Methods of treating depression using a muscarinic acetylcholine receptor m1 antagonist

Abstract

The present invention relates to methods of treating depression using a muscarinic acetylcholine receptor M1 antagonist.

Description

Attorney docket no. 29764-20006.40METHODS OF TREATING DEPRESSION USING A MUSCARINIC ACETYLCHOLINE RECEPTOR M1 ANTAGONISTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 720,561 , filed November 14, 2024, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.FIELD OF THE INVENTION

[0002] The present invention relates to methods of treating depression using a muscarinic acetylcholine receptor M1 antagonist.BACKGROUND OF THE INVENTION

[0003] Depression is a common and serious psychiatric disorder affecting approximately 280 million individuals worldwide (according to the World Health Organization [WHO] Fact Sheet 2021 [WHO 2023]). Major Depressive Disorder (MDD) is a debilitating, often long-term and relapsing disorder associated with high rates of morbidity and mortality (Doran and Kinchin, Aust Health Rev. 2019;43(1 ) :43-48; Chiu et al. J Affect Disord. 2018;234:117-123; de la Vega et al. Curr Psychiatry Rep. 2018;20(4) :29) . Current first-line standard of care for MDD includes serotonin reuptake inhibitors, norepinephrine uptake inhibitors, and dual-acting inhibitors; however, when used alone, these treatments decrease depressive symptoms in only about one-third of patients (Rush et al. Am J Psychiatry 2006;163(11 ):1905-1917). Additionally, conventional therapies have slow therapeutic onset (~3 to 6 weeks), which prolongs suffering, delays implementation of other treatments, and increases susceptibility to disease-related issues, including the possibility of suicide (Witkin et al. Curr Pharm Des. 2018;24(22):2556-2563).

[0004] Inadequate response to current first-line standard-of-care antidepressant treatment for MDD remains a significant problem. While switching antidepressants and using adjunctive treatments may improve response for some patients, almost 40% of patients remain symptomatic and fail to achieve remission; these patients are treatment-resistant (treatmentresistant depression; TRD). Overall, there is still a strong, unmet need for fast-acting and effective antidepressants as both first line treatments, and as treatments for TRD, as MDD impacts all races, ethnicities, and genders, as well as socioeconomic levels and cultures, worldwide.

[0005] Despite the strong, unmet need for fast-acting and effective antidepressants, and work on muscarinic antagonists, the development of muscarinic acetylcholine receptor M11MF-364290499Attorney docket no. 29764-20006.40antagonists in the treatment of depression has been hampered by the lack of availability of selective and potent compounds, which would present a favorable side effect profile, and which would also exhibit appropriate central penetration and pharmacokinetic profile.SUMMARY OF THE INVENTION

[0006] The present invention is directed to methods for the treatment of depression (e.g., major depressive disorder), with a muscarinic acetylcholine receptor M1 antagonist.

[0007] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as defined in the appended claims. Other aspects of the present disclosure will be apparent to those skilled in the art in view of the detailed description of the disclosure as provided herein.

[0008] In one aspect, methods of treating a patient suffering from or diagnosed with depression are provided, these methods comprise administering to a patient in need of such treatment a compound of formula (1)pharmaceutically acceptable salt thereof, wherein the compound of formula (1) or the pharmaceutically acceptable salt thereof is administered at a dose in the range of about 20 mg to about 80 mg.

[0009] In another aspect, the invention also relates to the use of compound (1 ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depression in a patient, in particular wherein the treatment of depression comprises administration of compound (1), or a pharmaceutically acceptable salt thereof at a dose in the range of about 20 mg to about 80 mg.

[0010] In a further aspect, the invention relates to compound (1 ), or a pharmaceutically acceptable salt thereof, for use in a method of treating depression, in particular, a method comprising administering the compound (1 ) or the pharmaceutically acceptable salt thereof at a dose in the range of about 20 mg to about 80 mg.

[0011] In other aspects, the invention further relates to a package or pharmaceutical product comprising compound (1) or a pharmaceutically acceptable salt thereof, together with instructions for the treatment of depression, the treatment comprising administering the compound (1 ) or the pharmaceutically acceptable salt thereof at a dose in the range of about 20 mg to about 80 mg.2MF-364290499Attorney docket no. 29764-20006.40

[0012] In another aspect, methods of treating a patient suffering from or diagnosed with depression are provided, these methods comprise administering to a patient in need of such treatment a compound of formula (1)pharmaceutically acceptable salt thereof, wherein the compound of formula (1) or the pharmaceutically acceptable salt thereof is administered in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.

[0013] In another aspect, the invention also relates to the use of compound (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depression in a patient, in particular wherein the treatment of depression comprises administration of compound (1), or a pharmaceutically acceptable salt thereof in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.

[0014] In a further aspect, the invention relates to compound (1 ), or a pharmaceutically acceptable salt thereof, for use in a method of treating depression, in particular, a method comprising administering the compound (1 ) or the pharmaceutically acceptable salt thereof in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.

[0015] In other aspects, the invention further relates to a package or pharmaceutical product comprising compound (1) or a pharmaceutically acceptable salt thereof, together with instructions for the treatment of depression, the treatment comprising administering the compound (1 ) or the pharmaceutically acceptable salt thereof in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.BRIEF DESCRIPTION OF THE FIGURES

[0016] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended figures:

[0017] FIG. 1 depicts a graph representing % occupancy of scopolamine after 4 pg / kg iv administration in non human primates (NHP) in different regions of the brain, at 0.25, 2, 4, 6 and 18 h timepoints. The five bars within each brain region correspond to the five timepoints, presented in order of increasing time from left to right.

[0018] FIG. 2 depicts a schematic representation of the two-compartment pharmacokinetic-pharmacodynamic (PK-PD) Emax model used for dose-receptor occupancy simulation. Emax = maximum effect; ALAG1 = lag time prior to absorption; KA, KD = rate constants; Q = inter- 3MF-364290499Attorney docket no. 29764-20006.40compartmental clearance; central = central compartment; peri = peripheral compartment; V = volume; CL = clearance; Cp = concentration of compound (1) in the central compartment (plasma).

[0019] FIG. 3 depicts the results from 1000 trial simulations for the percentage of subjects achieving 60-90% receptor occupancy after two weeks with twice weekly intermittent dosing frequency at different dose levels. Bars indicate 5-95thpercentile of 1000 replicates.

[0020] FIG. 4 depicts simulation of receptor occupancy-time profiles of 40 mg and 80 mg doses with twice a week dosing in 1000 simulated patients. The horizontal dashed lines indicate 60% and 80% receptor occupancy.

[0021] FIG. 5 depicts the schematic overview of the proof-of-concept clinical trial study design of Example 3.DETAILED DESCRIPTION OF THE INVENTION

[0022] The present disclosure may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure.

[0023] All individual features (e.g., particular embodiments or specific preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including particular embodiment or preferred feature) mentioned herein; hence, preferred features may be taken in conjunction with other preferred features, or independently of them (and likewise with particular embodiments).

[0024] All embodiments described herein for methods for depression are also applicable for use in treating said depression, and are also applicable for the manufacture of a medicament for the treatment of depression.

[0025] Also, as used in the specification including the appended claims, the singular forms ‘a’, ‘an’, and ‘the’ include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent ‘about’, it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.DEFINITIONS

[0026] Some of the quantitative expressions given herein are not qualified with the term ‘about’. It is understood that whether the term ‘about’ is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably inferred based on the ordinary skill in4MF-364290499Attorney docket no. 29764-20006.40the art, including approximations due to the experimental and / or measurement conditions for such given value.

[0027] As used herein, unless otherwise noted, the terms ‘treating’, ‘treatment’ and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and include the administration of a compound described herein to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder. Similarly, ‘treatment’ is used to encompass (a) reduction in the frequency of one or more symptoms, (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development or additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition, or any combination thereof.

[0028] As used herein, ‘effective amount’ means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject or patient, in particular a human, that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated.

[0029] As used herein, the term ‘depression’ (also referred to as depressive disorder), includes, but is not limited to, major depressive disorder, as defined in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA. American Psychiatric Association, 2013., Text Revision (DSM-5-TR™), and treatment resistant depression (TRD, which occurs when the patient has not responded to at least two antidepressants, e.g., oral antidepressants). In certain embodiments, the depression is major depressive disorder. In other embodiments, the depression is treatment resistant depression. In other embodiments, the depression is major depressive disorder with anxious distress (anxious distress specifier, as defined in the DSM-5-TR™).

[0030] A diagnosis based on a single episode is possible, although the disorder is a recurrent one in the majority of cases.

[0031] Treatment resistant depression (or treatment-refractory depression), is defined as a major depressive disorder that does not respond to at least two antidepressant regimens or treatment.

[0032] As used herein, the term ‘major depressive episode’ means a continuous period (e.g., about 2 weeks or more, in particular, minimum of 2 months, but no longer than 24 months in duration) in which a patient has symptoms of a major depressive disorder sufficient to meet criteria for major depressive disorder as specified in the DSM-5-TR™).

[0033] As used herein, unless otherwise noted, the terms ‘subject’ and ‘patient’ may be used interchangeably and refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject or patient has experienced and / or exhibited at least one symptom of the disease or 5MF-364290499Attorney docket no. 29764-20006.40disorder to be treated and / or prevented. One skilled in the art will further recognize that the methods of treatment are directed to subject or patients in need of such treatment, prevention or dosing regimen, more particularly to subject or patients diagnosed with or exhibiting at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) regardless of type or underlying cause.

[0034] Some of the quantitative expressions herein are recited as a range from about value X to about value Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about value X through about value Y, or any value or range of values therein.

[0035] As used herein, the terms ‘including’, ‘containing’ and ‘comprising’ are used herein in their open, non-limiting sense.

[0036] As used herein, the amount of compound (1 ) for administration according to the methods described herein, or as expressed in terms of dose in mg, are set forth on a compound (1 ) free base basis, that is, the amounts indicate that amount of the compound (1 ) molecule administered, exclusive of, for example, solvent or counterions (such as in pharmaceutically acceptable salts).

[0037] As used herein, ‘at bedtime’ or ‘near bedtime’ includes the period in a day that precedes sleep by a patient. For some patients, this may be at night (period from sunset to sunrise, occurring once each twenty-four hours), or depending on professional occupation, or habits, during the day.

[0038] As used herein, the terms ‘intermittent dosing regimen’, ‘intermittent dosing frequency’, ‘intermittently dosed’, ‘pulse dosing’, and ‘continuous intermittent dosing’, refer to a dosing schedule in which the pharmacologic treatment or therapeutic (e.g., the compound of formula (1)) is dosed less frequently than once daily every day, in discrete doses, and wherein any two doses are separated by intervals, e.g., 24 hours and greater than 24 hours throughout a week. Examples of intermittent or pulse dosing according to the invention are those in which the pharmacologic treatment or therapeutic (e.g., the compound of formula (1 )) is administered at a dosing frequency in the range of one dose per week to four or three doses per week.Additional examples of intermittent dosing frequency or regimens include, dosing regimens in which the pharmacologic treatment or therapeutic (e.g., the compound of formula (1 )) is administered once a week (QW, or Q.WK.), twice a week (BIW), every 3 days, every 4 days, or every 3-4 days (e.g., administration of a first dose and administration of a second dose 3 or 4 days thereafter, followed by administration of a third dose respectively 4 or 3 days thereafter, and so forth), every 2 days, or every other day. The term ‘twice a week’ or ‘twice weekly’ as used herein refers to a frequency that is two times in a weekly (7-day) period, for example, twice weekly can refer to a frequency that is day 1 and day 2 of a week. In some embodiments, twice weekly refers to a frequency that is day 1 and 3 of a week. In further embodiments, twice6MF-364290499Attorney docket no. 29764-20006.40weekly refers to a frequency that is day 1 and day 4 of a week. The ‘day 1 ’ may be any day of the week, including, Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with respect to administration of compound (1), twice weekly refers to a frequency that is day 1 and day 3, or day 1 and day 4, of a week.

[0039] The present invention provides methods of treating a patient suffering from, or diagnosed with, depression, comprising administering compound (1)pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein compound (1 ) is administered in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.

[0040] In an embodiment, the intermittent dosing frequency or regimen comprises administering compound (1 ), or a pharmaceutically acceptable salt thereof, once a week, or twice a week. It is understood that when compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at an intermittent dosing frequency or regimen of twice a week, this comprises administration of compound (1), or a pharmaceutically acceptable salt thereof, every approximately 3 to 4 days, i.e., every approximately, 3, or 4 days.

[0041] In a further embodiment, compound (1) or a pharmaceutically acceptable salt thereof is administered once a week to four or three times / doses a week.

[0042] Compound (1 ), (6-((1 R,5S)-3-(4,4-difluoro-4-(2-methoxypyridin-4-yl)butanoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)nicotinonitrile), is described as a muscarinic acetylcholine receptor M1 antagonist in WO2021 / 071843; a particular crystalline form (or polymorph) of this compound, method for producing the crystalline form, and pharmaceutical compositions comprising the compound in crystalline form, are described (in some instances referred to as free base Type A) in WO2022 / 221450, each of which is incorporated herein by reference. Such crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 13.4 ± 0.15° 20, 14.0 ± 0.15° 20, 15.2 ± 0.15° 20, 19.3 ± 0.15° 20, 20.0 ± 0.15° 20, and 21 .2 ± 0.15° 20, and having a differential scanning calorimetry endotherm onset at about 117 °C.

[0043] As used herein, ‘pharmaceutically acceptable salt’ includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0044] ‘Pharmaceutically acceptable acid addition salt’ refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise 7MF-364290499Attorney docket no. 29764-20006.40undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. eta!., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0045] ‘Pharmaceutically acceptable base addition salt’ refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A / ,A / -dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A / -methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A / -ethylpiperidine, polyamine resins and the like. See Berge etal., supra.

