodiment 33, wherein the film coating comprises Opadry II Orange.

[00214] The 35-form is an oral tablet comprising approximately 10 mg of aticaprant, wherein the oral tablet comprises a core tablet of approximately 200 mg, wherein the core tablet comprises an intragranular and an extragranular phase, wherein the intragranular phase comprises approximately 60 mg of microcrystalline cellulose, approximately 60 mg of lactose monohydrate, approximately 5 mg of croscarmellose sodium and approximately 1 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises approximately 57 mg of silicified microcrystalline cellulose, approximately 5 mg of croscarmellose sodium, approximately 1 mg of anhydrous colloidal silica and approximately 1 mg of magnesium stearate.

[00215] Modality 36 is the oral tablet of modality 35 which additionally comprises 3 mg of film coating.

[00216] Embodiment 37 is the oral tablet of embodiment 36, wherein the film coating comprises Opadry II Orange.

[00217] Modality 38 is a pharmaceutical composition comprising between approximately 2 mg and 20 mg of aticaprant, with the Petition 870260020670, dated 05 / 03 / 2026, p. 110 / 525 The 97 / 225 composition has a pharmacokinetic (PK) profile comprising one or more of the following parameters after administration of the composition to a human being following a fasting period of at least 10 hours (with dose normalization up to 10 mg): a. an average Cmax between approximately 30 and 40 ng / mL; b. an average AUCinfinite between approximately 300 and 430 h*ng / mL; c. an average ultimate AUC between approximately 280 and 430 h*ng / mL; d. an average tmax between approximately 1 and 4 hours.

[00218] Modality 39 is the pharmaceutical composition of modality 38, with an average Cmax between approximately 30 and 35 ng / mL.

[00219] Modality 40 is the pharmaceutical composition of either modality 38 or 39, and the average AUCinfinite is between approximately 300 and 320 h*ng / mL.

[00220] Modality 41 is the pharmaceutical composition of any of the modalities 38 to 40, with the average AUCúltima between approximately 280 and 310 h*ng / mL.

[00221] Modality 42 is the pharmaceutical composition of any of the modalities 38 to 41, and the average tmax is approximately 1.5 hours.

[00222] Modality 43 is the pharmaceutical composition of any of the embodiments 38 to 42, where the composition is an oral tablet.

[00223] Embodiment 44 is the pharmaceutical composition of any of the embodiments 38 to 43, wherein the composition additionally comprises one or more of: a filler, a disintegrant, a flow agent, a lubricant, a binder and a coloring agent.

[00224] Modality 45 is the pharmaceutical composition of any Petition 870260020670, dated 05 / 03 / 2026, p. 111 / 525 98 / 225 one of the modalities 38 to 44, the composition of which comprises between approximately 0.1% and 90% aticaprant by weight.

[00225] Modality 46 is the pharmaceutical composition of any of the embodiments 38 to 45, the composition comprising about 5 mg of aticaprant or about 10 mg of aticaprant.

[00226] Embodiment 47 is the pharmaceutical composition of any of the embodiments 38 to 46, wherein the composition comprises one or more of: an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrator ratio between 0.1 and 10 by weight; an aticaprant to flow agent ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight.

[00227] Embodiment 48 is the pharmaceutical composition of any of the embodiments 38 to 47, the composition comprising about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00228] Modality 49 is a method for the treatment of major depressive disorder (MDD) in a human patient, wherein the method comprises administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg of aticaprant, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaprant, and wherein the administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the following PK parameters (with dose normalization up to 10 mg) after administration of the composition to a human after fasting for at least 10 hours: e. an average Cmax between approximately 30 and 40 ng / mL; f. an average AUCinfinite between approximately 300 and 430 h*ng / mL; Petition 870260020670, dated 05 / 03 / 2026, p. 112 / 525 99 / 225 g. an average ultimate AUC between approximately 280 and 430 h*ng / mL; h. an average tmax between approximately 1 and 4 hours.

[00229] Modality 50 is the method of modality 49, with the average Cmax between approximately 30 and 35 ng / mL.

[00230] Modality 51 is the method of modality 49 or 50, with the mean infinity of the AUC between approximately 300 and 320 h*ng / mL.

[00231] Modality 52 is the method of any of the modalities 49 to 51, with the average AUCúltima between approximately 280 and 310 h*ng / mL.

[00232] Mode 53 is the method of any of the modes 49 to 52, and the average tmax is about 1.5 hours.

[00233] Modality 54 is the method of any of the modalities 49 to 53, and the composition is an oral tablet.

[00234] Embodiment 55 is the method of any of the embodiments 49 to 54, wherein the composition additionally comprises one or more of: a filler, a disintegrant, a flow agent, a lubricant, a binder and a dyeing agent.

[00235] Modality 56 is the method of any of the modalities 49 to 55, the composition comprising between about 0.1% and 90% aticaprant by weight.

[00236] Modality 57 is the method of any of the modalities 49 to 56, wherein the composition comprises between approximately 10% and 99.9% load by weight.

[00237] Embodiment 58 is the method of any of the embodiments 49 to 57, wherein the composition comprises one or more of: an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrator ratio between 0.1 and 10 by weight; an aticaprant to flow agent ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight. Petition 870260020670, dated 05 / 03 / 2026, page 113 / 525 100 / 225

[00238] Embodiment 59 is the method of any of the embodiments 49 to 58, the composition comprising about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00239] Modality 60 is the method of any of the modalities 49 to 59, where the patient has anhedonia.

[00240] Modality 61 is the method of any of the modalities 49 to 60, with the pharmaceutical composition comprising about 5 mg of aticaprant.

[00241] Modality 62 is the method of any of the modalities 49 to 60, with the pharmaceutical composition comprising about 10 mg of aticaprant.

[00242] Modality 63 is the method of any of the modalities 49 to 60, and the other antidepressant therapy comprised one or more antidepressants.

[00243] Modality 64 is the method of modality 63, wherein one or more antidepressants are comprised of an SSRI, an SNRI, or a combination thereof.

[00244] Modality 65 is the method of any of the modalities 49 to 64, where aticaprant is S-aticaprant.

[00245] Modality 66 is the method of any of the modalities 49 to 65 that additionally comprises treatment with an effective amount of one or more antidepressants.

[00246] Modality 67 is the method of modality 66, where one or more antidepressants are an SSRI, an SNRI, or a combination thereof.

[00247] Modality 68 is the method of any of the modalities 49 to 67, and the pharmaceutical composition comprising aticaprant is administered once daily. Petition 870260020670, dated 05 / 03 / 2026, p. 114 / 525 101 / 225

[00248] Modality 69 is a solid pharmaceutical composition comprising between about 2 mg and 20 mg of aticaprant, the composition having a dissolution profile comprising a Q-value between about 60% and 90% in 45 minutes, under the following operating conditions of dissolution: Apparatus: Spade (USP type 2, Ph. Eur., JP) Dissolution medium: 0.01 M hydrochloric acid Volume: 900 mL Temperature: 37 + / - 0.5 degrees Celsius Rotation speed: 50 rpm Analytical finish: UHPLC with UV detection at 247 nm.

[00249] Embodiment 70 is the solid pharmaceutical composition of embodiment 69, with the composition comprising about 5 mg or about 10 mg of aticaprant.

[00250] Modality 71 is the solid pharmaceutical composition of modality 69 or 70, with the Q value being between approximately 70% and 80% in 45 minutes.

[00251] Modality 72 is the solid pharmaceutical composition of modality 71, and the Q value is approximately 75% in 45 minutes.

[00252] Embodiment 73 is the solid pharmaceutical composition of any of the embodiments 69 to 72, where the composition is an oral tablet.

[00253] Embodiment 74 is the solid pharmaceutical composition of any of the embodiments 69 to 73, the composition additionally comprising one or more of: a filler, a disintegrant, a flow agent, a lubricant, a binder and a coloring agent.

[00254] Modality 75 is the solid pharmaceutical composition of Petition 870260020670, dated 05 / 03 / 2026, page 115 / 525 102 / 225 any of the modalities 69 to 74, the composition comprising between approximately 0.1% and 90% aticaprant by weight.

[00255] Embodiment 76 is the solid pharmaceutical composition of any of the embodiments 69 to 75, the composition comprising between about 10% and 99.9% filler by weight.

[00256] Embodiment 77 is the solid pharmaceutical composition of any of the embodiments 69 to 76, wherein the composition comprises one or more of: an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrator ratio between 0.1 and 10 by weight; an aticaprant to flow agent ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight.

[00257] Embodiment 78 is the solid pharmaceutical composition of any of the embodiments 69 to 77, the composition comprising about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00258] Modality 79 is a method for treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition of any of the embodiments 1 to 32 or 38 to 48, the oral tablet of any of the embodiments 33 to 37, or the solid pharmaceutical composition of any of the embodiments 69 to 78.

[00259] Modality 80 is a method of modality 79, where the patient has anhedonia.

[00260] Embodiment 81 is the method of any of the embodiments 79 to 80, wherein the pharmaceutical composition, oral tablet or solid pharmaceutical composition comprises about 5 mg of aticaprant. Petition 870260020670, dated 05 / 03 / 2026, page 116 / 525 103 / 225

[00261] Embodiment 82 is the method of any of the embodiments 79 to 81, wherein the pharmaceutical composition, oral tablet or solid pharmaceutical composition comprises about 10 mg of aticaprant.

[00262] Modality 83 is the method of any of the modalities 79 to 82, whereby the patient had an inadequate response to another antidepressant therapy before treatment with aticaprant.

[00263] Modality 84 is the method of modality 83, wherein the other antidepressant therapy comprised one or more antidepressants.

[00264] Modality 85 is the method of modality 84, wherein one or more antidepressants are comprised of an SSRI, an SNRI, or a combination thereof.

[00265] Modality 86 is the method of any of the modalities 79 to 85, where aticaprant is S-aticaprant.

[00266] Modality 87 is the method of any of the modalities 79 to 86 that additionally comprises treatment with an effective amount of one or more antidepressants.

[00267] Modality 88 is the method of modality 87, where one or more antidepressants are an SSRI, an SNRI, or a combination thereof.

[00268] Embodiment 89 is the method of any of the embodiments 79 to 88, and the pharmaceutical composition, oral tablet or solid pharmaceutical composition comprising aticaprant is administered once daily.

[00269] Modality 90 is a method for treating major depressive disorder in a human patient comprising administering a pharmaceutical composition comprising aticaprant and one or more excipients pharmaceutically acceptable to the human patient, wherein the patient has had an inadequate response prior to other Petition 870260020670, dated 05 / 03 / 2026, page 117 / 525 104 / 225 antidepressant therapy, and the pharmaceutical composition is administered orally once daily with or without food.

[00270] Modality 91 is the method of modality 90, wherein the pharmaceutical composition is an oral tablet.

[00271] Modality 92 is the method of embodiment 90 or 91, wherein the pharmaceutical composition comprises about 5 mg to 10 mg of aticaprant, about 5 mg of aticaprant or about 10 mg of aticaprant.

[00272] Modality 93 is the method of any of the modalities 90 to 92, wherein the other antidepressant therapy comprised one or more antidepressants.

[00273] Modality 94 is the method of modality 93, wherein one or more antidepressants are comprised of an SSRI, an SNRI, or a combination thereof.

[00274] Modality 95 is the method of any of the modalities 90 to 94, wherein the aticaprant is S-aticaprant, or the aticaprant is crystalline aticaprant.

[00275] Modality 96 is the method of any of the modalities 90 to 95 that additionally comprises treatment with an effective amount of one or more antidepressants.

[00276] Modality 97 is the method of modality 96, wherein one or more antidepressants are an SSRI, an SNRI, or a combination thereof.

[00277] Modality 98 is the method of any of the modalities 90 to 97, wherein the patient has anhedonia, optionally moderate to severe anhedonia.

[00278] Embodiment 99 is the method of any of the embodiments 90 to 98, wherein the pharmaceutical composition comprises one or more of: a filler, a disintegrant, a flow agent, a lubricant, a binder and a coloring agent. Petition 870260020670, dated 05 / 03 / 2026, page 118 / 525 105 / 225

[00279] Modality 100 is the method of modality 99, wherein the feedstock is selected from: microcrystalline cellulose, lactose monohydrate and silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the flow agent is anhydrous colloidal silica; and the lubricant is magnesium stearate.

[00280] Modality 101 is the method of any of the modalities 90 to 100, wherein the pharmaceutical composition comprises between about 0.1% and 90% aticaprant by weight.

[00281] Modality 102 is the method of any of the modalities 90 to 101, wherein the pharmaceutical composition comprises between about 10% and 99.9% filler by weight.

[00282] Embodiment 103 is the method of any of embodiments 90 to 102, wherein the pharmaceutical composition is a film-coated oral tablet comprising (i) a film coating and (ii) a core tablet, wherein the core tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

[00283] Embodiment 104 is the method in which the film-coated oral tablet comprises about 97% core tablet by weight and about 3% film coating by weight.

[00284] Embodiment 105 is the method of any of the embodiments 90 to 104, wherein the pharmaceutical composition is an oral tablet comprising approximately 10 mg of aticaprant, wherein the oral tablet comprises a core tablet of approximately 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises approximately 60 mg of microcrystalline cellulose, approximately 60 mg of lactose monohydrate, approximately 5 mg of croscarmellose sodium and approximately 1 Petition 870260020670, dated 05 / 03 / 2026, page 119 / 525 106 / 225 mg of anhydrous colloidal silica; and with the extragranular phase comprising approximately 57 mg of silicified microcrystalline cellulose, approximately 5 mg of croscarmellose sodium, approximately 1 mg of anhydrous colloidal silica and approximately 1 mg of magnesium stearate.

