Mefluleucin for use in the treatment of suicidal ideations associated with depression

Abstract

The present invention relates to methods, compositions, and unit dosage forms useful for selectively modulating mTORC1 activity.

Description

METHODS OF TREATMENT USING AN MTORCl MODULATORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 708,127, filed October 16, 2024, the content of which is herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to methods useful for modulating mTORCl activity. The present invention relates to methods useful for selectively modulating mTORCl activity. The present invention relates to methods useful for activating mTORCl.BACKGROUND OF THE INVENTION

[0003] The mechanistic target of rapamycin complex 1 (mTORCl) protein kinase is a master growth regulator that senses diverse environmental cues, such as growth factors, cellular stresses, and nutrient and energy levels. When activated, mTORCl phosphorylates substrates that potentiate anabolic processes, such as mRNA translation and lipid synthesis, and limits catabolic ones, such as autophagy7. mTORCl dysregulation occurs in a broad spectrum of diseases, including diabetes, epilepsy, neurodegeneration, immune response, suppressed skeletal muscle growth, and cancer among others (Howell et al., (2013) Biochemical Society transactions 41, 906-912; Kim et al., (2013) Molecules and cells 35, 463-473; Laplante and Sabatini, (2012) Cell 149, 274-293).

[0004] There is urgent and compelling unmet medical need for more effective treatments for diseases, disorders or conditions associated with mTORCl.SUMMARY OF THE INVENTION

[0005] The present invention provides, inter alia, methods of treating depression comprising administering to a patient in need thereof a therapeutically effective amount of ((S)- 2-amino-5.5-difluoro-4,4-dimethylpentanoic acid), i.e., compound A:33646993.1 Page 1 of 77 393499-013 WO (.222448)A, or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, the depression is treatment-resistant depression (TRD). In some embodiments, treatment comprises reducing suicidal ideations, as described further herein.BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1 depicts the proposed mechanism of action of Compound A.

[0007] Figure 2 shows Compound A significantly improved depressive symptoms by4 hours post-dose in a double-blind placebo controlled phase 2 trial. ES: effect size, CFB: change from baseline, LS: least squares. SE: standard error.

[0008] Figure 3 shows the demographics and baseline characteristics of participants (n=40) in Example 1. SD: standard deviation, BMI: body mass index, HAM-Dg: Hamilton Depression Rating Scale - 6 Items, MADRS: Montgomery-Asberg Depression Rating Scale, CGI-S: Clinical Global Impression - Severity of Illness.

[0009] Figure 4 shows a schematic illustration of the study design of Example 1. HAM-Dg: Hamilton Depression Rating Scale - 6 Items, MADRS: Montgomery-Asberg Depression Rating Scale.

[0010] Figure 5 shows a summary of the adverse events observed in Example 1 (n=40).

[0011] Figure 6 shows change from baseline in HAM-Dg and MADRS scores by visit in Example 1.

[0012] Figure 7 shows the MADRS responder rate (>50% reduction) by visit in Example 1. MADRS: Montgomery -Asberg Depression Rating Scale.

[0013] Figure 8 shows the MADRS remission rate (score <10) by visit in Example 1. MADRS: Montgomery-Asberg Depression Rating Scale.

[0014] Figure 9 shows suicidal ideation score by visit in Example 1.DETAILED DESCRIPTION OF THE INVENTIONGeneral Description of Certain Embodiments of the Invention

[0015] Major depressive disorder (MDD) is a common psychiatric disorder, with a lifetime prevalence rate of -13-17% in the United States. Although options for pharmacologic treatment have expanded significantly in the past 25 years, between one third and two thirds of patients will not respond to the first antidepressant prescribed, and up to 33 percent will not respond to multiple interventions. Novel antidepressants that relieve the symptoms of MDD33646993.1 Page 2 of 77 393499-013 WO (.222448)in patients who have failed to respond adequately to one or more treatments, without producing significant side effects, would represent an important advance in the treatment of treatmentresistant depression (TRD).

[0016] mTORCl, also known as mechanistic target of rapamycin complex 1, is a multiprotein complex that functions as a cellular nulricnt / encrgy / rcdox sensor and regulates overall metabolic homeostasis through multiple anabolic and catabolic activities, including protein, lipid, and nucleic acid synthesis. Recent data support a key role for mTORCl activity in neurons, including regulation of spine enlargement, axon elongation, dendritic arborization, and the involvement of mTORCl in cognition, mood, and learning and memory. Two compounds that require the activation of mTORCl for their antidepressant activity' in animal models, ketamine and rapastinel (also known as GLYX-13), have demonstrated efficacy in placebo-controlled trials in subjects with TRD.

[0017] Compound A [(S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid] is a novel, orally bioavailable, specific, small molecule that activates mTORCl pathway signaling in the brain, including those centers responsible for mood. In multiple preclinical rodent models of stress-induced depressive behavior, when compared head-to-head with ketamine, compound A demonstrated rapid antidepressant effects comparable to those of ketamine without producing significant adverse effects. The pharmacological activity of compound A was also found to be comparable to that of ketamine in a nonhuman primate model of anxiolytic / depressive behavioral responses. Lastly, like ketamine, the antidepressant effects of compound A were shown to be dependent on the post-synaptic activation of mTORCl and were associated with an increase in mTORCl downstream signaling, synaptic protein expression (e.g., GluRl and synapsin), and synaptic arborization in layer V pyramidal neurons in the medial pre-frontal cortex of rats. Unlike ketamine, however, the pharmacological efficacy of compound A was not associated with A-methyLD-aspartate (NMDA) receptor modulation. Taken together, these data demonstrate the antidepressant potential for compound A for the treatment of TRD.

[0018] Accordingly, in some embodiments the present invention provides a method of treating depression in a patient in need thereof comprising reducing suicidal ideation, comprising the step of administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, it has been surprisingly found that the present invention provides a method of reducing suicidal ideation, e.g., suicidal ideation associated with depression, in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof. For instance, it has been surprisingly found that33646993.1 Page 3 of 77 393499-013 WO (.222448)administering a total daily dose of about 800 to about 2400 mg compound A, or pharmaceutically acceptable salt thereof, wherein each dose is administered 72 hours after the prior dose, achieves a reduction in suicidal ideation wherein the reduction in suicidal ideation is rapid onset. There is a compelling need for methods of the present invention given the observed effects of antidepressants in certain patient populations. For instance, in certain patient populations, treatment with antidepressants may increase energy levels before reducing the severity of other symptoms of depression, e.g., suicidal ideations. In some such instances, the increased energy levels associated with treatment can lead to an increased likelihood of a patient acting on a suicidal ideation. By reducing suicidal ideations prior to or concurrently with such treatment, a patient may benefit from a lower risk of acting on a suicidal ideation during such treatment. Exemplary antidepressants for use with the present invention include, but are not limited to, those described herein.

[0019] In some embodiments, the depression is Major depressive disorder (“MDD”).

[0020] In some embodiments, the depression is treatment-resistant depression ( “TRD”).

[0021] In some embodiments, the depression is resistant to first line treatments.

[0022] In some embodiments, the depression is resistant to second line treatments.Definitions

[0023] As used herein, the term "compound A” refers to ((S)-2-amino-5.5-difluoro- 4,4-dimethylpentanoic acid), i.e.:or a pharmaceutically acceptable salt thereof. United States Pat. No. 10, 100.066 ("the ‘066 patent”) filed Oct. 21, 2016 as U.S. Pat. App. Serial No. U.S. 15 / 331,362 and published as U.S. Pat. App. Pub. No. U.S. 2017 / 0114080 (“the ‘080 publication”), the entirety of each is incorporated herein by reference, describe certain mTORCl modulating compounds, including compound A. Compound A is designated as compound 1-90 in the '066 patent and the synthesis of compound A is described in detail at Example 90 of the '066 patent. Compound A, and33646993.1 Page 4 of 77 393499-013 WO (222448)methods of use thereof, is further described in PCI7US2020 / 058475 filed November 2, 2020 and published as WO2021 / 087432 on May 6, 2021 (the “’432 publication”).

[0024] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate. hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate. 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0025] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary7ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0026] As used herein, the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%. 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.33646993.1 Page 5 of 77 393499-013 WO (.222448)Description of Exemplary Methods and Uses

[0027] As used herein, the term "‘patient,” means an animal, preferably a mammal, and most preferably a human.

[0028] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease, disorder, or condition or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0029] As used herein, the phrase “mTORCl -mediated disease, disorder, or condition” refers to any disease or other deleterious condition in which mTORCl is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which mTORCl is known to play a role.

[0030] Unless otherwise specified, it should be understood that when methods of the present invention described above and herein refer to administering compound A, or a pharmaceutically acceptable salt thereof, said methods also contemplate administering a pharmaceutically acceptable composition comprising compound A, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the present invention provides a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof. In some such embodiments, the method of treating depression comprises achieving a clinically significant reduction in suicidal ideations, as measured by any of the methods described above and herein, and / or known in the medical arts. For instance, in some such embodiments, a reduction in suicidal ideation is measured using C-SSRS (Columbia-Suicide Severity Rating Scale) or a comparable measure. In some embodiments, the present invention provides a method of reducing suicidal ideations, e.g.. suicidal ideations associated with depression, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof.

[0032] In some such embodiments, such methods comprise administering to the patient a therapeutically effective amount of compound A. or a pharmaceutically acceptable salt thereof, in an amount of about 800, 1600, or 2400 mg / day on every third day of a treatment33646993.1 Page 6 of 77 393499-013 WO (.222448)cycle. In some embodiments, a treatment cycle consists of three doses in total, administered three days apart from one and other. In some such embodiments, the total daily dose administered every three days is 800 mg / day. In some such embodiments, the total daily dose administered every three days is 1600 mg / day. In some such embodiments, the total daily dose administered every' three days is 2400 mg / day. Exemplary' such methods are further described in the Exemplification, supra. For instance, in some embodiments, the present invention provides a method of administering to a patient in need thereof a first total daily dose of 2400 mg compound A, followed by administering a second total daily dose of 2400 mg compound A 72 hours after administration of the first total daily dose, followed by administering a third total daily dose of 2400 mg compound A 72 hours after administration of the second dose. In some such embodiments, the present invention achieves a reduction of suicidal ideations as measured by methods described herein and / or known in the medical arts within an amount of time described herein.

[0033] In some embodiments, a treatment cycle consists of more than three doses in total, administered three days apart from one and other. In some such embodiments, the total daily dose administered every three days is 800 mg / day. In some such embodiments, the total daily dose administered every three days is 1600 mg / day. In some such embodiments, the total daily dose administered every three days is 2400 mg / day.

[0034] In some embodiments, methods described herein further comprise treatment with one or more additional therapeutic agents, e.g.. one or more antidepressant agents. In some embodiments, such treatment is a continuing treatment, i.e., a treatment begun prior to a first administration of compound A. In some embodiments, such treatment is a treatment begun concurrently with administration of compound A. In some embodiments, such treatment is a treatment begun after a first administration of compound A. In some embodiments, the one or more antidepressant agent is selected from those described herein or know n in the medical arts. In some embodiments, the one or more antidepressant agent is an SSRI (selective serotonin reuptake inhibitor). In some embodiments, the one or more antidepressant agent is an SNRI (serotonin, norepinephrine reuptake inhibitor). In some embodiments, the one or more antidepressant agent is an NDRI (norepinephrine / dopamine reuptake inhibitor). In some embodiments, the one or more antidepressant agent is a TCA (tricyclic antidepressant). In some embodiments, the one or more antidepressant agent is an MAOI (monoamine oxidase inhibitor). In some embodiments, the one or more antidepressant agent is an atypical antidepressant. Exemplary antidepressant agents include, but are not limited to, citalopram, escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (immediate release or33646993.1 Page 7 of 77 393499-013 WO (.222448)extended release), desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion, or dextromethorphan / bupropion. Various other antidepressant agents are known in the medical arts and are contemplated for use herein.

[0035] In some embodiments, the patient is diagnosed with major depressive disorder (“MDD”). In some such embodiments, the patient is diagnosed with major depressive disorder (MDD) without psychotic features, as described by DSM-5 criteria. In some embodiments, the patient does not have a history of psychotic disorder, for instance a psychotic disorder as described and defined in the Examples included herein.

[0036] In some embodiments, the depression is treatment-resistant depression (“TRD”).

[0037] In some embodiments, the depression is resistant to first line treatments.

[0038] In some embodiments, the treatment resistant depression is resistant to second line treatments.

[0039] In some embodiments, the patient is experiencing a depressive episode and has had at least one inadequate response to at least one antidepressant during the depressive episode. In some embodiments, the patient is experiencing a depressive episode and has had an inadequate response to two, three, or four different antidepressants during the depressive episode.

[0040] In some embodiments, the patient is assessed to have a Montgomeiy-Asberg Depression Rating Scale (MADRS) total score of > 21 prior to treatment with compound A.

[0041] In some embodiments, the patient is assessed to have a Raskin Depression Rating Scale score of > 9 prior to treatment with compound A.

[0042] In some embodiments, the patient has not used an antidepressant for at least one, two, three, or four weeks prior to treatment with compound A, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the patient is 18 years or older.

[0044] In some embodiments, the patient does not have a seizure disorder.

[0045] In some embodiments, the patient does not have a clinically significant abnormality on electroencephalogram (EEG).

[0046] In some embodiments, a patient does not have one or more of the exclusion criteria as set forth in the Examples included herein.

[0047] In some embodiments, a patient has one or more of the inclusion criteria as set forth in the Examples included herein.

[0048] In some embodiments, the present invention provides a method of treating33646993.1 Page 8 of 77 393499-013 WO (.222448)depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A. or a pharmaceutically acceptable salt thereof, wherein the patient experiences at least a 50% reduction in depression scale score. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within fewer than six weeks of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within fewer than four weeks of administration of compound A. or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score wi thin two weeks of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within fewer than two weeks of administration of compound A. or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within one week of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within seven days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within six days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within five days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within four days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within three days of administration of compound A. or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within two days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within one day of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 50% reduction in depression scale score within twenty-four hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 10%, 20%, 30%, or 40% reduction in depression scale score within twenty-four hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 10%, 20%, 30%, or 40% reduction in33646993.1 Page 9 of 77 393499-013 WO (.222448)depression scale score within twelve hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences at least a 10%, 20%, 30%, or 40% reduction in depression scale score within two, three, four, five, six, seven, eight, nine, ten, or eleven hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the depression scale score is selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD-6), the Inventory of Depression Symptomatology Self-Rated Scale (IDS-SR), and the Clinical Global Impression Severity Scale (CGI-S). In some embodiments, the depression scale score is selected from any of the depression rating scales described above and herein.