[0046] In an embodiment, compound (1) is administered as the only interventional therapy to treat the depression (e.g., the major depressive disorder, the treatment resistant depression 8MF-364290499Attorney docket no. 29764-20006.40or the major depressive disorder with anxious distress) i.e. compound (1) is administered alone as the (pharmacological) therapy for the treatment of the depression, but the patient or subject being treated may also require concomitant therapy for other comorbidities.

[0047] In an embodiment, compound (1) is administered (to a patient in need thereof) for the treatment of depression (including but not limited to major depressive disorder, treatment resistant depression or depression with anxious distress) as monotherapy.

[0048] In another embodiment, compound (1) is administered (to a patient in need thereof) for the treatment of depression (including but not limited to major depressive disorder, treatment resistant depression or depression with anxious distress) in combination with one or more additional antidepressant therapies; wherein said antidepressant therapies are pharmacological or non-pharmacological (e.g., psychotherapy).

[0049] In an embodiment, compound (1) is administered as a free base. In a further embodiment, compound (1) is administered as the crystalline form (free base Type A) as described in WO2022 / 221450, herein incorporated by reference, characterized by an X-ray powder diffraction pattern comprising peaks at 13.4 ± 0.15° 20, 14.0 ± 0.15° 20, 15.2 ± 0.15° 20, 19.3 ± 0.15° 20, 20.0 ± 0.15° 20, and 21.2 ± 0.15° 20, and having a differential scanning calorimetry endotherm onset at about 117 °C. When reference is made throughout to compound (1 ), it will be understood that reference is made to the free base, in particular to the crystalline form (free base Type A).

[0050] Compound (1 ), or a pharmaceutically acceptable salt thereof, can be administered orally, formulated in a pharmaceutical composition, for example, such as described in WO2021 / 071843 or WO2022 / 8221450, in a tablet or capsule.

[0051] In an embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, is administered near bedtime or at bedtime.

[0052] In a particular embodiment of the methods of the invention, compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at (a) a dose in the range of about 20-80 mg; or (b) a dose in the range of about 30-80 mg; or (c) a dose in the range of about 40-80 mg; or (d) a dose in the range of about 50-80 mg; or (e) a dose in the range of about 60-80 mg; or (f) a dose in the range of about 70-80 mg; or (h) in the range of about 20-60 mg; or (i) in the range of about 20-40 mg. In another embodiment, compound (1), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 80 mg. In a further embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg. In a further embodiment, compound (1), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg. In a further embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg. In a further embodiment, compound (1), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg. In a further embodiment, compound (1 ), or a pharmaceutically acceptable 9MF-364290499Attorney docket no. 29764-20006.40salt thereof, is administered at a dose of about 60 mg. In a further embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg.

[0053] In a further embodiment, the Compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at a first dose in the range of about 60 mg to about 80 mg, in particular 80 mg, during a first period, and the Compound (1 ), or a pharmaceutically acceptable salt thereof, is then administered at a second dose during a second period, wherein the second dose is lower than the first dose. For example, if the first administered dose is in the range of about 60 mg to about 80 mg, in particular about 80 mg, the second dose is in the range of about 20 mg to about 60 mg, respectively, in particular about 20 mg, in particular about 30 mg, in particular about 40 mg, in particular about 50 mg, in particular about 60 mg. In an embodiment, the period of dosing is about 6 to 12 weeks, followed by a second period of about 6 to 12 months, depending on the patient’s specific situation. In an embodiment, the first period of dosing is about 1 to 2 weeks, while the second period of dosing is at least 1 week, typically 6 to 12 weeks. In a further embodiment, the Compound (1 ), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 80 mg, during a first period of 1 week, and then administered at dose of about 20 mg a second dose during a second period of 1 week.

[0054] In a particular embodiment of the methods of the invention, the subject or patient in need of treatment is an adult (e.g., 18 to 64 years, inclusive) and suffers from, or has been diagnosed with, depression, in particular major depressive disorder, treatment resistant depression or major depressive disorder with anxious distress.

[0055] In certain embodiments, the patient has had an inadequate response to one or more prior antidepressant therapies (i.e., antidepressant medication or treatment used to treat depression other than compound (1)). “Inadequate response” or “incomplete response” as used herein refers to a patient not recovering fully on an antidepressant medication (i.e. not responding adequately), e.g., experiencing a less than about 50% reduction in depressive symptom severity from the start or initiation of treatment with the antidepressant medication.

[0056] A patient’s response may be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, the patient suffers from, or has been diagnosed with, depression, in particular, an episode of major depressive disorder and has undergone 0, 1 , or 2 antidepressant treatment regimens in the current depressive episode. By 0, 1 , or 2 antidepressant treatment regimens in the current depressive episode, it is meant that the patient (a - “0”) presents for a new episode of depression (e.g., major depressive disorder) on no antidepressant (pharmacological) treatment, but has been treated with antidepressant(s) of adequate dose and duration in a prior episode; (b - “1”) presents for a new episode of depression (e.g., major depressive disorder) on antidepressant treatment for said new episode but experiences incomplete response (i.e., the patient has not responded adequately) or intolerance to the current antidepressant treatment; or (c - “2”) presents for a 10MF-364290499Attorney docket no. 29764-20006.40new episode of depression (e.g., major depressive disorder) on antidepressant treatment for said new episode but experiences incomplete response (i.e., the patient has not responded adequately) or intolerance, and had one additional prior treatment for said new episode that was stopped due to incomplete response (i.e., the patient has not responded adequately) or intolerance, respectively. When a patient has had an inadequate or no response to 2 or more (at least 2) antidepressants in an episode (i.e. a current episode), the depression can be referred to as treatment resistant depression.

[0057] A patient presenting with an episode of depression can be assessed at the time of initial administration of, i.e. start of treatment with e.g., the compound (1) using for example, a validated or clinically accepted depression scale, in particular, in total score in a depression scale, and / or by physician / clinical judgment. The depression scale can be selected from one or a combination of scales available in clinical practice, for example the Montgomery-Asberg Depression Rating Scale (MADRS), the Inventory of Depressive Symptomatology, the Clinician Rating-30 (IDS-C30), the Clinician Global Impression-Severity (CGI-S), the Symptoms of Major Depressive Disorder Scale (SMDDS) and the like.

[0058] A patient that suffers from, or has been diagnosed with, major depressive disorder, would typically score > 11 in the Montgomery-Asberg Depression Rating Scale (MADRS) prior to initiating treatment with compound (1). A patient that suffers from, or has been diagnosed with, major depressive disorder, would typically score > 21 in the Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30) scale, prior to initiating treatment with compound (1 ). In an embodiment, the patient that suffers from, or has been diagnosed with, major depressive disorder would score >18, in particular > 20, in particular > 25 in the Montgomery-Asberg Depression Rating Scale (MADRS), and / or a total score of > 25 on the Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30) scale, prior to treatment with compound (1).

[0059] The patient suffering from or diagnosed with major depressive disorder may also experience anxious distress, i.e. suffer from, or be diagnosed with, major depressive disorder with anxious distress. Anxiety symptoms can be assessed at the time of initial administration of, i.e. start of treatment with e.g., the compound (1 ) using for example, a validated or clinically accepted scale or questionnaire (patient reported outcome), such as for example the Generalized Anxiety Disorder 7 (GAD-7) questionnaire.

[0060] In an embodiment, the patient experiences an improvement in symptoms of depression (i.e., or reduction of depression symptoms), as measured by the change (decrease) from baseline (last day prior to administration of, or start of treatment with, compound (1 )) in total score in a depression scale, e.g., the measured MADRS total score. In particular a patient may achieve a response as measured by a change (decrease) from baseline in total score in a depression scale following treatment with compound (1 ), e.g., in the MADRS and / or IDS-C3011MF-364290499Attorney docket no. 29764-20006.40total score, measured at a given timepoint or period of time after starting treatment with compound (1).

[0061] In the methods of the present invention, the period of time or timepoints after starting treatment, to measure for improvement in symptoms of depression (i.e., or reduction in depression symptoms), or onset of action, may be less than about 1 month, less than about 3 weeks, less than about 2 weeks, less than 1 week or shorter (e.g., within 3-4 days, within 2 days, within 24 hours). In a particular embodiment according to the methods of the invention, the period of time for improvement in symptoms of depression, or onset of action within less than or equal to about 1 week, in particular within 1 week, in particular within 5 days, in particular, within 2 days, in particular within 1 day (24 hours) after initiation of treatment with the compound (1 ). The onset of action can be observed through a change in total score at a given timepoint of administration of MADRS and / or CGI-S.

[0062] In a particular embodiment of the methods of the invention, the patient experiences an improvement in symptoms of depression, as measured by the change from baseline (last day prior to administration of, or start of treatment with, compound (1)) as measured by a decrease in MADRS total score; wherein the improvement occurs after a period of time that is less than or equal to about 3 weeks, for example after less than or equal to about 1 week, after starting treatment with compound (1 ). In a further embodiment, the patient experiences an improvement in symptoms of depression, as measured by the change from baseline (last day prior to administration of, or start of treatment with, compound (1 )) as measured by a decrease in MADRS total score after a period of time of less than or equal to about 5 days after starting treatment with compound (1 ). In a further embodiment, the patient experiences an improvement in symptoms of depression, as measured by the change from baseline (last day prior to administration of, or start of treatment with, compound (1 )) as measured by a decrease in MADRS total score after a period of time of less than or equal to about 2 days after starting treatment with compound (1 ). In a further embodiment, the patient experiences an improvement in symptoms of depression, as measured by the change from baseline (last day prior to administration of, or start of treatment with, compound (1 )) as measured by a decrease in MADRS total score after a period of time of less than or equal to about 1 day after starting treatment with compound (1).

[0063] The improvement in symptoms of depression can be measured by a change from baseline to, for example, day 7 in MADRS total score, in particular, by a change from baseline to day 5 in MADRS total score, in particular, by a change from baseline to day 2 in MADRS total score.

[0064] Improvement in symptoms of depression (also known as a positive response) can be measured as a reduction of depressive symptoms by at least 50% as measured by the change from baseline (prior to initiating treatment with compound (1 )) in total score in a depression 12MF-364290499Attorney docket no. 29764-20006.40scale following treatment with compound (1). In particular, the improvement in symptoms of depression can be measured as a decrease in MADRS total score, in particular a decrease in MADRS score of about 50% or greater, after starting treatment with compound (1), or alternatively, the improvement in symptoms of depression can be measured by a placebo subtracted change in total score MADRS from baseline (last day prior to administration of compound (1 )) of 2 points or greater.

[0065] Alternatively, or additionally, the treatment achieves an improvement in the overall severity of the depression or the depressive illness, as assessed by the clinician, in particular measured by a change from baseline (last day prior to administration of, or start of treatment with, compound (1)) in the Clinician Global Impression-Severity (CGI-S) scale, in particular after a period of time of about 1 week, or within about 1 week (e.g., after about 6 days, after about 5 days, after about 4 days, after about 3 days, after about 2 days, after about 1 day, etc.), after starting treatment with compound (1 ). In particular the improvement is measured after a period of about 5 days after starting treatment with compound (1), in particular, the improvement is measured after a period of time of about 2 days after starting treatment with compound (1), in particular, the improvement is measured after a period of time of about 1 day after starting treatment with compound (1).

[0066] The patient can also perceive or experience that the treatment with compound (1 ) achieves an improvement in depressive symptoms, as measured by a change from baseline (last day prior to administration of compound (1)) in Symptoms of Major Depressive Disorder Scale (SMDDS) total score, in particular after a period of time of about 1 week, or within 1 week (e.g., after about 6 days, after about 5 days, after about 4 days, after about 3 days, after about 2 days, after about 1 day, etc.), after starting treatment with compound (1). In particular, after a period of time of about 5 days after starting treatment with compound (1), in particular after a period of time of about 2 days after starting treatment with compound (1), in particular after a period of time of about 1 day after starting treatment with compound (1).

[0067] As already indicated, the patient can also present with major depressive disorder with anxious distress. The patient can also perceive or experience that the treatment with compound (1) achieves an improvement in depressive symptoms, as already indicated, but may in addition experience an improvement in anxiety symptoms, as measured by a change from baseline (last day prior to administration of, or start of treatment with, compound (1)), as measured by GAD-7.

[0068] When compound (1 ) or a pharmaceutically acceptable salt thereof is administered, in a pharmaceutical composition, at a dose range of about 20 mg to about 80 mg as described herein, a muscarinic M1 receptor occupancy may be achieved in the range of about 60% to about 90% at a time range of about 1 h to about 4 h after administration of the compound (1). Thus, the invention also relates to a method of effecting muscarinic M1 receptor occupancy in 13MF-364290499Attorney docket no. 29764-20006.40the range of about 60% to about 90% in patients, at a time range of about 1 h to about 4 h after administration of an effective amount the compound (1) to patients, wherein the effective amount is in the range of about 20 mg to about 80 mg. In particular, the invention also relates to a method of treating depression in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof to achieve a muscarinic M1 receptor occupancy in the range of about 60% to about 90% at a time range of about 1 h to about 4 h after administration of the compound (1 ), wherein the effective amount is in the range of about 20 mg to about 80 mg. In particular, the therapeutically effective amount is in the range of about 40 mg to about 80 mg. In particular, the therapeutically effective amount is in the range of about 60 mg to about 80 mg. In a further embodiment, when the therapeutically effective amount is in the range of about 60 mg to about 80 mg, the receptor occupancy is maintained above about 60% for a median duration of about half a day to about 1 day. In particular, the therapeutically effective amount is in the range of about 40 mg to about 60 mg. In a further embodiment, the therapeutically effective amount is about 80 mg. In a further embodiment, when the therapeutically effective amount is of about 80 mg, the receptor occupancy is maintained above about 60% for a median duration of about 22 h. In a further embodiment, the therapeutically effective amount is about 60 mg. In a further embodiment, when the therapeutically effective amount is about 60 mg, the receptor occupancy is maintained above about 60% for a median duration of about 14 h.