[00285] The following examples are presented to aid in understanding the invention, and are not intended to, and should not be interpreted as, limiting any aspect of the invention defined in the claims that follow. Abbreviations ABV Alcohol by volume AE Adverse event ALT Alanine aminotransferase Anti-HEV (IgM) Hepatitis E virus (Immunoglobulin M) ASEX Arizona Sex Scale AST Aspartate transaminase ATRQ Antidepressant Treatment History Questionnaire AV Atrioventricular BMI Body mass index CGI-S Clinical global impression - severity IC Confidence interval CPFQ Cognitive and physical function questionnaire CSF Cerebrospinal fluid C-SSRS Columbia Suicide Risk Assessment Scale CYP Cytochrome P450 DSC Differential scanning calorimeter DSM Diagnostic and Statistical Manual of Mental Disorders ECG Electrocardiogram eITT (Population) Intention-to-Treat enriched FAS Complete set of safety analyses Petition 870260020670, dated 05 / 03 / 2026, page 120 / 525 107 / 225 fITT (Population) with intent to treat total FSH Follicle-stimulating hormone G17 Gastrin-17 GI Gastrointestinal HAM-A | HDRS-17 Hamilton Depression Rating Scale HCV Hepatitis C virus HbsAg Hepatitis B surface antigen α-hCG α-Human chorionic gonadotropin HAM-A6 6-item subscale of the HAM-A HIV Human immunodeficiency virus HPA Hypothalamic-pituitary-adrenal IgG Helicobacter IgG antibodies ICH International Conference on Harmonisation KOR Kappa opioid receptor KSS Karolinsura Sleepiness Scale LBBB Left bundle branch block LC-MS / MS Liquid chromatography coupled to tandem mass spectrometry LOQ Limit of quantification LS Least squares LSD Lysergic acid diethylamide MADRS Montgomery-Asberg Depression Rating Scale MDD Major depressive disorder mDSC Modulated differential scanning calorimetry MedDRA Medical Dictionary for Regulatory Activities MINI International Mini-Interview MMRMMixed-effects model for repeated measures MOR Opioid receptor Mu NSAID Nonsteroidal anti-inflammatory drug PCP Phencyclidine PGI Pepsinogen I PGII Pepsinogen II Petition 870260020670, dated 05 / 03 / 2026, p. 121 / 525 108 / 225 PK Pharmacokinetics PPI Proton pump inhibitor PRO Patient-reported outcomes QD Once daily UR Relative humidity TA Room temperature SATE Self-assessment of treatment experience DP Standard deviation SHAPS Snaith-Hamilton Pleasure Scale SIGH-A Structured Interview Guide for the Hamilton Anxiety Scale SIGMA Structured Interview Guide for the MADRS SMDDS Major Depressive Disorder Symptom Scale SNRI Serotonin-norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitors EADT Treatment-related adverse event THF Tetrahydrofuran TSH Thyroid-stimulating hormone USN Upper limit of normal USP United States Pharmacopeia DRXP Powder X-ray diffraction Example 1: Instrument and methodology details A. X-ray powder diffraction (XRD) analysis Bruker AXS D8 Advance

[00286] XRD 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 passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and alignment knife. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye detector. The software used for data collection and analysis was Diffrac XRD Commander and Petition 870260020670, dated 05 / 03 / 2026, p. 122 / 525 109 / 225 Diffrac Plus EVA, respectively.

[00287] Samples were run under ambient conditions as flat plate specimens using as-received powder. The sample was prepared on a polished, zero baseline silicon wafer (510) by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.

[00288] The details of the standard Pharmorphix data collection method are: • Angular range: 2 to 42° 2Θ • Step size: 0.05° 2Θ • Collection time: 0.5 s / step (total collection time: 6.40 min)

[00289] When necessary, other methods for data collection are used in detail, as shown in Table 7. Table 7: Additional D8 DRXP Methods 4-Minute Method Angular Range 2 to 31° 2Θ Step Size 0.06° 2Θ Time per Step 0.5 s / step PAnalytical Empyrean

[00290] XRD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, a 4 mm mask, and 0.04 rad Soller slits with a focusing mirror were used in the incident beam. A PIXcel3D detector, positioned in the diffracted beam, was equipped with a receiving slit and 0.04 rad Soller slits. The software used for data collection was X'Pert Data Collector using the X'Pert Operator Interface. The data were analyzed and presented using Diffrac Plus EVA or HighScore Plus.

[00291] The samples were prepared and analyzed on a plate. Petition 870260020670, dated 05 / 03 / 2026, page 123 / 525 110 / 225 of 96 metal wells or Millipore in transmission mode. X-ray transparent film was used between the metal sheets in the metal well plate and powders (approximately 1 to 2 mg) were used as received. The Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a slight vacuum.

[00292] The scanning mode for the metal plate used the gonio scanning axis, while a 2Θ scan was used for the Millipore plate.

[00293] The details of the standard screening data collection method are: • Angular range: 2.5 to 32.0° 2Θ • Step size: 0.0130° 2Θ • Collection time: 12.75 s / step (total collection time of 2.07 min)

[00294] The software used for data collection was X'Pert Data Collector and the data were analyzed and presented using Diffrac Plus EVA. B. Differential scanning calorimeter (DSC) TA Instruments Q2000

[00295] DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5 to 3 mg of each sample, in an aluminum pan with a small hole, were heated at 10 °C / min from 25 °C to 275 °C. A dry nitrogen purge at 50 mL / min was maintained over the sample.

[00296] A temperature-modulated DSC was performed using an underlying heating rate of 2 °C / min and temperature modulation parameters of ±0.636 °C (amplitude) every 60 seconds.

[00297] The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Petition 870260020670, dated 05 / 03 / 2026, page 124 / 525 111 / 225 Universal Analysis or TRIOS. TA Instruments Discovery DSC

[00298] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5 to 3 mg of each sample, in an aluminum pan with a small hole, were heated at 10 °C / min from 25 °C to 275 °C. A dry nitrogen purge at 50 mL / min was maintained over the sample.

[00299] The instrument control software was TRIOS, and the data were analyzed using TRIOS or Universal Analysis. C. Determination of chemical purity by HPLC

[00300] The purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full method details are provided in Table 8. Table 8: HPLC method for chemical purity determinations Parameter Value Method Type Reversed phase with gradient elution Sample Preparation 0.2 mg / mL in acetonitrile:water 1:1 Column Supelco Ascentis Express C18 2.7 μm 100 x 4.6 mm Column Temperature (°C) 25 Injection (pL) 5 Detection: Wavelength, bandwidth (nm) 255, 90 Flow Rate (ml / min) 2 Phase A TFA at 0.1% in water Phase B 0.085% TFA in acetonitrile Timeline Time (minutes) % of phase A % of phase B 0 95 5 6 5 95 6.2 95 5 8 95 5 Petition 870260020670, dated 05 / 03 / 2026, p. 125 / 525 112 / 225 Example 2 - Preparation of Aticaprant THF solvate HOOC OH

[00301] Aqueous sodium hydroxide was added to compound 1 in 2-methyltetrahydrofuran. After phase separation, compound 2, i.e., the free base of compound 1, in 2-MeTHF was subjected to solvent exchange to tetrahydrofuran (THF). Reductive amination of compound 3 using compound 2 was performed by the addition of sodium triacetoxyborohydride and THF. After completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing the crude compound 4 was concentrated, and ethanol and water were added. The product was crystallized using THF, ethanol, and water to produce compound 4 as a solid.

[00302] Charge 7.3 L / kg of water into a reactor. Charge 6.6 L / kg of 2-MeTHF into the reactor. Charge 1.15 mol / mol of compound 1 into the reactor. Add 2.3 mol / mol of 50% aqueous NaOH to the reactor for at least 20 minutes at 22 °C during mixing. Rinse with 1.0 L / kg of water in the reactor. Stir for at least 30 minutes at 22 °C. Adjust for at least 30 minutes. Separate and discard the lower aqueous layer. Concentrate under vacuum to a minimum volume at a maximum of 45 °C. Charge portions of THF into the reactor and distill back to the minimum volume to complete the solvent exchange. Adjust the reactor to 20 °C. Charge 5.0 L / kg of THF into the reactor. Add 1.00 mol of compound 3 to the reactor. Add 10.0 L / kg of THF to the reactor. Adjust R1 to 32 °C and stir for at least 1 hour. Adjust the reactor to 15 °C. Add 1.50 mol / mol of NaBH(OAc)3 in portions to the reactor at 15 °C. Stir for at least 1 hour at 15 °C. Add 5.0 L / kg of water at 15 °C to the reactor.Dose 3.05 mol / mol of 50% aqueous NaOH at 15. Petition 870260020670, dated 05 / 03 / 2026, p. 126 / 525 Add 113 / 225 °C to the reactor and stir for at least 2 hours. Rinse with 0.5 L / kg of water. Adjust for at least 30 minutes. Separate and discard the lower aqueous layer. Charge 6.2 L / kg of 20% aqueous NaCl at 15 °C into the reactor and stir for at least 30 minutes. Adjust for at least 30 minutes. Separate and discard the lower aqueous layer. Concentrate under vacuum at 8.0 L / kg at a maximum of 45 °C. Adjust the reactor to 25 °C. Charge 8.0 L / kg of EtOH (2% MeOH) and 8.0 L / kg of water at 25 °C into the reactor. Dose 2.0 L / kg of water at 25 °C for at least 2.5 hours. Charge 0.03 kg / kg of initial particles of crude compound 4 into the reactor at 25 °C. Stir for at least 2 hours at 25 °C. Charge 6.0 L / kg of water at 25 °C into the reactor for at least 7.5 hours. Cool to 2.5 °C for at least 7 hours. Stir for at least 6 hours at 2.5 °C. Isolate the product and wash with THF / EtOH / water 1:1:2 (volume ratio). Dry the product at 25 °C. Example 3 - Preparation of pure aticaprant

[00303] Load 1.0 mol of crude compound 4 into a dissolution reactor. Add 1.91 L / mol of 2-MeTHF. Add 2.39 L / mol of n-heptane. Stir the reactor contents. Adjust the temperature to 42 °C and stir for at least 10 minutes until complete dissolution. Filter the solution through a polishing filter in a crystallization reactor to remove any insoluble matter that may be present. Rinse the polishing filter. Stir for at least 10 minutes at 40 °C. Cool to 20 °C for at least 1 hour. Stir for at least 10 minutes at 20 °C. Dose 1.23 L / mol of n-heptane for at least 30 minutes at 20 °C. Stir for at least 10 minutes at 20 °C. Inoculate with 0.02 mol / mol of JNJ 67953964 AAA at 20 °C. Stir for no time. Petition 870260020670, dated 05 / 03 / 2026, p. 127 / 525 114 / 225 minimum 8 hours at 20 °C. Dosage 3.68 L / mol of n-heptane over a minimum of 12 hours at 20 °C. Stir for at least 2 hours at 20 °C. Cool to 10 °C over a minimum of 3 hours. Stir for at least 4 hours at 10 °C. Isolate compound 5. Wash the wet cake with 2MeTHF / n-heptane (25 / 75% w / w). Dry compound 5 at 50 °C.

[00304] Characterization was performed on compound 5, and the results are shown in Table 9. Table 9: Characterization data for form III RDXP Crystalline Purity by HPLC 99.3% DSC • Endo. 121.0 °C, 75 J / g. • No degradation observed TGA • No weight loss observed before degradation. • Onset of degradation ~250 °C GVS • 0.4% maximum absorption at 90% relative humidity • No hysteresis observed • RDXP unchanged after GVS

[00305] Form III of aticaprant was found to be crystalline by XRD. 1H NMR showed that the material was consistent with the proposed structure, with the presence of residual ethyl acetate. Ion chromatography showed that no cations / anions were present, and HPLC showed 99.8% purity. DSC (heating from 20 to 131 °C at 10 °C / min) showed a peak temperature at 121 °C. See Figure 3. Example 4 - tablets containing aticaprant

[00306] The tablets containing aticaprant were prepared according to the scheme in Figure 24 containing the components in Table 10. Petition 870260020670, dated 05 / 03 / 2026, page 128 / 525 115 / 225 Table 10: Qualitative and quantitative composition of the aticaprant tablet Component Quantity (mg / tablet) Quantity (mg / tablet) Intragranular phase: Core tablet: Intragranular phase: Aticaprant (unmilled) or aticaprant microfinoa (milled) 5.00 10.00 Microcrystalline cellulose 30.00 60.00 Lactose monohydrateb 30.00 60.00 Croscarmellose sodium 2.50 5.00 Anhydrous colloidal silica 0.50 1.00 Extragranular phase: Silicified microcrystalline cellulose 28.50 57.00 Croscarmellose sodium 2.50 5.00 Anhydrous colloidal silica 0.50 1.00 Magnesium stearatec 0.05 1.00 Basic tablet weight: 100.00 200.00 Film coating: Purified water 12.00d 24.00d Opadry II orange 3.00 6.00 Total weight: 103.00 206.00 a aticaprant microfine is ground aticaprant (physically processed in grinding equipment). b Of animal origin. c Of vegetable origin. d Removed during processing.

[00307] The tablets were prepared in accordance with the following: 1. Mix the following sifted components into a blender using a suitable mixer: Petition 870260020670, dated 05 / 03 / 2026, page 129 / 525 116 / 225 the. Aticaprant or microfine aticaprant b. Microcrystalline cellulose c. Anhydrous colloidal silica d. Lactose monohydrate 2. Sift the mixture using a suitable screen. 3. Add the following sifted components to the mixture. Mix further using a suitable mixer: a. Microcrystalline cellulose b. Lactose monohydrate 4. Sift the mixture using a suitable screen. 5. Add the following sifted components to the mixture. Mix further using a suitable mixer. a. Microcrystalline cellulose b. Lactose monohydrate 6. Sift the mixture using a suitable screen. 7. Add the following sifted components to the mixture. Mix further using a suitable mixer: Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium 8. Produce a dry granulate using an appropriate compaction technique. 9. Add the following sifted components to the dry granules and mix using a suitable mixer: a. Silicified microcrystalline cellulose b. Croscarmellose sodium c. Anhydrous colloidal silica 10. Add the following sifted component to the mixture and blend using a suitable blender: a. Magnesium stearate Petition 870260020670, dated 05 / 03 / 2026, page 130 / 525 117 / 225 11. Compress the blend into nuclear tablets using a suitable tablet press. 12. Suspend the powder coating in purified water using a suitable container. 13. Spray the coating suspension onto the nuclear tablets using a suitable coating agent. 14. Collect the film-coated tablets and pack them in a suitable container. Example 5 - Testing tablets containing aticaprant

[00308] The tablets from Example 3 are tested to determine dissolution properties and chemical stability. See Table 11 for dissolution conditions and Tables 12 and 13 for results. Table 11: Dissolution Operating Conditions Parameter Conditions APPARATUS Paddle (USP type 2, Ph. Eur., JP). Dissolution medium 0.01 M hydrochloric acid Volume 900 mL Temperature 37 ± 0.5 °C Rotation speed 50 rpm Analytical finish UHPLC with UV detection at 247 nm Table 12 Characteristic Acceptance Result of criteria Specificity No interference with peak active dissolution or 100% placebo dissolution <2% No interference Accuracy Recovery at the 20% concentration level of the lowest dosage intensity 20% <X<50 % = 75 a 125 % 100 % Recuperação no nível de concentração de 100 % da menor intensidade de dosagem > 50% = 95 to 105% 102% Petition 870260020670, dated 05 / 03 / 2026, page 131 / 525 118 / 225 Table 12 Characteristic Acceptance Result of criteria Recovery at concentration level of 100% of the highest dosage intensity >50% = 95 to 105% 101% Recovery at concentration level of 120% of the lowest dosage intensity >50% = 95 to 105% 101% Precision - Repeatability of the system % of RSD of 5 injections of the same reference solution <2.0% 0.3% Linearity % of RSD of response factors <4% 0.8% Correlation coefficient (R) >0.995 1.00 Range The criteria of linearity, precision and accuracy are met for the range of 20 to 120% Approved Filtration recovery (Whatman Spartan RC 0.45 μμυ 30 mm) The difference between the % dissolution of the filtered and unfiltered solution The filtered concentration should be <2% for each of the 3 individual filters tested. 1% 0% 1% Solution stability The concentration of active ingredient is within the range of 97 to 103% of the initial value - Stock solutions stored in transparent volumetric bottles under ambient conditions.8 days 101% - Reference solutions stored in transparent volumetric flasks in the refrigerator, 8 days / hours 100% - Reference solutions stored in transparent volumetric flasks at ambient conditions, 8 days 101% - Sample solutions stored in transparent, non-perforated pre-slit flasks in the refrigerator, 7 days / hours 100% - Sample solutions stored in transparent, non-perforated pre-slit flasks at ambient conditions, 7 days 101% System Adequacy % of RSD <2.0% Approved Recovery Reference 1 = 97.0 to 103.0% Approved Recovery Reference 2 = 98.0 to 102.0% Approved Petition 870260020670, dated 05 / 03 / 2026, page 132 / 525 119 / 225 Table 13 - Dissolution (%) of aticaprant tablets Tablet 1 Tablet 2 Tablet 3 Tablet 4 Tablet 5 Tablet 6 98 97 100 98 98 95

