Methods for treating bipolar disorder by muscarinic receptor activation

Abstract

Methods of treating bipolar disorder in a subject in need thereof, for example, methods of alleviating a manic episode in the subject, comprising administering to the subject a composition comprising xanomeline or a salt thereof (e.g., xanomeline tartrate) and trospium or a salt thereof (e.g., trospium chloride).

Description

Attorney Docket No. 055920-814001WOMETHODS FOR TREATING BIPOLAR DISORDER BY MUSCARINIC RECEPTOR ACTIVATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present disclosure claims the benefit of priority from U.S. Patent Application No.63 / 789,223, filed April 15, 2025, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present disclosure relates to methods of treating mania, for example bipolar disorder related mania, in a subject in need thereof. The present disclosure also relates to methods of treating bipolar disorder or bipolar disorder related conditions. The methods of the present disclosure include administering to the subject a composition comprising xanomeline or a salt thereof and trospium or a salt thereof.BACKGROUND

[0003] Lithium carbonate was approved in the early 1970’s for the treatment of mania. However, it has a high failure rate, adverse events that limit its tolerability, slow onset of action, and narrow therapeutic window, which limits its use. The anticonvulsant valproate is also approved for the acute treatment of mania and has a more rapid onset effect and a broader spectrum of efficacy. Liver toxicity is a rare but recognized adverse effect associated with valproate, requiring some liver enzyme monitoring. Both lithium and valproate require serum monitoring of drug levels.

[0004] Conventional (first-generation) antipsychotics, dopamine D2 receptor antagonists, are effective in the treatment of acute mania, though extrapy rami dal symptoms (EPS), tardive dyskinesia (TD), neuroleptic malignant syndrome (NMS), hyperprolactinemia, orthostasis, seizures, oversedation, and QTc prolongation have limited their use. Many second-generation antipsychotics, namely serotonin-dopamine antagonists, are effective at reducing mania and mixed features, but are associated with significant weight gain, hyperglycemia, dyslipidemia, metabolic syndrome, and akathisia. There remains a need for safe, effective, and more tolerable treatments for acute mania and mania with mixed features.SUMMARY

[0005] The present disclosure includes, in one aspect, methods of alleviating a manic episode inAttorney Docket No. 055920-814001WOa subject in need thereof, for example, a manic episode associated with a bipolar disorder. In some embodiments, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising xanomeline or a salt thereof (e.g., xanomeline tartrate) and a trospium salt (e.g., trospium chloride) as described herein. The pharmaceutical composition can be administered to the subject at a daily dose equivalent to about 100 mg xanomeline free base and about 40 mg to about 75 mg trospium chloride, or equivalent to about 200 mg to about 300 mg xanomeline free base and about 40 mg to about 75 mg trospium chloride. It is expected that the methods disclosed herein could alleviate mania (e.g., in patients with bipolar-I disorder) in one or more aspects, including, but not limited to, changes in baseline in Young Mania Rating Scale (YMRS), changes in baseline in Clinical Global Impression-Bilopar (CGI-BP), improving cognition (which may be measured by the Brief Assessment of Cognition score), changes in pro-inflammatory biomarkers and / or Brain-derived neurotrophic Factor (BDBF) levels, changes in baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score, and / or improving quality of life.

[0006] Unless explicitly disclosed, the amount of xanomeline in a dose, dosage amount, or dosage strength described herein refers to a molar equivalent amount of xanomeline free base, when a xanomeline salt such as xanomeline tartrate is used in the pharmaceutical composition disclosed herein. For example, a drug can be formulated using a pharmaceutically acceptable salt form, e.g. xanomeline tartrate, while the dose or dosage strength is expressed in the weight amount of the molar equivalent of the corresponding free base, e.g. xanomeline. As an example, 76 mg of xanomeline tartrate is the molar equivalent of 50 mg of xanomeline free base, and vice versa.

[0007] The amount of trospium chloride in a dose, dosage amount or dosage strength described herein refers to the amount of trospium chloride. The pharmaceutical composition described herein is formulated with trospium salt, e.g. trospium chloride.

[0008] In some embodiments, the manic episode is related to bipolar disorder. For example, the manic episode can be related to bipolar-I disorder. Bipolar-I disorder can be established based on the Diagnostic and Statistical Manual of Mental Disorders (5thEdition, Text Revision) (DMS 5-TR) criteria.

[0009] In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 100 mg to about 250 mg xanomeline free base and about 40 mg to about 60 mg trospium chloride. For example, the pharmaceutical composition can be administered to the subject at a daily dose equivalent to about 200 mg or about 250 mg xanomeline free base, and equivalent to about 40 mg or 60 mg trospium chloride. In someAttorney Docket No. 055920-814001WOembodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 200 mg xanomeline free base, and equivalent to about 40 mg trospium chloride. In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 250 mg xanomeline free base, and equivalent to about 60 mg trospium chloride.