[0069] Where the invention, as described herein in the different particular embodiments, is said to relate to a method of treatment of a subject or a patient, comprising administering to a subject or patient in need thereof of such treatment, it is understood that such methods and embodiments are to be interpreted in certain jurisdictions as a medical use, i.e. , to relate to the compound (1 ), or a pharmaceutically acceptable salt, for use in a method of treatment; or to relate to the compound (1 ), or a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a patient or a subject.ASPECTS

[0070] Aspect 1. A method of treating a patient suffering from, or diagnosed with, depression, comprising administering to a patient in need of such treatment, compound (1)pharmaceutically acceptable salt thereof, wherein compound (1 ) is administered at a dose in the range of about 20 mg to about 80 mg.

[0071] Aspect 2. The method according to Aspect 1 , wherein compound (1 ) is administered according to an intermittent dosing frequency or regimen.14MF-364290499Attorney docket no. 29764-20006.40

[0072] Aspect 3. The method according to Aspect 1 or 2, wherein compound (1) is administered on Day 1 at a dose of 80 mg, and then administered according to an intermittent dosing frequency or regimen.

[0073] Aspect 4. The method according to Aspect 3, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and wherein subsequent doses are administered according to an intermittent dosing frequency or regimen in an amount in the range of from about 20 mg to about 80 mg.

[0074] Aspect 5. A method of treating a patient suffering from, or diagnosed with, depression, comprising administering to a patient in need of such treatment a compound of formula (1)pharmaceutically acceptable salt thereof, wherein the compound of formula (1) or the pharmaceutically acceptable salt thereof is administered in an intermittent dosing frequency or regimen at a dose of about 20 mg to about 80 mg.

[0075] Aspect 6. The method according to any one of Aspects 1 to 5, wherein the compound is administered at a dosing frequency in the range of once per week to up to four doses per week.

[0076] Aspect 7. The method according to any one of Aspects 1 to 6, wherein the compound is administered at a dosing frequency in the range of once per week to up to three times / doses per week.

[0077] Aspect 8. The method according to any one of Aspects 1 to 7, wherein the compound is administered once a week (i.e., the compound is administered at a frequency of once a week).

[0078] Aspect 9. The method according to any one of Aspects 1 to 7, wherein the compound is administered twice a week (i.e., the compound is administered at a frequency of twice a week).

[0079] Aspect 10. The method according to any one of Aspects 1 to 7, wherein the compound is administered every approximately 3 to 4 days.

[0080] Aspect 11. The method according to aspect 10, wherein the compound is to be administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0081] Aspect 12. The method according to any one of Aspects 1 to 7, wherein the compound is administered every approximately 2 days.15MF-364290499Attorney docket no. 29764-20006.40

[0082] Aspect 13. The method according to any one of Aspect 1 to 7, wherein the compound is administered every other day.

[0083] Aspect 14. The method according to any one of Aspects 1 to 13, wherein the compound is administered near bedtime or at bedtime.

[0084] Aspect 15. The method according to any one of Aspects 1 to 14, wherein the compound is administered as the free base.

[0085] Aspect 16. The method according to any one of Aspects 1 to 15, wherein the compound is administered as the free base Type A, as described in WO2022 / 221450.

[0086] Aspect 17. The method according to any one of Aspects 1 to 16, wherein the compound is administered orally.

[0087] Aspect 18. The method according to Aspect 17, wherein the compound is administered in a tablet or a capsule.

[0088] Aspect 19. The method according to any one of Aspects 1 to 18, wherein the compound is administered at a dose in the range of about 40 mg to about 80 mg.

[0089] Aspect 20. The method according to any one of Aspects 1 to 19, wherein the compound is administered at a dose of about 60 mg to about 80 mg.

[0090] Aspect 21. The method according to Aspect 19 or 20, wherein the compound is administered at a dose of about 80 mg.

[0091] Aspect 22. The method according to Aspect 19 or 20, wherein the compound is administered at a dose of about 70 mg.

[0092] Aspect 23. The method according to Aspect 19 or 20, wherein the compound is administered at a dose of about 60 mg.

[0093] Aspect 24. The method according to Aspect 19, wherein the compound is administered at a dose of about 50 mg.

[0094] Aspect 25. The method according to Aspect 19, wherein the compound is administered at a dose of about 40 mg.

[0095] Aspect 26. The method according to any one of Aspects 1 to 18, wherein the compound is administered at a dose of about 30 mg.

[0096] Aspect 27. The method according to any one of Aspects 1 to 18, wherein the compound is administered at a dose of about 20 mg.

[0097] Aspect 28. The method according to any one of Aspects 1 to 20, wherein the compound is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0098] Aspect 29. The method according to Aspect 28, wherein the second dose is in the range of about 20 mg to about 60 mg.16MF-364290499Attorney docket no. 29764-20006.40

[0099] Aspect 30. The method according to Aspect 29, wherein the second dose is in the range of about 20 mg to about 40 mg.

[0100] Aspect 31. The method according to any one of Aspects 29 or 30, wherein the second dose is 20 mg.

[0101] Aspect 32. The method according to any one of Aspects 29 or 30, wherein the second dose is 30 mg.

[0102] Aspect 33. The method according to any one of Aspects 29 or 30, wherein the second dose is 40 mg.

[0103] Aspect 34. The method according to Aspect 29, wherein the second dose is 50 mg.

[0104] Aspect 35. The method according to Aspect 29, wherein the second dose is 60 mg.

[0105] Aspect 36. The method according to any one of Aspects 28 to 35, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.

[0106] Aspect 37. The method according to any one of Aspects 28 to 35, wherein the first period of dosing lasts 1 to 2 weeks, while the second period of dosing lasts at least 1 week.

[0107] Aspect 38. The method according to any one of Aspects 1 to 37, wherein the depression is major depressive disorder.

[0108] Aspect 39. The method according to any one of Aspects 1 to 38, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to other antidepressant therapy or treatment prior to treatment with compound (1).

[0109] Aspect 40. The method according to Aspect 39, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to 0, 1 , or 2 antidepressant treatment regimens in the current depressive episode, prior to treatment with compound (1).

[0110] Aspect 41. The method according to Aspect 40, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to 2 antidepressant treatment regimens in the current depressive episode, prior to treatment with compound (1).

[0111] Aspect 42. The method according to Aspect 41, wherein the depression is treatment resistant depression.

[0112] Aspect 43. The method according to any one of Aspects 1 to 42, wherein the patient is an adult.

[0113] Aspect 44. The method according to any one of Aspects 1 to 43, wherein the patient in need of such treatment is assessed at the time of initial administration of compound (1 ).

[0114] Aspect 45. The method according to Aspect 44, wherein the patient is assessed at the time of initial administration of compound (1 ) in total score in a depression scale.

[0115] Aspect 46. The method according to Aspect 44 or 45, wherein the patient is assessed at the time of initial administration of compound (1) in total score in the Montgomery- 17MF-364290499Attorney docket no. 29764-20006.40Asberg Depression Rating Scale (MADRS) and / or Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30).

[0116] Aspect 47. The method according to Aspect 46, wherein the patient scores > 18, in particular, > 20 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score prior to treatment with compound (1 ).

[0117] Aspect 48. The method according to Aspect 46 or 47, wherein the patient scores > 25 in the Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30) prior to treatment with compound (1).

[0118] Aspect 49. The method according to any one of Aspects 1 to 48, wherein the patient has major depressive disorder with anxious distress.

[0119] Aspect 50. The method according to any one of Aspects 1 to 49, wherein the patient experiences an improvement or reduction in symptoms of depression, as measured by the change from baseline, i.e. the last day prior to administration of, or start of treatment with, compound (1 ), after a period of treatment, i.e., after treatment, with compound (1 ).

[0120] Aspect 51. The method according to Aspect 50, wherein the reduction of depressive symptoms is achieved following less than 3 weeks, in particular following 1 week, of treatment with compound (1).

[0121] Aspect 52. The method according to Aspect 50, wherein the reduction of depressive symptoms is achieved following 5 days of treatment with compound (1).

[0122] Aspect 53. The method according to Aspect 50, wherein the reduction of depressive symptoms is achieved following 2 days of treatment with compound (1).

[0123] Aspect 54. The method according to Aspect 50, wherein the reduction of depressive symptoms is achieved following 1 day of treatment with compound (1).

[0124] Aspect 55. The method according to any one of Aspects 44 to 54, wherein the patient is assessed at the time of initial administration of compound (1 ) in total score in the Symptoms of Major Depressive Disorder Scale (SMDDS).

[0125] Aspect 56. The method according to Aspect 55, wherein the patient experiences a reduction in symptoms of depression, as measured by the change from baseline, i.e. the last day prior to administration of, or start of treatment with, compound (1), in total score in the Symptoms of Major Depressive Disorder Scale.

[0126] Aspect 57. The method according to any one of Aspects 44 to 56, wherein the patient experiences a reduction of depressive symptoms by at least 50% as measured by the change from baseline (prior to treatment with compound (1 )) in total score in a depression scale following treatment with compound (1).

[0127] Aspect 58. The method according to Aspect 57, wherein the depression scale is the Montgomery-Asberg Depression Rating Scale (MADRS).18MF-364290499Attorney docket no. 29764-20006.40

[0128] Aspect 59. The method according to any one of Aspects 44 to 57, wherein the patient experiences a reduction of depressive symptoms or improvement in the symptoms of depression measured by a placebo subtracted change in total score MADRS from baseline (last day prior to administration of compound (1)) 2 points or greater.

[0129] Aspect 60. The method according to any one of Aspects 44 to 59, wherein the patient experiences an improvement in anxiety symptoms, as measured by a change from baseline in Generalized Anxiety Disorder-7.

[0130] Aspect 61. The method according to Aspect 60, wherein the reduction of anxiety symptoms is achieved following less than 3 weeks, in particular following 1 week, of treatment with compound (1).

[0131] Aspect 62. The method according to Aspect 61 , wherein the reduction of anxiety symptoms is achieved following 5 days of treatment with compound (1).

[0132] Aspect 63. The method according to Aspect 61 , wherein the reduction of anxiety symptoms is achieved following 1 or 2 days of treatment with compound (1).

[0133] Aspect 64. The method according to any one of Aspects 1 to 63, wherein the patient does not receive any additional antidepressant treatment, i.e. compound (1) is administered as monotherapy, i.e., as the only antidepressant (pharmacological) treatment administered to the patient.

[0134] Aspect 65. A method of treating a patient suffering from, or diagnosed with, major depressive disorder, according to Aspect 1 , comprising administering to a patient in need ofsuch treatment compoundwherein compound (1) is administered as monotherapy, at a dose in the range of about 20 mg to about 80 mg.

[0135] Aspect 66. The method according to Aspect 65, wherein compound (1) is administered according to an intermittent dosing frequency or regimen.

[0136] Aspect 67. The method according to Aspect 65 or 66, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and then administered according to an intermittent dosing frequency or regimen.

[0137] Aspect 68. The method according to any one of Aspects 65 to 67, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and wherein subsequent doses are administered according to an intermittent dosing frequency or regimen in an amount in the range of from about 20 mg to about 80 mg.19MF-364290499Attorney docket no. 29764-20006.40

[0138] Aspect 69. The method according to any one of Aspects 65 to 68, wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to four doses per week.

[0139] Aspect 70. The method according to any one of Aspects 65 to 69, wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to three doses per week.

[0140] Aspect 71. The method according to any one of Aspects 65 to 70, wherein the compound of formula (1 ) is administered twice a week.

[0141] Aspect 72. The method according to any one of Aspects 65 to 70, wherein the compound of formula (1 ) is administered once a week.

[0142] Aspect 73. The method according to any one of Aspects 65 to 71 , wherein the compound of formula (1 ) is administered every 3 to 4 days.

[0143] Aspect 74. The method according to any one of Aspects 65 to 70, wherein the compound is administered every approximately 2 days.

[0144] Aspect 75. The method according to any one of Aspects 65 to 69, wherein the compound is administered every other day.

[0145] Aspect 76. The method according to any one of Aspects 65 to 75, wherein the compound is administered near bedtime or at bedtime.

[0146] Aspect 77. The method according to any one of Aspects 65 to 76, wherein the compound is administered as the free base.

[0147] Aspect 78. The method according to any one of Aspects 65 to 77, wherein the compound is administered as the free base Type A, as described in WO2022 / 221450.

[0148] Aspect 79. The method according to any one of Aspects 65 to 78, wherein the compound is administered orally.

[0149] Aspect 80. The method according to Aspect 79, wherein the compound is administered in a tablet or a capsule.

[0150] Aspect 81. The method according to any one of Aspects 65 to 80, wherein the compound is administered at a dose in the range of about 40 mg to about 80 mg.

[0151] Aspect 82. The method according to any one of Aspects 65 to 81 , wherein the compound is administered at a dose of about 60 mg to about 80 mg.

[0152] Aspect 83. The method according to any one of Aspects 65 to 82, wherein the compound is administered at a dose of about 80 mg.

[0153] Aspect 84. The method according to any one of Aspects 65 to 82, wherein the compound is administered at a dose of about 70 mg.

[0154] Aspect 85. The method according to any one of Aspects 65 to 82, wherein the compound is administered at a dose of about 60 mg.20MF-364290499Attorney docket no. 29764-20006.40

[0155] Aspect 86. The method according to any one of Aspects 65 to 81 , wherein the compound is administered at a dose of about 50 mg.

[0156] Aspect 87. The method according to any one of Aspects 65 to 81 , wherein the compound is administered at a dose of about 40 mg.

[0157] Aspect 88. The method according to any one of Aspects 65 to 80, wherein the compound is administered at a dose of about 30 mg.

[0158] Aspect 89. The method according to any one of Aspects 65 to 80, wherein the compound is administered at a dose of about 20 mg.