[00309] The chemical stability of the tablets is evaluated over a period of 28 days using a risk-based predictive stability study (RiBPS). The stability protocols for the studies are provided in Tables 14 and 15. Table 14 Storage conditions and test frequency for the accelerated stability study Storage time 40 °C / 75% relative humidity 50 °C / 30% relative humidity 60 °C / 10% relative humidity 60 °C / 50% relative humidity 60 °C / 75% relative humidity 70 °C / 30% relative humidity 70 °C / 50% relative humidity 70 °C / 75% relative humidity 80 °C / 10% relative humidity 3 days -- -- -- -- AAAAAA 7 days -- -- AAAAAAAA 14 days -- AAA -- A Aa AAA 21 days -- AAA Aa AAA -- -- 28 days Ab AAAA — — — — — duplicates; triplicates; --: Not tested; A = Chromatographic assay and purity Table 15 Storage time at 5 °C Storage conditions and test frequency for the accelerated stability study 50 °C / 10% relative humidity 50 °C 60 °C / 10% relative humidity 60 °C / 50% relative humidity 70 °C / 30% relative humidity 70 °C / 50% relative humidity 80 °C / 10% relative humidity 80 °C / 50% relative humidity 30% relative humidity 3 days — — — — AAAAA 7 days — AAAAAAAA 14 days — AAA — Aa AAA 21 days Ab AAA Aa AA — — duplicates; triplicates; --: Not tested; A = Assay and chromatographic purity

[00310] The ICH stability protocol is shown in Table 16. Petition 870260020670, dated 05 / 03 / 2026, p. 133 / 525 120 / 225 Table 16: Storage conditions and test frequency for the stability study Storage time (months) Long-term storage conditions Accelerated / stress conditions 5 °C 25 °C / 60% relative humidity 30 °C / 75% relative humidity 40 °C / 75% relative humidity 50 °C Light ICH b unprotected Lux ​​ICHb protected (primary packaging) Initial — A — — — A (A) 3 A (A) AAA — — 6 — (A) AA — — — 9 — (A) A — — — — 12 (A) AA — — — — 18 — (A) A — — — — 24 (A) AA — — — — 36 (A) AA — — — — b Light ICH: CIE85-ID65, energy with integrated near UV not less than 200 Wh / m2, global illumination not less than 1200 klux*h Tests Performed: A = Appearance, assay, chromatographic purity and dissolution; --: Not tested; Tests given in parentheses are kept in reserve and are activated if stability information becomes relevant or if problems arise at the active time points.

[00311] During the RiBPS study, 3 main degradation products (RRT 0.399, RRT 0.466 and RRT 0.874) showed an increasing trend throughout the storage period. Degradation levels ranged from 0.06% to 0.98% for RRT 0.399, from <0.05% to 0.39% for RRT 0.466 and from <0.05% to 0.99% for RRT 0.874.

[00312] The results of the RiBPS study showed that a degrading RRT of 0.466 is the limiting attribute of the pharmaceutical product shelf life.

[00313] The results demonstrated that for the drug stored in an open plate, the probability of passing 12 months is 99% for the specification limit of 0.30% when stored at 25 °C / 60% relative humidity and 30 °C / 75% relative humidity. Example 6

[00314] This was a multicenter, placebo-controlled study, Petition 870260020670, dated 05 / 03 / 2026, p. 134 / 525 A 121 / 225 randomized, double-blind trial was conducted in individuals with MDD who had an inadequate response to SSRI / SNRI treatment. Aticaprant was evaluated as an adjunctive therapy; therefore, eligible individuals were maintained on their SSRI / SNRI treatments without alteration throughout the study. At least 50% of recruited individuals had to be anhedonic (as measured by a total SHAPS score > 20). A. Objectives

[00315] The primary objective was to evaluate the efficacy of aticaprant compared with placebo when administered as adjunctive therapy in individuals with MDD partially responsive to SSRI / SNRI treatment in terms of reducing depressive symptoms, as assessed by the change from baseline in the MADRS in non-responders during the placebo initiation period.

[00316] The secondary objectives are: i. To evaluate the efficacy of aticaprant compared with placebo when administered as adjunctive therapy in individuals with MDD partially responsive to SSRI / SNRI treatment in terms of reducing depressive symptoms, as assessed by the change from baseline in the MADRS in both responders and non-responders during the placebo initiation period. ii. to investigate the safety and overall tolerability of adjunctive aticaprant treatment in individuals with MDD when used in combination with an SSRI or SNRI. iii. To investigate the effect of aticaprant versus placebo on depression-related anhedonia, as assessed by the SHAPS. iv. to investigate the effect of aticaprant on depression symptoms Petition 870260020670, dated 05 / 03 / 2026, page 135 / 525 122 / 225 are with the use of the Clinical Global Impression - Severity (CGI-S), the patient reported the Major Depressive Disorder Symptom Scale (SMDDS) and self-assessment of treatment experience (SATE). v. investigate the effect of aticaprant on anxiety symptoms using HAM-A and on the main symptoms of anxiety using the HAM-A6 subscale. vi. To evaluate the plasma PK of aticaprant in individuals with MDD and explore its relationship with efficacy and safety parameters.

[00317] Secondary exploratory objectives include: i. to explore the effect of aticaprant on aspects of cognitive and executive function using the CPFQ. ii. to explore mood-related biomarkers (including, but not limited to, growth factors, HPA axis markers, immune system activation, metabolic markers) and genetic / epigenetic variation that may be related to clinical response parameters, non-response parameters, or safety and tolerability parameters of aticaprant. B. Study design

[00318] For each individual, the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. See Figure 4.

[00319] Individuals with MDD who had initiated treatment with an approved SSRI / SNRI and experienced an inadequate or only partial response to that treatment were screened. Assessments included the MINI, the Treatment History Questionnaire (TRQ), and the MADRS.

[00320] The treatment phase consisted of 3 periods. A placebo initiation period of concealed duration, after which subjects entered the double-blind treatment period when they were randomly assigned to receive 10 mg of aticaprant (two 5 capsules). Petition 870260020670, dated 05 / 03 / 2026, page 136 / 525 123 / 225 mg) or continue with placebo for 6 weeks. Each capsule contained aticaprant (5 mg), microcrystalline cellulose (94.95 mg), and magnesium stearate (0.05 mg) in a hard gelatin capsule. Individuals who completed the treatment period entered the withdrawal period and were treated with placebo for the remainder of the treatment phase. The total duration for each individual was approximately 16 weeks. There were 11 scheduled visits, including screening. A general flowchart is shown in Figure 4.

[00321] Individuals were screened within 35 to 2 days prior to Day 1 to verify their eligibility according to the inclusion and exclusion criteria. Symptoms of depression were assessed using the MADRS structured interview guide. Double-blind treatment phase

[00322] The duration of the double-blind treatment phase was 11 weeks divided into 3 periods. The individual received the medication after the completion of the visit on Day 1. The first dose was taken at home on Day 2. All medication was taken on an empty stomach. At Visits 3, 4, and 5, individuals were again randomized to conceal from individuals the duration of the placebo start period. During the double-blind phase, individuals visited the center for outpatient visits every 1 to 2 weeks. See Table 17. Table 17: Timeline of Times and Events Screening Phase a Treatment Phase Number of Visits 1 2 3 4 5 6 7 8 9 10 b11 or EW Week (end) -5 to 0 0 1 2 3 4 6 7 8 9 11 Day -3 5 to -2 1 8 15 22 29 43 50 57 64 78 Safety Assessments Physical and Neurological Examination XXXX ASEX XXXXXX KSS XXXXXX Petition 870260020670, dated 05 / 03 / 2026, page 137 / 525 124 / 225 Suicidal behavior according to C-SSRS XXXXXXXXXXX Dosage Randomization XXXX Provide new medication XXXXXXXXX Oral dose medication Day 2 through and including Day 7 Meal after dosing x1 x1 x1 x1 x1 x1 x1 x1 x1 x1 Clinical assessments MADRS Structured Interview Guide Xj XXXXXXXXXX SIGH-A Structured Interview Guide XXXXXXXXXX CGI-S XXXXXXXXXX SMDDS XXXXX CPFQ XXXXX SHAPS XXXXXXXXXXX SATEk once a week, at home Continuous individual analysis Assessment of individual engagementk X up to 3 occasions, when at home Adverse events Continuous Concomitant medications Continuous EW = early withdrawal; a. Visits should be conducted ±3 days from the scheduled day (based on Visit 2, not the previous visit). b. If an individual discontinues treatment before the end of the double-blind treatment phase, the EW visit should be completed. d. at home: on an empty stomach.At the clinic, on visit days: use the blisters dispensed at the previous visit. Fasting condition after completion of pre-dose assessments. e. when Visit 11 is scheduled up to 3 days later, continue medication. j. during the first screening visit and by telephone up to 4 days before Visit 2, if 2 weeks or more have elapsed between the MADRS classification at screening and Visit 2. k. using the Q1.6-app on the individual's smartphone. l. breakfast, lunch, or dinner after taking the medication on site.

[00323] Start period: Individuals who completed with su Petition 870260020670, dated 05 / 03 / 2026, page 138 / 525 125 / 225 patients who completed their baseline examination visit at the clinical site / unit were treated with placebo throughout the initiation period.

[00324] Treatment period: At the end of the initial period, both placebo responders and non-placebo responders were randomized to receive placebo or 10 mg of aticaprant in a 1:1 ratio for 6 weeks. Subjects remained blinded to the exact timing of randomization, response criteria, and drug treatment assignment for each individual.

[00325] Withdrawal period: Individuals who completed the double-blind treatment period before the end of Week 11 entered the withdrawal period, where they were treated with placebo for the remainder of the treatment phase. C. Dosage and administration

[00326] Aticaprant was provided as 5 mg capsules. The placebo was provided as corresponding capsules. All subjects took 2 capsules QD. The capsules were taken daily from Day 2 to Day 78 on an empty stomach with a little water (fasting for at least 4 hours before dose administration). The medication was taken before breakfast. If the subject forgot to take the medication before breakfast, it was taken before the next meal, at the latest at dinner on the same day. If the subject remembered after dinner, that day's dose was omitted and the subject took the dose before breakfast the following day.

[00327] When Visit 11 was scheduled up to 3 days later, the individual continued medication until Visit 11.

[00328] The capsules were swallowed whole and not chewed, divided, dissolved, or crushed. After taking the medication, individuals did not eat or drink for at least 30 minutes. Petition 870260020670, dated 05 / 03 / 2026, page 139 / 525 126 / 225

[00329] The first dose was taken on an empty stomach on Day 2 of the double-blind phase. The medication dose was: • 10 mg of aticaprant: 2 capsules of 5 mg of aticaprant • Placebo: 2 placebo capsules.

[00330] The medication dose was adjusted as needed to 5 mg QD based on the results of a blinded review of safety data. When a dose reduction was decided upon, it applied only to new subjects, and the medication dose was: • 5 mg of aticaprant: 1 capsule containing 5 mg of aticaprant • Placebo: 1 placebo capsule.

[00331] As used herein, the enriched ITT analysis set (eITT) is defined as all enrolled placebo nonresponders at baseline who were randomized to a treatment period, received at least one dose of study medication during the treatment period, and have at least one post-baseline MADRS assessment during the treatment period. Similarly, the complete ITT analysis set (fITT) is defined as all enrolled individuals who were randomized to a treatment period, received at least one dose of study medication during the treatment period, and have at least one post-baseline MADRS assessment during the treatment period. D. Clinical Assessments (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression - Severity (CGI-S), Major Depressive Disorder Symptom Scale (SMDDS), and Self-Assessment of Treatment Experience (SATE) (ii) Anhedonia: Snaith-Hamilton Pleasure Scale (SHAPS) (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and HAM-A6 Petition 870260020670, dated 05 / 03 / 2026, page 140 / 525 127 / 225 (iv) Effects on cognition: Cognitive and Physical Function Questionnaire (CPFQ) (v) Safety assessments

[00332] Standard safety assessments were performed, including physical and neurological examination, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI complaints in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical laboratory test panel to assess the gastric mucosal status. (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Effects of central sedation: Karolinsura Sleepiness Scale (ix) Sexual dysfunction: ASEX E. Patient population