[0010] In some embodiments, the method of the present disclosure includes:(i) administering to the subject the composition at a first total daily dose equivalent to about 100 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride for a first period;(ii) administering to the subject, after the first period, the composition at a second daily dose equivalent to about 200 mg xanomeline free base and equivalent to about 40 mg of trospium chloride for a second period.

[0011] Depending on, for example, how the subject tolerates the daily dose administered, the daily dose can be modified, for example by reducing or increasing the daily dose, or it can be maintained. The reducing of the daily dose can be assessed for example based on whether the subject tolerates the daily dose in the second period. In some embodiments, the method of the present disclosure further includes reducing the daily dose to an amount equivalent to about 150 mg xanomeline free base and equivalent to about 40 mg of trospium chloride to the subject who is not tolerating the daily dose in the second period.

[0012] In some embodiments, the methods of the present disclosure further comprise (iii) administering to the subject, after the second period, the composition at a third daily dose equivalent to about 250 mg xanomeline free base and equivalent to about 60 mg of trospium chloride for a third period. The reducing of the daily dose can be assessed for example based on whether the subject tolerates the daily dose in the third period. For example, if the subject does not tolerate the daily dose in the third period, the daily dose can be reduced to an amount equivalent to about 200 mg of xanomeline free base and 40 mg of trospium chloride.

[0013] In some embodiments, the methods of the present disclosure further comprise terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride.

[0014] If the subject tolerates the daily dose in the third period, the daily dose can be maintained. In some embodiments, the method of the present disclosure further includes maintaining the daily dose equivalent to about 250 mg of xanomeline free base and equivalent to about 60 mg of trospium chloride to the subject, who is tolerating the daily dose in the third period.Attorney Docket No. 055920-814001WO

[0015] In some embodiments, the first period is about 2 days to about 9 days, optionally about 2 days or 7 days. In some embodiments, the second period is about 3 days to about 9 days, optionally about 5 days to about 7 days.

[0016] The third period can be at least two weeks. In some embodiments, the third daily dose is administered for about 2 weeks. In some embodiments, the third daily dose is administered for at least about 2 weeks. In some embodiments, the third period is about 2 weeks to about 49 weeks.

[0017] In some embodiments, the methods of the present disclosure include(a) administering to the subject the composition as described herein to the subject two times a day orally for about two days, wherein the composition comprises a unit dosage strength equivalent to about 50 mg xanomeline free base and equivalent to about 20 mg trospium chloride; and(b) administering to the subject, after step (a), the composition two times a day orally for about five days; wherein the composition comprises a unit dosage strength of about 100 mg xanomeline free base and a unit dose strength of about 20 mg trospium chloride; and

[0018] In some embodiments, when the subject is not tolerating the doses administered in step (b), the method further includes reducing the doses by administering to the subject the composition a unit dosage strength equivalent to about 75 mg xanomeline free base and equivalent to about 20 mg trospium chloride two times per day orally. In some embodiments, when the subject is tolerating the doses administered in step (b), the method further comprises (c) administering to the subject the composition comprising a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg trospium chloride two times per day orally.

[0019] In some embodiments, when the subject is not tolerating the doses administered in step (c), the method further includes reducing the doses by administering to the subject (a) the composition comprising a unit dosage strength equivalent to about 100 mg xanomeline free base and equivalent to about 20 mg trospium chloride two times per day orally, or (b) the composition comprising a unit dosage strength equivalent to about 75 mg xanomeline and about 20 mg trospium chloride two times per day orally.

[0020] In some embodiments, the method further comprises terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg xanomeline and equivalent to about 40 mg trospium chloride.

[0021] In some embodiments, the composition of the present disclosure has:(a) a unit dosage strength equivalent to about 50 mg xanomeline free base andAttorney Docket No. 055920-814001WOabout 20 mg trospium chloride;(b) a unit dosage strength equivalent to about 75 mg xanom eline free base and about 20 mg trospium chloride;(c) a unit dosage strength equivalent to about 100 mg xanom eline free base and about 20 mg trospium chloride; or(d) a unit dosage strength equivalent to about 125 mg xanom eline free base and about 30 mg of trospium chloride.

[0022] In some embodiments, the compositions of the present disclosure comprise a plurality of xanomeline beads, and a plurality of trospium beads, the xanomeline beads comprising the xanomeline tartrate and the trospium beads comprising the trospium chloride. In some embodiments, the compositions are as described herein.

[0023] In some embodiments, the xanomeline beads and / or the trospium beads have a size of about 0.425 mm to about 1.18 mm; optionally about 0.6 mm to about 0.85 mm. In some embodiments, the plurality of xanomeline beads and / or the plurality of trospium beads have a dissolution rate of more than about 95% within about the first 45 minutes following entry of the composition into an aqueous solution; optionally wherein the dissolution rate is more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.