[0159] Aspect 90. The method according to any one of Aspects 65 to 80 or 82, wherein the compound of formula (1 ) is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0160] Aspect 91. The method according to Aspect 90, wherein the second dose is administered 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0161] Aspect 92. The method according to Aspect 90 or 91 , wherein the second dose is in the range of about 20 mg to about 60 mg.

[0162] Aspect 93. The method according to any one of Aspects 90 to 92, wherein the second dose is in the range of about 20 mg to about 40 mg.

[0163] Aspect 94. The method according to Aspect 92 or 93, wherein the second dose is 20 mg.

[0164] Aspect 95. The method according to Aspect 92 or 93, wherein the second dose is 30 mg.

[0165] Aspect 96. The method according to Aspect 92 or 93, wherein the second dose is 40 mg.

[0166] Aspect 97. The method according to Aspect 92, wherein the second dose is 50 mg.

[0167] Aspect 98. The method according to Aspect 92, wherein the second dose is 60 mg.

[0168] Aspect 99. The method according to any one of Aspects 90 to 98, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.

[0169] Aspect 100. The method according to any one of Aspects 65 to 99, wherein the major depressive disorder is treatment-resistant depression.

[0170] Aspect 101. The method according to any one of Aspects 65 to 100, wherein the major depressive disorder is major depressive disorder with anxious distress.

[0171] Aspect 102. A method of treating depression in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising compound (1)21MF-364290499Attorney docket no. 29764-20006.40pharmaceutically acceptable salt thereof to achieve a muscarinic M1 receptor occupancy in the range of about 60% to about 90% at a time range of about 1 h to about 4 h after administration of the compound (1 ), wherein the effective amount is in the range of about 20 mg to about 80 mg.

[0172] Aspect 103. The method according to Aspect 102, wherein the therapeutically effective amount is in the range of about 40 mg to about 80 mg.

[0173] Aspect 104. The method according to Aspect 102, wherein the therapeutically effective amount is in the range of about 60 mg to about 80 mg.

[0174] Aspect 105. The method according to Aspect 102 or 103, wherein the therapeutically effective amount is in the range of about 40 mg to about 60 mg.

[0175] Aspect 106. The method according to any one of Aspects 102 to 104, wherein the therapeutically effective amount is about 80 mg.

[0176] Aspect 107. The method according to any one of Aspects 102 to 105, wherein the therapeutically effective amount is about 60 mg.

[0177] Aspect 108. The method according to any one of Aspects 102 to 105, wherein the therapeutically effective amount is about 50 mg.

[0178] Aspect 109. The method according to any one of Aspects 102, 103 or 105, wherein the therapeutically effective amount is about 40 mg.

[0179] Aspect 110. The method according to Aspect 102, wherein the therapeutically effective amount is about 30 mg.

[0180] Aspect 111. The method according to Aspect 102, wherein the therapeutically effective amount is about 20 mg.

[0181] Aspect 112. The method according to Aspect 104, wherein the receptor occupancy is maintained above about 60% for a median duration of about half a day to about 1 day.

[0182] Aspect 113. The method according to Aspect 106, wherein the receptor occupancy is maintained above about 60% for a median duration of about 22 h.

[0183] Aspect 114. The method according to Aspect 106, wherein the receptor occupancy is maintained above about 60% for a median duration of about 22 h.

[0184] Aspect 115. The method according to Aspect 107, wherein the receptor occupancy is maintained above about 60% for a median duration of about 14 h.

[0185] Aspect 116. The method according to any one of Aspects 102 to 115, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about once per week to up to four doses per week.22MF-364290499Attorney docket no. 29764-20006.40

[0186] Aspect 117. The method according to any one of Aspects 102 to 116, wherein the dosing frequency is in the range of once per week to up to three doses per week.

[0187] Aspect 118. The method according to any one of Aspects 102 to 117, wherein the dosing frequency is once per week.

[0188] Aspect 119. The method according to any one of Aspects 102 to 117, wherein the dosing frequency is twice per week.

[0189] Aspect 120. The method according to any one of Aspects 102 to 117, wherein the dosing frequency is about 3 to 4 days.

[0190] Aspect 121. The method according to Aspect 120, wherein the dosing frequency comprises dosing a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0191] Aspect 122. The method according to any one of Aspects 102 to 117 wherein the dosing frequency is about once every 2 days, or once every other day.

[0192] Aspect 123. The method according to any one of Aspects 102 to 122, wherein the pharmaceutical composition is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0193] Aspect 124. The method according to Aspect 123, wherein the second dose is in the range of about 20 mg to about 60 mg.

[0194] Aspect 125. The method according to Aspect 123, wherein the second dose is in the range of about 20 mg to about 40 mg.

[0195] Aspect 126. The method according to any one of Aspects 123 to 125, wherein the second dose is 20 mg.

[0196] Aspect 127. The method according to any one of Aspects 123 to 125, wherein the second dose is 30 mg.

[0197] Aspect 128. The method according to any one of Aspects 123 to 125, wherein the second dose is 40 mg.

[0198] Aspect 129. The method according to any one of Aspects 123 to 124, wherein the second dose is 50 mg.

[0199] Aspect 130. The method according to any one of Aspects 123 to 124, wherein the second dose is 60 mg.

[0200] Aspect 131. The method according to any one of Aspects 123 to 130, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.

[0201] Aspect 132. The method according to any one of Aspects 102 to 131, wherein the muscarinic M1 receptor occupancy is achieved in about 60% or more of the patients.23MF-364290499Attorney docket no. 29764-20006.40

[0202] Aspect 133. The method according to any one of Aspects 102 to 132, wherein the compound of formula (1 ) is administered as free base.

[0203] Aspect 134. The method according to any one of Aspects 102 to 133, wherein the compound of formula (1 ) is administered as free base Type A.

[0204] Aspect 135. The method according to any one of Aspects 102 to 134, wherein the pharmaceutical composition is a tablet or a capsule.

[0205] Aspect 136. The method according to any one of Aspects 102 to 135, wherein the depression is major depressive disorder.

[0206] Aspect 137. The method according to any one of Aspects 102 to 136, wherein the depression is treatment resistant depression.

[0207] Aspect 138. The method according to any one of claims 102 to 137, wherein the depression is major depressive disorder with anxious distress.

[0208] Aspect 1 a. A compound of formula (1 )pharmaceutically acceptable salt thereof, for use in a method of, or use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for, treating depression, - the method -comprising administering to a patient a dose in the range of about 20 mg to about 80 mg of the compound of formula (1 ) or a pharmaceutically acceptable salt thereof.

[0209] Aspect 2a. The compound for use, or the use, according to Aspect 1 a, wherein compound (1 ) is administered according to an intermittent dosing frequency or regimen.

[0210] Aspect 3a. The compound for use, or the use, according to Aspect 1 a or 2a, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and then administered according to an intermittent dosing frequency or regimen.

[0211] Aspect 4a. The compound for use, or the use, according to Aspect 3a, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and wherein subsequent doses are administered according to an intermittent dosing frequency or regimen in an amount in the range of from about 20 mg to about 80 mg.

[0212] Aspect 5a. A compound of formula (1 )24MF-364290499Attorney docket no. 29764-20006.40pharmaceutically acceptable salt thereof, for use in a method of, or use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for, treating depression, - the treatment -comprising administering to a patient a dose in the range of about 20 mg to about 80 mg of the compound of formula (1 ) or the pharmaceutically acceptable salt, in an intermittent dosing frequency or regimen.

[0213] Aspect 6a. The compound for use, or the use, according to any one of Aspects 1a to 5a, wherein the compound is administered at a dosing frequency in the range of once per week to up to four doses per week.

[0214] Aspect 7a. The compound for use, or the use, according to any one of Aspects 1 a to 6a, wherein the compound is administered at a dosing frequency in the range of once per week to up to three times / doses per week.

[0215] Aspect 8a. The compound for use, or the use, according to any one of Aspects 1 a to 7a, wherein the compound is administered once a week (i.e., the compound is administered at a frequency of once a week).

[0216] Aspect 9a. The compound for use, or the use, according to any one of Aspects 1 a to 7a, wherein the compound is administered twice a week (i.e., the compound is administered at a frequency of twice a week).

[0217] Aspect 10a. The compound for use, or the use, according to any one of Aspects 1 a to 7a, wherein the compound is administered every approximately 3 to 4 days.

[0218] Aspect 11a. The compound for use, or the use, according to Aspect 10a, wherein the compound is to be administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0219] Aspect 12a. The compound for use, or the use, according to any one of Aspects 1 a to 7a, wherein the compound is administered every approximately 2 days.

[0220] Aspect 13a. The compound for use, or the use, according to any one of Aspects 1a to 7a, wherein the compound is administered every other day.

[0221] Aspect 14a. The compound for use, or the use, according to any one of Aspects 1 a to 13a, wherein the compound is administered near bedtime or at bedtime.

[0222] Aspect 15a. The compound for use, or the use, according to any one of Aspects 1 a to 14a, wherein the compound is administered as the free base.25MF-364290499Attorney docket no. 29764-20006.40

[0223] Aspect 16a. The compound for use, or the use, according to any one of Aspects 1 a to 15a, wherein the compound is administered as the free base Type A, as described in WO2022 / 221450.

[0224] Aspect 17a. The compound for use, or the use, according to any one of Aspects 1 a to 16a, wherein the compound is administered orally.

[0225] Aspect 18a. The compound for use, or the use, according to Aspect 17a, wherein the compound is administered in a tablet or a capsule.

[0226] Aspect 19a. The compound for use, or the use, according to any one of Aspects 1a to 18a, wherein the compound is administered at a dose in the range of about 40 mg to about 80 mg.

[0227] Aspect 20a. The compound for use, or the use, according to any one of Aspects 1 a to 19a, wherein the compound is administered at a dose of about 60 mg to about 80 mg.

[0228] Aspect 21 a. The compound for use, or the use, according to Aspect 19a or 20a, wherein the compound is administered at a dose of about 80 mg.

[0229] Aspect 22a. The compound for use, or the use, according to Aspect 19a or 20a, wherein the compound is administered at a dose of about 70 mg.

[0230] Aspect 23a. The compound for use, or the use, according to Aspect 19a or 20a, wherein the compound is administered at a dose of about 60 mg.

[0231] Aspect 24a. The compound for use, or the use, according to Aspect 19a, wherein the compound is administered at a dose of about 50 mg.

[0232] Aspect 25a. The compound for use, or the use, according to Aspect 19a, wherein the compound is administered at a dose of about 40 mg.

[0233] Aspect 26a. The compound for use, or the use, according to any one of Aspects 1 a to 18a, wherein the compound is administered at a dose of about 30 mg.

[0234] Aspect 27a. The compound for use, or the use, according to any one of Aspects 1 a to 18a, wherein the compound is administered at a dose of about 20 mg.

[0235] Aspect 28a. The compound for use, or the use, according to any one of Aspects 1 a to 20a, wherein the compound is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0236] Aspect 29a. The compound for use, or the use, according to Aspect 28a, wherein the second dose is in the range of about 20 mg to about 60 mg.

[0237] Aspect 30a. The compound for use, or the use, according to Aspect 29a, wherein the second dose is in the range of about 20 mg to about 40 mg.

[0238] Aspect 31 a. The compound for use, or the use, according to any one of Aspects 29a or 30a, wherein the second dose is 20 mg.26MF-364290499Attorney docket no. 29764-20006.40

[0239] Aspect 32a. The compound for use, or the use, according to Aspect 29a or 30a, wherein the second dose is 30 mg.

[0240] Aspect 33a. The compound for use, or the use, according to Aspect 29a or 30a, wherein the second dose is 40 mg.

[0241] Aspect 34a. The compound for use, or the use, according to Aspect 29a, wherein the second dose is 50 mg.

[0242] Aspect 35a. The compound for use, or the use, according to Aspect 29a, wherein the second dose is 60 mg.

[0243] Aspect 36a. The compound for use, or the use, according to any one of Aspects 28a to 35a, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.

[0244] Aspect 37a. The compound for use, or the use, according to any one of Aspects 28a to 35a, wherein the first period of dosing lasts 1 to 2 weeks, while the second period of dosing lasts at least 1 week.

[0245] Aspect 38a. The compound for use, or the use, according to any one of Aspects 1 a to 37a, wherein the depression is major depressive disorder.

[0246] Aspect 39a. The compound for use, or the use, according to any one of Aspects 1 a to 38a, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to other antidepressant therapy or treatment prior to treatment with compound (1 ).

[0247] Aspect 40a. The compound for use, or the use, according to Aspect 39a, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to 0, 1 , or 2 antidepressant treatment regimens in the current depressive episode, prior to treatment with compound (1).

[0248] Aspect 41 a. The compound for use, or the use, according to Aspect 40a, wherein the patient had an inadequate response (i.e., the patient had not responded adequately) to 2 antidepressant treatment regimens in the current depressive episode, prior to treatment with compound (1).

[0249] Aspect 42a. The compound for use, or the use, according to Aspect 41 a, wherein the depression is treatment resistant depression.

[0250] Aspect 43a. The compound for use, or the use, according to any one of Aspects 1 a to 42a, wherein the patient is an adult.

[0251] Aspect 44a. The compound for use, or the use, according to any one of Aspects 1 a to 43a, wherein the patient in need of such treatment is assessed at the time of initial administration of compound (1).

[0252] Aspect 45a. The compound for use, or the use, according to Aspect 44a, wherein the patient is assessed at the time of initial administration of compound (1 ) in total score in a depression scale.27MF-364290499Attorney docket no. 29764-20006.40

[0253] Aspect 46a. The compound for use, or the use, according to Aspect 44a or 45a, wherein the patient is assessed at the time of initial administration of compound (1) in total score in the Montgomery-Asberg Depression Rating Scale (MADRS) and / or Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30).