[0049] In some embodiments, a method of the present invention is characterized as achieving a clinically significant antidepressant effect, as measured using standardized effect size statistics, wherein an effect size of 0.40 or higher is considered to be indicative of a clinically significant effect. For instance, in some embodiments, an effect size is measured according to any of the depression scales described above and herein, wherein the effect size at a particular time interval is > 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90. or 1.0. In some embodiments, an effect size is measured according to any of the depression scales described above and herein, wherein the effect size at 2-4 hours is > 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0. In some embodiments, an effect size is measured according to any of the depression scales described above and herein, wherein the effect size at 4-8 hours is > 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0. In some embodiments, an effect size is measured according to any of the depression scales described above and herein, wherein the effect size at 8-12 hours is > 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0. In some embodiments, an effect size is measured according to any of the depression scales described above and herein, wherein the effect size as measured at 12, 24, 36, 48, or 72 hours is > 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0. In some such embodiments, the size effect is > 0.40. In some such embodiments, the size effect is > 0.50.

[0050] In some embodiments, the present invention provides a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, wherein the patient experiences a reduction in depression scale score comparable to ketamine administered via i.p. injection. In some embodiments, the reduction in depression scale score results from a single administration. In some such embodiments, administration is oral. In some embodiment, the reduction in depression scale score results from at least two administrations.33646993.1 Page 10 of 77 393499-013 WO (.222448)In some such embodiments, administration is oral. In some embodiments, the reduction in depression scale score results from a plurality of oral administrations. In some such embodiments, administration is oral. In some such embodiments, the reduction in depression scale score encompasses or is in addition to a reduction in suicidal ideations.

[0051] In some embodiments, the present invention provides a method of eliciting a rapid onset antidepressant activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A. or a pharmaceutically acceptable salt thereof. In some such embodiments, the patient suffers from TRD. In some embodiments, the rapid onset antidepressant activity occurs within two weeks of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within one week of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity' occurs within seven days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within six days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within five days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within four days of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within three days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within two days of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within one day of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within less than 24 hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset antidepressant activity occurs within less than 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 hours of administration of compound A, or pharmaceutically acceptable salt thereof. In some such embodiments, the rapid onset antidepressant activity comprises a reduction in suicidal ideations.

[0052] In some embodiments, the present invention provides a method of eliciting a long-lasting, sustained antidepressant activity, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient in need thereof33646993.1 Page 11 of 77 393499-013 WO (.222448)suffers from TRD. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least twenty-four hours after a single administration of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least two days. In some embodiments, the long-lasting, sustained antidepressant activity' persists for at least three days. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least four days. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least five days. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least six days. In some embodiments, the long-lasting, sustained antidepressant activity persists for at least seven days. In some such embodiments, the long-lasting, sustained antidepressant activity comprises a reduction in suicidal ideations.

[0053] In some embodiments, the present invention provides a method of eliciting antidepressant activity' that is both rapid onset and long-lasting, sustained. In some such embodiments, the antidepressant activity that is both rapid onset and long-lasting, sustained comprises a reduction in suicidal ideations.

[0054] In some embodiments, the present invention provides a method of eliciting a positive behavioral response in a patient in need thereof, comprising administering to the patient a composition comprising compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient suffers from TRD. In some embodiments, the positive behavioral response correlates with an improvement in mood. In some embodiments, the positive behavioral response correlates with a reduction of anxiety. In some embodiments, the positive behavioral response correlates with an improved ability to cope with stress. In some embodiments, the positive behavioral response correlates with an improvement in apparent sadness. In some embodiments, the positive behavioral response correlates with an improvement in reported sadness. In some embodiments, the positive behavioral response correlates with an improvement in sleep. In some embodiments, the positive behavioral response correlates with an improvement in appetite. In some embodiments, the positive behavioral response correlates with an improvement in ability to concentrate. In some embodiments, the positive behavioral response correlates with an improvement in self-esteem. In some embodiments, the positive behavioral response correlates with an improvement in level of lassitude. In some embodiments, the positive behavioral response correlates with a reduction in pessimistic or suicidal thoughts / ideations. In some embodiments, the positive behavioral response correlates with an increased interest in work or other activities. In some embodiments, the positive behavioral response correlates with a reduction in somatic33646993.1 Page 12 of 77 393499-013 WO (.222448)symptoms. In some embodiments, the positive behavioral response correlates with a reduction in symptoms of psychomotor retardation.

[0055] In some embodiments, the present invention provides a method of eliciting a rapid onset, positive behavioral response is a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, in an amount and for a duration of time as described above and herein. In some embodiments, the patient suffers from TRD. In some embodiments, the positive behavioral response occurs within less than twenty-four hours of administration. In some embodiments, the positive behavioral response occurs within one day of administration. In some embodiments, the positive behavioral response occurs within two days of administration. In some embodiments, the positive behavioral response occurs within three days of administration. In some embodiments, the positive behavioral response occurs within four days of administration. In some embodiments, the positive behavioral response occurs within five days of administration. In some embodiments, the positive behavioral response occurs within six days of administration. In some embodiments, the positive behavioral response occurs within seven days of administration. In some embodiments, the positive behavioral response occurs within one week of administration.

[0056] In some embodiments, the present invention provides a method of eliciting a long-lasting, sustained positive behavioral response in a patent in need thereof, comprising administering to the patient a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient suffers from TRD. In some embodiments, the long-lasting, sustained positive behavioral response persists for longer than one day. In some embodiments, the long -lasting, sustained positive behavioral response persists for at least two days. In some embodiments, the long-lasting, sustained positive behavioral response persists for at least three days. In some embodiments, the long- lasting, sustained positive behavioral response persists for at least four days. In some embodiments, the long-lasting, sustained positive behavioral response persists for at least five days. In some embodiments, the long-lasting, sustained positive behavioral response persists for at least six days. In some embodiments, the long-lasting, sustained positive behavioral response persists for at least seven days.

[0057] In some embodiments, the present invention provides a method of eliciting a positive behavioral response that is both rapid onset and long-lasting, sustained.33646993.1 Page 13 of 77 393499-013 WO (.222448)

[0058] In some embodiments, the present invention provides a method wherein any of the above responses comprise and / or correlate to, and / or occur in addition to a reduction in pessimistic or suicidal ideations.

[0059] In some embodiments, the present invention provides a method of reducing suicidal ideations associated with depression, comprising administering to a patient in need thereof an amount of compound A, or pharmaceutically acceptable salt thereof, wherein the compound is administered in a total daily dose of about 800 to about 2400 mg. and wherein each administration occurs about 72 hours after the prior administration. In some such embodiments, the total daily dose is about 800 mg. In some such embodiments, the total daily dose is about 1600 mg. In some such embodiments, the total daily dose is about 2400 mg. In some such embodiments, such methods elicit a response comprising the reduction of suicidal ideations that is rapid onset. In some such embodiments, such methods elicit a response comprising the reduction of suicidal ideations that is long lasting, sustained. In some such embodiments, such methods elicit a response comprising the reduction of suicidal ideations that is both rapid onset and long-lasting, sustained.

[0060] In some embodiments, suicidal ideations as measured by methods described above and herein, and / or known in the art, are rapidly reduced. In some such embodiments, the reduction in suicidal ideations occurs in less than about two months. For instance, in some embodiments, the reduction in suicidal ideations occurs in less than about seven weeks, less than about six weeks, less than about five weeks, less than about four weeks, less than about three weeks, less than about two weeks, or less than about one week, as measured by methods described above and herein, and / or known in the art.Dosing

[0061] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 10 mg to about 5000 mg, or about 20 mg to about 4000 mg, or about 40 mg to about 4000 mg, or about 60 mg to about 4000 mg. or about 80 mg to about 4000 mg, or about 100 mg to about 4000 mg, or about 120 mg to about 4000 mg, or about 130 mg to about 4000 mg, or about 140 mg to about 4000 mg, or about 100 mg to about 3000 mg, or about 150 mg to about 3000 mg, or about 160 mg to about 3000 mg, or about 170 mg to about 3000 mg, or about 180 mg to about 3000 mg, or about 190 mg to about 3000 mg, or about 200 mg to about 3000 mg, or about 210 mg to about 3000 mg, or about 220 mg to33646993.1 Page 14 of 77 393499-013 WO (.222448)about 3000 mg, or about 230 mg to about 3000 mg, or about 240 mg to about 3000 mg, or about 250 mg to about 3000 mg. or about 260 mg to about 3000 mg, or about 270 mg to about 3000 mg, or about 280 mg to about 3000 mg, or about 290 mg to about 3000 mg, or about 300 mg to about 3000 mg, or about 310 mg to about 3000 mg, or about 320 mg to about 3000 mg, or about 330 mg to about 3000 mg, or about 340 mg to about 3000 mg, or about 350 mg to about 3000 mg, or about 360 mg to about 3000 mg, or about 370 mg to about 3000 mg, or about 380 mg to about 3000 mg. or about 390 mg to about 3000 mg, or about 400 mg to about 3000 mg, or about 410 mg to about 3000 mg, or about 420 mg to about 3000 mg, or about 430 mg to about 3000 mg, or about 440 mg to about 3000 mg, or about 450 mg to about 3000 mg, or about 460 mg to about 3000 mg, or about 470 mg to about 3000 mg, or about 480 mg to about 3000 mg, or about 490 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 510 mg to about 3000 mg, or about 520 mg to about 3000 mg, or about 530 mg to about 3000 mg, or about 540 mg to about 3000 mg, or about 550 mg to about 3000 mg, or about 560 mg to about 3000 mg, or about 570 mg to about 3000 mg, or about 580 mg to about 3000 mg, or about 590 mg to about 3000 mg, or about 600 mg to about 3000 mg, or about 610 mg to about 3000 mg, or about 620 mg to about 3000 mg, or about 630 mg to about 3000 mg, or about 640 mg to about 3000 mg, or about 650 mg to about 3000 mg, or about 660 mg to about 3000 mg, or about 670 mg to about 3000 mg, or about 680 mg to about 3000 mg, or about 690 mg to about 3000 mg, or about 700 mg to about 3000 mg, or about 710 mg to about 3000 mg, or about 720 mg to about 3000 mg. or about 730 mg to about 3000 mg, or about 740 mg to about 3000 mg, or about 750 mg to about 3000 mg, or about 760 mg to about 3000 mg, or about 770 mg to about 3000 mg, or about 780 mg to about 3000 mg, or about 790 mg to about 3000 mg, or about 800 mg to about 3000 mg, or about 810 mg to about 3000 mg, or about 820 mg to about 3000 mg, or about 830 mg to about 3000 mg, or about 840 mg to about 3000 mg, or about 850 mg to about 3000 mg, or about 860 mg to about 3000 mg, or about 870 mg to about 3000 mg, or about 880 mg to about 3000 mg, or about 890 mg to about 3000 mg, or about 900 mg to about 3000 mg, or about 910 mg to about 3000 mg, or about 920 mg to about 3000 mg. or about 930 mg to about 3000 mg, or about 940 mg to about 3000 mg, or about 950 mg to about 3000 mg, or about 960 mg to about 3000 mg, or about 970 mg to about 3000 mg, or about 980 mg to about 3000 mg, or about 990 mg to about 3000 mg, or about 1000 mg to about 3000 mg, or about 1000 mg to about 2500 mg, or about 1000 mg to about 2000 mg, or about 400 mg to about 2400 mg, or about 800 mg to about 2400 mg, or about 800 mg to about 1600 mg. or about 1600 mg to about 2400 mg.33646993.1 Page 15 of 77 393499-013 WO (.222448)

[0062] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 50 mg to about 1600 mg, or about 50 mg to about 1500 mg, or about 50 mg to about 1400 mg, or about 50 mg to about 1300 mg, or about 50 mg to about 1200 mg, or about 50 mg to about 1100 mg, or about 50 mg to about 1000 mg. or about 50 mg to about 900 mg, or about 50 mg to about 800 mg. or about 50 mg to about 700 mg, or about 50 mg to about 400 mg, or about 50 mg to about 300 mg, or about 50 mg to about 200 mg, or about 50 mg to about 100 mg, or about 100 mg to about 500 mg, or about 100 mg to about 400 mg, or about 100 mg to about 300 mg, or about 100 mg to about 200 mg, or about 200 mg to about 1000 mg, or about 200 mg to about 900 mg, or about 200 mg to about 800 mg, or about 200 mg to about 700 mg, or about 200 mg to about 600 mg, or about 200 mg to about 500 mg, or about 200 mg to about 400 mg.

[0063] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg. about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg. about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 me, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg. In some such embodiments, a total daily dose is about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400, or about 3000 mg.

[0064] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose between about 1 to about 100 mg / kg, or about 1 to about 90 mg / kg, or about 1 to about 80 mg / kg, or about 1 to about 70 mg / kg, or about 1 to about 60 mg / kg, or33646993.1 Page 16 of 77 393499-013 WO (.222448)about 1 to about 50 mg / kg, or about 1 to about 40 mg / kg, or about 1 to about 35 mg / kg, or about 1 to about 30 mg / kg, or about 1 to about 25 mg / kg. or about 1 to about 20 mg / kg, or about 1 to about 19 mg / kg, or about 1 to about 18 mg / kg, or about 1 to about 17 mg / kg, or about 1 to about 16 mg / kg, or about 1 to about 15 mg / kg, or about 1 to about 14 mg / kg, or about 1 to about 13 mg / kg, or about 1 to about 12 mg / kg, or about 1 to about 11 mg / kg, or about 1 to about 10 mg / kg, or about 1 to about 9 mg / kg, or about 1 to about 8 mg / kg, or about 1 to about 7 mg / kg, or about 1 to about 6 mg / kg. or about 1 to about 5 mg / kg, or about 1 to about 4 mg / kg, or about 1 to about 3 mg / kg. In some embodiments, a total daily dose is between about 2 mg / kg and about 40 mg / kg, or about 5 mg / kg and about 40 mg / kg, or about 10 mg / kg and about 40 mg / kg, or about 15 mg / kg and about 40 mg / kg, or about 20 mg / kg and about 40 mg / kg, or about 25 mg / kg and about 40 mg / kg, or about 30 mg / kg and about 40 mg / kg, or about 35 mg / kg and about 40 mg / kg of the patient’s body weight per day.