[00333] Of the 184 individuals, 169 were randomized during the treatment period and included in the safety population, while 166 individuals were considered in the full ITT population. Of the 166 individuals in the full ITT population, 121 (73%) were non-responders to placebo at baseline (enriched ITT population) and the remaining 45 (27%) were placebo responders at baseline. Of the 121 individuals in the enriched population, 112 (92.6%) were Caucasian and 84 (69.4%) were female. The mean age was 41.6 years, ranging from 19 to 64 years. All individuals had anhedonia (defined as a total SHAPS score > 20) at treatment baseline. A high level of anhedonia (defined as a total SHAPS score > 38) was observed in 43.8% of individuals. In general, the treatment groups were similar with respect to baseline characteristics. Demographic data for participants for the eITT and safety analyses are available in Tables 18 and 19. Petition 870260020670, dated 05 / 03 / 2026, p. 141 / 525 128 / 225 19. Table 18: Summary of demographic and baseline characteristics: Complete safety analysis Placebo (N=84) aticaprant 10 mg (N=85) Total (N=169) Age (years) N ​​84 85 169 Mean (SD) 42.1 (12.54) 43.0 (12.81) 42.6 (12.65) Median 43.5 43.0 43.0 Range (19; 64) (21; 64) (19;64) Gender N 84 85 169 Female 62 (73.8%) 60 (70.6%) 122 (72.2%) Male 22 (26.2%) 25 (29.4%) 47 (27.8%) Race N 84 85 169 Amerindian or Alaska Native 1 (1.2%) 0 1 (0.6%) Asian 2 (2.4%) 2 (2.4%) 4 (2.4%) Black or African American 2 (2.4%) 5 (5.9%) 7 (4.1%) White 79 (94.0%) 78 (91.8%) 157 (92.9%) Ethnicity N 84 85 169 Hispanic or Latino 10 (11.9%) 13 (15.3%) %) 23 (13.6%) Non-Hispanic or Latino 74 (88.1%) 72 (84.7%) 146 (86.4%) Country N 84 85 169 Germany 4 (4.8%) 5 (5.9%) 9 (5.3%) Moldova 15 (17.9%) 14 (16.5%) 29 (17.2%) Russia 25 (29.8%) 21 (24.7%) 46 (27.2%) Ukraine 9 (10.7%) 7 (8.2%) 16 (9.5%) United Kingdom 10 (11.9%) 15 (17.6%) 25 (14.8%) United States of America 21 (25.0%) 23 (27.1%) 44 (26.0%) Height baseline (cm) N 84 85 169; Petition 870260020670, dated 05 / 03 / 2026, page 142 / 525 129 / 225 Mean (SD) 167.4 (7.91) 168.2 (8.64) 167.8 (8.27) Median 167.5 167.6 167.6 Range (150; 183) (152; 195) (150; 195) Baseline weight (kg) N 84 85 169 Mean (SD) 76.2 (14.73) 78.7 (15.23) 77.4 (14.99) Median 75.3 78.9 77.1 Range (47; 116) (42; 119) (42; 119) Baseline BMI (kg / m2) N 84 85 169 Mean (SD) 27.2 (4.92) 27.7 (4.56) 27.5 (4.73) Median 26.6 28.1 27.6 Range (19; 35) (18; 35) (18; 35) Presence of anhedonia at baseline N 84 85 169 No 0 1 (1.2%) 1 (0.6%) Yes 84 (100.0%) 84 (98.8%) 168 (99.4%) Response status at baseline N 84 85 169 No 62 (73.8%) 62 (72.9%) 124 (73.4%) Yes 22 (26.2%) 23 (27.1%) 45 (26.6%) Table 19: Summary of demographic and baseline characteristics: eITT Placebo (N=61) aticaprant 10 mg (N=60) Total (N=121) Age (years) N ​​61 60 121 Mean (SD) 41.6 (12.34) 41.6 (12.78) 41.6 (12.51) Median 43.0 40.5 42.0 Range (19; 64) (21; 64) (19; 64) Gender N 61 60 121 Female 42 (68.9%) 42 (70.0%) 84 (69.4%) Petition 870260020670, dated 05 / 03 / 2026, p. 143 / 525 130 / 225 Male 19 (31.1%) 18 (30.0%) 37 (30.6%) Race N 61 60 121 Amerindian or Alaska Native 1 (1.6%) 0 1 (0.8%) Asian 2 (3.3%) 1 (1.7%) 3 (2.5%) Black or African American 2 (3.3%) 3 (5.0%) 5 (4.1%) White 56 (91.8%) 56 (93.3%) 112 (92.6%) Ethnicity N 61 60 121 Hispanic or Latino 3 (4.9%) 7 (11.7%) 10 (8.3%) Non-Hispanic or Latino 58 (95.1%) 53 (88.3%) 111 (91.7%) Country N 61 60 121 Germany 4 (6.6%) 4 (6.7%) 8 (6.6%) Moldova 15 (24.6%) 14 (23.3%) 29 (24.0%) Russia 19 (31.1%) 18 (30.0%) 37 (30.6%) Ukraine 7 (11.5%) 5 (8.3%) 12 (9.9%) United Kingdom 6 (9.8%) 10 (16.7%) 16 (13.2%) United States of America 10 (16.4%) 9 (15.0%) 19 (15.7%) Height at baseline (cm) N 61 60 121 Average (SD) 168.1 (8.19) 167.3 (8.10) 167.7 (8.13) Median 168.0 166.3 167.0 Range (151; 183) (152; 186) (151; 186) Baseline weight (kg) N 61 60 121 Mean (SD) 74.7 (14.19) 76.8 (15.12) 75.7 (14.63) Median 74.2 77.1 75.6 Range (47; 116) (42; 119) (42;119) Baseline BMI (kg / m2) N 61 60 121 Mean (SD) 26.4 (4.67) 27.3 (4.36) 26.9 (4.52) Median 25.7 27.8 26.7 Range (19; 35) (18; 35) (18; 35) Presence of anhedonia at baseline; Petition 870260020670, dated 05 / 03 / 2026, page 144 / 525 131 / 225 N 61 60 121 No 0 0 0 Yes 61 (100.0%) 60 (100.0%) 121 (100.0%) Response status at the beginning N 61 60 121 No 61 (100.0%) 60 (100.0%) 121 (100.0%) Yes 0 0 0 E. Effectiveness evaluations

[00334] At the end of the initiation period, the subjects' response status was assessed according to double-blind response criteria based on the reduction in MADRS from baseline at baseline. Both placebo responders at baseline and non-responders at baseline were randomly assigned in a 1:1 ratio to aticaprant or placebo during the treatment period. Randomization was stratified by response status at baseline (non-responders: reduction < 30% from baseline in total MADRS score at the end of the initiation period vs. responders: reduction > 30% from baseline at the end of the initiation period) and presence / absence of anhedonia (presence defined as a total SHAPS score > 20).

[00335] Treatment duration: The study consisted of two periods: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. The double-blind treatment phase of the trial consisted of 3 periods. The first period was a 3-week placebo start period, after which subjects entered the treatment period when they were randomly assigned to aticaprant or continuation on placebo for 6 weeks. Subjects who successfully completed the treatment period were treated with placebo during a 2-week withdrawal period, i.e., Period 3. The total duration for each subject was approximately 16 weeks. Petition 870260020670, dated 05 / 03 / 2026, page 145 / 525 132 / 225

[00336] Primary analysis set for efficacy: The efficacy analysis is based on the eITT set defined as all non-responders enrolled at baseline with placebo who were randomized to the treatment period, received at least one dose of medication, and have at least one MADRS assessment after baseline during the treatment period. The primary analysis set is used for all efficacy outcomes.

[00337] Secondary analysis set for efficacy: A secondary analysis set is the fITT set defined as all enrolled individuals who were randomized to the treatment period, received at least one dose of medication, and have at least one assessment on the MADRS after baseline during the treatment period. The secondary analysis set is used for all efficacy outcomes to examine the effect on the overall population, which can be useful for designing subsequent studies in the development program.

[00338] Safety analysis set: The safety analysis is based on the complete safety analysis set, defined as all enrolled individuals who received at least one dose of medication during the treatment period.

[00339] Efficacy outcomes were presented for both eITT and fITT.

[00340] Significance level: The analysis of the primary efficacy outcome was performed at a significance level of 0.20 (one-sided). The analysis of the secondary efficacy outcomes was performed at a significance level of 0.20 (two-sided). No adjustment for multiple comparisons was performed. F. Results

[00341] (i) Primary outcome: Change from treatment baseline in the total MADRS score at treatment week 6 in non- Petition 870260020670, dated 05 / 03 / 2026, page 146 / 525 133 / 225 responders during the placebo initiation period. Enriched ITT analysis suite

[00342] The mean total MADRS score (SD) at treatment baseline was 29.0 (4.61), in the range of 19 to 41. See Figure 5. The mean change from treatment baseline (SD) in the total MADRS score at week 6 of treatment was -10.2 (8.44) for aticaprant and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 20 and 22, and Figure 8. Table 20: Summary of psychiatric rating scales at the beginning of the preliminary assessment and treatment periods; eITT MADRS Analysis Set Total Score SHAPS Total Score N Mean (SD) Median (Range) N Mean (SD) Median (Range) Baseline at baseline Placebo 61 33.4 (4.25) 34.0 (26; 42) 61 38.0 (6.28) 38.0 (22; 55) Aticaprant 60 32.5 (4.18) 32.0 (25; 45) 60 38.3 (5.66) 38.0 (21; 53) Total 121 32.9 (4.22) 33.0 (25; 45) 121 38.1 (5.96) 38.0 (21; 55) Baseline at treatment Placebo 61 29.2 (5.47) 29.0 (19; 41) 61 36.8 (5.75) 37.0 (23; 50) Aticaprant 60 28.7 (3.58) 28.5 (21; 36) 60 36.4 (5.16) 36.5 (20; 49) Total 121 29.0 (4.61) 29.0 (19; 41) 121 36.6 (5.45) 37.0 (20; 50) Table 21: Total score on MADRS: Mean changes from placebo during the treatment period; eITT analysis set Treatment analysis visit N Mean change from baseline (SD) Mean change to placebo (pooled SD) 90% CI for mean change from placebo Effect size Treatment Week 1 Placebo 61 -2.2 (3.73) Aticaprant 60 -3.3 (5.21) -1.1 (4.52) [-2.4, 0.3] -0.24 Treatment Week 3 Placebo 59 -4.3 (5.99) Aticaprant 59 -5.7 (6.38) -1.4 (6.18) [-3.3, 0.5] -0.22 Petition 870260020670, dated 05 / 03 / 2026, page 147 / 525 134 / 225 Week 4 of treatment: Placebo 60 -6.4 (6.66) Aticaprant 57 -7.3 (7.35) -0.9 (7.00) [-3.1, 1.2] -0.14 Week 5 of treatment: Placebo 60 -7.4 (7.15) Aticaprant 55 -8.4 (7.36) -1.1 (7.25) [-3.3, 1.2] -0.14 Week 6 of treatment: Placebo 59 -8.2 (8.53) Aticaprant 59 -10.2 (8.44) -2.0 (8.49) [-4.6, 0.6] -0.23 A negative change from baseline indicates improvement. A negative change for placebo indicates a favorable effect of aticaprant. The size of the negative effect favors aticaprant; the size of the positive effect favors placebo. Table 22: Total score on MADRS: MMRM results - estimated mean LS compared to placebo; eITT Analysis Set Treatment Analysis Visit N Mean (SD) Mean (SD) Mean LS (SE) Difference from mean LS (SE) / placebo treatment 60% confidence interval on difference value ^a pa Treatment Week 1 Placebo 61 26.9 (6.77) -2.2 (3.73) -2.0 (0.92) aticaprant 60 25.4 (5.93) -3.3 (5.21) -3.2 (0.93) -1.2 (1.24) [-2.28, 0.19] 0.1604 Treatment Week 3 Placebo 59 24.8 (8.25) -4.3 (5.99) -4.2 (0.92) aticaprant 59 23.1 (6.58) -5.7 (6.38) -5.6 (0.93) -1.5 (1.25) [-2.55, 0.44] 0.1159 Week 4 of treatment Placebo 60 22.7 (9.10) -6.4 (6.66) -6.2 (0.92) aticaprant 57 21.5 (7.49) -7.3 (7.35) -7.3 (0.93) -1.1 (1.25) [-2.19, 0.09] 0.1811 Petition 870260020670, dated 05 / 03 / 2026, page 148 / 525 135 / 225 Week 5 of treatment Placebo 60 21.7 (9.54) -7.4 (7.15) -7.2 (0.92) aticaprant 55 20.5 (7.44) -8.4 (7.36) -8.7 (0.94) -1.5 (1.25) [-2.60, 0.48] 0.1103 Week 6 of treatment Placebo 59 20.9 (10.54) -8.2 (8.53) -8.0 (0.92) aticaprant 59 18.6 (8.14) -10.2 (8.44) -10.1 (0.93) -2.1 (1.25) [-3.20, 1.09] 0.0443 a One-tailed test for no difference between treatments from an MMRM model with individual as effect Randomized; country, treatment, time, and time-per-treatment interaction as factors; and total MADRS score at baseline as a continuous covariate. An AR(1) variance-covariance matrix was used.

[00343] Based on the results of an MMRM model with individual as the random effect; country, treatment, time, and time-per-treatment interaction as factors; and with the baseline MADRS total score as a continuous covariate, a significant positive efficacy signal was detected for aticaprant versus placebo at the one-sided significance level of 0.20. The estimated mean LS difference at week 6 of treatment between aticaprant and placebo was -2.1, with an 80% upper limit of one-sided CI of -1.09. The corresponding p-value was 0.044. The treatment effect was larger in the fITT population than in the eITT population: -3.1 with an 80% upper limit of one-sided CI of -2.2 (p = 0.002). The effect size was 0.36 and 0.23, respectively. See Figures 2 and 3. Complete set of ITT analyses

[00344] The mean baseline (SD) total MADRS score at treatment baseline was 25.3 (7.86), in the range of 0 to 41. See Figures 7A and 7B. Mean changes from treatment baseline in total MADRS score at Treatment Week Petition 870260020670, dated 05 / 03 / 2026, page 149 / 525 136 / 225 ment 6 for fITT were smaller than for eITT: -9.7 (8.02) for aticaprant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results illustrate a statistical superiority over placebo with a durability of effect with the greatest difference observed at week 6. See Table 23. Table 23: Summary of psychiatric rating scales at the beginning of the preliminary assessment and treatment periods; Set of analyses fITT MADRS Total score SHAPS Total score N Mean (SD) Median (Range) N Mean (SD) Median (Range) Baseline at baseline Placebo 83 32.8 (4.25) 33.0 (26; 42) 83 37.8 (6.01) 38.0 (22; 55) Aticaprant 83 32.4 (4.27) 32.0 (21; 45) 83 37.3 (6.23) 38.0 (14; 53) Total 166 32.6 (4.25) 32.0 (21; 45) 166 37.6 (6.11) 38.0 (14; 55) Baseline in treatment Placebo 83 25.7 (7.73) 26.0 (10; 41) 83 36.3 (5.44) 36.0 (23; 50) Aticaprant 83 24.8 (8.02) 27.0 (0; 36) 83 35.0 (5.85) 36.0 (14; 49) Total 166 25.3 (7.86) 26.5 (0; 41) 166 35.6 (5.67) 36.0 (14; 50)

[00345] A significant effect was also detected for aticaprant versus placebo in the fITT population. The estimated mean LS difference at week 6 of treatment between aticaprant and placebo was -3.1, with an 80% upper limit of one-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 24 and 25, and Figure 6. Table 24: Total score on MADRS: MMRM results - estimated mean LS compared to placebo; fITT analysis set Change from baseline Treatment analysis visit N Mean (SD) Mean (SD) Mean LS (SE) Difference from mean LS (SE) / treatment with placebo 60% confidence interval for difference pa Week 1 of treatment Placebo 83 24.0 (8.12) -1.8 (4.00) -1.7 (0.78) aticaprant 83 21.7 (8.78) -3.1 (4.81) -3.2 (0.77) -1.6 (1.03) [-2.44, 0.70] 0.0653 Week 3 of treatment Petition 870260020670, dated 05 / 03 / 2026, page 150 / 525 137 / 225 Week 4 of treatment: Placebo 81 22.2 (9.28) -3.4 (6.50) -3.4 (0.78) aticaprant 80 20.0 (8.53) -5.1 (6.74) -5.2 (0.78) -1.9 (1.04) [-2.74, 0.99] 0.0368 Week 5 of treatment: Placebo 82 20.8 (9.24) -4.9 (7.02) -4.8 (0.78) aticaprant 78 17.9 (9.32) -7.2 (7.02) -7.3 (0.78) -2.5 (1.04) [-3.34, 1.59] 0.0093 -6.3 (0.78) aticaprant 76 16.7 (9.47) -8.3 (7.48) -8.7 (0.78) -2.4 (1.05) [-3.24, 1.47] 0.0125 Week 6 of treatment Placebo 81 19.0 (10.35) -6.6 (8.57) -6.5 (0.78) aticaprant 77 15.9 (9.09) -9.7 (8.02) -9.6 (0.79) -3.1 (1.05) [-3.97, 2.21] 0.0017 a One-tailed test for no difference between treatments from an MMRM model with individual as random effect; country, treatment, time and time-per-treatment interaction as factors; and total score on the MADRS at baseline as continuous covariate. An AR(1) variance-covariance matrix was used. Table 25: Total score (Glomery-Asberg): Change in MADRS (mean scales in relation to placebo; Set of analyses of depression from Monção to placebo during the treatment analysis period. Treatment analysis visit N Mean change to placebo (pooled SD) 90% CI for mean change from placebo Effect size Treatment week 1 Placebo 83 Aticaprant 83 -1.3 (4.43) [-2.4, -0.2] -0.29 Treatment week 3 Placebo 81 Aticaprant 80 -1.7 (6.62) [-3.4, 0.0] -0.26 Treatment week 4 Placebo 82 Aticaprant 78 -2.3 (7.02) [-4.1, -0.4] -0.32 Treatment week 5 Placebo 82 Aticaprant 76 -1.9 (7.31) [-3.9, -0.0] -0.26 Week 6 of treatment Placebo 81 Aticaprant 77 -3.0 (8.31) [-5.2, -0.8] -0.36 A negative change from baseline indicates improvement. A negative change for placebo indicates a favorable effect of aticaprant. The size of the negative effect favors aticaprant; the size of the positive effect favors placebo. Petition 870260020670, dated 05 / 03 / 2026, page 151 / 525 138 / 225 Impact of COVID-19 on the primary assessment of effectiveness