[0254] Aspect 47a. The compound for use, or the use, according to Aspect 46a, wherein the patient scores > 18, in particular, > 20 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score prior to treatment with compound (1).

[0255] Aspect 48a. The compound for use, or the use, according to Aspect 46a or 47a, wherein the patient scores > 25 in the Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30) prior to treatment with compound (1 ).

[0256] Aspect 49a. The compound for use, or the use, according to any one of Aspects 1 a to 48a, wherein the patient has major depressive disorder with anxious distress.

[0257] Aspect 50a. The compound for use, or the use, according to any one of Aspects 1 a to 49a, wherein the patient experiences an improvement or reduction in symptoms of depression, as measured by the change from baseline, i.e. the last day prior to administration of, or start of treatment with, compound (1), after a period of treatment, i.e., after treatment, with compound (1).

[0258] Aspect 51 a. The compound for use, or the use, according to Aspect 50a, wherein the reduction of depressive symptoms is achieved following less than 3 weeks, in particular following 1 week, of treatment with compound (1).

[0259] Aspect 52a. The compound for use, or the use, according to Aspect 50a, wherein the reduction of depressive symptoms is achieved following 5 days of treatment with compound (1).

[0260] Aspect 53a. The compound for use, or the use, according to Aspect 50a, wherein the reduction of depressive symptoms is achieved following 2 days of treatment with compound (1).

[0261] Aspect 54a. The compound for use, or the use, according to Aspect 50a, wherein the reduction of depressive symptoms is achieved following 1 day of treatment with compound (1 ).

[0262] Aspect 55a. The compound for use, or the use, according to any one of Aspects 44a to 54a, wherein the patient is assessed at the time of initial administration of compound (1 ) in total score in the Symptoms of Major Depressive Disorder Scale (SMDDS).

[0263] Aspect 56a. The compound for use, or the use, according to Aspect 55a, wherein the patient experiences a reduction in symptoms of depression, as measured by the change from baseline, i.e. the last day prior to administration of, or start of treatment with, compound (1 ), in total score in the Symptoms of Major Depressive Disorder Scale.

[0264] Aspect 57a. The compound for use, or the use, according to any one of Aspects 44a to 56a, wherein the patient experiences a reduction of depressive symptoms by at least 50% as measured by the change from baseline (prior to treatment with compound (1)) in total score in a depression scale following treatment with compound (1).28MF-364290499Attorney docket no. 29764-20006.40

[0265] Aspect 58a. The compound for use, or the use, according to Aspect 57a, wherein the depression scale is the Montgomery-Asberg Depression Rating Scale (MADRS).

[0266] Aspect 59a. The compound for use, or the use, according to any one of Aspects 44a to 57a, wherein the patient experiences a reduction of depressive symptoms or improvement in the symptoms of depression measured by a placebo subtracted change in total score MADRS from baseline (last day prior to administration of compound (1 )) 2 points or greater.

[0267] Aspect 60a. The compound for use, or the use, according to any one of Aspects 44a to 59a, wherein the patient experiences an improvement in anxiety symptoms, as measured by a change from baseline in Generalized Anxiety Disorder-7.

[0268] Aspect 61 a. The compound for use, or the use, according to Aspect 60a, wherein the reduction of anxiety symptoms is achieved following less than 3 weeks, in particular following 1 week, of treatment with compound (1 ).

[0269] Aspect 62a. The compound for use, or the use, according to Aspect 61 a, wherein the reduction of anxiety symptoms is achieved following 5 days of treatment with compound (1).

[0270] Aspect 63a. The compound for use, or the use, according to Aspect 61 a, wherein the reduction of anxiety symptoms is achieved following 2 days of treatment with compound (1).

[0271] Aspect 64a. The compound for use, or the use, according to any one of Aspects 1 a to 63a, wherein the patient does not receive any additional antidepressant treatment, i.e. compound (1) is administered as monotherapy, i.e., as the only antidepressant (pharmacological) treatment administered to the patient.

[0272] Aspect 65a. A compound of formula (1 )pharmaceutically acceptable salt thereof for use in a method of, or use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for, treating major depressive disorder, according to Aspect 1, - the method - comprising administering to a patient compound (1) administered as monotherapy, at a dose in the range of about 20 mg to about 80 mg.

[0273] Aspect 66a. The compound for use, or the use, according to Aspect 65a, wherein compound (1 ) is administered according to an intermittent dosing frequency or regimen.

[0274] Aspect 67a. The compound for use, or the use, according to Aspect 65a or 66a, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and then administered according to an intermittent dosing frequency or regimen.

[0275] Aspect 68a. The compound for use, or the use, according to any one of Aspects 65a to 67a, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and wherein 29MF-364290499Attorney docket no. 29764-20006.40subsequent doses are administered according to an intermittent dosing frequency or regimen in an amount in the range of from about 20 mg to about 80 mg.

[0276] Aspect 69a. The compound for use, or the use, according to any one of Aspects 65a to 68a, wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to four doses per week.

[0277] Aspect 70a. The compound for use, or the use, according to any one of Aspects 65a to 69a, wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to three doses per week.

[0278] Aspect 71 a. The compound for use, or the use, according to any one of Aspects 65a to 70a, wherein the compound of formula (1 ) is administered twice a week.

[0279] Aspect 72a. The compound for use, or the use, according to any one of Aspects 65a to 70a, wherein the compound of formula (1 ) is administered once a week.

[0280] Aspect 73a. The compound for use, or the use, according to any one of Aspects 65a to 71 a, wherein the compound of formula (1 ) is administered every 3 to 4 days.

[0281] Aspect 74a. The compound for use, or the use, according to any one of Aspects 65a to 70a, wherein the compound is administered every approximately 2 days.

[0282] Aspect 75a. The compound for use, or the use, according to any one of Aspects 65a to 69a, wherein the compound is administered every other day.

[0283] Aspect 76a. The compound for use, or the use, according to any one of Aspects 65a to 75a, wherein the compound is administered near bedtime or at bedtime.

[0284] Aspect 77a. The compound for use, or the use, according to any one of Aspects 65a to 76a, wherein the compound is administered as the free base.

[0285] Aspect 78a. The compound for use, or the use, according to any one of Aspects 65a to 77a, wherein the compound is administered as the free base Type A, as described in WO2022 / 221450.

[0286] Aspect 79a. The compound for use, or the use, according to any one of Aspects 65a to 78a, wherein the compound is administered orally.

[0287] Aspect 80a. The compound for use, or the use, according to Aspect 79a, wherein the compound is administered in a tablet or a capsule.

[0288] Aspect 81 a. The compound for use, or the use, according to any one of Aspects 65a to 80a, wherein the compound is administered at a dose in the range of about 40 mg to about 80 mg.

[0289] Aspect 82a. The compound for use, or the use, according to any one of Aspects 65a to 81 a, wherein the compound is administered at a dose of about 60 mg to about 80 mg.

[0290] Aspect 83a. The compound for use, or the use, according to any one of Aspects 65a to 82a, wherein the compound is administered at a dose of about 80 mg.30MF-364290499Attorney docket no. 29764-20006.40

[0291] Aspect 84a. The compound for use, or the use, according to any one of Aspects 65a to 82a, wherein the compound is administered at a dose of about 70 mg.

[0292] Aspect 85a. The compound for use, or the use, according to any one of Aspects 65a to 82a, wherein the compound is administered at a dose of about 60 mg.

[0293] Aspect 86a. The compound for use, or the use, according to any one of Aspects 65a to 81 a, wherein the compound is administered at a dose of about 50 mg.

[0294] Aspect 87a. The compound for use, or the use, according to any one of Aspects 65a to 81 a, wherein the compound is administered at a dose of about 40 mg.

[0295] Aspect 88a. The compound for use, or the use, according to any one of Aspects 65a to 80a, wherein the compound is administered at a dose of about 30 mg.

[0296] Aspect 89a. The compound for use, or the use, according to any one of Aspects 65a to 80a, wherein the compound is administered at a dose of about 20 mg.

[0297] Aspect 90a. The compound for use, or the use, according to any one of Aspects 65a to 80a or 82a, wherein the compound of formula (1 ) is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0298] Aspect 91 a. The compound for use, or the use, according to Aspect 90a, wherein the second dose is administered 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0299] Aspect 92a. The compound for use, or the use, according to Aspect 90a or 91 a, wherein the second dose is in the range of about 20 mg to about 60 mg.

[0300] Aspect 93a. The compound for use, or the use, according to any one of Aspects 90a to 92a, wherein the second dose is in the range of about 20 mg to about 40 mg.

[0301] Aspect 94a. The compound for use, or the use, according to Aspect 92a or 93a, wherein the second dose is 20 mg.

[0302] Aspect 95a. The compound for use, or the use, according to Aspect 92a or 93a, wherein the second dose is 30 mg.

[0303] Aspect 96a. The compound for use, or the use, according to Aspect 92a or 93a, wherein the second dose is 40 mg.

[0304] Aspect 97a. The compound for use, or the use, according to Aspect 92a, wherein the second dose is 50 mg.

[0305] Aspect 98a. The compound for use, or the use, according to Aspect 92a, wherein the second dose is 60 mg.

[0306] Aspect 99a. The compound for use, or the use, according to any one of Aspects 90a to 98a, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.31MF-364290499Attorney docket no. 29764-20006.40

[0307] Aspect 100a. The compound for use, or the use, according to any one of Aspects 65a to 99a, wherein the major depressive disorder is treatment-resistant depression.

[0308] Aspect 101 a. The compound for use, or the use, according to any one of Aspects 65a to 100a, wherein the major depressive disorder is major depressive disorder with anxious distress.

[0309] Aspect 102a. A compound of formula (1 )pharmaceutically acceptable salt thereof for use in a method of, or use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for, treating depression, - the method - comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof to achieve a muscarinic M1 receptor occupancy in the range of about 60% to about 90% at a time range of about 1 h to about 4 h after administration of the compound (1), wherein the effective amount is in the range of about 20 mg to about 80 mg.

[0310] Aspect 103a. The compound for use, or the use, according to Aspect 102a, wherein the therapeutically effective amount is in the range of about 40 mg to about 80 mg.

[0311] Aspect 104a. The compound for use, or the use, according to Aspect 102a, wherein the therapeutically effective amount is in the range of about 60 mg to about 80 mg.

[0312] Aspect 105a. The compound for use, or the use, according to Aspect 102a or 103a, wherein the therapeutically effective amount is in the range of about 40 mg to about 60 mg.

[0313] Aspect 106a. The compound for use, or the use, according to any one of Aspects 102a to 104a, wherein the therapeutically effective amount is about 80 mg.

[0314] Aspect 107a. The compound for use, or the use, according to any one of Aspects 102a to 105a, wherein the therapeutically effective amount is about 60 mg.

[0315] Aspect 108a. The compound for use, or the use, according to any one of Aspects 102a to 105a, wherein the therapeutically effective amount is about 50 mg.

[0316] Aspect 109a. The compound for use, or the use, according to any one of Aspects 102a, 103a or 105a, wherein the therapeutically effective amount is about 40 mg.

[0317] Aspect 110a. The compound for use, or the use, according to Aspect 102a, wherein the therapeutically effective amount is about 30 mg.

[0318] Aspect 111a. The compound for use, or the use, according to Aspect 102a, wherein the therapeutically effective amount is about 20 mg.32MF-364290499Attorney docket no. 29764-20006.40

[0319] Aspect 112a. The compound for use, or the use, according to Aspect 104a, wherein the receptor occupancy is maintained above about 60% for a median duration of about half a day to about 1 day.

[0320] Aspect 113a. The compound for use, or the use, according to Aspect 106a, wherein the receptor occupancy is maintained above about 60% for a median duration of about 22 h.

[0321] Aspect 114a. The compound for use, or the use, according to Aspect 106a, wherein the receptor occupancy is maintained above about 60% for a median duration of about 22 h.

[0322] Aspect 115a. The compound for use, or the use, according to Aspect 107a, wherein the receptor occupancy is maintained above about 60% for a median duration of about 14 h.

[0323] Aspect 116a. The compound for use, or the use, according to any one of Aspects 102a to 115a, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about once per week to up to four doses per week.

[0324] Aspect 117a. The compound for use, or the use, according to any one of Aspects 102a to 116a, wherein the dosing frequency is in the range of once per week to up to three doses per week.

[0325] Aspect 118a. The compound for use, or the use, according to any one of Aspects 102a to 117a, wherein the dosing frequency is once per week.

[0326] Aspect 119a. The compound for use, or the use, according to any one of Aspects 102a to 117a, wherein the dosing frequency is twice per week.

[0327] Aspect 120a. The compound for use, or the use, according to any one of Aspects 102a to 117a, wherein the dosing frequency is about 3 to 4 days.

[0328] Aspect 121 a. The compound for use, or the use, according to Aspect 120a, wherein the dosing frequency comprises dosing a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

[0329] Aspect 122a. The compound for use, or the use, according to any one of Aspects 102a to 117a wherein the dosing frequency is about once every 2 days, or once every other day.

[0330] Aspect 123a. The compound for use, or the use, according to any one of Aspects 102a to 122a, wherein the pharmaceutical composition is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound is administered at a second dose during a second period, in particular wherein the second dose is lower than the first dose.

[0331] Aspect 124a. The compound for use, or the use, according to Aspect 123a, wherein the second dose is in the range of about 20 mg to about 60 mg.

[0332] Aspect 125a. The compound for use, or the use, according to Aspect 123a, wherein the second dose is in the range of about 20 mg to about 40 mg.33MF-364290499Attorney docket no. 29764-20006.40

[0333] Aspect 126a. The compound for use, or the use, according to any one of Aspects 123a to 125a, wherein the second dose is 20 mg.

[0334] Aspect 127a. The compound for use, or the use, according to any one of Aspects 123a to 125a, wherein the second dose is 30 mg.

[0335] Aspect 128a. The compound for use, or the use, according to any one of Aspects 123a to 125a, wherein the second dose is 40 mg.