[0065] In some embodiments, a total daily dose of compound A, or pharmaceutically acceptable salt thereof, is administered as once a day (QD). In some such embodiments, a total daily dose is any of those described above and herein. In some such embodiments, a total daily dose is about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about2400, or about 3000 mg.

[0066] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 800 mg. In some such embodiments, the total daily dose is administered every three days. In some such embodiments, the total daily dose is administered every three days for three total doses. In some such embodiments, the total daily dose is administered every three days for more than three total doses, e.g., four, five, six, seven, eight, nine, ten or more doses. In some such embodiments, a reduction in suicidal ideations is achieved as measured by any of those methods described above and herein and / or known in the medical arts.

[0067] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 1600 mg. In some such embodiments, the total daily dose is administered every three days. In some such embodiments, the total daily dose is administered every three days for three total doses. In some such embodiments, the total daily dose is administered every three days for more than three total doses, e.g., four, five, six, seven.33646993.1 Page 17 of 77 393499-013 WO (.222448)eight, nine, ten or more doses. In some such embodiments, a reduction in suicidal ideations is achieved as measured by any of those methods described above and herein and / or known in the medical arts.

[0068] In some embodiments, a method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount comprises a total daily dose of about 2400 mg. In some such embodiments, the total daily dose is administered every three days. In some such embodiments, the total daily dose is administered every three days for three total doses. In some such embodiments, the total daily dose is administered every three days for more than three total doses, e.g., four, five, six, seven, eight, nine, ten or more doses. In some such embodiments, a reduction in suicidal ideations is achieved as measured by any of those methods described above and herein and / or known in the medical arts.

[0069] In some embodiments, a total daily dose is administered once a day orally. In some such embodiments, the total daily dose comprises multiple unit dosages administered simultaneously.

[0070] In some embodiments, a total daily dose is administered to a patient under fed conditions. In some such embodiments, a total daily dose is any of those described above and herein. In some such embodiments, a total daily dose is administered QD. In some such embodiments, a total daily dose is administered orally. In some such embodiments, a total daily dose is administered daily every three days.

[0071] In some embodiments, a total daily dose is administered to a patient under fasted conditions. In some such embodiments, a total daily dose is any of those described above and herein. In some such embodiments, a total daily dose is administered QD. In some such embodiments, a total daily dose is administered orally. In some such embodiments, the patient fasts for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours prior to administration. In some such embodiments, the patient fasts for at least about two to eight hours prior to administration. In some such embodiments, the patient fasts for about two hours, about four hours, or about eight hours prior to administration.

[0072] In some embodiments, the patient fasts for an amount of time after administration. For instance, in some embodiments a patient fasts for about 1, 2, 3, 4, 5, 6, 7, or 8 hours after administration. In some embodiments, a patient fasts for about two hours after administration.33646993.1 Page 18 of 77 393499-013 WO (.222448)

[0073] In some embodiments, a total daily dose of about 800 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fasted conditions. In some embodiments, a total daily dose of about 800 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fed conditions. In some embodiments, a total daily dose of about 1600 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fasted conditions. In some embodiments, a total daily dose of about 1600 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fed conditions. In some embodiments, a total daily dose of about 2400 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fasted conditions. In some embodiments, a total daily dose of about 2400 mg of compound A, or pharmaceutically acceptable salt thereof, is administered to a patient once a day under fed conditions.

[0074] In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, comprising administering a single dose. In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, comprising administering at least two doses. In some such embodiments, administering the at least two doses comprises administering a first dose about 72 hours prior to administering a second dose. In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, comprising administering a plurality of doses. In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, comprising administenng compound A every third day of a treatment cycle, wherein the length of the treatment cycle is decided by the treating clinician. In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of compound A, or pharmaceutically acceptable salt thereof, comprising administering compound A at the same time each day of administration. For instance, in some embodiments, compound A is administered at the same time each morning of administration. In some embodiments, compound A is administered at the same time each evening of administration.Unit Dosage Forms33646993.1 Page 19 of 77 393499-013 WO (.222448)

[0075] In some embodiments, methods of the present invention comprise administering to a patient in need thereof a pharmaceutical composition comprising one or more unit doses of compound A, or pharmaceutically acceptable salt thereof. In some such embodiments, a unit dose is about 10 mg to about 5000 mg, or about 20 mg to about 4000 mg, or about 40 mg to about 4000 mg, or about 60 mg to about 4000 mg, or about 80 mg to about 4000 mg, or about 100 mg to about 4000 mg, or about 120 mg to about 4000 mg, or about 130 mg to about 4000 mg. or about 140 mg to about 4000 mg, or about 150 mg to about 3000 mg. or about 160 mg to about 3000 mg, or about 170 mg to about 3000 mg, or about 180 mg to about 3000 mg, or about 190 mg to about 3000 mg, or about 200 mg to about 3000 mg, or about 210 mg to about 3000 mg, or about 220 mg to about 3000 mg, or about 230 mg to about 3000 mg, or about 240 mg to about 3000 mg. or about 250 mg to about 3000 mg, or about 260 mg to about 3000 mg, or about 270 mg to about 3000 mg, or about 280 mg to about 3000 mg, or about 290 mg to about 3000 mg, or about 300 mg to about 3000 mg, or about 310 mg to about 3000 mg, or about 320 mg to about 3000 mg, or about 330 mg to about 3000 mg, or about 340 mg to about 3000 mg, or about 350 mg to about 3000 mg, or about 360 mg to about 3000 mg, or about 370 mg to about 3000 mg, or about 380 mg to about 3000 mg, or about 390 mg to about 3000 mg, or about 400 mg to about 3000 mg, or about 410 mg to about 3000 mg, or about 420 mg to about 3000 mg, or about 430 mg to about 3000 mg, or about 440 mg to about 3000 mg, or about 450 mg to about 3000 mg, or about 460 mg to about 3000 mg, or about 470 mg to about 3000 mg, or about 480 mg to about 3000 mg, or about 490 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 510 mg to about 3000 mg, or about 520 mg to about 3000 mg, or about 530 mg to about 3000 mg, or about 540 mg to about 3000 mg, or about 550 mg to about 3000 mg, or about 560 mg to about 3000 mg, or about 570 mg to about 3000 mg, or about 580 mg to about 3000 mg, or about 590 mg to about 3000 mg, or about 600 mg to about 3000 mg, or about 610 mg to about 3000 mg, or about 620 mg to about 3000 mg, or about 630 mg to about 3000 mg, or about 640 mg to about 3000 mg, or about 650 mg to about 3000 mg, or about 660 mg to about 3000 mg, or about 670 mg to about 3000 mg, or about 680 mg to about 3000 mg, or about 690 mg to about 3000 mg, or about 700 mg to about 3000 mg, or about 710 mg to about 3000 mg. or about 720 mg to about 3000 mg, or about 730 mg to about 3000 mg, or about 740 mg to about 3000 mg, or about 750 mg to about 3000 mg, or about 760 mg to about 3000 mg, or about 770 mg to about 3000 mg, or about 780 mg to about 3000 mg, or about 790 mg to about 3000 mg, or about 800 mg to about 3000 mg, or about 810 mg to about 3000 mg, or about 820 mg to about 3000 mg, or about 830 mg to about 3000 mg, or about 840 mg to about 3000 mg, or about 850 mg to about 3000 mg, or about 860 mg to33646993.1 Page 20 of 77 393499-013 WO (.222448)about 3000 mg, or about 870 mg to about 3000 mg, or about 880 mg to about 3000 mg, or about 890 mg to about 3000 mg. or about 900 mg to about 3000 mg, or about 910 mg to about 3000 mg, or about 920 mg to about 3000 mg, or about 930 mg to about 3000 mg, or about 940 mg to about 3000 mg, or about 950 mg to about 3000 mg, or about 960 mg to about 3000 mg, or about 970 mg to about 3000 mg, or about 980 mg to about 3000 mg, or about 990 mg to about 3000 mg, or about 1000 mg to about 3000 mg, or about 1000 mg to about 2500 mg, or about 1000 mg to about 2000 mg, or about 400 mg to about 2400 mg, or about 800 mg to about 2400 mg, or about 800 mg to about 1600 mg, or about 1600 mg to about 2400 mg.

[0076] In some such embodiments, a unit dose is 50 mg to about 1600 mg, or about 50 mg to about 1500 mg, or about 50 mg to about 1400 mg, or about 50 mg to about 1300 mg, or about 50 mg to about 1200 mg. or about 50 mg to about 1100 mg, or about 50 mg to about 1000 mg, or about 50 mg to about 900 mg, or about 50 mg to about 800 mg, or about 50 mg to about 700 mg, or about 50 mg to about 400 mg, or about 50 mg to about 300 mg, or about 50 mg to about 200 mg, or about 50 mg to about 100 mg, or about 100 mg to about 400 mg, or about 100 mg to about 300 mg, or about 100 mg to about 200 mg. or about 200 mg to about 1000 mg, or about 200 mg to about 900 mg, or about 200 mg to about 800 mg, or about 200 mg to about 700 mg, or about 200 mg to about 600 mg, or about 200 mg to about 500 mg, or about 200 mg to about 400 mg.

[0077] In some embodiments, a unit dose of compound A, or pharmaceutically acceptable salt thereof, is about 50 mg, about 100 mg. about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg. about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 me, about 2700 mg, about 2750 mg. about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg. In some such embodiments, a unit dose of compound A, or pharmaceutically acceptable salt thereof, comprises about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400 mg, or about 3000 mg.Pharmaceutically Acceptable Compositions33646993.1 Page 21 of 77 393499-013 WO (.222448)

[0078] In some embodiments, a method of the present invention comprises administering a composition comprising a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, compositions for use in methods provided herein are formulated for administration to a patient in need of such composition, for instance a patient suffering from depression. In some embodiments, such compositions are formulated for oral administration to a patient.

[0079] The term ’‘pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0080] Compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0081] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive33646993.1 Page 22 of 77 393499-013 WO (.222448)oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0082] Pharmaceutically acceptable compositions for use in provided methods may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0083] In some embodiments, pharmaceutically acceptable compositions for use in provided methods are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions for use in provided methods are administered without food. In some embodiments, pharmaceutically acceptable compositions for use in provided methods are administered with food.

[0084] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfur}' 1 alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.33646993.1 Page 23 of 77 393499-013 WO (.222448)

[0085] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary' ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0086] Solid compositions of a similar ty pe may also be employ ed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and w axes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0087] The compound can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s)33646993.1 Page 24 of 77 393499-013 WO (.222448)only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0088] Alternatively, pharmaceutically acceptable compositions for use in provided methods may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0089] Pharmaceutically acceptable compositions for use in provided methods may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0090] Topical application for the lower intestinal tract can be effected in a rectal suppository’ formulation (see above) or in a suitable enema formulation. Topically -transdermal patches may also be used.

[0091] For topical applications, pharmaceutically acceptable compositions for use in provided methods may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0092] Pharmaceutically acceptable compositions for use in provided methods may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0093] The amount of compound A that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and33646993.1 Page 25 of 77 393499-013 WO (.222448)the particular mode of administration. In some embodiments, compositions for use in provided methods should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0094] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

[0095] As described above and herein, pharmaceutically acceptable compositions for use in provided methods can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, Compound A may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0096] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0097] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0098] In order to prolong the effect of a compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility'. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by33646993.1 Page 26 of 77 393499-013 WO (.222448)dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-poly glycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0099] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0100] All features of each of the aspects of the invention apply to all other aspects mutatis mutandis.

[0101] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

[0102] EXEMPLIFICATIONExample 1: An Open-Label, Single-Group Study to Evaluate the Efficacy and Safety of Compound A in Adults With Major Depressive Disorder

[0103] Major depressive disorder (MDD) is one of the most common psychiatric conditions with almost 9 million adults treated annually in the United States. Conventional antidepressants fail to provide adequate symptom relief for most individuals with MDD (—1 / 3 remitters) and can take weeks to months to provide meaningful benefit. Subsequent augmentation trials likewise have low success rates (remission rates typically <30%). More33646993.1 Page 27 of 77 393499-013 WO (.222448)recently, antidepressants capable of achieving rapid response (hours to days) have been developed but their use can be hampered by undesirable side effects such as dissociative symptoms. Compound A is a first-in-class, rapid-acting antidepressant drug with a novel mechanism of action. In vitro research demonstrates that Compound A increases neuroplasticity7(often decreased in MDD) by acting intracellularly to increase activity7of the neuronal signaling protein mechanistic target of rapamycin complex 1 (mTORCl) (Figure 1).