[00346] The supplementary analysis was conducted using the same MMRM model as described for the primary analysis on all data collected before March 15, 2020 (estimated date of COVID-19 lockdowns in most participating countries). Seventeen percent of individuals in the fITT group and 19% in the eITT population had at least one assessment on the MADRS excluded from the model due to the impact of COVID-19. The results of the analysis corroborated the findings of the primary efficacy analysis in both the eITT and fITT populations. The LS mean difference estimate was -3.0 (upper limit of the one-sided 80% CI of -1.88) for eITT and -3.4 (upper limit of the one-sided 80% CI of -2.51) for fITT. (ii) Secondary outcomes MADRS remission rates relative to treatment period

[00347] At week 6 of treatment, the percentage of individuals with MADRS remission (total MADRS score < 10) in the eITT population was 16.9% for aticaprant and 16.9% for placebo. Remission rates at week 6 of treatment in the fITT population were 31.2% for aticaprant and 22.2% for placebo. For both populations (eITT and fITT), no significant treatment difference was detected at week 6 of treatment using the chi-square test (p = 0.999 and p = 0.203 two-sided, respectively). See Figures 11 and 12. Response rates on MADRS (at least 30% improvement) relative to the treatment period.

[00348] The percentage of individuals with > 30% improvement in the total MADRS score at week 6 of treatment in the eITT population was 57.6% for aticaprant and 45.8% for placebo. Response rates at week 6 of treatment in the fITT population were 61.8% for aticaprant and 44.4% for placebo. For both populations Petition 870260020670, dated 05 / 03 / 2026, page 152 / 525 139 / 225 tions, the treatment differences in treatment week 6 were significant at the 20% two-sided significance level (chi-square test, p = 0.197 for eITT and p = 0.029 for fITT). Response rates on MADRS (at least 50% improvement) relative to the treatment period.

[00349] The percentage of individuals with > 50% improvement in total MADRS score at week 6 of treatment in the eITT population was 35.6% for aticaprant and 22.0% for placebo. Response rates at week 6 of treatment in the fITT population were 38.2% for aticaprant and 23.5% for placebo. For both populations, 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 26 and Figures 13 and 16. Table 26: Change from treatment baseline in total MADRS score at treatment week 6 in both responders and non-responders during the placebo initiation period. Endpoint values ​​of the test: Placebo aticaprant at 10 milligrams (mg). Number of individuals analyzed: 81 77. Units: score on a scale. Measurement type: Least squares mean (standard error). -6.5 ± 0.78 -9.6 ± 0.79 p-value = 0.0017. Parameter type: Least squares mean difference. Point estimate: -3.1. Confidence interval: 80% level. One-sided. Petition 870260020670, dated 05 / 03 / 2026, page 153 / 525 140 / 225 Lower limit - Upper limit -2.21 Variability estimate Standard error of the mean Dispersion value 1.05 Changes in the total SHAPS score from treatment baseline to treatment week 6. Enriched ITT analysis suite

[00350] In the eITT population, in a subgroup of individuals with high levels of anhedonia (baseline SHAPS total score > 38), greater differences between placebo and aticaprant at week 6 were observed than in individuals with low levels of anhedonia (20 < baseline SHAPS total score < 38). The effect sizes were 0.38 and 0.11, respectively.

[00351] The mean total SHAPS score (SD) at treatment baseline was 36.6 (5.45), in the range of 20 to 50. The mean change from treatment baseline (SD) in the total SHAPS score at week 6 of treatment was -4.6 (6.23) for aticaprant and -4.2 (5.04) for placebo. The observed effect size was 0.07. See Table 27 and Figures 17 and 37. Table 27: Total SHA score during the iPS period: Mean changes from placebo treatment; eITT Analysis Set Treatment Analysis Visit N Mean Change from Baseline (SD) Mean Change to Placebo (pooled SD) 90% CI for Mean Change from Placebo Effect Size Treatment Week 1 Placebo 61 -1.3 (3.17) aticaprant 60 -1.9 (4.30) -0.6 (3.77) [-1.7, 0.6] -0.15 Treatment Week 3 Placebo 59 -2.2 (4.65) aticaprant 59 -3.4 (5.25) -1.2 (4.96) [-2.8, 0.3] -0.25 Treatment Week 4 Placebo 60 -3.3 (4.47) aticaprant 57 -4.5 (5.89) -1.2 (5.21) [-2.8, 0.4] -0.23 Treatment Week 5 Placebo 60 -3.9 (4.88) aticaprant 56 -4.3 (6.07) -0.4 (5.49) [-2.1, 1.3] -0.08 Petition 870260020670, dated 05 / 03 / 2026, page 154 / 525 141 / 225 Week 6 of treatment Placebo 59 -4.2 (5.04) aticaprant 59 -4.6 (6.23) -0.4 (5.66) [-2.1, 1.3] -0.07 Negative change in re to placebo indicates effect favors aticaprant action to baseline indicates improvement. Negative change to aticaprant favorable. The size of the negative effect it; the size of the positive effect favors placebo.

[00352] Changes in the total SHAPS score were analyzed using the same MMRM model used for the total MADRS score. The estimated mean LS difference with a two-sided 80% CI at week 6 of treatment between aticaprant and placebo was -0.7 [-1.81, 0.41]. See Figure 7, Tables 28 and 29, and Figure 18. The corresponding p-value was 0.419. Table 28: Total score on SHAPS: MMRM results - estimated mean LS compared to placebo; eITT Analysis Set Change from Baseline Treatment Analysis Visit N Mean (SD) Mean (SD) Mean LS (SE) Difference from mean LS (SE) / placebo treatment 60% confidence interval for difference pa value Treatment Week 1 Placebo 61 35.5 (6.00) -1.3 (3.17) -0.9 (0.63) aticaprant 60 34.5 (5.63) -1.9 (4.30) -1.7 (0.64) -0.8 (0.86) [-1.90, 0.31] 0.3542 Treatment Week 3 Placebo 59 34.9 (6.09) -2.2 (4.65) -1.8 (0.64) aticaprant 59 33.0 (6.39) -3.4 (5.25) -3.2 (0.64) -1.4 (0.86) [-2.53, -0.31] 0.1005 Week 4 of treatment Placebo 60 33.7 (5.89) -3.3 (4.47) -2.9 (0.63) aticaprant 57 32.0 (6.24) -4.5 (5.89) -4.3 (0.64) -1.4 (0.86) [-2.48, -0.26] 0.1131 Week 5 of treatment Placebo 60 33.1 (5.88) -3.9 (4.88) -3.5 (0.64) aticaprant 56 32.4 (6.61) -4.3 (6.07) -4.0 (0.64) -0.5 (0.87) [-1.65, 0.57] 0.5332 Week 6 of Placebo treatment 59 32,9 (6.04) -4.2 (5.04) -3.7 (0.64) aticaprant 59 31.9 (6.60) -4.6 (6.23) -4.4 (0.64) -0.7 (0.87) [-1.81, 0.41] 0.4188 a Two-tailed test of MMRM correlation with time as a covariate for no difference in individual as a random effect, treatment as factors; and continuous. A variance matrix between treatments from a single month; country, treatment, time and total interaction in the SHAPS at baseline variance-covariance AR(1) was used. Petition 870260020670, dated 05 / 03 / 2026, page 155 / 525 142 / 225 Table 29: Total score on SHAPS: MMRM results - estimated mean LS compared to placebo; fITT Analysis Set Change from Baseline Treatment Analysis Visit N Mean (SD) Mean (SD) Mean LS (SE) Difference from mean LS (SE) / placebo treatment 60% confidence interval in the difference pa value Treatment Week 1 Placebo 83 34.8 (5.86) -1.5 (3.57) -1.0 (0.54) aticaprant 83 32.9 (6.09) -2.0 (4.05) -1.9 (0.54) -1.0 (0.72) [-1.88, 0.02] 0.1888 Treatment Week 3 Placebo 81 34.3 (6.36) -2.2 (5.11) -1.7 (0.54) aticaprant 80 31.9 (6.54) -3.2 (5.07) -3.1 (0.54) -1.4 (0.73) [-2.32, 0.45] 0.0580 Week 4 of treatment Placebo 82 33.4 (5.70) -3.0 (4.41) -2.5 (0.54) aticaprant 78 30.8 (6.37) -4.2 (5.70) -4.1 (0.55) -1.6 (0.73) [-2.51, 0.63] 0.0321 Week 5 of treatment Placebo 82 32.6 (5.63) -3.8 (4.76) -3.3 (0.55) aticaprant 77 30.9 (6.76) -4.3 (5.70) -4.1 (0.55) -0.8 (0.73) [-1.71, 0.17] 0.2912 Week 6 of Placebo treatment 81 32,2 (5.81) -4.2 (4.98) -3.7 (0.55) aticaprant 77 30.5 (6.98) -4.7 (5.91) -4.5 (0.55) -0.8 (0.73) [-1.79, 0.10] 0.2503 a Two-tailed test for no MMRM with individual as and time per treatment as a continuous covariate. A π difference between treatments from a random effect; country, treatment, time and interaction; and total score on the SHAPS at baseline variance-covariance matrix AR(1) was used,

[00353] The estimated mean LS difference with a two-sided 80% CI at week 6 of treatment between aticaprant and placebo was -0.8 [1.79, 0.10]. The corresponding p-value was 0.250. See Figures 7 and 8. Complete set of ITT analyses

[00354] A similar trend was observed in the fITT population and the differences were greater in magnitude than those observed in the fITT population. Petition 870260020670, dated 05 / 03 / 2026, page 156 / 525 143 / 225 served in the eITT population. The effect size was 0.51 and 0.29, respectively. The mean baseline SHAPS total score at treatment baseline was 35.6 (5.67), in the range of 14 to 50. The mean changes from treatment baseline in the SHAPS total score at week 6 of treatment for the fITT population were similar to the changes in the eITT population: -4.7 (5.91) for aticaprant and -4.2 (4.98) for placebo. The observed effect size was 0.08. See Table 30. Table 30: Total SHAPS score: Mean changes from placebo during the treatment period; fITT Analysis Set Analysis Visit Treatment N Mean change from baseline (SD) Mean change to placebo (pooled SD) 90% CI for mean change from placebo Effect size Treatment Week 1 Placebo 83 -1.5 (3.57) aticaprant 83 -2.0 (4.05) -0.6 (3.82) [-1.5, 0.4] -0.15 Treatment Week 3 Placebo 81 -2.2 (5.11) aticaprant 80 -3.2 (5.07) -1.0 (5.09) [-2.4, 0.3] -0.20 Treatment Week 4 Placebo 82 -3.0 (4.41) aticaprant 78 -4.2 (5.70) -1.2 (5.08) [-2.5, 0.1] -0.23 Treatment Week 5 Placebo 82 -3.8 (4.76) aticaprant 77 -4.3 (5.70) -0.5 (5.24) [-1.8, 0.9] -0.09 Week 6 of treatment Placebo 81 -4.2 (4.98) aticaprant 77 -4.7 (5.91) -0.5 (5.45) [-1.9, 1.0] -0.08 Negative change from baseline indicates improvement. Negative change for placebo indicates a favorable effect of aticaprant.The magnitude of the negative effect favors aticaprant; the magnitude of the positive effect favors placebo. Changes in total MADRS score from treatment baseline to treatment week 6 by baseline anhedonia level. Enriched ITT analysis suite. Petition 870260020670, dated 05 / 03 / 2026, page 157 / 525 144 / 225

[00355] In the subgroup of individuals with high levels of anhedonia (total SHAPS score > 38) at baseline, n = 53, larger differences between aticaprant and placebo at week 6 of treatment were observed than in individuals with low levels of anhedonia (20 < total SHAPS score at baseline < 38), n = 65: 3.4 with a two-sided 90% CI of [-7.5, 0.7] and -0.9 with a two-sided 90% CI of [-4.2, 2.5], respectively (Table 31). The observed effect sizes were 0.38 and 0.11, respectively. Table 31: Total score on the MADRS (Montgomery-Asberg Depression Rating Scale): Mean changes from placebo during the treatment period by baseline anhedonia level; eITT Analysis Set Treatment Analysis Visit N Mean Change from Baseline (SD) Mean Change to Placebo (pooled SD) 90% CI for Mean Change from Placebo Effect Size Low Anhedonia Treatment Week 1 Placebo 34 -1.8 (3.43) aticaprant 34 -2.3 (5.03) -0.5 (4.30) [-2.2, 1.2] -0.12 Treatment Week 3 Placebo 32 -4.8 (5.70) aticaprant 33 -4.9 (5.99) -0.1 (5.85) [-2.5, 2.4] -0.01 Treatment Week 4 Placebo 33 -6.5 (6.16) aticaprant 32 -6.4 (7.40) 0.0 (6.80) [-2.8, 2.9] 0.01 Week Week 5 of treatment Placebo 33 -7.6 (6.80) aticaprant 29 -7.2 (6.46) 0.3 (6.65) [-2.5, 3.2] 0.05 Week 6 of treatment Placebo 32 -8.3 (8.25) aticaprant 33 -9.2 (8.01) -0.9 (8.13) [-4.2, 2.5] -0.11 High anhedonia Week 1 of treatment Placebo 27 -2.7 (4.08) aticaprant 26 -4.6 (5.25) -1.8 (4.69) [-4.0, 0.3] -0.39 Week 3 of treatment Placebo 27 -3.6 (6.35) aticaprant 26 -6.7 (6.83) -3.0 (6.59) [-6.1, 0.0] -0.46 Week 4 of treatment Placebo 27 -6.3 (7.34) aticaprant 25 -8.5 (7.26) -2.2 (7.30) [-5.6, 1.2] -0.30 Week 5 of treatment Placebo 27 -7.1 (7.67) aticaprant 26 -9.7 (8.18) -2.6 (7.93) [-6,3, 1,0] -0,33, Petition 870260020670, dated 05 / 03 / 2026, page 158 / 525 145 / 225 Week 6 of treatment Placebo 27 -8.1 (9.01) aticaprant 26 -11.5 (8.95) -3.4 (8.98) [-7.5, 0.7] -0.38 Low level of anhedonia (total score on SH >= 20 and < 38), high level of anhedonia (treatment score >= 38). A higher total score on MAD indicates greater APS at baseline. The total score on SHAPS at baseline is in the range of 0 to 60, with the severity of depression. Complete set of ITT analyses