[0336] Aspect 129a. The compound for use, or the use, according to any one of Aspects 123a to 124a, wherein the second dose is 50 mg.

[0337] Aspect 130a. The compound for use, or the use, according to any one of Aspects 123a to 124a, wherein the second dose is 60 mg.

[0338] Aspect 131a. The compound for use, or the use, according to any one of Aspects 123a to 130a, wherein the first period of dosing lasts about 6 to 12 weeks, while the second period of dosing lasts about 6 to 12 months, depending on the patient’s specific situation.

[0339] Aspect 132a. The compound for use, or the use, according to any one of Aspects 102a to 131a, wherein the muscarinic M1 receptor occupancy is achieved in about 60% or more of the patients.

[0340] Aspect 133a. The compound for use, or the use, according to any one of Aspects 102a to 132a, wherein the compound of formula (1 ) is administered as free base.

[0341] Aspect 134a. The compound for use, or the use, according to any one of Aspects 102a to 133a, wherein the compound of formula (1 ) is administered as free base Type A.

[0342] Aspect 135a. The compound for use, or the use, according to any one of Aspects 102a to 134a, wherein the pharmaceutical composition is a tablet or a capsule.

[0343] Aspect 136a. The compound for use, or the use, according to any one of Aspects 102a to 135a, wherein the depression is major depressive disorder.

[0344] Aspect 137a. The compound for use, or the use, according to any one of Aspects 102a to 136a, wherein the depression is treatment resistant depression.

[0345] Aspect 138a. The compound for use, or the use, according to any one of claims 102a to 137a, wherein the depression is major depressive disorder with anxious distress.EXAMPLES

[0346] The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

[0347] EXAMPLE 1 : POSITRON EMISSION TOMOGRAPHY STUDIES IN NON-HUMAN PRIMATES WITH SCOPOLAMINE34MF-364290499Attorney docket no. 29764-20006.40

[0348] Non-human primates (NHP) were given an intravenous (iv) dose of 4 pg / kg of scopolamine (the dose observed previously to be effective in the clinic) and receptor occupancy was measured up to 18 hours. As shown in Table 1 , and FIG. 1 peak receptor occupancy in extrastriatal region was observed 4-6 hours after dosing at 60%, and 45% occupancy was maintained at 18h post-dose. Lower values were measured in striatal regions.

[0349] Table 1. Mean occupancy displayed by scopolamine in NHP after 4 pg / kg iv administration.

[0350] EXAMPLE 2: POPULATION PHARMACOKINETICS-PHARMACODYNAMICS (PK-PD) MODEL

[0351] The population pharmacokinetics-pharmacodynamics (PK-PD) analysis was performed using a nonlinear mixed-effects model to characterize the population average and inter-individual variability. A two compartment (central compartment, peripheral compartment) model with a first order rate of absorption was used to describe the PK of Compound (1 ) after given orally. The relationship between the plasma concentration of Compound (1) and its M1 receptor occupancy (ROCC) in the CNS was described with an Emax model, as shown in Fig. 2. Using this model, the PK and the M1 receptor occupancy of Compound (1 ) at steady state (Day 11 -12) at 10-80 mg twice weekly dosing regimens in 1000 trials were simulated (N=40 patients / dose cohort per each trial). The simulation indicates that for a dose regimen starting with an intermittent, twice-weekly dosing of 20mg, which would be required to achieve a minimum suggested receptor occupancy of 60% at the peak plasma concentration (Cmax) for antidepressant efficacy.

[0352] The dose projection for a higher M1 RO range of 80-90% was also performed, to model for greater efficacy, and to address the uncertainty around the target RO of 60% in the NHP scopolamine study.

[0353] As shown in Table 2 and FIG. 3, the median of 93% of patients in 1000 trials would achieve 80% RO at Cmax following twice-weekly dosing of 80mg, with the median of 25% of patients achieving 90% RO.

[0354] Table 2. Median (90% prediction interval) percent of patients achieving RO following twice-weekly dosing of compound (1) at different dose levels> > >35MF-364290499Attorney docket no. 29764-20006.40

[0355] At steady state, an 80 mg dose will maintain 60% M1 receptor occupancy for the median duration of approximately 23 hours over the dosing interval; a 40 mg dose will maintain 60% receptor occupancy for the median duration of approximately 9 hours over the dosing interval, as shown in Table 3 and FIG. 4. Additionally, the simulated PK profile parameters shown in Table 5 estimate accumulation with either dosing regimen is ~4% and ~7% for Cmax and AUC, respectively.

[0356] Table 4. Median duration when RO above 60% as a function of dose BIW

[0357] Table 5. % Accumulation as a function of dose every 4 days (Q4D) and BIW36MF-364290499Attorney docket no. 29764-20006.40

[0358] Based on population pharmacokinetic simulations, compound (1) is to be administered every 3 to 4 days, or twice a week (BIW). Thus, a patient can be administered a second dose of compound (1 ) up to 3 to 4 days (3, 4 days) after the first dose, and then every 3 to 4 days for every subsequent dose thereafter. In particular, compound (1) is to be administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days. Dosing typically takes place in the evening (i.e. , near bedtime or at bedtime), although for monitoring purposes, the first dose can be administered during the day, and subsequent doses can be administered during the evening (i.e., near bedtime or at bedtime).

[0359] The dose administered is about 20 mg to about 80 mg, in particular about 60 mg to about 80 mg.

[0360] EXAMPLE 3: RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO-CONTROLLED, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF COMPOUND (1 ) AS MONOTHERAPY IN ADULT PARTICIPANTS WITH MAJOR DEPRESSIVE DISORDER (MDD)

[0361] This example describes a plan for a randomized, double-blind, placebo-controlled, parallel-group, multicenter proof-of-concept study to assess the efficacy, safety, and tolerability of compound (1) as monotherapy in adult participants (18 to 64 years, inclusive) with major depressive disorder (MDD) who have experienced 0, 1 , or 2 treatment regimens in the current depressive episode.

[0362] Eligible participants are randomly assigned in this study, with an equal number of participants planned to the active treatment group and participants planned to the placebo group, equivalent to an overall 50 / 50 chance of assignment to drug vs placebo. Enrolment is continued until sufficient (e.g., 92) participants are enrolled who meet the predefined MADRS severity criteria.

[0363] A flow chart of the study design is shown in Fig. 5.

[0364] The target study population includes participants, between 18 and 64 years of age inclusive, with a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of MDD and who have had at least 1 previous recovered MDD episode prior to their current episode. Participants’ current episode of MDD must be a minimum of 2 months, but no longer than 24 months in duration; they would have an incomplete response or intolerance to their antidepressant medication(s) in the current depressive episode; participants must have a total score of >25 on the IDS-C30 at Screening and at Baseline (prior to randomization). Note, IDS-C30 total score is used for eligibility of participants entering the study. Montgomery-Asberg Depression Rating Scale (MADRS) is also administered.37MF-364290499Attorney docket no. 29764-20006.40

[0365] Participants who are medically stable according to clinical judgement, currently on 1 or 2 pharmacological antidepressant treatment and willing, begin washout of antidepressant medication.

[0366] Once the participant is in the two-week antidepressant-free period of the screening phase, the participant must not start any new prohibited psychopharmacological or pharmacotherapy regimens until after completion of the final study visit of the observational phase, or discontinuation from the double-blind treatment phase or the observational phase.

[0367] The study is conducted in 4 phases: a screening phase of up to 8 weeks, a 2-week double-blind treatment phase consisting of 2 periods (1-week each), a 2-week observational phase for duration of effect, and a 6-week standard of care (SOC) follow-up phase.

[0368] The informed consent form(s) (ICF(s)) must be signed before performance of any study-related activity.

[0369] The screening phase includes assessment of study inclusion / exclusion criteria, medical history, psychiatric history and demographics, medication history in the current depressive episode, Mini International Neuropsychiatric Interview (MINI), Placebo Control Reminder Script, practice Cogstate battery test, Inventory of Depressive Symptomatology Clinician Rating-30 (IDS-C30), MADRS, Clinician Global Impression-Severity (CGI-S), physical and neurological examination, psychiatric and safety evaluations, standard lab and medical tests. Upon signing the ICF, recording of adverse events (AEs) and concomitant medication starts. Participants who continue through the screening process are interviewed by an independent rater (SAFER Interview, Targum et al. CNS Neurosci. Ther. 2008; 14(1 ):2-9) to confirm the participants current major depressive episode, depression symptom severity, and assess their responses to antidepressant (AD) treatment in the current episode.

[0370] For participants currently taking AD medication, medication(s) should be tapered and discontinued during this phase per the local prescribing information, guidelines or clinical judgement. Tapering / discontinuation of any antidepressant medication(s) should not be started until the SAFER Interview is completed and the site has received confirmation that the participant has ‘passed’ the SAFER Interview.

[0371] All participants have a minimum of 2 weeks in the screening phase without any antidepressant / prohibited medication treatment(s) immediately prior to randomization.

[0372] On Day 1 of the double-blind treatment phase, after eligibility is confirmed, the assigned study intervention (blinded placebo or doses of compound (1)) is administered at the study site after baseline assessments are conducted. After the first week of treatment (Period 1 ), participants who received compound (1 ) either continue to receive 80 mg (twice-weekly) or are switched to a lower dose of 20 mg (twice-weekly) during the second week of treatment (Period 2). In addition to evaluating the rapid antidepressant effect of 80 mg compound (1) in38MF-364290499Attorney docket no. 29764-20006.40Period 1 , the study design explores whether a sustained effect can be attained at a lower dose in Period 2 or if maintenance of the initial dose is required for the full treatment duration.

[0373] During the double-blind treatment phase, key efficacy assessments include MADRS, CGI-S, Symptoms of Major Depressive Disorder Scale (SMDDS), and Change from Baseline in Generalized Anxiety Disorder-7 (GAD-7). Key safety assessments include monitoring of AEs, clinical laboratory tests, physical and neurological examinations, body weight, vital signs measurements, 12-lead electrocardiogram (ECGs), Suicidal Ideation Assessment Using Columbia Suicide Severity Rating Scale (C-SSRS) and cognition as assessed by a Cogstate test battery (optional), paper-pencil Hopkins Verbal Learning Test-Revised (HVLT-R) and paper-pencil Digit Symbol Substitution Test (DSST). Pharmacokinetic and biomarker assessments are also performed.

[0374] After the double-blind treatment phase, participants enter into the 2-week observational phase. On Day 20, participants are contacted by telephone call for remote assessments. Participants then attend a clinic visit on Day 27.

[0375] Following the 2-week observational phase, participants enter into a 6-week SOC follow-up phase. This SOC for the treatment of depression is determined by the study investigator and / or the participant’s treating physician and medication changes are permitted.

[0376] If a participant discontinues treatment before the end of the double-blind treatment phase, early withdrawal and post-treatment assessments should be obtained. The first follow-up visit should take place 7 days (±2 days) after the last dose intake or early withdrawal.

[0377] If the participant withdraws from the study before the end of the double-blind treatment phase, the observational phase or the SOC follow-up phase, the participant is advised to complete an early withdrawal visit for follow-up assessments.

[0378] A Data Monitoring Committee is commissioned for this study to ensure the continuing safety of the participants enrolled in the study.Number of Participants

[0379] A target of 124 participants is randomly assigned in this study, to ensure a minimum of 92 participants who meet the predefined MADRS severity criteria is randomized for the primary efficacy analysis set in Period 1. Enrolment is continued until 92 participants are enrolled who meet the predefined severity criteria.Study Arms and Duration

[0380] Participants who successfully complete the screening phase are randomized in a 1 :1 :2 ratio to 1 of 3 treatment groups:

[0381] 80 mg compound (1 ) in both Periods 1 and 2

[0382] 80 mg compound (1) in Period 1 followed by 20 mg compound (1) in Period 239MF-364290499Attorney docket no. 29764-20006.40

[0383] Placebo in both Periods 1 and 2

[0384] Overall, participants have a 50 / 50 chance of assignment of drug versus placebo. The duration of individual study participation is up to a maximum of 18 weeks.Efficacy Evaluations

[0385] The efficacy of study intervention is evaluated using the MADRS, CGI-S, SMDDS, and GAD-7. Note, the MADRS assessment is performed by site-based raters via video teleconferencing assessment during the study. Different site-based raters perform the placebo control reminder script (PCRS) and MADRS versus the other assessments.Pharmacokinetic Evaluations

[0386] Plasma samples are collected at predetermined days / times to evaluate the pharmacokinetics (PK) of compound (1). In addition, blood samples are collected for determination of plasma concentrations in participants who discontinue study drug for an AE, or have an serious adverse event (SAE), if the sample can be obtained within 72 hours of the last study drug administration.Safety Evaluations

[0387] Safety evaluations include collection of adverse events and concomitant medications, as well as assessment of physical and neurological examination, vital signs, 12-lead ECG, Cogstate test battery, paper-pencil HVLT-R, paper-pencil DSST and clinical laboratory tests. Serum and urine pregnancy tests are performed for all participants able to become pregnant.In addition, emergence of suicidal ideation and / or behavior is assessed using the C-SSRS.Safety Analyses

[0388] All safety and tolerability analyses are performed based on the safety analysis set, which include all randomized participants who have received at least one dose of study intervention. Safety summaries are provided by study intervention group, unless otherwise specified.