[0104] In an exploratory, randomized, double-blind, single-dose study in participants with treatment resistant depression (N=32) Compound A rapidly improved Hamilton Depression Rating Scale scores versus placebo as early as 4 hours post-dose (P =0.02) (Figure 2). Phase 1 studies of Compound A show good tolerability without reports of dissociative or psychotomimetic side effects.List of AbbreviationsAbbreviation Definition of TermACE angiotensin-converting enzymeADHD attention-deficit / hyperactivity disorderADR adverse drug reactionADT antidepressant therapyAE adverse eventAUC area under the concentration-time curveBDNF brain-derived neurotrophic factorBPRS+ Brief Psychiatric Rating Scale Positive SubscaleCADSS Clinician- Administered Dissociative State ScaleCFR Code of Federal RegulationsCGI-S Clinical Global Impression - Severity of IllnessClinRO clinician-reported outcomeCmax maximum observed concentrationCRA Clinical Research AssociateCRO Contract Research OrganizationCSF cerebrospinal fluidC-SSRS Columbia Suicide Severity Rating ScaleCtrou h trough concentrationDSM-5 Diagnostic and Statistical Manual of Mental Disorders - 5thEditionECG electrocardiography eCRF electronic case report formEOS end of studyES effect sizeET early terminationFAS full analysis setFDA Food and Drug AdministrationFOCP female subjects of childbearing potentialFPC follow-up phone callFSH follicle-stimulating hormoneFT4 free thyroxineGCP Good Clinical Practice33646993.1 Page 28 of 77 393499-013 WO (.222448)Abbreviation Definition of TermHAM-D6Hamilton Depression Rating Scale - 6 ItemsHBsAg hepatitis B surface antigenHCV Ab hepatitis C antibodyHIV l / 2 Ag / Ab human immunodeficiency virus 1 / 2 antigen / antibody¬IB investigator’s BrochureICF informed consent formICH International Council for Harmonisation IND Investigational New Drug Application IRB Institutional Review Board MADRS Montgomery-Asberg Depression Rating Scale MDD major depressive disorder MDE major depressive episode MINI Mini International Neuropsychiatric Review mTORCl mechanistic target of rapamycin complex 1 NMD AR N-methyl-D-aspartate receptor PD pharmacodynamics PK pharmacokinetics POC point-of-care PT Preferred Term QTcF QT corrected using Fridericia’s method SADR suspected adverse drug reaction SAE serious adverse event SAP statistical analysis plan SM study medication soc System Organ Class TDD total daily dose TEAE treatment-emergent adverse event Tmax time to maximum observed concentration TRD treatment-resistant depression ULN upper limit of normalStudy Objectives and Endpoints:

[0105] Primary Objective: To evaluate the efficacy of Compound A administered once every 3 days for a 7-day treatment period in adults with MDD.

[0106] Secondary7Objectives:• To evaluate the safety and tolerability of Compound A administered once every 3 days for a 7-day treatment period in adults with MDD.• To characterize the pharmacokinetics (PK) of Compound A in plasma after multiple administrations of Compound A.

[0107] Exploratory Objective: To characterize the effect of Compound A on brain- derived neurotrophic factor (BDNF) concentrations.Study Endpoints:33646993.1 Page 29 of 77 393499-013 WO (.222448)

[0108] Primary Efficacy Endpoint: Change from baseline to each time point in the Hamilton Depression Rating Scale-6 Items (HAM-De) total score.

[0109] Secondary Efficacy Endpoints:• Change from baseline to each time point in the Montgomery -Asberg Depression Rating Scale (MADRS) total score.• Change from baseline to each time point in the Clinical Global Impression - Severity of Illness (CGI-S) total score.• Proportion of subjects achieving a >50% reduction from baseline in the MADRS total score.• Proportion of subjects in remission (MADRS total score <10) at each time point.• Percentage of subjects with a CGI-S score of 1 or 2 at each time point.

[0110] Pharmacokinetic Endpoint: PK parameters on days 1 , 4, and 7: maximum observed concentration (Cmax), time to maximum observed concentration (Tmax), and trough concentration (Ctrough) in plasma.

[0111] Safetv Endpoints:• Treatment-emergent adverse events (TEAEs).• Clinical safety laboratory test results.• Vital sign measurements including orthostatic blood pressure and pulse rate.• Body weight.• Electrocardiography (ECG) findings.• Physical examination findings.• Suicidal ideation and behavior as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) score.• Dissociative symptomatology7as measured by Clinician- Administered Dissociative State Scale (CADSS) score.• Psychopathology severity as measured by Brief Psychiatric Rating Scale Positive Subscale (BPRS+) score.

[0112] Exploratory Endpoint: Change from baseline to each time point for BDNF concentrations.Investigational Study Plan:

[0113] This is an open-label study of Compound A administered orally every73 days for a 7-day treatment period in adult subjects with MDD. The study consists of a 28-day screening period, a 10-day evaluation period (clinic and home), and a safety follow-up phone call approximately 5 (+2) days after the last administration of study medication (SM). See Figure 4 for a schematic representation of the study design.33646993.1 Page 30 of 77 393499-013 WO (.222448)

[0114] The Schedule of Events and Assessments is provided in Table 1, and a detailed Schedule of Timed Assessments with windows is provided in Table 2.

[0115] Screening Period (up to 28 davs. Dav -28 to Dav -1): The screening period is up to 28 days, and after informed consent is obtained, subjects will undergo initial screening evaluations as outlined in Table 1. Subjects will have their diagnosis of MDD confirmed by the Mini International Neuropsychiatric Interview (MINI). To be eligible, subjects must be taking 1 study-approved antidepressant medication (i.e., an approved therapy for depression; Appendix) at a stable dosage for a minimum of 6 weeks before the screening visit. If a subject is taking a second antidepressant or an augmentation therapy, the investigator will decide the appropriate medication that should be discontinued. The second medication should be discontinued for at least 5 half-lives before baseline.

[0116] Subjects should maintain their current, stable antidepressant therapeutic dose for their study-approved antidepressant therapy (ADT) through the screening period. Dose adjustment of ADT will not be allowed at any time during the study.

[0117] Subjects must maintain a MADRS total score >22, a CGI-S score >4, and a detectable level of ADT during the screening period to be eligible. If the MADRS total scores vary >25% between the highest and the lowest score from screening to baseline (Day 1), subj ects will be excluded.

[0118] Evaluation Period (Day 1 [baseline] to Dav 10): All eligible subjects will receive Compound A orally at 2400 mg (six 400 mg capsules) once every 3 days for a 7-day treatment period (on days 1, 4, and 7). The 10-day evaluation period consists of 4 clinic visits (on days 1, 4, 7, and 10) and 6 at-home phone call assessments (on days 2, 3, 5, 6, 8, and 9). All safety , efficacy, PK, and PD assessments will be performed as outlined in Table 1 (Schedule of Events and Assessments) and Table 2 (Detailed Schedule of Timed Assessments).

[0119] Subjects should maintain their current, stable antidepressant therapeutic dose for the study -approved ADT through the evaluation period. Subjects will take their ADT at home and record the administration in a paper ADT adherence diary'. Dose adjustments of ADTs will not be allowed at any time during the study.

[0120] Clinic Visits

[0121] On days 1 (baseline), 4, and 7, during their in-clinic visits, subjects will receive a single, oral dose of Compound A 2400 mg (six 400 mg capsules). After Day 7, SM will be discontinued, and subjects should continue with their ADT.

[0122] At-Home Phone Call Assessments33646993.1 Page 31 of 77 393499-013 WO (.222448)

[0123] On days 2, 3, 5, 6, 8, and 9, subjects will continue taking their ADT at home. Subjects will receive a telephone call for remote efficacy (i.e., HAM-Dg and MADRS) and safely (i.e., review of AEs, review of concomitant medications, C-SSRS, CADSS, and BPRS+) assessments.

[0124] End of Study / Early Termination

[0125] Subjects will have completed the study after completing the safety follow-up phone call at Day 12 (±2). After completion of the end of study (EOS) study procedures, subjects should continue with their ADT. If the subject withdraws or is terminated early, he / she will complete, at the earliest convenience, early termination (ET) assessments as outlined in Table 1 (Day 10).

[0126] Unscheduled visits may be conducted at the discretion of the investigator throughout the study. AEs and concomitant medications will be assessed at all scheduled and unscheduled visits.

[0127] Safety' Follow-Up Phone Call (Day 12 1+21): Subjects will receive a safety follow-up phone call approximately 5 (+2) days after the last administration of SM on Day 7.

[0128] Study Population

[0129] Number of subjects: Approximately 50 subjects will be enrolled to complete approximately 40 subjects.

[0130] Inclusion criteria:1. Is male or female, aged 18 to 65 years (inclusive) at screening.2. Capable of giving signed informed consent, able to understand and comply with protocol requirements, instructions, and protocol-related restrictions, and likely to complete the study as planned.3. Idas a body mass index 19.0 to 40.0 kg / m2(inclusive).4. Is able to swallow capsules whole, without crushing, chewing, or opening.5. Idas a current diagnosis of MDD according to the DSM-5 for either recurrent or single episode MDD without psychotic features that is confirmed by the MINI at screening.6. Has a MADRS score of >22 for the current major depressive episode (MDE) at screening and baseline (Day 1) before SM administration.7. Has a CGI-S score of >4 (moderately ill or worse) at screening and baseline (Day 1) before SM administration.33646993.1 Page 32 of 77 393499-013 WO (.222448)8. Has been on a stable therapeutic dose of one of the following study-approved ADTs for the current MDE for >6 weeks prior to screening: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (immediate release or extended release), desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion, or dextromethorphan / bupropion. Subject must be on antidepressant monotherapy before baseline. Note: If a subject is taking a second ADT or augmentation therapy at screening, the investigator should decide if it is medically appropriate to discontinue the second drug before baseline. If so, the second drug should be discontinued for at least 5 half-lives prior to baseline. If not, the subject should be excluded from the study.9. Agrees to maintain a stable therapeutic dose of the approved ADT throughout the study.10. Non-pregnant female subjects of childbearing potential (FOCP) who are exclusively in a same-sex relationship are included without the need of acceptable birth control methods. FOCP who are sexually active with a male partner (who is biologically capable of having children), must agree to use one of the following acceptable birth control methods after signing the informed consent form (ICF), throughout the study, and for 30 days following the last dose of SM: a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 4 weeks prior to the first administration of SM. b. Simultaneous use of a male condom and diaphragm with spermicide. c. Established hormonal contraceptive (started at least 4 weeks prior to the first dose of SM).Females are considered not to be of childbearing potential if they are either postmenopausal (amenorrhea for at least 2 years and serum follicle-stimulating hormone (FSH) level of >40 IU / L) or permanently sterilized (e.g., bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy, etc.) for a minimum of 6 months prior to screening. All FOCP must have a negative serum pregnancy test result before administration of SM.11. Male subjects:33646993.1 Page 33 of 77 393499-013 WO (.222448)a. Who have been surgically sterilized (6 months minimum) prior to Screening visit are eligible to participate without any contraception. b. Who are biologically capable of having children and have female partners of childbearing potential must use one or more methods of contraception as stated in inclusion criterion #10 which must be used from the time of signing the ICF until 90 days after the last dose of SM. c. Who are exclusively in a same-sex relationship or have female partners considered not to be of childbearing potential are required to use a condom from the first administration of SM through 7 days after the last administration of SM.

[0131] All male subjects must refrain from donating sperm from the first administration of SM until 90 days after the last administration of SM.

[0132] Exclusion Criteria:1. Has a MADRS total score improvement of >25% from the highest to the lowest score from screening to baseline.2. Has been treated with electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve stimulation for the current MDE within 6 months prior to screening.3. Has received treatment with long-acting injectable antipsychotics within 3 months prior to screening.4. Has demonstrated a non-response to esketamine or off-label use of ketamine; or has taken esketamine or ketamine <6 months prior to screening.5. If treated with trazodone, is unable to discontinue treatment with doses >1 0 mg daily for a minimum of 5 half-lives before baseline. Note: trazodone <150 mg / day for sleep is permitted as needed if the subject has been taking the same low dose of trazodone for insomnia for at least 3 months.6. Has unstable hypothyroidism. If the thyroid-stimulating hormone value is out of range (>4.0 mIU / L), regardless of thyroid history, a free thyroxine (FT4) will be measured. If the FT4 value is abnormal (levels <0.8 mIU / L) and considered to be clinically significant (after discussion with the Medical Monitor), the subject will not be eligible. Note: treatment with thyroid hormones is allowed if taken at a stable dose for >3 months and the subject’s thyroid levels are normal.7. Has clinically significant abnormal laboratory profiles (alanine aminotransferase or33646993.1 Page 34 of 77 393499-013 WO (.222448)aspartate aminotransferase values >3 x upper limit of normal (ULN) or total bilirubin >1.5 x ULN), vital sign measurements, or ECGs at screening, per investigator judgment (see Note below). If there are any abnormalities that are not specified in the inclusion and exclusion criteria, the investigator must determine their clinical significance and record it in the subject's source documents.8. Has abnormal renal function as demonstrated by an estimated glomerular filtration rate <60 rnL / min according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening and baseline.9. Has a history of substance use disorder within 6 months prior to screening or is currently using or has a positive result (urine drug screen) at screening or baseline for drugs of abuse (except for cannabis, see exclusion criteria #1 1).10. Has a history of alcohol use disorder within 6 months prior to screening. A subject who has a positive alcohol test result at screening and, if based on the investigator’s opinion, the subject does not have a history7of alcohol use disorder, the subject may continue to the baseline visit. Subjects who have a positive alcohol test result at baseline will be excluded. Subjects should refrain from using alcohol during the study. Subjects who have a positive alcohol test result on days 1 , 4, or 7 will be withdrawn from the study.11 . Has a diagnosis of cannabis use disorder within 6 months before screening and has a positive urine drug screen for cannabis at screening. a. At the discretion of the Sponsor, recreational use (not daily) is allowed and should be kept consistent during the study. Subjects must agree to refrain from using cannabis 48 hours prior to the clinic visits. b. Medical cannabis prescribed for a medical condition (e g., muscle spasms, nausea, vomiting, pain) other than depression and seizures is allowed if taken at a stable regimen for at least 3 months prior to screening (Permitted Concomitant Medications, Appendix). Newly prescribed cannabis treatment and / or change to the existing regimen are / is prohibited. When applicable, subjects should showproof of their prescription for medical cannabis.12. Has had any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) based on the C-SSRS in the 1 year before screening; a33646993.1 Page 35 of 77 393499-013 WO (.222448)history of suicide attempt in the last 2 years; or more than 2 lifetime suicide attempts.13. Has a lifetime history of psychotic disorder, including but not limited to schizophrenia, MDD with psychotic features, or bipolar I / II disorder with and without psychotic features.14. Has a diagnosis within the last 12 months before screening or current diagnosis of post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder or has history7of intellectual disability, autism, or cluster A or B personality disorder (per DSM-5 criteria). a. Current diagnosis of co-morbid generalized anxiety7disorder is allowed but is subject to medication restrictions (anticonvulsants and beta-blockers are allowed if the subject is on a stable regimen for 2 months prior to screening). b. Established attention-defidt / hyperactivity disorder (ADHD) diagnosis is allowed. Subjects must provide confirmation of ADHD diagnosis (i.e., provide medical records for prescribed ADHD medications) and be on a stable dose of ADHD medication for at least 3 months prior to screening.15. Has ahistory7of a psychiatric or neurologic conditions or symptoms that could impose undue risk or compromise the study including but not limited to: a. History' of seizure disorder or history of epilepsy (except history of absence or uncomplicated childhood febrile seizures). b. History' of clinically' significant or moderate head trauma that, in the investigator's opinion, is likely to affect central nervous system functioning. c. Has current evidence of delirium or dementia.16. Has a history7of cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder that could impose undue risk or compromise the study, in the investigator's opinion, including but not limited to: a. Cardiovascular: i. Clinically significant symptomatic orthostatic hypotension. ii. Uncontrolled hypertension despite diet, exercise, and antihypertensive medications. iii. Acute coronary7syndrome.33646993.1 Page 36 of 77 393499-013 WO (.222448)iv. History of unexplained loss of consciousness, unexplained syncope, unexplained irregular heartbeats. v. QT interval corrected using Fridericia’s method >450 msec (for men) or >470 msec (for women) at screening (see Note below). vi. Subject or family history of congenital long QT syndrome. b. Oncological: i. Malignant tumors within 5 years prior, with the exception of benign skin tumors. ii. Diagnosis or family history' of tuberous sclerosis complex. c. Positive result for human immunodeficiency virus 1 / 2 antigen / antibody (HIV 1 / 2 Ag / Ab). hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV Ab) at screening, unless: i. HIV 1 / 2 Ag / Ab positive: subjects must have an HIV confirmation test. If the confirmatory' test is positive, subjects are eligible if they are on chronic suppressive antiviral medication for >6 months yvith an undetectable viral load at screening. ii. HBsAg positive: subjects should be tested for immunoglobulin M antibody to hepatitis B core antigen and hepatitis B surface antibody to detect acute or chronic infection (ineligible). Subjects yvhose results indicate immunity (either by natural infection or vaccination) yvith no active infection are eligible. iii. HCV Ab positive: subjects must have undetectable HCV ribonucleic acid to be eligible. d. Unintended recent clinically significant weight loss in the investigator’s opinion. e. Has chronic urinary tract infections. f. Blood donation or loss of >500 mL yvithin 56 days prior to screening. g. Is on any medication that could, in the investigator's opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the study.33646993.1 Page 37 of 77 393499-013 WO (.222448)17. Requires treatment with a medication or other substance that is prohibited by the protocol.18. Has history of severe drug allergy or hypersensitivity, or hypersensitivity to the SM or excipients.19. Female subjects who are pregnant or lactating or planning to become pregnant while enrolled in the study.20. In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason.21. Has previously enrolled in a Compound A study.22. Is currently participating in another clinical trial or has received an investigational product in another clinical trial within 30 days of screening.23. Is a member of study personnel or of their immediate families or is a subordinate (or immediate family member of a subordinate) to any of the study personnel.