[00356] A similar trend was observed in the fITT population. The differences were larger in magnitude compared to the eITT population: -4.6 with a two-sided 90% CI of [-8.4, -0.8] for individuals with high levels of anhedonia (n = 63) and -2.3 with a two-sided 90% CI of [-5.0, 0.4] for individuals with low levels of anhedonia (n = 94). See Table 32. The observed effect size was 0.51 and 0.29, respectively. Table 32: Total score on the MADRS (Montgomery-Asberg Depression Rating Scale): Mean changes from placebo during the treatment period by baseline anhedonia level;fITT Analysis Set Treatment Analysis Visit N Mean Change from Baseline (SD) Mean Change to Placebo (pooled SD) 90% CI for Mean Change from Placebo Effect Size Low Anhedonia Treatment Week 1 Placebo 49 -1.3 (4.17) aticaprant 52 -2.4 (4.59) -1.0 (4.39) [-2.5, 0.4] -0.24 Treatment Week 3 Placebo 47 -3.6 (6.04) aticaprant 49 -4.1 (6.67) -0.5 (6.37) [-2.7, 1.7] -0.08 Treatment Week 4 Placebo 48 -4.9 (6.53) aticaprant 48 -6.4 (6.77) -1.5 (6.65) [-3.8, 0.8] -0.23 Week 5 of treatment Placebo 48 -6.6 (6.82) aticaprant 45 -7.3 (6.90) -0.7 (6.86) [-3.1, 1.7] -0.10 Week 6 of treatment Placebo 47 -6.5 (8.11) aticaprant 47 -8.8 (7.48) -2.3 (7.80) [-5.0, 0.4] -0.29 High anhedonia Week 1 of treatment Placebo 34 -2.4 (3.71) aticaprant 30 -4.4 (5.04) -2.0 (4.38) [-3.8, -0.1] -0.45 Week 3 of treatment Placebo 34 -3.1 (7.17); Petition 870260020670, dated 05 / 03 / 2026, page 159 / 525 146 / 225 aticaprant 30 -6.9 (6.66) -3.8 (6.94) [-6.7, -0.9] -0.54 Week 4 of treatment Placebo 34 -4.8 (7.75) aticaprant 29 -8.6 (7.32) -3.8 (7.56) [-7.0, -0.6] -0.50 Week 5 of treatment Placebo 34 -6.2 (7.72) aticaprant 30 -10.2 (8.04) -4.0 (7.87) [-7.3, -0.7] -0.51 Week 6 of treatment Placebo 34 -6.8 (9.30) aticaprant 29 -11.3 (8.69) -4.6 (9.03) [-8.4, -0.8] -0.51 Low level of anhedonia (total score in SHAPS score at baseline >= 20 and < 38), high level of anhedonia (total SHAPS score at baseline >= 38). A total MADRS score ranges from 0 to 60, with higher scores indicating greater severity of depression.

[00357] These data illustrate that targeting high versus low anhedonia had a benefit in the treatment of MDD: a greater treatment effect for aticaprant. Furthermore, the placebo response was lower in patients with high anhedonia compared to those with low anhedonia. Change from treatment baseline in the total CGI-S score during treatment. Table 33: Change from baseline in total CGI-S score in treatment. Endpoint values ​​of the test. Placebo aticaprant at 10 milligrams (mg). Number of individuals analyzed: 59. Units: Scores on a scale. Measurement type: Arithmetic mean (SD). -0.76 ± 0.858 -0.92 ± 1.039 Change from treatment baseline in the total score SMDDS in week 6 of treatment Table 34: Change from baseline in total SMDDS score at treatment week. Endpoint values ​​of the test. Placebo aticaprant at 10 milligrams (mg). Number of individuals analyzed: 59. Units: Scores on a scale. Measurement type: Arithmetic mean (SD). -8.49 ± 9.567 -8.03 ± 9.957 Petition 870260020670, dated 05 / 03 / 2026, page 160 / 525 147 / 225 Number of individuals with a SATE score at week 6 of treatment. Table 35: Number of individuals with SATE score at week 6 of treatment. Endpoint values ​​of the test. Placebo aticaprant at 10 milligrams (mg). Number of individuals analyzed: 61, 60. Units: individuals. Depression overall (worsened) (n = 40, 30): 1, 0. Depression overall (no change) (n = 40, 30): 12, 9. Depression overall (improved) (n = 40, 30): 27, 21. Depression worsened (slightly worse) (n = 1.0): 1, 0. Depression worsened (much worse) (n = 1.0): 0, 0. Depression worsened (extremely worse) (n = 1.0): 0, 0. Depression slightly improved (n = 27, 21): 13, 15. Depression much improved (n = 27, 21): 11, 6. Depression extremely improved (n = 27, 21): 11, 6. 21) 3 0 Change from treatment baseline in the total score HAM-A6 in week 6 of treatment Table 36: Change from baseline in total HAM-A6 score at week 6 of treatment. Endpoint values ​​of the test. Placebo aticaprant 10 milligrams (mg). Number of individuals analyzed: 59. Units: scale scores. Measurement type: Arithmetic mean (SD). -2.19 ± 2.837 -2.73 ± 2.651

[00358] These data show a greater improvement in the score of HAMA6 of patients treated with aticaprant compared with placebo. Change from baseline in the structured interview guide for the SIGH-A score at week 6 of treatment. Table 37: Change from baseline in the structured interview guide for the SIGH-A score at week 6 of treatment. Endpoint values ​​of the test. Placebo aticaprant at 10 milligrams (mg). Number of individuals analyzed: 59. Units: scale scores. Measurement type: Arithmetic mean (SD). -5.37 ± 6.549 -5.85 ± 5.369 Petition 870260020670, dated 05 / 03 / 2026, page 161 / 525 148 / 225 Maximum plasma concentration (Cmax) of aticaprant

[00359] Cmax is defined as the maximum plasma concentration of aticaprant. The eITT population included all baseline placebo nonresponders who were randomized to a treatment period, received at least 1 dose of the study medication, and had at least 1 assessment on the MADRS after baseline during the treatment period. Here, N (number of individuals analyzed) includes the number of individuals evaluable for this outcome. Here, n (number analyzed) includes all individuals evaluable for specified time point categories. Table 38: Cmax of aticaprant (10 mg) Number of individuals analyzed: 58 Units: nanograms per milliliter (ng / mL) Measurement type: Arithmetic mean (SD) Week 1 (n = 56) 32.7 ± 10.9 Week 3 (n = 56) 33.5 ± 11.1 Week 6 (n = 56) 34.3 ± 11.1 No statistical analysis of this test endpoint. (iii) Final points of the security test

[00360] Overall, in a complete set of safety analyses, 40 / 85 (47.1%) of individuals in the aticaprant group and 30 / 84 (35.7%) of individuals in the placebo group experienced at least one TEAE during the treatment period. See Table 39. Table 39: General summary of adverse events resulting from treatment up to the end of the study; Complete set of safety analyses Placebo (N=84) n (%) aticaprant a 10 mg (N = 85) n (%) Total (N = 169) n (%) Individuals with 1 or more AEs 30 (35.7) 40 (47.1) 70 (41.4) Total individuals affected by non-serious adverse events 9 (10.7%) 23 (27.1%) Individuals with drug-related AEs a 13 (15.5) 20 (23.5) 33 (19.5) Individuals with AEs leading to death 0 0 0 Individuals with 1 or more serious AEs 1 (1.2) 0 1 (0.6) Individuals with AEs leading to discontinuation of the agent 1 (1.2) 1 (1.2) 2 (1.2) a Possible, probable, drug interactions from the study Many are included in this category. Individuals are presented with skin received during the treatment period. The likely treatment... Petition 870260020670, dated 05 / 03 / 2026, page 162 / 525 149 / 225

[00361] The most common TEAEs during the treatment period were headache (experienced by 10 / 85 individuals - 11.8% in the aticaprant group and by 6 / 84 individuals - 7.1% in the placebo group) and diarrhea (experienced by 7 / 85 individuals - 8.2% in the aticaprant group and by 2 / 84 individuals - 2.4% in the placebo group). See Table 40. Table 40: Treatment-emergent adverse events by body system or organ class and dictionary-derived term >= 5% of individuals in any treatment group during the treatment period; Complete set of safety analyses Placebo (N = 84) aticaprant 10 mg (N = 85) Total (N = 169) Body System Preferred term n (%) n (%) n (%) Total number of individuals with adverse events 30 (36) 40 (47) 70 (41) Infections and infestations 9 (11) 13 (15) 22 (13) Nasopharyngitis 2 (2) 5 (6) 7 (4) Nervous system disorders 9 (11) 13 (15) 22 (13) Headache 6 (7) 10 (12) 16 (10) Gastrointestinal disorders 9 (11) 12 (14) 21 (12) Diarrhea 2 (2) 7 (8) 9 (5) Skin and subcutaneous tissue disorders 3 (4) 6 (7) 9 (5) Pruritus 0 5 (6) 5 (3) Percentages calculated with the number of individuals in the treatment. Reported dictionary version: MedDRA 2.1. Individuals are presented with the treatment received during the treatment period.

[00362] There were 2 individuals in total who discontinued during the treatment period due to treatment-emergent adverse events: 1 individual in the aticaprant 10 group due to diarrhea, nausea, vomiting, and headache, and another individual in the placebo group due to acute calculous cholecystitis.

[00363] Overall, 17 / 169 individuals experienced TEAEs of special interest during the treatment period: 13 / 85 (15.3%) in the aticaprant group and 4 / 84 (4.8%) in the placebo group. The most common treatment-emergent adverse events during the treatment phase were headache and diarrhea. The most common TEAEs of special interest during the treatment period were diarrhea and pruritus (experienced by 5 / 85 individuals - 5.9% in the aticaprant group). Petition 870260020670, dated 05 / 03 / 2026, page 163 / 525 150 / 225 patients in the placebo group, and 0 / 84 in the placebo group). Additionally, 1 patient in the placebo group (1.19%) experienced acute cholecystitis, compared to 0 patients who received aticaprant. See Table 41. Table 41: Treatment-emergent adverse events of interej during the treatment period; Complete set of analyses of special interest and safety Placebo (N=84) aticaprant 10 mg (N = 85) Total (N = 169) Body System Preferred term n (%) n (%) n (%) Total number of individuals with adverse events of special interest 4 (4.8) 13 (15.3) 17 (10.1) Gastrointestinal disorders 4 (4.8) 9 (10.6) 13 (7.7) Treatment-related deaths / all Diarrhea 2 (2.4) 7 (8.2) 9 (5.3) Upper abdominal pain 2 (2.4) 0 2 (1.2) Dyspepsia 1 (1.2) 1 (1.2) 2 (1.2) Abdominal pain 0 1 (1.2) 1 (0.6) Skin and subcutaneous tissue disorders 0 5 (5.9) 5 (3.0) Pruritus 0 5 (5.9) 5 (3.0) Percentages calculated with the number of individuals in each group as the denominator. Dictionary version reported: MedDRA 22.1. Individuals are presented by treatment received during the treatment period.

[00364] Two serious adverse events occurred. One individual in the placebo group developed acute calculous cholecystitis during the treatment period and another individual experienced suicidal ideation during the initiation period. Both individuals discontinued treatment due to these AEs.

[00365] No deaths were reported.

[00366] (iv) Anhedonia analysis

[00367] Patients in the larger fITT group maintained baseline depression levels and anhedonia severity consistent with the eITT group. See Tables 42–44. Table 42: Frequency of individuals with anhedonia at baseline treatment; fITT N analysis set No anhedonia (Total SHAPS score <20) Anhedonia (Total SHAPS score >=20) Baseline / Day 22) Placebo 83 0 83 (100%) aticaprant 83 1 (1.2%) 82 (98.8%) Total 166 1 (0.6%) 165 (99.4%) The classification of anhedonia is based on the total score calculated on SHAPS on Visit Day 22 Petition 870260020670, dated 05 / 03 / 2026, page 164 / 525 151 / 225

[00368] The results illustrate that the treatment effect is greater in patients with more anhedonia at baseline. See Figure 19. Table 432: Frequency of individuals with different levels of anhedonia at the beginning of treatment and at week 6 of treatment; eITT Analysis Set N No anhedonia (Total SHAPS score <20) Low-level anhedonia (20 ≤ total SHAPS score <38) High-level anhedonia (Total SHAPS score ≥38) Baseline treatment Placebo 61 0 34 (55.74%) 27 (44.26%) aticaprant 60 0 34 (56.67%) 26 (43.33%) Total 121 0 68 (56.2%) 53 (43.8%) Week 6 of treatment Placebo 59 0 46 (77.97%) 13 (22.03%) aticaprant 59 3 (5.08%) 48 (81.36%) 8 (13.56%) Total 118 3 (2.54%) 94 (79.66%) 21 (17.8%) The classification of anhedonia is based on the total SHAPS score recalculated at the initial treatment review visits and at week 6 of treatment. Table 44: Frequency of individuals at the start of treatment and in week 6 with different levels of treatment; Set of anhedonia in the fITT analysis No anhedonia (Total SHAPS score <20) Low level of anhedonia (20 >= total SHAPS score <38) High level of anhedonia (Total SHAPS score >=38) Baseline treatment Placebo 83 0 49 (59.04%) 34 (40.96%) aticaprant 83 1 (1.2%) 52 (62.65%) 30 (36.14%) Total 166 1 (0.6%) 101 (60.84%) 64 (38.55%) Week 6 of treatment Placebo 81 0 66 (81.48%) 15 (18.52%) aticaprant 77 7 (9.09%) 62 (80.52%) 8 (10.39%) Total 158 7 (4.43%) 128 (81.01%) 23 (14.56%) The classification of anhedonia is based on the total SHAPS score recalculated at the initial treatment review visits and at week 6 of treatment.