[0389] STUDY RATIONALE

[0390] Nonclinical StudiesPharmacologic Profile

[0391] Compound (1 ) is a high affinity (Ki=4.6 nM) M1 antagonist with selectivity against other muscarinic receptors. Compound (1) occupies M1 binding sites in the rodent brain after oral administration in a time and dose-dependent manner. This was confirmed in a positron 40MF-364290499Attorney docket no. 29764-20006.40emission tomography (PET) study in nonhuman primate (unbound plasma EC5o=O.86 nM). At 30 mg / kg, given as a single oral administration, compound (1) improved depression-like behavior in a mouse model of depression, the Porsolt Swim Test, and increased miniature excitatory synaptic currents and presynaptic release events in the mouse prefrontal cortex 24-hours after dosage. No clinically relevant off-target effects were noted during in vitro binding and functional assays covering G-protein coupled receptors, nuclear hormone receptors, kinases, ion channels, transporters, and enzymes.Safety Pharmacology

[0392] Compound (1 ) was evaluated in a battery of in vitro and in vivo safety pharmacology studies. No adverse findings were noted in any of the safety pharmacology studies.Toxicology

[0393] A comprehensive program of in vitro and in vivo toxicology studies was conducted to define the nonclinical safety profile of compound (1).The combined nonclinical safety studies suggest that compound (1 ) may have a favorable clinical safety profile.

[0394] Clinical StudiesPhase 1 clinical studies

[0395] Two Phase 1 clinical studies with oral compound (1 ) tablets have been completed and finalized:

[0396] A total of 70 healthy participants (52 received active treatment and 18 received placebo) have been assessed in a study to assess the safety and tolerability profile of compound (1) when administered in single ascending dose (SAD), multiple ascending dose (MAD) and effect of food cohorts.

[0397] An additional study was conducted in a total of 6 healthy participants to determine M1 brain occupancy using [11C]-labelled compound (1) PET imaging, following a single oral dose of compound (1).Human Pharmacokinetics

[0398] To date, PK information is available from 2 Phase 1 clinical studies, in which single-and multiple-dose PK of compound (1) were evaluated. Additionally, the effect of food on the absorption of compound (1) and receptor occupancy were also evaluated.

[0399] Single oral doses of compound (1 ) under fasted conditions, mean values for Cmax and AUC increased in a generally dose-proportional manner across the range of 1 -80 mg. The median Tmax ranged from 0.25 to 3.5 hours and the mean t2ranged from 19.32 to 34.71 hours.41MF-364290499Attorney docket no. 29764-20006.40Following multiple ascending doses of compound (1) (5-20 mg) given once daily for 7 days, mean values for Cmax and AUC increased with increasing dose after administration of the first dose on Day 1 and after administration of the last dose on Day 7. Mean accumulation ratio for Cmax and AUC were 1 .27 to 1 .54, and 1.59 to 1.76, respectively, across the 3 dose levels on Day 7.

[0400] In a PET study in healthy volunteers, M1 occupancy of compound (1 ) was successfully measured using [11C]-labelled compound (1) PET at 2 time points after single oral administration of 3 doses. A positive relationship was observed between M1 occupancy values and compound (1) plasma concentrations, with an overall occupancy coverage of 45 to 85%, and an estimated ECso of 28.8 ng / mL (95% confidence interval: 21.3-36.2 ng / mL).Efficacy / Safety Studies

[0401] To date, safety and tolerability data are available from two Phase 1 Studies in healthy volunteers.

[0402] There was no apparent trend of increasing frequency of treatment emergent adverse events (TEAEs) with increasing single doses. No clinically significant difference in the AE profile of compound (1) was observed between the fasted and fed conditions. In summary, no dose limiting AEs / toxicities were identified with administration of single doses of compound (1 ) up to 80 mg.

[0403] TEAEs were generally categorized as mild and transient, and appeared to be dosedependent after multiple doses of compound (1 ).

[0404] Overall, no dose limiting AEs / toxicities were identified with administration of multiple doses of compound (1 ) up to 20 mg / day for 7 days in healthy volunteers.

[0405] No SAEs have been reported in participants after treatment with compound (1 ).

[0406] BENEFIT-RISK ASSESSMENT

[0407] To date, two Phase 1 clinical studies have been performed in healthy volunteers. No significant safety concerns, including SAEs or deaths, were encountered in these 2 studies after single dose administration up to 80 mg and multiple-dose administration up to 20 mg for 7 days.

[0408] The primary objective of this study is to investigate the efficacy of compound (1) as a monotherapy in participants with MDD. After completing a screening phase, which includes an as-needed medication wash-out, participants receive the double-blind treatment for a period of 2 weeks which consists of either active treatment (intermittent, twice-weekly) of compound (with placebo doses between the active treatment days) or placebo daily. The double-blind treatment phase is followed by an observational 2-week antidepressant-free phase to assess durability of effect and safety. After the completion of the observational phase, participants enter a standard of care (SOC) follow-up phase that lasts up to 6 weeks. Participants may not benefit from the 42MF-364290499Attorney docket no. 29764-20006.40study in terms of improvements of their symptoms. However, participants who are currently untreated, or who are not responding to their current antidepressant medication, may benefit from the comprehensive psychiatric evaluation, general medical assessment, and follow-up during the study.

[0409] Taking into account the measures taken to minimize risk to participants of this study, the potential risks identified in association with compound (1) are justified by the anticipated benefits that may be afforded to participants with MDD.

[0410] OBJECTIVES AND ENDPOINTS43MF-364290499Attorney docket no. 29764-20006.40

[0411] SCIENTIFIC RATIONALE FOR STUDY DESIGNBlinding, Control, Intervention Groups

[0412] A placebo control is used to establish the frequency and magnitude of changes in clinical endpoints that may occur in the absence of active intervention. Randomization is used to minimize bias in the assignment of participants to intervention groups, to increase the likelihood that known and unknown participant attributes (e.g., demographic and baseline characteristics) are evenly balanced across intervention groups, and to enhance the validity of statistical comparisons across intervention groups. Blinded intervention is used to reduce potential bias during data collection and evaluation of clinical endpoints.Study Population

[0413] The target population for this study includes participants with MDD who are aged 18 to 64 years old, inclusive, and who have had at least 1 MDD episode prior to their current episode.

[0414] Unlike many other psychiatric disorders, the age of onset of depression has a wide range, with a median onset of early to mid-20s, although significant proportions of participants may experience onset between late adolescence to late adulthood. Hence, the age of the study population in this protocol is intentionally broad. This study requires that participants were diagnosed with depression prior to age 55 in order to decrease heterogeneity of the patient population.

[0415] Screening for eligible participants is performed within 56 days before administration of the study intervention.

[0416] The inclusion and exclusion criteria for enrolling participants in this study are described below.44MF-364290499Attorney docket no. 29764-20006.40Inclusion Criteria

[0417] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

[0418] 18 to 64 years of age, inclusive.

[0419] Primary psychiatric diagnosis of recurrent major depressive disorder, without psychotic features, based on clinical assessment using DSM-5 criteria and confirmed with the MINI.

[0420] Participant had to have at least one previous MDD episode prior to their current episode.

[0421] First MDD diagnosis made before the age of 55 years old.

[0422] Current episode of MDD: must be a minimum of 2 months but not longer than 24 months in duration.

[0423] Have taken 0, 1 , or 2 treatments for depression in current episode.

[0424] Body mass index (BMI) within the range 18 to 35 kg / m2(inclusive) at Screening.

[0425] A participant must be either not of childbearing potential, or of childbearing potential and not pregnant, breastfeeding or not planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention, and practicing a highly effective, preferably user-independent method of contraception.Exclusion Criteria

[0426] Any potential participant who meets any of the following criteria is excluded from participating in the study:

[0427] Treatment with vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), or ketamine / esketamine within the current or past major depressive episodes.Current or past DSM-5 diagnosis of bipolar disorder, psychotic disorders, borderline personality disorder, antisocial personality disorder, or current obsessive-compulsive disorder.

[0428] Post-traumatic stress disorder within the past three years of Screening.Dementia, any dementing disease, intellectual disability, or neurocognitive disorder.History of Alcohol Use Disorder within 6 months of Screening according to the MINI and Clinical Assessment.

[0429] History of Substance Use Disorders within 6 months of Screening, with the exclusion of Nicotine, Caffeine, and Mild Cannabis Use Disorder, according to the MINI and Clinical Assessment.

[0430] Known allergies, hypersensitivity, or intolerance to compound (1) or its excipients.Choice of Efficacy Assessments45MF-364290499Attorney docket no. 29764-20006.40

[0431] The MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

[0432] The scale has been validated, is reliable and is acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression. This trial uses either 24-hour or 7-day and since last visit recall.

[0433] The MADRS assessment is performed by site-based raters via video teleconferencing assessment during the study. To minimize the risk of unblinding the treatment assignment, different site-based raters perform the PCRS and MADRS versus the other assessments. In other words, clinicians who perform the PCRS and MADRS only perform those two tasks.

[0434] MADRS raters are different from raters who evaluate other efficacy and safety assessments.

[0435] Raters for the MADRS are not allowed to access or to review participant safety records, supervise administration of study medication nor observe patients in the 4-hour post dose observation period on Day 1 ; therefore, they do not provide clinical care for participants.

[0436] The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Participant is assessed on severity of illness at the time of rating according to: 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill participants. Higher score indicating greater severity.

[0437] The CGI-S scale is a well-established rating tool (Busner and Targum, Psychiatry (Edgmont) 2007;4(7):28-37) and permits a global evaluation of the participant’s condition at a given time.

[0438] Apart from the clinician-administered assessment of the severity of depression, the subjective self-reported ratings by the participant could contribute to the correct interpretation of the clinical efficacy of compound (1).

[0439] The SMDDS (McCarrier et al. Patient 2016;9(2):117-134) is a 16-item patient reported outcome (PRO). Each item is rated by the participant according to a 5-point Likert scale, where 0 denotes "Not at all" or "Never" and 4 denotes "Extremely" or "Always". Before summing the items to create a total score, item 11 and item 12 are combined into a single score by selecting the highest severity on either item. The total score is then created by summing the responses on the 15 items, which range from 0 to 60. Higher score indicates more severe depressive symptomatology. It is qualified by FDA for use in drug development to support46MF-364290499Attorney docket no. 29764-20006.40medical product labeling. The SMDDS uses a 7-day recall period and each item has a 5-point verbal rating scale.

[0440] Comorbid anxiety occurs with significant frequency in participants with MDD and leads to greater refractoriness to treatment, more severe illness, and higher risk for suicide. The GAD-7 scale is a self-administered questionnaire designed to measure anxiety. GAD-7 has seven items, which measure frequency of various signs of GAD using a 4-point Likert scale (where, Not at all = 0, Several days = 1 , More than half the days = 2, and Nearly every day = 3). The total score ranges from 0 to 21 with increasing scores indicative of greater severity of symptoms of anxiety. Severity of anxiety on the GAD-7 is rated as follows: none (0-4), mild (5-9), moderate (10-14) and severe (15-21).Safety Assessments

[0441] Standard safety assessments comprising physical examination (including neurological examination), vital signs (supine blood pressure, pulse / heart rate, respiratory rate, oral temperature), 12-lead ECG, clinical chemistry, hematology, and urinalysis are performed. Urine drug testing and alcohol breath testing are also performed.

[0442] Additionally, emergence of suicidal ideation and / or behavior is assessed using the C-SSRS. The C-SSRS scale consists of 28 items in 4 sections: suicide behavior, actual attempts, suicidal ideation, and intensity of ideation. Suicidal ideation consists of 5 'yes / no' items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, active suicidal ideation with specific plan and intent. Only items with yes responses are listed. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline. This scale has been used frequently in clinical studies and is a standard measure for suicidal ideation assessment according to FDA guidance (US FDA 2012).

[0443] Changes in cognition can be assessed with tests from a Cogstate test battery, paper-pencil HVLT-R, and paper-pencil DSST:

[0444] The Cogstate Battery of tests includes 5 tests: Detection (simple reaction time task measuring processing speed [lower score = better performance]); Identification (choice reaction time paradigm measuring attention [lower score = better performance]); One Card Learning (visual episodic memory measure [higher score = better performance]); One Back ("n-back" working memory measure [higher score = better performance]); and, Groton Maze Learning Test (executive function measure; total number of errors made in attempting to learn the same hidden pathway on five consecutive trials at a single session [lower score = better performance]).

[0445] The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 47MF-364290499Attorney docket no. 29764-20006.40recognition list (including 12 target and 12 foil words). The test administrator reads instructions and word lists aloud, and records words recalled / recognized by the participant. Three learning trials are combined to calculate a total recall score learning, delayed recall, and recognition trials.

[0446] The DSST is recognized as covering all of the cognitive performance aspects: speed of processing, executive functioning, and attention. The DSST measures attention, working memory, sustained visual attention and psychomotor speed. Participants are given a table that pairs digits and symbols, and asked to decipher a code using the table, completing as many as possible in 90 seconds.Pharmacokinetic Sampling

[0447] Pharmacokinetic sampling allows for comparison of the systemic exposure to Compound (1), relative to that in previous studies.Justification for Dose

[0448] At the doses where scopolamine was observed to be effective (4.0 pg / kg), it is estimated that the receptor occupancy at the M1 receptor is approximately 60%. Based on population PK-PD model simulations, twice-weekly dosing of 80 mg of compound (1 ) is hypothesized to achieve at least 80% receptor occupancy at Cmax in >80% of study participants. Additionally, after a dose of 80 mg, it is estimated that 60% receptor occupancy will be maintained for approximately 23 hours over the dosing interval, which is similar to the estimated occupancy duration for scopolamine. In addition, model simulations projected twice-weekly dosing of 20 mg would be required to achieve the minimum suggested receptor occupancy at Cmax Of 60%.

[0449] Thus, twice-weekly dosing of 80 mg was selected to test the hypothesis that compound (1 ) is rapidly acting within one-week of treatment initiation. After the first week of treatment (Period 1), participants who received compound (1) either continue to receive 80 mg (twice-weekly) or are switched to a lower dose of 20 mg (twice-weekly) during the second week of treatment (Period 2). The current design evaluates whether a sustained effect can be attained at a lower dose during the second week of treatment or if the initial dose is required for the full treatment duration.