[0133] Note: Repeat testing for clinical laboratory parameters, vital signs, and ECG is permitted one time for each test, at the discretion of the investigator, as long as the repeat test result is available within the 28-day screening period to determine eligibility. Repeat testing is not allowed without justification from the study site and agreement from the Medical Monitor and the Sponsor on a case-by-case basis.

[0134] Completion of Study

[0135] Subjects will be considered to have completed the study if they complete the safety follow-up phone call at Day 12 (±2).

[0136] Discontinuation or Early Termination of Subjects

[0137] Subjects who receive SM but withdraw or are withdrawn from participation in the study by the investigator before completion of the study (i.e., after SM administration on Day 1 but prior Day 10), should complete at the earliest time an ET visit. Procedures and assessments listed for Day 10 (see Table 1) should be completed at the ET visit.

[0138] If subject’s ET visit occurs >72 h after the date of subject’s last dose, efficacy assessments should not be performed / collected at the ET visit.

[0139] The investigator or subjects themselves may stop SM administration at any time for safety or personal reasons. A subject is free to withdraw from the study at any time for any reason without prejudice to their future medical care by the investigator or at the institution.33646993.1 Page 38 of 77 393499-013 WO (.222448)The Sponsor may also withdraw the subject at any time in the interest of the subject’s safety'. Subjects removed from the study for any reason will not be replaced.

[0140] Reasons for a subject’s early discontinuation may include:• Withdrawal of consent• Noncompliance of study procedures• Occurrence of unmanageable AEs• Lost to follow-up• Lack of efficacy• The investigator or the Sponsor believes it is in the best interest of the subject to discontinue the study (i.e. , for safety or tolerability reasons)• Other

[0141] If the subject withdraws consent or the investigator discontinues the subjects from the study, the primary reason for the subject’s withdrawal, or the investigator’s discontinuation of the subject should be documented and captured in the eCRF. If a subject is withdrawn for more than one reason, each reason should be documented in the source document and the primary reason should be entered in the eCRF.

[0142] If the subject is lost to follow-up, every' effort must be made by the study site to contact the subject and to determine the reason for discontinuation / withdrawal. This should include at minimum 3 phone calls, certified letters, email, etc. The measures taken to followup must be documented. Subjects who withdraw will not be replaced.Treatments:

[0143] Study Medication Identity'. Packaging, and Labelling

[0144] SM is supplied by the Sponsor as capsules packaged in bottles. Each capsule will contain 400 mg of Compound A. The capsule is Size 00 elongated (00 EL), white opaque cap and body. Each bottle will contain 40 capsules of 400 mg Compound A. Each bottle will be labelled yvith the protocol number.

[0145] Study Medication Administration

[0146] SM will be administered orally in the clinic once every 3 days for a 7-day treatment period. SM should be administered in the morning, approximately 3 hours after breakfast.

[0147] Subjects will receive a single dose of Compound A: 2400 mg as six 400 mg capsules on days 1. 4, and 7. The capsules will be consumed intact, and splitting the daily dose33646993.1 Page 39 of 77 393499-013 WO (.222448)(e.g., taking part of the daily dose in the morning and the remainder of the daily dose in the evening) is not permitted.

[0148] Subjects who cannot tolerate 2400 mg of Compound A should be discontinued from the study at the discretion of the investigator.

[0149] Subject will not receive SM on days 2, 3, 5, 6, 8, 9, or 10.

[0150] Missed Study Medication Administrations or At-Home Phone Calls

[0151] Subjects may be discontinued from the study at the discretion of the investigator and in consultation with the Medical Monitor and the Sponsor if:• the subject misses 1 of the 3 SM administrations, or• the subject misses >1 of the at-home phone calls.

[0152] All discontinuation procedures will be followed as listed on Day 10 of Table 1.

[0153] Subjects’ Antidepressant Therapy

[0154] All subjects must be on stable (for >6 weeks before screening) therapeutic doses of one of the study-approved ADTs for treatment of their current MDE. The following are the antidepressants approved for the study: citalopram, escitalopram. paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (immediate release or extended release), desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion, or dextromethorphan / bupriopion (see Appendix for study-approved ADTs). If a subject is taking a second ADT or augmentation therapy at screening, the investigator should decide if it is medically appropriate to discontinue the second drug before baseline. If so, the second drug should be discontinued at least 5 halflives prior to baseline.

[0155] Subjects will continue to take their ADT for their current MDE throughout the study and after completion of the study. Subjects will bring their daily supply of ADT at each clinic visit and continue to take their ADT at home (on days 2,3,5, 6, 8 and 9). Dose adjustments or changes of subjects’ ADTs will not be allowed at any time during the study.

[0156] Subjects will receive a paper ADT adherence diary at screening and document the day of each dose of their ADT throughout the study. Subjects must bring their diaries to each clinic visit for review of subject's compliance. This should be reinforced at each clinic visit.

[0157] Method of Assigning Subjects to Treatment

[0158] All eligible subjects will receive Compound A (2400 mg, six 400 mg capsules) on each dosing day.

[0159] Study Medication Handling and Accountability33646993.1 Page 40 of 77 393499-013 WO (.222448)

[0160] All SM will be supplied by the Sponsor to the investigator. SM supplies must be stored at 20 to 25°C in an appropriate, secure area (e.g., locked cabinet) and stored according to the conditions specified on the SM label.

[0161] Concomitant and Prohibited Medications

[0162] Subjects may not be on any prohibited medications as indicated in the Inclusion / Exclusion Criteria. Additional concomitant medications may be permitted on a case- by-case basis at the discretion of the Medical Monitor and the Sponsor. Lists of permitted and prohibited medications are provided in the Appendix.

[0163] Permitted Concomitant Medications: A comprehensive list of permitted medications is show n in the Appendix. The list is not all inclusive. Most of the concomitant medications are allowed if on a stable dose for at least 3 months prior to screening or otherwise specified in the Appendix.• Treatment for hypercholesterolemia (e.g., statins, gemfibrozil) and hyperlipidemia if on a stable dose for >3 months prior to screening.• Treatment for hypertension with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta-blockers, alone or in combination with diuretics if on a stable dose for >2 weeks before screening.• Inhalers for the treatment of asthma, if the subject has stable, controlled asthma and no changes for >6 months prior to screening.• Treatment for diabetes if on a stable dose for >3 months before screening. Insulin will not be permitted.• For ADHD treatment, psychostimulants, atomoxetine, guanfacine, and clonidine are allowed, if on a stable dose for >3 months before screening. Confirmation of ADHD diagnosis will be required.

[0164] The stable dose of all concomitant medications permitted in the study must be maintained throughout the duration of the study participation. As needed, the following treatments will also be permitted:• For sleeping, the following medications are permitted if on a stable dose (dose incrementation is prohibited) for >4 weeks prior to screening (Appendix): o Hypnotics (e.g., zaleplon and zolpidem). o Benzodiazepines: lorazepam (2 mg total daily dose (TDD)), clonazepam33646993.1 Page 41 of 77 393499-013 WO (.222448)(0.5 mg TDD), and flurazepam (30 mg TDD). Benzodiazepines should be taken >12 hours prior to any study visits. o Trazodone (<150 mg / day) as needed if the subject has been taking the same low dose of trazodone for insomnia for >3 months.• Nutritional supplements (e.g., multivitamins, fish oil, melatonin).• EMLARor other numbing cream for venipuncture.• Common over-the-counter therapies for minor, transient ailments (e.g., acetaminophen or ibuprofen for headaches, fever, etc.).

[0165] Subjects must be on a stable dose of 1 study-approved antidepressant medication; a list of these ADTs is provided in the Appendix.

[0166] Prohibited Concomitant Medications: A list of prohibited medications is provided in the Appendix. The list is not all inclusive.

[0167] Prohibited medications should be discontinued for 5 half-lives before baseline. Where a washout of a prohibited medication(s) is required prior to baseline, the tapering rate is at the discretion of the investigator and is to be determined on an individual basis, with consideration to subject state, dose, and known PK of the medication being discontinued. The subject must be consented before any medication tapering is started or any medication is discontinued.Study Methods:

[0168] The Schedule of Events and Assessments is provided in Table 1, and a detailed schedule of timed assessments (Window) is provided in Table 2.

[0169] All subjects who are enrolled and receive the initial administration of SM on Day 1 will be followed according to the protocol regardless of the number of doses of SM taken, unless consent for follow-up is withdrawn. The Sponsor or Sponsor's designee must be notified of all deviations from the protocol clinic visits or procedures, except as noted, and these procedures, if applicable, will be rescheduled or performed at the nearest possible time to the original schedule. AEs should be reported during clinic visits and during at-home contacts. Subjects will also be instructed to call study personnel to report any AEs during the intervals outside the established study contacts and to come to the clinic / or seek medical care if medical evaluation is needed and as the urgency of the situation indicates. For emergencies and other unscheduled visits to a medical facility other than the clinic, medical records will be obtained by the investigator or qualified designee as source data for study follow-up.33646993.1 Page 42 of 77 393499-013 WO (.222448)Table 1: Schedule of Events and AssessmentsADT = antidepressant therapy; AE = adverse event; BDNF = brain-derived neurotrophic factor; BPRS+ = Brief Psychiatric Rating Scale Positive Subscale; CADSS = Clinician- Administered Dissociative State Scale; CGI-S = Clinical Global Impression - Severity of Illness; C- SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiography; EOS = End of Study; ET = Early Termination; FOCP = females of childbearing potential; FPC = Follow-Up Phone Call; FSH = follicle-stimulating hormone; HAM-De = Hamilton Depression Rating Scale-6 Items; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; MINI = Mini International Neuropsychiatric Review; PK = pharmacokinetics; SM = study medicationNote: An attempt will be made to have the same qualified rater administer the same scales (efficacy) throughout the study for each subject. Administration of the HAM-De and MADRS will be performed by 2 different raters. a. The follow-up assessments will be performed through a safety follow-up phone call. The safety follow-up phone call will occur approximately 5 days after the last administration of SM. b. AEs reported during screening will be recorded as part of the subject’s medical history. c. A complete physical examination will be performed at screening and baseline visits; a brief physical examination will be performed atd. Vital signs measurements include orthostatic blood pressure / pulse rate, respiratory rate, and oral temperature. Orthostatic blood pressure and pulse rate should be measured after the subject has been sitting for 5 minutes and again within 3 minutes of subject standing. e. ECGs should be performed prior to blood draws. f. Serology7tests include human immunodeficiency 1 / 2 antigen / antibody, hepatitis B surface antigen, and hepatitis C virus antibody. g. A standard urine drug screen will be performed at screening and point-of-care urine drug screen together with the breathalyzer will be performed at baseline (Day 1) and all post-baseline clinic visits (days 4, 7, and 10). h. On days 2, 3. 5. 6, 8, and 9, the HAM-Ds questionnaire will be administered remotely by telephone. i. SAEs will be captured from the time of ICF signing, and AEs will be captured following the first administration of SM and continue through the FPC. j. Seven total blood samples will be collected for measurement of BDNF concentrations: 3 pre-dose collections on days 1, 4 and 7; 3 postdose collections 4 hours after SM administration on days 1, 4, and 7; and 1 collection on Day 10. k. Subjects will take their SM in the clinic. l. Subjects will receive a paper ADT adherence diary at screening and document the day of each dose of their ADT throughout the study. Subjects will bring their ADT adherence diaries to each clinic visit for review of subject compliance. m. ADT will not be provided by the Sponsor. Subject's ADT will have started and have been stable for at least 6 weeks prior to screening and will continue through the safety follow-up phone call.Table 2: Detailed Schedule of Timed Assessments (Window)BDNF = brain-derived neurotrophic factor; CGI-S = Clinical Global Impression - Severity of Illness; h = hours; HAM-Dg = Hamilton Depression Rating Scale-6 Items; MADRS = Montgomery-Asberg Depression Rating Scale; min = minutes; PK = pharmacokinetics a. Time either before (pre-dose) or after SM administration. b. Administration of the HAM-Dg and MADRS will be performed preferably by 2 different raters. c. Seven total blood samples will be collected for measurement of BDNF concentrations: 3 pre-dose collections on days 1. 4 and 7; 3 postdose collections 4 hours after SM administration on days 1, 4 and 7; and 1 collection on Day 10. d. The 2- and 4-hour PK blood collections will occur after the HAM-Dg assessment. e. The HAM-Dg will be administered remotely on days 2, 5, and 8, approximately 24 hours (±2 hours) after SM was administered in the clinic on days 1, 4, and 7. respectively. f. The HAM-Dg will be administered remotely on days 3, 6, and 9, approximately 48 hours (±2 hours) after SM was administered in the clinic on days 1, 4, and 7. respectively. g. The HAM-Dg, MADRS, and CGI-S will be administered on Day 10, approximately 72 hours (±2 hours) after SM was administered in the clinic on Day 7. The HAM-Dg, MADRS, and CGI-S will be administered prior to any safety assessments.