[00369] The results illustrate that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 20-A and 20-B. In Figure 20-A, that is, in the high anhedonia group, the placebo + oral antidepressant group shows less response to placebo compared to the low anhedonia group in Figures 7 and 8. Similarly, the treatment effect of the aticaprant + oral antidepressant group is greater in the high anhedonia group compared Petition 870260020670, dated 05 / 03 / 2026, page 165 / 525 152 / 225 with the low anhedonia group. Overall, the effect size is larger at each single time point (from week 1 onward) in the high anhedonia group. The LSMD in the high anhedonia group is more than double that of the low anhedonia group at week 6. Furthermore, when observing the symptom level, a greater improvement is observed in the items related to anhedonia and dysphoria in the high anhedonia subgroup compared to the low anhedonia group. See Figure 21. (v) Weight change

[00370] At baseline, the mean weight for subjects in the placebo group was 76.17 kg compared to 78.66 kg in the aticaprant group. After 6 weeks in the double-blind treatment phase, the mean weight in the placebo group was 75.75 kg compared to 78.57 kg in the aticaprant group. This indicates that weight in both groups remained relatively stable throughout the 6-week double-blind treatment period. This is unexpected, as other adjunctive treatments for MDD result in a mean weight increase. 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 to 932; Marcus, J. Clin. Psychopharmacol. 2008, 28:156 to 165; Berman, J. Clin. Psychiatry 2007; 68:843 to 853; Berman, American College of Neuropsychopharmacology, 2008, Annual Meeting Abstracts (Scottsdale, Ariz, December 7-11, 2008).Nashville, Tenn., ACNP, 2008; Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Boca Raton, Fla, December 9-13, 2007). Nashville, TN, ACNP, 2007). See table 45. Table 45: Mean weight by treatment group (kg) Placebo n = 84 Aticaprant n = 85 Screening, mean (SE) 76.39 (1.61) 78.42 (1.65) Baseline at withdrawal, mean (SE) 76.17 (1.61) 78.66 (1.65) Baseline at withdrawal, mean (SE) 75.75 (1.62) 78.57 (1.71) Absolute change (withdrawal - baseline) -0.42% -0.09% Relative change -0.55% -0.11% (vi) Completion rate Petition 870260020670, dated 05 / 03 / 2026, p. 166 / 525 153 / 225

[00371] Patients who passed the screening phase entered an initial phase, followed by a double-blind phase. Patients who responded to the placebo during the initial phase were classified as non-responders. Patients who did not respond to the placebo were classified as non-responders. The double-blind treatment phase continued for a further 6 weeks, after which patients entered a withdrawal period.

[00372] Of the 121 individuals in the enriched population (60 in the aticaprant group and 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate for the complete ITT analysis set is 95%. This contrasts with completion rates of approximately 85% for adjunctive aripiprazole studies (Pae, CNS Drugs, 2011; 25, 109-127) and 45-62% for adjunctive quetiapine (El Khalili, cited above). In total, 4 individuals (3.3%) discontinued the study: 2 individuals in the placebo group and 2 individuals in the aticaprant treatment group. See Tables 46 and 47. Table 46: Early completion / withdrawal information; eITT analysis set Placebo (N=61) aticaprant 10 mg (N=60) Total (N=121) Treatment / trial completed by individual Completed 59 (96.7%) 58 (96.7%) 117 (96.7%) Dropout 2 (3.3%) 2 (3.3%) 4 (3.3%) Reason for withdrawal / termination Lack of efficacy 0 1 (1.7%) 1 (0.8%) Non-adherence to medication 0 1 (1.7%) 1 (0.8%) Individual dropout 1 (1.6%) 0 1 (0.8%) Other 1 (1.6%) 0 1 (0.8%) Percentages calculated with the number of individuals in each group as the denominator. Petition 870260020670, dated 05 / 03 / 2026, page 167 / 525 154 / 225 Table 47: Early completion / withdrawal information; Complete set of safety analyses Placebo (N=84) aticaprant 10 mg (N=85) Total (N=169) Treatment / trial completed by individual Completed 81 (96.4%) 79 (92.9%) 160 (94.7%) Dropout 3 (3.6%) 6 (7.1%) 9 (5.3%) Reason for withdrawal / termination Adverse event 1 (1.2%) 1 (1.2%) 2 (1.2%) Lack of efficacy 0 2 (2.4%) 2 (1.2%) Non-adherence to drug 0 1 (1.2%) 1 (0.6%) Deviation from protocol 0 1 (1.2%) 1 (0.6%) Individual dropout 1 (1.2%) 0 1 (0.6%) Other 1 (1.2%) 1 (1.2%) 2 (1.2%) Percentages calculated using the number of individuals in each group as the denominator. (vii) Sexual function

[00373] Impairments in sexual function are a common side effect of antidepressant treatment and can be very distressing for patients and their sexual partners. Major depression itself is associated with increased sexual dysfunction, and many pharmacological treatments are known to further worsen sexual function. In a large survey of nearly 5000 patients in France, it is estimated that in untreated MDD patients, the prevalence of sexual dysfunction was 65%. The prevalence of sexual dysfunction increased to 71% for patients treated with antidepressant therapy.

[00374] Sexual pleasure is an important component of hedonic toning. The brain's reward circuit is controlled by several areas: nucleus accumbens, ventral tegmental area, and amygdala. It is hypothesized Petition 870260020670, dated 05 / 03 / 2026, page 168 / 525 155 / 225 It has been shown that treatment with kappa opioid receptors can restore normal homeostatic balance in patients with overactivation. Treatment with aticaprant could potentially improve the symptoms of anhedonia. Other symptoms associated with the reward circuit include: sexual pleasure, lack of interest, and lack of pleasure.

[00375] Patients had their sexual function measured using a well-accepted standard rating scale: ASEX. See Table 48. Table 48: ASEX scores by treatment group Placebo n = 84 Aticaprant n = 85 Baseline 22.04 21.26 Test endpoint 21.36 19.79 Absolute change -0.68 -1.47 % Relative change -3.09 % -6.91 %

[00376] The mean change from treatment baseline (SD) in the total ASEX score through week 6 was -1.5 (4.02) points for aticaprant compared with -0.7 (2.98) points for placebo. A lower ASEX score indicates improvement. The reduction in score at week 6 was greater in the aticaprant group compared with placebo. This is unexpected because adjunctive treatments with other agents are expected to worsen sexual function, i.e., increase the ASEX score over time. See Figure 22.

[00377] Patients who received aticaprant showed notable improvements in sexual function. An examination of individual item-level changes was also conducted and revealed that the greatest changes were observed in items related to consummatory pleasure: orgasm satisfaction, orgasm attainment, and vaginal lubrication / erection. Most of the improvements are shown in items 3, 4, and 5 of Figure 23. Petition 870260020670, dated 05 / 03 / 2026, page 169 / 525 156 / 225 (viii) Onset of effect

[00378] The onset of the aticaprant effect can be estimated from the study. Figure 10-B represents the least squares mean change from baseline. A significant treatment effect favoring aticaprant was observed at the beginning of week 3. At this point, aticaprant showed a statistically superior effect compared to placebo. Example 7 - Aticaprant single dose as adjunctive antidepressant therapy

[00379] Study design: A 6-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of aticaprant in adult and elderly subjects (18 to 74 years) who have MDD with prominent anhedonia (ANH+ MDD) and who have had an inadequate response to an SSRI or a serotonin and SNRI in the current depressive episode. See Figure 34.

[00380] For all individuals, this study will consist of 3 phases: an eligibility screening phase (up to 4 weeks before administration of the first dose), a 6-week double-blind treatment phase, and a 1-2 week follow-up. Individuals who complete the double-blind phase may participate in an open-label, long-term safety study.

[00381] Sample size and randomization: Approximately 544 individuals with MDD with prominent anhedonia (ANH+ MDD) and without prominent anhedonia (ANH- MDD) will be randomized in a 1:1 ratio to adjuvant placebo or aticaprant to achieve a minimum of 314 adult individuals who meet the predefined criteria for ANH+ MDD, eligible for inclusion in the primary analysis. Randomization will be stratified by study site, age group (adults [<65 years], elderly [>65 years]), anhedonia in the line of Petition 870260020670, dated 05 / 03 / 2026, page 170 / 525 157 / 225 baseline and total score on the MADRS relative to baseline. All individuals will continue to take their baseline antidepressants (SSRI / SNRI) throughout the study.

[00382] Dosage and administration All eligible individuals will receive aticaprant or placebo in addition to their baseline SSRI / SNRI, which will continue throughout the study. The study medication will be taken daily.

[00383] Inclusion criteria: 1. Ages 18 to 74 (inclusive). 2. Be clinically stable based on physical examination (including a brief neurological examination), medical history, vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. If there are any abnormalities not specified in the inclusion and exclusion criteria, their significance should be determined. 3. The individual must be clinically stable based on clinical laboratory tests performed during screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, retesting of abnormal laboratory values ​​that may lead to exclusion will be permitted once during the screening phase. 4. Meet the DSM-5 diagnostic criteria for single or recurrent MDD without psychotic features (DSM-5 296.22, 296.23, 296.32, or 296.33), based on clinical assessment and SCID-CT. Individuals aged 65 years or older must have had their first depressive episode before age 55. The duration of the current depressive episode must be < 18 months. 5. Having an inadequate response to at least one, but no more than two, antidepressants (SSRIs / SNRIs) administered at an adequate dose and duration during the current depressive episode. An inadequate response is defined as a 26% to <50% reduction in the severity of depressive symptoms and good overall tolerability, as assessed by the MGH-ATRQ. An adequate trial is defined as antidepressant treatment for at least six weeks (and no more than 12 months during the current episode) at or above the stable therapeutic dose specified in the MGH-ATRQ, and must include the individual's current antidepressant treatment. If the individual has received two SSRI / SNRI treatments of sufficient dose and duration during the current episode, and has shown <25% improvement in both, then the individual would not qualify based on the exclusion criterion (first exclusion criterion). Petition 870260020670, dated 05 / 03 / 2026, page 171 / 525 158 / 225 6. The current major depressive episode, the severity of the depressive symptom, the presence of anhedonia, and the response to antidepressant treatment in the current depressive episode must be confirmed. The patient must be receiving and tolerating well any of the following SSRIs or SNRIs for depressive symptoms, in any formulation and available in the participating country: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine at a stable dose (at the therapeutic dose level) for at least 6 weeks and for no more than 12 months in the current episode, at screening. The SSRI / SNRI above must be approved for the treatment of MDD. Individuals using fluvoxamine as an SSRI and who have normal renal and hepatic function are eligible. 7. Total HDRS-17 score > 22 at baseline and must not demonstrate a clinically significant improvement (defined as a > 20% improvement in total HDRS-17 score) from baseline to end of screening (from the first to the last independent HDRS-17 classification). 8. Symptoms of anhedonia based on clinical assessment and confirmed by a positive response for anhedonia (item 2 of MDE symptoms) on the SCID-CT at screening and baseline (Day 1 before randomization). 9. BMI between 18 and 40 kg / m2 (inclusive). 10. Outpatient in triage. 11. A woman with the potential to become pregnant must have a negative highly sensitive serum pregnancy test (β-hCG) at screening and a negative urine pregnancy test before dosing on Day 1 of the double-blind phase prior to randomization. 12. The use of contraceptives by men and women must be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies. 13. A woman should: • Being postmenopausal • Being permanently infertile • If you can become pregnant, you should use a highly effective contraceptive method (failure rate <1% per year when used consistently and correctly). 14. A woman must agree not to donate eggs (female gametes, oocytes) or freeze them for future use for assisted reproduction purposes during the study and for a period of at least 1 month after receiving the last dose of the study medication. Petition 870260020670, dated 05 / 03 / 2026, page 172 / 525 159 / 225 15. During the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 3 months) after receiving the last dose of the study medication, a man: • Anyone who is sexually active with a woman who could become pregnant should use a barrier method of contraception (e.g., condom with foam / gel / film / cream / spermicidal suppository) and their partner should use a highly effective method of contraception. • Anyone who is sexually active with a pregnant woman should use a condom. • He should not donate sperm.