[0450] Each of these doses are estimated to have less than 10% accumulation in exposures after two weeks of twice-weekly intermittent dosing. Therefore, the exposures in these participants are estimated to be similar to exposures observed in a prior phase 1 study in healthy volunteers, which were considered safe and well tolerated.End of Study Definition48MF-364290499Attorney docket no. 29764-20006.40

[0451] The end of study is considered as the last scheduled study assessment for the last participant in the study.Participant Phase and Study Completion Definitions

[0452] A participant is considered to have completed the double-blind treatment phase of the study if the Day 13 study visit is completed. Note: If all scheduled study procedures for the Day 13 visit are not performed, at least the MADRS for this visit must be completed for the participant to be considered as having completed the double-blind treatment phase.

[0453] A participant is considered to have completed the observation phase of the study if the Day 27 study visit is completed.

[0454] A participant is considered to have completed the study if they completed the double-blind treatment phase, observational phase, and SOC follow-up phase.Participants who prematurely discontinue study intervention for any reason before completion of the study are not considered to have completed the study. However, any participant who withdraws after receiving at least 1 dose of study intervention is encouraged to have an early withdrawal evaluation.Study Intervention(s) Administered

[0455] Investigational Medicinal Product(s) compound (1) administered in tablet form

[0456] Placebo comparator.Other Evaluations

[0457] The Placebo-Control Reminder Script (PCRS) ©Hassman and Cohen, 2019, Version 5.0, educates clinical trial participants of key causes of the placebo and nocebo effects, namely the tempering of participant study expectations, reminding participants what a placebo is and how that relates to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differ from their experience with previous providers. To do this, the PCRS informs participants that they are to be honest about their symptoms, site staff have no expectations of symptom improvement or worsening and would not be disappointed if they feel better, worse or the same, and asks participants to explain in their own words its content to ensure comprehension. Per the instructions on the PCRS, the MADRS rater reads the script verbatim immediately before administering this scale. The PCRS is read to EACH participant at EACH visit, typically taking about 3 minutes to read. There is a full and short version of the PCRS provided to the participant. The PCRS has been empirically found to significantly manage (reduce) the placebo and nocebo effects (Cohen et al.Neuropsychopharmacology 2021 ;46(4):844-850).49MF-364290499Attorney docket no. 29764-20006.40

[0458] Remote, independent psychiatrists / psychologists perform the SAFER Interview (Targum et al. CNS Neurosci. Ther. 2008;14(1 ):2-9) for all participants to assess the validity of a diagnosis of depression and eligibility for the study.STATISTICAL CONSIDERATIONS

[0459] A general description of the statistical methods to be used to analyze the efficacy and safety data is outlined below.Statistical Hypotheses

[0460] The primary hypothesis of the study is that treatment with 80 mg compound (1 ) as monotherapy is superior to placebo in improving symptoms of depression, as measured by the change from baseline to Day 5 in MADRS total score, in participants with MDD who have experienced 0, 1 , or 2 treatment regimens in the current depressive episode.General Considerations

[0461] The assessment of primary and secondary endpoints will be conducted on the modified full analysis set. Analyses of the primary endpoint will additionally be performed on the full analysis set.

[0462] Primary Estimand and AnalysisClinical Question of Interest

[0463] For a participant with MDD for whom acute drug monotherapy would be indicated, what would be the expected effect of 80 mg compound (1 ) on symptoms of depression at Day 5, if taken as directed from Day 1 to Day 5 without starting other pharmacological treatments for MDD.Estimand

[0464] The primary estimand for the primary efficacy endpoint is defined by the following attributes:Treatment: compound (1) 80 mg versus placeboPopulation: Adult participants with MDD, who have experienced 0, 1 , or 2 treatment regimens in the current depressive episodeVariable / Endpoint: Change from baseline to Day 5 in MADRS total scorePopulation-level Summary: Difference in mean change from baseline in MADRS total score at Day 5 between compound (1) 80 mg and placeboIntercurrent Events (ICE) and Corresponding Strategy: Discontinuation of study intervention, with or without starting other pharmacological treatments for MDD, is addressed with a hypothetical strategy, targeting the treatment effect had all participants 50MF-364290499Attorney docket no. 29764-20006.40continued study intervention as assigned to Day 5 without starting other pharmacological treatments for MDD.

[0465] The primary efficacy analysis is performed based on the estimand defined above and using the hypothetical strategy. The change from baseline in MADRS total score during the double-blind treatment Period 1 is analyzed using a mixed effect model for repeated measures (MMRM) with intervention group (compound (1) 80 mg or placebo), sex assigned at birth, number of past treatment regimens in the current episode, visit, and visit-by-intervention group interaction as factors, and baseline MADRS total score as a continuous covariate. Data post ICEs is considered as missing. The within-participant covariance between visits is estimated via an unstructured variance-covariance matrix. Comparison between compound (1) 80 mg and placebo is performed using the appropriate contrast.

[0466] A key assumption of the MMRM is missing at random (MAR), i.e., participants with missing data would have efficacy outcomes like those in similar participants in their randomized intervention group. Given the short intervention period before the primary endpoint, the proportion of participants with missing outcomes due to early discontinuation of the study intervention is expected to be low. Missing data is closely monitored and if necessary, to assess the robustness of the primary efficacy analysis results to the missing data assumptions.Secondary Endpoints

[0467] The change from baseline in CGI-S score to Days 2 and 5 is analyzed using the same MMRM model as described for the primary endpoint analysis, except that the change in CGI-S score is used as the dependent variable.

[0468] The changes from baseline to Day 5 in SMDDS total score and in GAD-7 total score is analyzed using an ANCOVA model with study intervention group, sex assigned at birth, number of past treatment regimens in the current depressive episode as factors, and corresponding baseline score as a continuous covariate. Comparisons between compound (1) 80 mg and placebo are performed using the appropriate contrasts.

[0469] This study is ongoing and remains blinded.

[0470] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

[0471] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore intended, that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.51MF-364290499

Claims

Attorney docket no. 29764-20006.40CLAIMSWhat is claimed is:1 . A method of treating a patient suffering from, or diagnosed with, depression, comprising administering to a patient in need of such treatment a compound (1 )pharmaceutically acceptable salt thereof, wherein the compound of formula (1) or the pharmaceutically acceptable salt thereof is administered in an intermittent dosing frequency or regimen at a dose in the range of about 20 mg to about 80 mg.

2. The method according to claim 1 , wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to four doses per week.

3. The method according to claim 1 , wherein the compound of formula (1 ) is administered twice a week.

4. The method according to claim 1 , wherein the compound of formula (1 ) is administered once a week.

5. The method according to claim 1 , wherein the compound of formula (1 ) is administered every 3 to 4 days.

6. The method according to claim 1 , wherein the compound of formula (1 ) is administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

7. The method according to claim 1 , wherein the compound of formula (1 ) is administered near bedtime or at bedtime.

8. The method according to claim 1 , wherein the compound (1 ) is administered as the free base.

9. The method according to claim 1 , wherein the compound (1 ) is administered as the free base Type A.

10. The method according to claim 1 , wherein the compound of formula (1 ) is administered orally.11 . The method according to claim 1 , wherein the compound of formula (1 ) is administered in a tablet.

12. The method according to claim 1 , wherein the compound of formula (1 ) is administered at a dose in the range of from about 60 mg to about 80 mg.52MF-364290499Attorney docket no. 29764-20006.4013. The method according to claim 1 , wherein the compound of formula (1 ) is administered at a dose in the range of about 40 mg to about 80 mg.

14. The method according to claim 1 , wherein the compound of formula (1 ) is administered at a first dose in the range of about 60 mg to about 80 mg during a first period, and wherein the compound of formula (1 ) is administered at a second dose during a second period, and wherein the second dose is lower than the first dose.

15. The method according to claim 14, wherein the second dose is in the range of about 20 mg to about 40 mg.

16. The method according to claim 1 , wherein the depression is major depressive disorder.

17. The method according to claim 1 , wherein the depression is treatment resistant depression.

18. The method according to claim 1 , wherein the patient is an adult.

19. The method according to claim 1 , wherein the patient had not responded adequately to at least one prior antidepressant therapy or treatment.

20. The method according to claim 1 , wherein the patient had not responded adequately to 0, 1 , or 2 prior antidepressant therapies or treatments.

21. The method according to claim 1 , wherein the patient in need of such treatment is assessed at the time of initial administration of compound (1).

22. The method according to claim 1 , wherein the patient is assessed at the time of initial administration of compound (1) in total score in a depression scale.

23. The method according to claim 1 , wherein the patient is assessed at the time of initial administration of compound (1) in total score in the Montgomery-Asberg Depression Rating Scale (MADRS) and / or Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30).

24. The method according to claim 23, wherein the patient scores > 20 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score prior to treatment with compound (1).

25. The method according to claim 23, wherein the patient scores > 25 in the Inventory of Depressive Symptomatology, Clinician Rating-30 (IDS-C30) prior to treatment with compound (1).

26. The method of claim 1 , wherein the patient has major depressive disorder with anxious distress.

27. The method according to claim 1 , wherein the patient experiences an improvement in symptoms of depression, as measured by the change from baseline.

28. The method according to claim 27, wherein the reduction of depressive symptoms is achieved following 1 week of treatment with compound (1).

29. The method according to claim 27, wherein the reduction of depressive symptoms is achieved following 5 days of treatment with compound (1 ).53MF-364290499Attorney docket no. 29764-20006.4030. The method according to claim 27, wherein the reduction of depressive symptoms is achieved following 2 days of treatment with compound (1).

31. The method according to claim 27 wherein the reduction of depressive symptoms is achieved following 1 day of treatment with compound (1).

32. The method according to claim 27, wherein the patient experiences a reduction of at least 50% in depressive symptoms as measured by the change from baseline in total score in a depression scale.

33. The method according to claim 32, wherein the depression scale is the Montgomery-Asberg Depression Rating Scale (MADRS).

34. The method according to claim 27, wherein the patient experiences an improvement in symptoms of depression as measured by a placebo subtracted change in total score MADRS from baseline of at least 2 points.

35. The method according to claim 1 , wherein the compound of formula (1 ) is administered as monotherapy.

36. A method of treating a patient suffering from, or diagnosed with, depression, comprising administering to a patient in need of such treatment compound (1)or a pharmaceutically acceptable salt thereof, wherein compound (1 ) is administered at a dose in the range of about 10 mg to about 80 mg, in particular in the range of about 20 mg to about 80 mg.

37. The method of claim 36, wherein compound (1 ) is administered as the free base.

38. The method of claim 36, wherein compound (1 )is administered as the free base Type A.

39. The method of claim 36, wherein compound (1) is administered according to an intermittent dosing frequency or regimen.

40. The method of claim 36, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg; and then administered according to an intermittent dosing frequency or regimen.

41. The method of claim 36, wherein compound (1 ) is administered on Day 1 at a dose of 80 mg, and wherein subsequent doses are administered according to an intermittent dosing frequency or regimen in an amount in the range of from about 20 mg to about 80 mg.

42. The method of Claim 36, wherein administration of compound (1 ) provides an improvement in symptoms of depression, as measured by a decrease from baseline in MADRS score of at least 2 points.54MF-364290499Attorney docket no. 29764-20006.4043. A method of treating a patient suffering from, or diagnosed with, major depressive disorder, comprising administering to a patient in need of such treatment, compound (1)wherein compound (1) is administered as monotherapy, at a dose in the range of about 20 mg to about 80 mg.

44. The method of claim 43, wherein compound (1) is administered according to an intermittent dosing frequency or regimen.

45. The method according to claim 43, wherein the compound of formula (1 ) is administered at a dosing frequency in the range of one dose a week to four doses per week.

46. The method according to claim 43, wherein the compound of formula (1 ) is administered twice a week.

47. The method according to claim 43, wherein the compound of formula (1 ) is administered once a week.

48. The method according to claim 43, wherein the compound of formula (1 ) is administered every 3 to 4 days.

49. The method according to claim 43, wherein the compound of formula (1 ) is administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.

50. The method according to claim 49, wherein the first dose is in the range of about 60 mg to about 80 mg during a first period, and second dose, during a second period, is lower than the first dose.

51. The method according to any one of claims 43, wherein the major depressive disorder is treatment-resistant depression.

52. The method according to any one of claims 43, wherein the major depressive disorder is major depressive disorder with anxious distress.

53. A method of treating depression in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising compound (1)pharmaceutically acceptable salt thereof to achieve a muscarinic M1 receptor occupancy in the range of about 60% to about 90% at a time 55MF-364290499Attorney docket no. 29764-20006.40range of about 1 h to about 4 h after administration of the compound (1 ), wherein the effective amount is in the range of about 20 mg to about 80 mg.

54. The method according to claim 53, wherein the therapeutically effective amount is in the range of about 40 mg to about 80 mg.

55. The method according to claim 53, wherein the therapeutically effective amount is in the range of about 60 mg to about 80 mg.

56. The method according to claim 53, wherein the therapeutically effective amount is in the range of about 40 mg to about 60 mg.

57. The method according to claim 53, wherein the therapeutically effective amount is about 80 mg.

58. The method according to claim 53, wherein the therapeutically effective amount is about 60 mg.

59. The method according to claim 55, wherein the receptor occupancy is maintained above about 60% for a median duration of about half a day to about 1 day.

60. The method according to claim 57, wherein the receptor occupancy is maintained above about 60% for a median duration of about 22 h.

61. The method according to claim 58, wherein the receptor occupancy is maintained above about 60% for a median duration of about 14 h.

62. The method according to claim 53, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about once per week to up to four doses per week.

63. The method according to claim 53, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about once per week to up to three doses per week.

64. The method according to claim 53, the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about twice per week.

65. The method according to claim 53, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a dosing frequency in the range of about 3 to 4 days.

66. The method according to claim 53, wherein the compound (1 ) or a pharmaceutically acceptable salt thereof is administered at a first dose followed by a second dose 3 days after the first dose, and then every subsequent dose every 4 or 3 days.56MF-364290499

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