[0170] Clinic Study Visits and Procedures

[0171] Visit 1 - Screening (Day -28 to Day -1):

[0172] The following assessments will be conducted:• Obtain written informed consent• Confirm MDD diagnosis and conduct the MINI• Review Inclusion / Exclusion Criteria• Confirm stable, therapeutic dose of one study-approved ADT• Record relevant history (including social alcohol and cannabis consumption), medical, psychiatric, family psychiatric, and neurological• Record demographics, height, and body weight• Record prior and concomitant medications• Perform a complete physical examination, including the calculation of body mass index• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and oral temperature)• Perform 12-lead ECG• Collect blood sample for: o FSH (postmenopausal females only) o Serum pregnancy test (FOCP only) o Hematology and serum chemistry' (non-fasted sample allowed) o Serology (i.e.. HIV 1 / 2 Ag / Ab, HBsAg. and HCV Ab)• Collect urine sample for: o Urinalysis o Drug and alcohol screen (Table 3)• Administer efficacy assessments (HAM-De, MADRS, and CGI-S)• Administer safety- assessments (C-SSRS [Screening / Basehne Version], CADSS, and BPRS+ scales)• Provide the subject a paper ADT adherence diary

[0173] Visit 2 - Baseline (Day 1):33646993.1 Page 48 of 77 393499-013 WO (.222448)

[0174] The assessments listed below will be conducted. See Table 2 for details for efficacv assessments and blood collections for PK and BDNF.• Review eligibility criteria• Record body weight• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and oral temperature)• Perform complete physical examination• Perform 12-lead ECG• Collect blood samples for: o Hematology and serum chemistry (non-fasted sample allowed) o BDNF pre-dose o PK pre-dose• Collect urine sample for: o Urine pregnancy test (FOCP only) o Urinalysis o Drug and alcohol screen• Administer efficacy assessments (pre-dose HAM-De, MADRS, and CGI-S)• Administer safety’ assessments (C-SSRS, CADSS, and BPRS+ scales)• Review concomitant medications• Administer SM• Review AEs• Administer efficacy assessments following SM administration (HAM-De and MADRS)• Collect blood samples for PK analysis following SM administration (after efficacy assessments)• Collect blood sample for BDNF concentration following SM administration (after efficacy assessments)• Review ADT adherence diary

[0175] Visit 3 (Day 4):33646993.1 Page 49 of 77 393499-013 WO (.222448)

[0176] The assessments listed below will be conducted. See Table 2 for details for efficacv assessments and blood collections for PK and BDNF.• Record body weight• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and oral temperature)• Perform 12-lead ECG• Collect blood samples for: o BDNF pre-dose o PK pre-dose• Collect urine sample for: o Urine pregnancy test (FOCP only) o Drug and alcohol screen• Administer efficacy assessments (pre-dose HAM-De, MADRS, and CGI-S)• Administer safety assessments (C-SSRS)• Review AEs• Review concomitant medications• Administer SM• Administer efficacy assessments following SM administration (HAM-De and MADRS)• Collect blood samples for PK analysis following SM administration (after efficacy assessments)• Collect blood sample for BDNF concentration following SM administration (after efficacy assessments)• Review ADT adherence diary

[0177] Visit 4 (Day 7):

[0178] The assessments listed below will be conducted. See Table 2 for details for efficacy assessments and blood collections for PK and BDNF.• Record body weight• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and oral temperature)33646993.1 Page 50 of 77 393499-013 WO (.222448)• Perform 12-lead ECG• Collect blood samples for: o Hematology’ and serum chemistry (non-fasted sample allowed) o BDNF pre-dose o PK pre-dose• Collect urine sample for: o Urine pregnancy test (FOCP only) o Urinalysis o Drug and alcohol screen• Administer efficacy assessments (pre-dose HAM-De, MADRS, and CGI-S)• Administer safety assessments (C-SSRS, CADSS, and BPRS+ scales)• Review AEs• Review concomitant medications• Administer SM• Administer efficacy assessments following SM administration (HAM-De and MADRS)• Collect blood samples for PK analysis following SM administration (after efficacy assessments)• Collect blood sample for BDNF concentration following SM administration (after efficacy assessments)• Review ADT adherence diary

[0179] Visit 5 - End of Study (Day 10)

[0180] The assessments listed below will be conducted. See Table 2 for details of efficacy assessments.• Administer HAM-De, MADRS, and CGI-S (approximately 72 hours after the SM administration on Day 7)• Perform a brief physical examination• Record body weight• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and oral temperature)33646993.1 Page 51 of 77 393499-013 WO (.222448)• Perform 12-lead ECG• Collect blood samples for: o Hematology’ and serum chemistry (non-fasted sample allowed) o BDNF• Collect urine sample for: o Urine pregnancy test (FOCP only) o Urinalysis o Drug and alcohol screen• Administer safety assessments (C-SSRS [Since Last Visit Version], CADSS, and BPRS+ scales)• Review AEs• Review concomitant medications• Review and collect ADT adherence diary

[0181] Home Evaluations

[0182] On days 2, 3, 5, 6, 8, and 9, subjects will receive a telephone call for safety and efficacy assessments. Subjects will continue to take their ADT.

[0183] Days 2, 3. 5, 6, 8 and 9

[0184] The following assessments will be conducted remotely by telephone:• Review AEs.• Review concomitant medications.• Confirm compliance and remind subject to complete the ADT adherence diary• Administer HAM-De remotely approximately 24 and 48 hours (±2 hours) after each administration of SM on days 1, 4, and 7 as detailed in Table 2.

[0185] Safety’ Follow-Up Phone Call (Day 12)

[0186] Subjects who complete EOS / Study Day 10 will receive a safety follow-up phone call approximately 5 days (+2 days) after the administration of SM on Day 7. The following assessments will be conducted:• Administer safety assessments (C-SSRS, CADSS, and BPRS+ scales)• Review AEs• Review concomitant medications33646993.1 Page 52 of 77 393499-013 WO (.222448)

[0187] Unscheduled Visits

[0188] At the discretion of the investigator throughout the study, unscheduled visits may be conducted to perform or repeat assessments, including to record an ECG, measure vital signs (orthostatic blood pressure / pulse rate) or body weight, draw a blood sample for hematology and / or serum chemistry' or serum pregnancy test (FOCP) or alcohol drug screen, obtain urine sample for urine pregnancy test and / or drug screen, administer the C-SSRS, and / or perform a physical examination. AEs and concomitant medications should be reviewed and recorded at all unscheduled visits.

[0189] Urine Drug and Alcohol Screen

[0190] The urine drug screen should be completed, and results known before any efficacy assessments are conducted at baseline and all post-baseline clinic visits. Subjects should refrain from taking alcohol during the study after the first administration of SM. The urine drug screen will be performed as point-of-care (POC) testing with POC kits provided to study site(s).

[0191] If a subject has a positive drug screen or tests positive for ethanol at baseline or any post-baseline clinic visits (days 1, 4, and 7), then the subject should be withdrawn from the study' and no efficacy assessments (HAM-De, MADRS, and CGI-S) should be performed at that visit. All safety' assessments should still be performed. The subject should receive a followup phone call approximately 1 week following discontinuation from the study.

[0192] Pharmacokinetic Blood Sampling

[0193] Separate, additional blood draws will be collected to assess the PK characteristics of Compound A. On days 1, 4, and 7, subjects will take the morning dose of SM at the clinic after the pre-dose PK blood draw. A total of 4 blood samples (2.0 mL each) will be collected at clinic visits on days 1, 4, and 7, as follows:• Pre-dose (within 60 minutes of SM administration)• 1 hour (±15 minutes) following SM administration• 2 hours (±30 minutes) following SM administration• 4 hours (±30 minutes) following SM administration

[0194] Pharmacodynamic Blood Sampling

[0195] Separate, additional blood draws will be collected to measure BDNF concentrations. Six blood samples (2.0 mL each) will be collected at clinic visits on days 1, 4, and 7, as follows:33646993.1 Page 53 of 77 393499-013 WO (.222448)Pre-dose (within 60 minutes of SM administration)4 hours (±30 minutes) following SM administration

[0196] One blood sample (2.0 mL) will be collected at the clinic visit on Day 10 approximately 72 hours after SM administration on Day 7.• 72 hours (±60 minutes) following SM administrationStudy Variables and Assessments:

[0197] All clinical outcome assessments will be collected using paper scales / questionnaires.

[0198] Rater Qualification Process

[0199] Identified raters from each study site will be asked to provide information regarding their highest degree of education, field of study, study indication and scale administration experience, and previous certifications using a rater qualification form provided by the Sponsor. Based on the information entered on the qualification form and accompanying certificates, the Sponsor or Sponsor’s designee will determine if raters are qualified to administer scales or require Sponsor provided training. Raters can appeal their qualification status; final determination will be made by the Sponsor. All qualified study coordinators, investigators, and designees must complete the Sponsor rater trainings.

[0200] A site will be considered activated once at least one rater per scale training is completed. An attempt will be made to have the same qualified rater administer the same scales (efficacy) throughout the study for each subject.

[0201] Hamilton Depression Rating Scale - 6 Items

[0202] The Hamilton Depression Rating Scale is one of the most widely used clinician- administered depression scales (Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(l):56-62. doi: 10.1136 / jnnp.23.1.56.; Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988 Aug;45(8): 742-7. doi: 10. 1001 / archpsyc. 1988.01800320058007.). The original version contains 17 items related to symptoms of depression over the past week developed for hospital inpatients. The HAM-De derived from the original 17-item version of the scale offers sensitivity for measuring severity' of detecting improvement of depression comparable to other more complex versions (O'Sullivan RL, Fava M, Agustin C, Baer L, Rosenbaum JF. Sensitivity of the six-item Hamilton Depression Rating Scale. ActaPsychiatr Scand. 1997 May;95(5):379- 84. doi: 10.111 1 / j. 1600-0447.1997.tb09649.).33646993.1 Page 54 of 77 393499-013 WO (.222448)

[0203] Five of the 6 items (Depressed Mood, Low Self-Esteem and Guilt, Social Life Activities / Interests, General Psychomotor Retardation, and Psychic Anxiety) are scored on a scale of 0 to 4, and 1 item (Tiredness and Pains) is scored on a scale of 0 to 2, for a possible total score of 0 to 22.

[0204] The scale is a clinician-reported outcome (ClinRO) administered by a qualified rater at all clinic visits, and it will be administered remotely on days 2, 3 5, 6, 8, and 9 to subjects while at home.

[0205] Montgomery-Asberg Depression Rating Scale

[0206] The MADRS is a 10-item investigator-rated diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders and is designed to be sensitive to changes brought on by treatment (Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10. 1192 / bjp. 134.4.382.). Each question is scored from 0 to 6, the sum of the 10 subtests score will yield a total score ranging from 0 to 60. A higher MADRS score indicates more severe depression.

[0207] Successful therapy is indicated by a lower total score in subsequent testing (Montgomery-Asberg Depression Rating Scale Past Week [Follow-Up Evaluation]).

[0208] There are 10 subtests based on each item:1. Reported sadness2. Apparent sadness3. Inner tension4. Reduced sleep5. Reduced appetite6. Concentration difficulties7. Lassitude8. Inability to feel9. Pessimistic thoughts10. Suicidal thoughts

[0209] The rater will use a structured interview that standardizes the administration of the 10 MADRS items known as structured interview guide for the MADRS, a structured interview was developed by Dr. Janet Williams and Dr. Kenneth Kobak in order to increase inter-rater reliability, thus improving signal detection (Williams JB, Kobak KA. Development33646993.1 Page 55 of 77 393499-013 WO (.222448)and reliability of a structured interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008 Jan; 192(1): 52-8. doi: 10.1192 / bjp.bp.l06.032532.).

[0210] The Standard (including comparison to euthymic baseline for 3 items) and Past Week versions will be administered, with the Standard Version administered at screening and the Past Week Version administered on days 1, 4, 7, and 10. Euthymic baseline is auto populated based on the information captured at the first administration.

[0211] The scale is a ClinRO administered by a qualified rater at all clinic visits.

[0212] Clinical Global Impression - Severity of Illness

[0213] The CGI scale was developed to provide a brief, stand-alone assessment of the clinician's view of a subject's global functioning prior to and after administration of SM (Guy W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology, revised (DHEW Publ. No. ADM 76-338). National Institute of Mental Health (Rockville, MD); 1976:218-222.). The CGI-S is a single-item, clinician rating of the clinician’s assessment of the severity of symptoms in relation to the clinician’s total experience with patients with MDD. The CGI-S is evaluated on a 7-point scale, where:• l=Normal, not at all ill, asymptomatic• 2=Borderline ill• 3=Mildly ill• 4=Moderately ill• 5=Markedly ill• 6=Severely ill• 7=Extremely ill

[0214] Successful therapy is indicated by a lower overall score in subsequent testing.