[00384] Exclusion criteria: 1. History of treatment-resistant MDD, defined as lack of response to 2 or more appropriate antidepressant treatments in the current episode, as indicated by no improvement or minimal improvement (improvement < 25%) when treated with an antidepressant of appropriate dose (by MGH ATRQ) and duration (for at least 6 weeks). 2. Current or previous DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by SCID-CT), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8 and 319), autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorders, or somatoform disorders. 3. Current active DSM-5 diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder, anorexia nervosa, or bulimia nervosa. 4. Primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia that has been the primary focus of psychiatric treatment in the last 2 years. These are permitted as secondary diagnoses if MDD is the primary focus of treatment. 5. History or evidence of clinically significant non-compliance with current antidepressant therapy. 6. History of moderate to severe substance use disorder, including alcohol use disorder, according to DSM-5 criteria, within 6 months prior to screening, or positive test results for alcohol and / or drug abuse (e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, CBD, barbiturates, MDMA) at screening or baseline. Retesting during screening is permitted. Tobacco and caffeine use are not exclusionary. Petition 870260020670, dated 05 / 03 / 2026, page 173 / 525 160 / 225 7. In the last 5 years, have received any prior antidepressant treatment with ketamine / esketamine, electroconvulsive therapy, vagus nerve stimulation, or a deep brain stimulation device? Individuals who previously took up to 2 doses of ketamine / esketamine and did not continue (e.g., did not benefit from the treatment or experienced tolerability problems) may be considered for enrollment purposes. 8. Homicidal intent / ideation or suicidal ideation with some intent to act in the 3 months prior to the start of the screening phase, according to clinical judgment or based on the C-SSRS, corresponding to a Yes response to Item 4 (active suicidal ideation with some intent to act, without a specific plan) or Item 5 (active suicidal ideation with a specific plan and intent) for suicidal ideation in the C-SSRS, or a history of suicidal behavior in the year prior to the start of the screening phase. Individuals who reported suicidal ideation with intent to act or suicidal behavior before the start of the double-blind induction phase were excluded. 9. Cognitive impairment that would render informed consent invalid or limit the individual's ability to meet the study requirements. The individual has a neurodegenerative disorder (e.g., Alzheimer's disease, vascular dementia, Parkinson's disease with clinical evidence of cognitive dysfunction) or evidence of MCI. Individuals aged > 65 years: have an MMSE < 25 or < 23 for those individuals with less than a high school education. 10. History or current episodes of seizures (uncomplicated febrile seizures in childhood without sequelae are not a reason for exclusion). 11. Clinically significant ECG abnormalities at screening or Day 1 before randomization that may compromise the safety of subjects or the integrity of the study, defined as: • During screening and / or Day 1, corrected QT interval according to Fridericia's formula (QTcF): > 450 ms (men); > 470 ms (women). • Evidence of second- and third-degree atrioventricular block. • Characteristics of new ischemia. • Arrhythmia or other clinically significant cardiac abnormalities. 12. History of, or symptoms and signs suggestive of, liver cirrhosis (e.g., esophageal varices, ascites, and increased prothrombin time) OR ALT or AST values ​​> 3 x ULN or total bilirubin > 1.5 x ULN at the screening phase. Repeat screening for abnormal ALT and AST is permitted during the screening period; there is an alternative explanation for the Petition 870260020670, dated 05 / 03 / 2026, page 174 / 525 161 / 225 value outside the range. 13. For elevated bilirubin levels, if the bilirubin elevation is consistent with Gilbert's disease, the individual may participate. 14. Positive test result for drugs of abuse (e.g., barbiturates, methadone, opiates, cocaine, PCP, MDMA, and amphetamine / methamphetamine) at the beginning of the screening phase or on Day 1 of the double-blind treatment phase before randomization. 15. Individuals who test positive on screening for prescribed psychostimulants taken for any indication must discontinue the medication at least 2 weeks prior to Day 1 of the double-blind treatment phase (before randomization). The Day 1 test result (before randomization) for drugs of abuse must be negative for the individual to be randomized. Patients who test positive on screening for prescribed / over-the-counter opiates or barbiturates may continue in the screening phase if the medication has been discontinued at least 1 week or 5 half-lives, whichever is longer, prior to Day 1 of the double-blind induction phase (before randomization). The Day 1 test result (before randomization) for drugs of abuse must be negative for the individual to be randomized. • Intermittent use of cannabinoids prior to the start of the screening phase is not exclusionary, provided the individual does not meet the criteria for substance use disorders. • A positive test for cannabinoids early in the screening phase is not exclusionary; however, a positive test result for cannabinoids before dosing on Day 1 of the double-blind induction phase was exclusionary. 16. Taking a total daily dose of benzodiazepines greater than the equivalent of 6 mg / day of lorazepam at the start of the screening phase. 17. Recent history (last 3 months) or current signs and symptoms of: • Severe renal insufficiency (creatinine clearance < 30 mL / min) • Clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurological, hematological, rheumatological, immunological, or endocrine disorders. • Uncontrolled type 1 or type 2 diabetes mellitus. Individuals with type 1 or type 2 diabetes mellitus who are controlled (hemoglobin A1c < 8.0% and glucose < 150 mg / dL at screening) may be eligible to participate if they are otherwise clinically healthy and have been on a stable glucose-lowering medication regimen for at least 2 months prior to screening. 18. Current signs / symptoms of hypothyroidism or hyperthyroidism. For individuals Petition 870260020670, dated 05 / 03 / 2026, page 175 / 525 162 / 225 duos with a history of thyroid disease and for individuals who, regardless of thyroid history, have a TSH value outside the range, an FT4 test will be performed. If the FT4 value is abnormal and considered clinically significant, the individual is not eligible. 19. Individuals with a pre-existing history of thyroid disease / disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase. Individuals taking thyroid supplementation for antidepressant purposes cannot participate. Having Cushing's disease, Addison's disease, primary amenorrhea, or other evidence of significant medical disorders of the hypothalamic-pituitary-adrenal axis. 20. Significant medical condition, particularly unstable medical problem. 21. Ongoing psychological treatments (e.g., cognitive behavioral therapy, interpersonal psychotherapy, psychodynamic psychotherapy, etc.) initiated within 6 weeks prior to the start of screening. An individual who has received ongoing psychological treatment for a period longer than 6 weeks is eligible if the psychological treatment is of stable duration and frequency. 22. Significant medical illness, particularly unstable medical problem. 23. Clinically relevant gastrointestinal complaints according to clinical judgment (unless they are symptoms of Axis I disorder) at screening or baseline or a history of documented gastric disease (including, without limitation, documented peptic ulcer disease, gastritis [including atrophic gastritis], upper gastrointestinal bleeding, Barrett's esophagus, Crohn's disease, ulcerative colitis, gastrointestinal precancerous conditions or any other clinically relevant gastrointestinal disease (such as irritable bowel syndrome). 24. Requires chronic use of a PPI. History of chronic use of NSAIDs or aspirin. (Low-dose aspirin, for example, in the prevention of cardiovascular disease, is permitted). 25. History of malignancy within 5 years prior to the start of the screening phase (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix or malignancy that is considered cured with minimal risk of recurrence). 26. Known allergies, hypersensitivity or intolerance, or contraindications to aticaprant and / or its excipients. 27. Taking any prohibited therapies that would prevent dosing on Day 1. 28. Received an experimental drug (including experimental vaccines), or Petition 870260020670, dated 05 / 03 / 2026, page 176 / 525 163 / 225 used an investigational invasive medical device within 60 days prior to the start of the screening phase, or participated in 2 or more clinical interventional studies in MDD or another psychiatric condition (with different experimental medications) in the last 1 year prior to the start of the screening phase, or is currently participating in an interventional research study. 29. Being a woman who is pregnant, breastfeeding, or planning to become pregnant while enrolled or within 6 weeks of the last administration of the study medication. 30. You plan to have a child while enrolled in or within 90 days after the last dose of the study intervention. 31. Diagnosis of acquired immunodeficiency syndrome. Testing for the human immunodeficiency virus is not necessary. 32. Any condition or situation / circumstance in which participation would not be in the individual's best interest (for example, it would compromise well-being) or that could prevent, limit, or confound the assessments specified by the protocol. A. Effectiveness objectives and outcomes

[00385] The assessment of primary and secondary (main and other) endpoints will be conducted in the FAS, which includes adult (non-elderly) individuals with ANH+ MDD who have taken at least 1 dose of the study medication.

[00386] Primary: To evaluate the efficacy of aticaprant compared with placebo as adjunctive therapy to an antidepressant (SSRI or SNRI) in improving depressive symptoms in adult individuals with ANH+ MDD and inadequate response to current antidepressant, as assessed by the change from baseline in the total MADRS score from day 1 (pre-randomization) to the end of the 6-week double-blind treatment phase (day 43): • Change from the baseline to Day 43 in the total score on MADRS.

[00387] Primary secondary objective: To evaluate the efficacy of aticaprant compared with placebo in adult subjects with ANH+ MDD as adjunctive therapy to an antidepressant in the reported assessment. Petition 870260020670, dated 05 / 03 / 2026, page 177 / 525 164 / 225 by the patient of the anhedonia results; • Change from baseline up to Day 43 in the total score on the Two-Dimensional Anhedonia Rating Scale (DARS).

[00388] Other secondary objectives: To evaluate the efficacy of aticaprant compared with placebo in adult individuals with ANH+ MDD as adjunctive therapy based on the following: • Proportion of responders on Day 43 (reduction >50% in total score on MADRS). • Proportion of individuals with remission of depressive symptoms, defined as a total MADRS score < 12 on Day 43. • Change from the baseline up to Day 43 in MADRS 6. • Change from baseline to Day 43 in the total PHQ-9 score. • Change from baseline to Day 43 in the total SHAPS score. • Change from baseline to Day 43 in anxiety symptoms using TAG-7.

[00389] Exploratory part: To evaluate the efficacy of aticaprant compared with placebo in adult individuals with ANH+ MDD, and all individuals with MDD (adult and elderly individuals with ANH+ and ANH- MDD) as adjunctive therapy when considering the following: • Change from baseline over time in the total score on the MADRS. • Change from baseline over time in the factor score of the anhedonia items on the MADRS. • Change from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). • Change from the baseline over time in Petition 870260020670, dated 05 / 03 / 2026, page 178 / 525 165 / 225 total score on the PHQ-9. • Change from baseline to Day 43 in health-related quality of life and health status, as assessed by the EQ-5D-5L questionnaire. • Change from baseline to Day 43 in the total score on the SDS. • Change from baseline over time in the CGI-S score. • Change from baseline over time in relation to anxiety symptoms using TAG-7. • Change from baseline over time in relation to depressive symptoms using PGI-S. • Change from baseline to Day 43 in sexual function reported by the patient using ASEX.

[00390] To evaluate the efficacy of aticaprant compared with placebo in adult subjects with ANH-MDD as adjunctive therapy based on the following: • Change from baseline over time in the total score on the MADRS. • Change from baseline over time in the total score on the DARS.

[00391] Safety objectives (all): The following safety outcomes will be assessed separately for adult and elderly subjects; the set of safety analyses for each age group will include all randomized subjects who received at least one dose of the study medication: • Adverse events (AEs) including adverse events. An AE can therefore be any unintended adverse sign (including an abnormal finding), symptom or illness temporally associated with the use of a medicinal product (experimental or non-experimental), whether or not they are related. Petition 870260020670, dated 05 / 03 / 2026, page 179 / 525 166 / 225 related to that medicinal product (experimental or non-experimental). TEAEs were adverse events that began during the treatment phase and worsened from baseline. The complete safety analysis set included all enrolled individuals who received at least 1 dose of the study medication during the treatment period. • Vital signs • ECG, laboratory values ​​• Weight / BMI • Assessment of suicidal behavior using C-SSRS • Assessment of withdrawal symptoms using PWC-20 B. Concomitant therapies and prohibited therapies

[00392] Background therapy: All subjects will continue to take their baseline antidepressants (SSRIs / SNRIs) throughout the study. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue only one of these permitted antidepressants at an appropriate and tolerated dose (i.e., monotherapy) during the study. No changes in antidepressant or dose are permitted from screening until the end of the study.

[00393] Prohibited therapies: Individuals should not use the following medications or dietary supplements before or during the study, as directed, except to treat an adverse event or disruptive symptom, preferably after the end-of-treatment (EOT) visit: • MAOIs within 4 weeks prior to screening up to the first follow-up visit. • Antipsychotic medications from at least 14 days prior to Day 1 until the first follow-up visit. • Hypnotic drugs or dietary supplements (from Petition 870260020670, dated 05 / 03 / 2026, page 180 / 525 167 / 225 at least 7 days prior to Day 1 until the first follow-up appointment), including, but not limited to, benzodiazepines, non-benzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon), sedative antihistamines, including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine and hydroxyzine) and melatonin / agomelatine. • Individuals who were taking benzodiazepines and / or non-benzodiazepine sleep medications permitted during the screening phase may continue to use these medications (at dosages equal to or less than the equivalent of 6 mg / day of lorazepam) during the double-blind treatment phase. No dose increases beyond the equivalent of 6 mg / day of lorazepam, or new benzodiazepine medications, are permitted during the double-blind treatment phase. • Non-SSRI / SNRI antidepressants, for example, doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine and SAMe) from at least 7 days before Day 1 until the first follow-up visit. • Any form of new psychotherapy or alteration to current psychotherapy is prohibited during the screening and double-blind phase. • Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days before Day 1 until the first follow-up visit. • Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine) and isoxsuprine from at least 7 days before Day 1 until EOT. • Magnetic and electrical stimulation therapies: electroconvulsive therapy, vagus nerve stimulation, deep brain stimulation, TMS of any type, or DCS or electrical stimulation, provided Petition 870260020670, dated 05 / 03 / 2026, page 181 / 525 168 / 225 screening up to the end-of-study visit. TMS or DCS, or the use of electrical stimulation prior to screening, are not mutually exclusive. • T3, thyroid hormone, or other thyroid function supplement prescribed for depression. • These medications are permitted when administered to control pre-existing thyroid diseases / disorders...

Claims

1. Pharmaceutical composition, characterized in that it comprises from about 2 mg to about 20 mg of aticaprant and a filler, the composition comprising from about 0.1% to about 90% aticaprant by weight.

2. Pharmaceutical composition, according to claim 1, characterized in that it further comprises one or more of: a disintegrant, a flow agent, a lubricant, a solvent, a dyeing agent and a binder.

3. Pharmaceutical composition, according to claim 1 or 2, characterized in that it comprises between about 10% and about 99.9% filler by weight.

4. Pharmaceutical composition, according to any one of claims 1 to 3, characterized in that it comprises a disintegrant.

5. Pharmaceutical composition, according to claim 4, characterized in that it comprises between about 0.5% and about 50% of disintegrant by weight.

6. Pharmaceutical composition, according to any one of claims 1 to 5, characterized in that it comprises a flow agent.

7. Pharmaceutical composition, according to claim 6, characterized in that it comprises between about 0.1% and about 10% of flow agent by weight.

8. Pharmaceutical composition, according to any one of claims 1 to 7, characterized in that it comprises a lubricant.

9. Pharmaceutical composition, according to claim 8, characterized in that it comprises between about 0.05% and about 5% lubricant by weight. Petition 870260020670, dated 05 / 03 / 2026, page 240 / 525 2 / 4 10. Pharmaceutical composition, according to any one of claims 1 to 9, characterized in that it comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% flow agent by weight and about 0.5% lubricant by weight.

11. Pharmaceutical composition, according to any one of claims 1 to 10, characterized in that it is an oral tablet.

12. Pharmaceutical composition, according to any one of claims 1 to 11, characterized in that it is an oral tablet comprising a core tablet of about 200 mg, wherein the core tablet comprises about 10 mg of aticaprant, about 10 mg of disintegrant, about 177 mg of filler, about 2 mg of flow agent and about 1 mg of lubricant.

13. Pharmaceutical composition according to claim 12, characterized in that it further comprises 6 mg of film coating.

14. Pharmaceutical composition, according to any one of claims 1 to 13, characterized in that the filler is selected from: microcrystalline cellulose, lactose monohydrate and silicified microcrystalline cellulose.

15. Pharmaceutical composition, according to any one of claims 2 to 14, characterized in that the disintegrant is croscarmellose sodium.

16. Pharmaceutical composition, according to any one of claims 2 to 14, characterized in that the flow agent is anhydrous colloidal silica.

17. Pharmaceutical composition, according to any one of claims 2 to 16, characterized in that the lubricant is magnesium stearate. Petition 870260020670, dated 05 / 03 / 2026, page 241 / 525 3 / 4 18. Pharmaceutical composition, according to any one of claims 1 to 17, characterized in that it is an oral tablet comprising about 10 mg of aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg of microcrystalline cellulose, about 60 mg of lactose monohydrate, about 5 mg of croscarmellose sodium and about 1 mg of anhydrous colloidal silica; and wherein the extragranular phase comprises about 57 mg of silicified microcrystalline cellulose, about 5 mg of croscarmellose sodium, about 1 mg of anhydrous colloidal silica and about 1 mg of magnesium stearate.

19. Use of aticaprant, characterized by the fact that it is in the manufacture of a medicine, pharmaceutical composition or product for treating major depressive disorder (MDD) in a human patient.

20. Use according to claim 19, characterized in that the patient has anhedonia.

21. Use, according to claim 19 or 20, characterized in that the medicine, pharmaceutical composition or product comprises about 2 mg to about 20 mg of aticaprant, about 5 mg to about 10 mg of aticaprant, about 5 mg of aticaprant or about 10 mg of aticaprant.

22. Use, according to any of claims 19 to 21, characterized in that the patient had an inadequate response to other antidepressant therapy before treatment with aticaprant.

23. Use, according to claim 22, characterized in that the other antidepressant therapy comprised one or more antidepressants. Petition 870260020670, dated 05 / 03 / 2026, page 242 / 525 4 / 4 24. Use according to claim 23, characterized in that one or more antidepressants comprise an SSRI, SNRI or a combination thereof.

25. Use, according to any one of claims 19 to 24, characterized in that the aticaprant is S-aticaprant.

26. Use, according to any one of claims 19 to 25, characterized in that the aticaprant is crystalline aticaprant.

27. Use, according to any one of claims 19 to 26, characterized in that it further comprises the use of an effective amount of one or more antidepressants.

28. Use according to claim 27, characterized in that one or more antidepressants are an SSRI, SNRI or a combination thereof.

29. Use, according to any one of claims 19 to 28, characterized in that the medicine, pharmaceutical composition or product comprising aticaprant is manufactured to be administered orally once daily.

30. Use according to claim 29, characterized in that the medicine, pharmaceutical composition or product comprising aticaprant is manufactured to be administered with or without food.

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