[0215] The scale is a ClinRO administered by a qualified rater at all clinic visits.

[0216] Safety' Variables and Assessments

[0217] Safety' assessments include monitoring, evaluation, and recording of all concomitant medications and AEs, and the evaluation of clinical laboratory test results, vital sign measurements, body weight. 12-lead ECGs, C-SSRS, CADSS, BPRS+, and the performance of physical examinations as detailed in the Schedule of Events and Assessments (Table 1).

[0218] Adverse Events33646993.1 Page 56 of 77 393499-013 WO (.222448)

[0219] As defined by the ICH Guideline for Good Clinical Practice (GCP), an AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with treatment. An AE can be, for example:• Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated wi th the use of a medicinal product, whether or not considered related to the medicinal product.• Any new disease, intercurrent injuries, or exacerbation of an existing disease.• Any deterioration in a laboratory value or other clinical test (e g., ECG) that results in symptoms, a change in treatment, or discontinuation from SM.• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline.

[0220] Surgical procedures are not AEs; they are therapeutic measures for conditions that require surgery. The condition for which the surgery is required is an AE, if it occurs or is detected during the study.

[0221] Overdose: No data are available. Should an overdose of Compound A be administered or ingested, the subject should be closely monitored for adverse signs and symptoms and appropriate supportive medical care administered.

[0222] Causality:: AEs may be categorized as either adverse drug reactions (ADRs) or suspected adverse drug reactions (SADRs) based on their relationship to SM and the degree of certainty about causality. SADRs are a subset of AEs for which there is evidence to suggest a causal relationship between the SM and the AE (i.e., there is a reasonable possibility that the SM caused the AE). ADRs are a subset of all SADRs for which there is reason to conclude that the SM caused the event.

[0223] Recording and Evaluation of Adverse Events: All subj ects who are screened will be questioned regarding any current and prior medical health status or diagnoses and any medical records will be documented as medical history. At each contact with the subject following the first administration SM on Day 1, The investigator must seek information on AEs by specific questioning and, as appropriate, by examination. Information on all AEs should be recorded immediately in the source document, and also in the appropriate AE module of the eCRF. All clearly related signs, symptoms, and abnormal diagnostic procedure results should be recorded in the source document, though they may be grouped under one diagnosis. For33646993.1 Page 57 of 77 393499-013 WO (.222448)example, fever, elevated white blood cell count, cough, abnormal chest X-ray, etc., can all be reported as “pneumonia.”

[0224] All AEs occurring after administration of SM throughout the study must be recorded. A TEAE is defined as an AE with a start date on or after the first dose of SM administration, or that worsened following first administration of SM. All AEs in this study will be recorded after administration of SM, therefore all will be considered TEAEs. The clinical course of each AE should be followed for at least 30 days following the date of last administration of SM (either due to EOS or ET) or until resolution, or until, in the medical judgment of the investigator, the event has stabilized or is assessed as chronic.

[0225] The investigator is responsible for evaluating AEs and determining the following:• Serious versus non-serious: Is the event a serious adverse event (SAE)?• Causality: Was the AE related or not related to the SM?• Severity: How pronounced is the incapacity / discomfort caused by an AE?

[0226] Criteria for Assessing Severity: The investigator will evaluate the comments of the subject and the response to treatment in order that he or she may judge the true nature and severi ty of the AE. Severity refers to the accumulated intensity of discomfort / impairment of health since the last recording of an AE and will be assessed according to the following criteria:• Mild: Awareness of sign, symptom, or event, but easily tolerated.• Moderate: Discomfort is enough to interfere wdth usual activity and may warrant intervention.• Severe: Incapacitating with inability to do usual activities or significantly affects clinical status and warrants intervention.

[0227] The criteria for assessing severity are different from those used for seriousness.

[0228] Criteria for Assessing Causality:: The investigator is responsible for determining the relationship betw een the administration of SM and the occurrence of an AE as not suspected or as a suspected reaction to SM, as defined below-:

[0229] Not suspected'. The temporal relationship of the AE to SM administration makes a causal relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions provide a sufficient explanation for the observed event.Not related: Temporal relationship to SM administration is missing or implausible, or there is an evident other cause.33646993.1 Page 58 of 77 393499-013 WO (.222448)Unlikely related: Temporal relationship to SM administration makes a causal relationship improbable; and other drugs, chemicals, or underlying disease provide plausible explanations.

[0230] Suspected: The temporal relationship of the AE to SM administration makes a causal relationship possible, and other drugs, therapeutic interventions, or underlying conditions do not provide a sufficient explanation for the observed event.• Possibly related: Temporal relationship to SM administration is plausible, but concurrent disease or other drugs or chemicals could also explain event. Information on drug withdrawal may be lacking or unclear. This event will be reported as a SADR.• Definitely related: Temporal relationship to SM administration is plausible, and concurrent disease or other drugs or chemicals cannot explain event. The response to withdrawal of the medication (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. This event will be reported as an ADR.

[0231] Serious Adverse Events: AEs are classified as serious or non-serious. An AE or ADR is considered “serious’7if, in the view of either the investigator or Sponsor, it results in one of the following outcomes:• Death• Life-threatening AE (i. e. , the subject was at immediate risk of death from the AE as it occurred. This does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death)• In-patient hospitalization or prolongation of existing hospitalization• Persistent or significant disability or incapacity or substantial disruption of the abi 1 i ty to conduct normal life functions• A congenital anomaly or birth defect• An important medical event

[0232] Important medical events are those events that may not be immediately lifethreatening or result in death or hospitalization but are clearly of major clinical significance. They may jeopardize the subject and may require intervention to prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, blood dyscrasias, a33646993.1 Page 59 of 77 393499-013 WO (.222448)seizure that did not result in in-patient hospitalization or intensive treatment for allergic bronchospasm in an emergency department would typically be considered serious.

[0233] Other Events Requiring Immediate Reporting: The investigator must report a pregnancy that occurs in a subject during the study to the Drug Safety Team within 24 hours of first becoming aware of the event.

[0234] Subjects who become pregnant during the study should be discontinued from SM immediately. The investigator must follow any pregnant subject until 3 months after the child is bom. Any AEs concerning the pregnancy of the subject during pregnancy or the child after birth must be documented and reported to the Sponsor or designee.

[0235] Clinician-Administered Dissociative States Scale: The CADSS is a 23-item, clinician-administered scale that measures present-state dissociative symptoms (Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of dissociative states with the Clinician- Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998 Jan;ll(l):125-36. doi: 10.1023 / A:1024465317902.).

[0236] The subjective component of this scale consists of items administered by the clinician who begins each question with anchors and then reads the item to the subject. The subject then rates items on a 4-point Likert scale: 0=not at all, l=mild, 2=moderate, 3=severe, and 4=extreme, with a total score ranging from 0 to 92.

[0237] The scale is a ClinRO administered by a qualified rater at screening, days 1, 7, and 10 of the evaluation period, and during the safety follow-up phone call.

[0238] Brief Psychiatric Rating Scale: The BPRS is one of the most widely used instruments enabling the clinician to quickly gather information about the possible presence and severity7of various psychiatric symptoms (Zanello A, Berthoud L, Ventura J, Merlo MC. The Brief Psychiatric Rating Scale (version 4.0) factorial structure and its sensitivity7in the treatment of outpatients with unipolar depression. Psychiatry Res. 2013 Dec 15;210(2): 626-33. doi: 10.1016 / j.psychres.2013.07.001.). Varying in the number and type of symptoms assessed, clarity7of anchor point definitions and administration and rating instructions, the BPRS exists in various forms. Originally in the early 1960s, the BPRS was developed as a 16-item instrument (Overall JE. Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962; 10(3): 799-812. doi: 10.2466 / pr0.1962.10.3.799), that was later extended to 18 items and was used for many years (Overall JE. Sample size required to observe at least k rare events. Psychol Rep. 1967 Aug;21(l):70-2. doi: 10.2466 / pr0.1967.21.1.70.). In order to increase its sensitivity to psychotic and affective disorders as well as to be used with patients living in the community, the BPRS was expanded to 24 items (Version 2, Lukoff D, Liberman RP,33646993.1 Page 60 of 77 393499-013 WO (.222448)Nuechterlein KH. Symptom monitoring in the rehabilitation of schizophrenic patients. Schizophr Bull. 1986;12(4):578-602. doi: 10.1093 / schbul / 12.4.578.). In its latest version (Version 4.0), the manual of administration of the 24-item BPRS+ (Ventura J, L. D., Nuechterlein KH, Liberman RP, Green M, Shaner A. Appendix 1: Brief Psychiatric Rating Scale (BPRS) Expanded version (4.0) scales, anchor points and administration manual. Int J Met Psych Res. 1993(b); 3:227-244.) not only offers a more detailed semi-structured interview containing more probe questions for each symptom but also provides supplementary rules for the rating (e g., delusions) with better-defined anchor points.

[0239] The version used for this study is adapted from the original BPRS+. The scale is comprised of 4 items assessing a subject’s experience of psychosis, often referred to as positive symptoms of Suspiciousness, Hallucinatory Behavior, Unusual Thought Content, and Conceptual Disorganization. Of the 4 items assessed, the first 3 items are based on questions asked by the clinician to the subject. Conceptual Disorganization is a clinician-rated item based on observation of a subject’s behavior and speech during the assessment.

[0240] The scale is a ClinRO administered by a qualified rater at screening, days 1, 7, and 10 of the evaluation period, and during the safety follow-up phone call.

[0241] Treatment-Emergent Suicidal Ideation

[0242] Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of the safety evaluations for any drug developed for a psychiatric indication (US Food and Drug Administration: Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials. Rockville, MD: US Food and Drug Administration, US Department of Health and Human Services; 2012.). In this study, the initial evaluation of subjects will be conducted prior to enrollment to assess lifetime suicidal ideation and to identify subjects who must not participate in the study due to a pre-existing suicidality risk. The assessment will then be repeated at each subsequent clinic visit as well as during the safety follow-up phone call to monitor the occurrence of new suicidal and self-injurious tendencies.

[0243] Columbia Suicide Severity Rating Scale: Assessment of suicidal ideation and behavior will be conducted using the C-SSRS (Baseline / Screening Version and Since Last Visit Version) (Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity7and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12): 1266-77. doi:10. 1176 / appi.ajp.201 1.101 11704.). The C-SSRS is an FDA-recommended, prospective33646993.1 Page 61 of 77 393499-013 WO (.222448)assessment instrument that directly classifies suicidal ideation and behavior events into 11 preferred categories, including 5 levels of suicidal ideation, 5 levels of suicidal behavior, and the category of self-injurious behaviors with no suicidal intent.

[0244] The instrument has been validated and used successfully in adult patients with various psychiatric disorders that do not involve cognitive impairment. The C-SSRS outcomes that can be used for clinical management and safety monitoring are suicidal lethality rating, suicidal ideation score, and suicidal ideation intensity rating.

[0245] The scale is a ClinRO administered by a qualified rater at screening, days 1, 4, 7, and 10 of the evaluation period, and during the safety follow-up phone call.

[0246] Suicide Risk Management Plan: The protocol procedures related to clinical care of patients with treatment-emergent suicidal ideation and behavior must be implemented to ensure proper management of the event and protection of subjects’ safety.

[0247] Assessment of Suicide Risk: Any indication of suicidal ideation should be evaluated as soon as possible by appropriately trained staff.Clinical Measurements

[0248] Screening and Clinical Safety Laboratory Assessments

[0249] The Schedule of Events and Assessments (Table 1) shows the time points at which blood and urine samples will be collected. Table 3 lists the clinical laboratory tests to be performed.Table 3: Clinical Laboratory Tests33646993.1 Page 62 of 77 393499-013 WO (.222448)ADHD = attention-deficit / hyperactivity disorder; FOCP = females of childbearing potential; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HIV = human immunodeficiency virus 1 / 2 antigen / antibody; POC = point-of-care a. Glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at screening only. b. Confirmatory serology’ testing for positive HIV. hepatitis B and HCV at screening will be performed. c. A microscopic examination will be performed on abnormal findings unless otherwise specified. d. Standard urine drug screen will be performed at screening. A positive test must be confirmed against medical history and concomitant medications. e. Amphetamine, methamphetamine, and methylphenidate (methylphenidate will not be tested during the treatment period) positive tests are allowed only for subjects diagnosed with ADHD confirmed by a prescription record. Benzodiazepine positive test is allowed if used for insomnia. f. POC urine drug screen together with the breathalyzer will be performed at baseline (Day 1) and all post-baseline visits (days 4, 7, and 10). g. A serum pregnancy test will be performed at screening; a urine pregnancy test will be performed on days 1, 4, 7, and 10.

[0250] Vital Signs and Weight: Vital signs measurements (includes orthostatic blood pressure / pulse rate, respiratory rate, and oral temperature) and body weight will be obtained at the time points shown in the Schedule of Events and Assessments (Table 1). Orthostatic blood pressure and pulse rate should be measured after the subject has been sitting for 5 minutes and again w ithin 3 minutes of subject standing. Vital sign measurements may be taken at any other time, as deemed necessary by the investigator.33646993.1 Page 63 of 77 393499-013 WO (.222448)

[0251] Physical Examinations and Height: Physical examinations and measurement of height will be obtained at the time points shown in the Schedule of Events and Assessments (Table 1). The complete physical examination conducted at screening and baseline visits will include assessments of all body systems except genitourinary. Any abnormal findings during screening will be recorded as medical history and any clinically significant abnormal findings following the first administration of SM on Day 1 will be recorded as TEAEs. Only changes from baseline observations will be noted during the brief physical examination at the EOS.

[0252] Electrocardiography: A 12-lead ECG will be obtained at the time points shown in the Schedule of Events and Assessments (Table 1). Additional ECGs may be performed at other times if deemed necessary by the investigator.

[0253] The ECG will be recorded while the subject is resting in a supine position for at least 5 minutes. The ECG will electronically measure the PR, QRS, QT, QTc intervals, and heart rate. All ECG tracings will be reviewed within 24 hours by the investigator or qualified sub-investigator. PR intervals will be determined for each of these ECGs from a single reading. Invalid measurements will be repeated. QTc will be reported as QT interval corrected using Fndencia’s method (QTcF).

[0254] Pharmacokinetic Variables and Assessments

[0255] PK blood samples for measurement of plasma concentrations of Compound A will be collected on days 1, 4, and 7 as shown in Table 2. The PK parameters Cmax, Tmax, and Ctrough will be reported.

[0256] Pharmacodynamic Variables and AssessmentsConcentrations of BDNF will be measured from blood samples collected as outlined in Table 2.

[0257] Screening Scales and Assessment Tools

[0258] Mini International Neuropsychiatric Interview: The diagnosis of MDD will be made by the investigator and supported by the MINI. The MINI is a short, structured diagnostic interview developed by psychiatrics and clinicians in the US and Europe for Diagnostic and Statistical Manual of Mental Disorders and has been updated to map to the DSM-5 (Hergueta T, Weiller E. Evaluating depressive symptoms in hypomanic and manic episodes using a structured diagnostic tool: validation of a new Mini International Neuropsychiatric Interview (M.I.N.I.) module for the DSM-5 'With Mixed Features' specifier. Int J Bipolar Disord. 2013 Oct 17;1 :21. doi: 10.1186 / 2194-7511-1-21.; Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E. Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured33646993.1 Page 64 of 77 393499-013 WO (.222448)diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57.). With an administration time of approximately 15 minutes, the MINI is often used for psychiatric evaluation in clinical studies and is the most widely used psychiatric structured diagnostic interview instrument in the world.

[0259] Montgomery-Asberg Depression Rating Scale: Subjects must have a MADRS total score of >22 for their current MDE at screening and baseline (Day 1) before SM administration. The MADRS total score cannot vary >25% between the highest and the lowest score from screening to baseline (Day 1 ).

[0260] Clinical Global Impression - Severity of Illness: Subjects must have a CGI-S score of >4 (moderately ill or worse) at screening and baseline (Day 1) before SM administration.STATISTICAL METHODS

[0261] General Considerations

[0262] Where appropriate, variables will be summarized descriptively (frequency count and percentage for categorical variables; number of subjects, mean, standard deviation, median, interquartile range [QI and Q3], minimum, and maximum for continuous variables).

[0263] The data summaries will be accompanied by individual subject data listings sorted by unique subject identifier.

[0264] Sample Size and Power Considerations

[0265] Approximately 50 subjects will be enrolled to achieve approximately 40 subjects completed.

[0266] Handling of Dropout or Missing Data

[0267] For safety analyses, a missing date for an AE and non-study medication use will be imputed as described in the SAP. Missing data for all other safety endpoints will not be imputed.

[0268] Analysis Populations

[0269] The full analysis set (FAS) includes all subjects who receive at least one dose of SM and have a baseline and at least one post-baseline measurement of HAM-Dg. The safety population includes all subjects who receive at least one dose of SM. The PK population includes all subjects who receive at least one dose of SM and have a sufficient PK profile to estimate the PK parameters. The PD population includes all subjects who receive at least one dose of SM and have a baseline and at least one post-baseline BDNF concentration.

[0270] Demographics and Baseline Analysis33646993.1 Page 65 of 77 393499-013 WO (.222448)

[0271] Demographic variables including age, sex, ethnicity, race, height, body weight, body mass index, and other baseline efficacy measurements will be summarized descriptively using the safely population and the FAS.

[0272] Population Disposition

[0273] A disposition of subjects will include the number and percentage of subjects in each of the analysis populations.

[0274] The number and percentage of subjects who completed, discontinued from the study, and the primary reason for early discontinuation will be summarized. The reason for early discontinuation may include any of the following:• Withdrawal of consent• Noncompliance with study procedures• Occurrence of unmanageable AEs• Lost to follow-up• Lack of efficacy• The investigator or the Sponsor believes it is in the best interest of the subject to discontinue the study (i.e., for safety or tolerability reasons)• Other

[0275] Study Medication Exposure

[0276] Duration of exposure is defined as the total number of days a subject is exposed to any SM. This will be calculated for each subject by taking the difference between the date of last administration of SM minus the date of the first administration of SM + 1 (date of last dose - date of first dose + 1). Duration of treatment exposure will be summarized using descriptive statistics. The amount of the dosage will be summarized descriptively by visit and overall.

[0277] Medical History

[0278] Medical histories will be tabulated and listed by subject.

[0279] Prior and Concomitant Medications

[0280] A tabular summary of concomitant medications by drug class will be presented for the safety population.

[0281] Efficacy Analyses

[0282] All efficacy data will be summarized descriptively and listed.33646993.1 Page 66 of 77 393499-013 WO (.222448)

[0283] Primary: The change from baseline to each time point in the I lAM-Dr, total score will be analyzed using descriptive statistics. The primary efficacy analysis will be performed with the FAS.

[0284] Secondary: The change from baseline at each time point in the MADRS and CGI-S total scores will be analyzed using descriptive statistics. Analyses for responders (proportion of subjects achieving a >50% reduction from baseline in the MADR total score), remission (proportion of subjects achieving MADRS <10 total score), and percentage of subjects with a CGT-S score of 1 or 2 will be summarized. The secondary efficacy analyses will be performed using the FAS population.

[0285] Pharmacokinetic Analysis

[0286] The PK analysis will be performed using the PK population. Individual Cmax, Tmax, and Ctrou h values will be determined from the concentration-time data for Compound A; these values will be summarized and listed by subject. Plasma concentrations of Compound A will be summarized using descriptive statistics (including geometric mean and coefficient of variation), and individual plasma concentrations of Compound A will be listed by subject.

[0287] Pharmacodynamic Analysis

[0288] The PD analysis is an exploratory analysis and will be performed using the PD population. The change from baseline to each time point for BDNF concentration will be analyzed descriptively.

[0289] Safety Analysis

[0290] Safety analysis is a secondary analysis and will be performed using the safety population. Summaries will be presented for TEAEs and data from the clinical laboratory tests, vital sign measurements, body weight, ECGs, C-SSRS, CADSS, and BPRS+. Physical examination results will be listed by subject.

[0291] TEAEs: The incidence rate for all TEAEs will be summarized for each System Organ Class (SOC) and Preferred Term (PT). The severity of the TEAEs, the relationship to SM, SAEs, AEs leading to SM withdrawn, and deaths will be summarized for each SOC and PT. Common TEAEs (>5%) will be summarized by PT. The verbatim descriptions with Medical Dictionary for Regulatory Activities coded SOCs and PTs for all AEs will be contained in the subject data listings.

[0292] Clinical Laboratory Values, Vital Sign Measurements, and Body Weight: Both actual values and change from baseline and shift from baseline will be summarized for clinical laboratory values, vital sign measurements, and body weight.33646993.1 Page 67 of 77 393499-013 WO (.222448)

[0293] ECG results will be summarized using descriptive statistics (for quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, including the overall ECG finding).

[0294] C-SSRS outcomes will be summarized using number and percentage of subjects by categories for suicidal ideation only, suicidal behavior only, and suicidality (ideation and behavior combined).

[0295] CADSS outcomes will be summarized using descriptive statistics.

[0296] BPRS+ outcomes will be summarized using descriptive statistics.Documentation

[0297] Bioanalytical Sample Handling

[0298] Compound A concentrations in plasma samples will be determined by the Sponsor-designated bioanalytical laboratory using a validated achiral chromatographic tandem mass spectrometry method. Compound A concentrations will be reported. BDNF concentrations will be determined using a validated enzy me-linked immunosorbent assay method as specified in the laboratory’ manual.Appendix

[0299] Prohibited and Permitted Concomitant Medications

[0300] These lists of medications are not all inclusive. Additional concomitant medications may be permitted on a case-by-case basis at the discretion of the investigator, the Medical Monitor, and the Sponsor.

[0301] Medications on the prohibited medications list should be discontinued for 5 halflives prior to the first administration of SM (Day 1, baseline).

[0302] Where discontinuation of prohibited medications is required prior to Day 1 (baseline), tapering rates are at the discretion of the investigator and are to be determined on an individual basis, with consideration to subject state, dose, and known PK of the medication being discontinued. The subject must be consented prior to any tapering of medication is started or any discontinuation of medication occurs.

[0303] Note: If a medication is part of the study-approved ADT regimen (FDA approved and at a stable dose) initiated prior to screening, it must be continued until the end of the study.

[0304] Permitted Concomitant Medications

[0305] Permitted concomitant medications for pre-existing medical conditions should be taken at a stable dose for at least 3 months prior to screening or as otherwise specified in the list below:33646993.1 Page 68 of 77 393499-013 WO (.222448)33646993.1 Page 69 of 77 393499-013 WO (.222448)33646993.1 Page 70 of 77 393499-013 WO (.222448)ACE = angiotensin-converting enzyme; ADHD = attention-deficit / hyperactivity disorder;IM = intramuscular; IV = intravascular; NS AID = nonsteroidal anti-inflammatory drug; PRN = pro re nata (as needed); TSH = thyroid-stimulating hormone

[0306] Prohibited Concomitant Medications33646993.1 Page 71 of 77 393499-013 WO (222448)33646993.1 Page 72 of 77 393499-013 WO (.222448)CGRP = calcitonin gene-related peptide; COMT = catechol-O-methyltransferase; IM = intramuscular; MAO-B = monoamine oxidase B; QTc = corrected QT interval; SM = study medication; T3 = triiodothyronine

[0307] Approved Antidepressant Treatments

[0308] This list includes all FDA approved antidepressants treatments allowed in the study. Note: Subjects should be on 1 of the medications listed at a stable, therapeutic dose for at least 6 weeks before screening. If a subject is taking a second antidepressant or augmentation therapy at screening, the investigator should decide if it is medically appropriate to discontinue the second drug before randomization. In that case, the second drug should be discontinued at least 5 half-lives prior to baseline. If not, the subject should be excluded from the study.

[0309] Selective Serotonin Reuptake Inhibitors

[0310] Serotonin-Norepinephrine Reuptake Inhibitors

[0311] Other Antidepressants33646993.1 Page 73 of 77 393499-013 WO (.222448)Results

[0312] The participants were selected according to the criteria outlined above and the study was conducted according to the study design outlined above. The demographics and baseline characteristics of participants in the study are shown in Figure 3.

[0313] Efficacy

[0314] At the first assessment point (2h after dosing), the HAM-Dg score had decreased by -6.1±3.9 points, which corresponds to a -45% improvement from baseline (13.6±1.7, Figure 6). In addition, at the first assessment point (4h after dosing), the MADRS score decreased by -16.6±10.1 points, which corresponds to a -50% improvement from baseline (33.1±5.4, Figure 6). Half of participants (50.0%) met the MADRS response criteria at 4h (Figure 7). Over a third of participants (35.0%) met the MADRS remission criteria at 4h (Figure 8). Improvement progressed through day 10 with additional doses of Compound A.

[0315] Safety-

[0316] Treatment was well-tolerated with only 1 participant experiencing an AE leading to withdrawal (worsening hypertension, considered unrelated to Compound A treatment by the investigator). No serious AEs were reported. See Figure 5 for a summary' of the AEs observed.

[0317] Suicidal ideation decreased during the study from 12.5% (past 6 months and on Day 1) to 5.1% by Day 4, and 2.6% by Day 10 and at safety follow-up (Figure 9). CADSS and BPRS+ assessments showed no changes regarding dissociative events.

[0318] Overall, participants receiving 2400 mg of Compound A, administered once every 3 days x 3 doses, experienced rapid improvement in depressive symptoms, with meaningful (-50% reduction) HAM-Dg and MADRS reduction within hours of the first dose. Reduction in depressive symptoms improved with subsequent doses. Results are consistent with a prior monotherapy trial that showed rapid (4h) and significant HAM-Dg improvement versus placebo. These results suggest promise for Compound A as a first-in-class antidepressant with RAAD properties, favorable tolerability profile and convenient, oral administration.33646993.1 Page 74 of 77 393499-013 WO (.222448)

Claims

CLAIMSWe Claim:

1. A method of reducing suicidal ideations associated with depression, comprising administering to a patient in need thereof an amount of compound A:or pharmaceutically acceptable salt thereof, wherein the compound is administered in a total daily dose of about 800 to about 2400 mg, and wherein each administration occurs about 72 hours after the prior administration.

2. The method of claim 1, wherein the total daily dose is about 2400 mg.

3. The method of claim 1 or 2, wherein administration occurs at least three times.

4. The method of any of claims 1-3, wherein the method elicits a rapid onset reduction of suicidal ideations.

5. The method of any of claims 1-4, wherein the method elicits long lasting, sustained reduction of suicidal ideations.

6. The method of any of claims 1-5, wherein the total daily dose is administered QD.

7. The method of any of claims 1-6. wherein the total daily dose is administered orally.

8. The method of any of claims 1-7, wherein the depression is treatment-resistant depression.

9. The method of any of claims 1-8, wherein the depression is resistant to first line treatments.33646993.1 Page 75 of 77 393499-013 WO (.222448)10. The method of any of claims 1-9, wherein the depression is resistant to second line treatments.

11. The method of any of claims 1-10, wherein the patient is diagnosed with major depressive disorder (“MDD ’).

12. The method of any of claims 1-11, wherein the patient is experiencing a depressive episode and has had at least one inadequate response to at least one antidepressant during the depressive episode.

13. The method of any of claims 1-12, wherein the patient is experiencing a depressive episode and has had at least one inadequate response to at least two, three, or four different antidepressants during the depressive episode.

14. The method of any of claims 1-13. wherein the patient is assessed to have a Montgomery- Asberg Depression Rating Scale (MADRS) total score of > 21 prior to treatment.

15. The method of any of claims 1-14, wherein the patient is assessed to have a Raskin Depression Rating Scale score of > 9 prior to treatment.

16. The method of any of claims 1-15, wherein the method further comprises treatment with one one or more antidepressant agents.

17. The method of claim 16. wherein the one or more antidepressant agent is selected from the group consisting of SSRIs, SNRIs, and NDRIs.

18. The method of claim 16, wherein the one or more antidepressant agent is selected from citalopram, escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (immediate release or extended release), desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion, and dextromethorphan / bupropion.33646993.1 Page 76 of 77 393499-013 WO (.222448)

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