[0024] In some embodiments, the xanomeline beads comprise(a) about 30 wt.% to about 80 wt.% xanomeline tartrate, optionally about 66 wt.% xanomeline tartrate;(b) about 15 wt.% to about 65 wt.% microcrystalline cellulose, optionally about 33.5 wt.% microcrystalline cellulose; and(c) about 0 wt.% to about 2 wt.% talc; optionally about 0.5 wt.% talc.

[0025] In some embodiments, the trospium beads comprise(a) about 8 wt.% to about 35 wt.% trospium chloride; optionally about 17.7 wt.% trospium chloride;(b) about 25 wt.% to about 80 wt.% microcrystalline cellulose; optionally about 46.8 wt.% microcrystalline cellulose;(c) about 15 wt.% to about 70 wt.% lactose monohydrate; optionally about 35 wt.% lactose monohydrate; and(d) about 0 wt.% to about 2 wt.% talc; optionally about 0.5 wt.% talc.

[0026] In some embodiments, the composition is comprised in a capsule, the capsule containing the plurality of xanomeline beads and the plurality of trospium beads.Attorney Docket No. 055920-814001WO

[0027] In some embodiments, the composition further comprises ascorbic acid, butylated hydroxytoluene, or a combination thereof. In some embodiments, the composition comprises about 0.2 wt.% to about 1 wt.% ascorbic acid, optionally about 0.5 wt.% ascorbic acid. In some embodiments, the composition comprises about 0.01 wt.% to about 0.1 wt.% butylated hydroxytoluene; optionally about 0.05 wt.% butylated hydroxytoluene.

[0028] In some embodiments, the subject is a human patient. In some embodiments, the subject is at least 18 years old. For example, the subject can be between 18 to 65 years old.

[0029] The subjects can be assessed for suitability for the methods of the present disclosure. In some embodiments, prior to the administration, the subject has one or more of the following characteristics. In some embodiments, the subject has a Young Mania Rating Scale (YMRS) of at least 14. In some embodiments, the subject has a YMRS of at least 20. In some embodiments, the subject has a Clinical Global Impressions-Bipolar (CGI-BP) score of at least 3. In some embodiments, the subject has a CGI-BP score of at least 4. In some embodiments, the subject is diagnosed with bipolar-I disorder. In some embodiments, the subject has bipolar-I disorder that is not with rapid cycling. In some instances, the subject further has experienced an acute episode or relapse of mania with mixed features. In some instances, the subject further has a need for hospitalization for the acute episode or acute exacerbation, or relapse of mania.

[0030] In some embodiments, suitable subjects are free of one or more of the following characteristics. In some embodiments, the subject is free of a diagnosis of mental disorders other than bipolar I. For example, mental disorders other than bipolar I can include bipolar-II disorder, major depressive disorder, and / or primary psychotic disorder. The diagnosis for the mental disorders can be made based on DSM 5-TR standards. In some embodiments, the subject is free of a diagnosis of moderate or severe substance use disorder within 12 months before the administering. For example, the moderate or severe substance use disorder does not include tobacco use disorder. For example, the subject is free of a moderate or severe substance use disorder that is concurrent with the administering, as measured by urine toxicology screen or alcohol test. In some embodiments, the subject is free from risk of suicidal behaviour as determined by clinical assessment with 6 months to 12 months of the administering. In some embodiments, the subject is free of a history of or is free from a high risk of irritable bowel syndrome or severe constipation requiring treatment. In some embodiments, the subject is free of a history or free from high risk of urinary retention, gastric retention or untreated narrowangle treatment.

[0031] In some instances, the methods further include assessing treatment efficacy. The treatment efficacy can include monitoring one or more of the following parameters. In someAttorney Docket No. 055920-814001WOembodiments, the methods include monitoring a decrease of CGI-BP score from a baseline CGI-BP score of the subject prior to the administering. For example, the decrease in CGI-BP score can be 1 or at least 1. In some embodiments, the decrease in CGI-BP score can be 4 or at least 4. In some embodiments, the methods include monitoring a decrease of YMRS score from a baseline YMRS score of the subject prior to the administering. For example, the decrease in YMRS score can be about 50% or at least 50%. In some embodiments, the methods of the present disclosure include monitoring a change in Brief Assessment of Cognition (BAC) from a baseline assessment of BAC of the subject prior to the administering. In some embodiments, the methods of the present disclosure include monitoring a decrease in Montgomery-Asberg Depression Rating Scale (MADRS) total score from a baseline assessment of MADRS total score of the subject prior to the administering. For example, the MADRS total score can decrease by about 20% to about 50%. In some embodiments, the methods of the present disclosure include monitoring a change in a level of inflammatory biomarkers based on a baseline level of the inflammatory biomarkers of the subject prior to the administering. In some embodiments, the inflammatory biomarkers are selected from TNF-a, IL-2, IL-6, IL- 10, IL-17, CRP, and combinations thereof. In some embodiments, the methods of the present disclosure include monitoring a change in a level of brain-derived neurotropic factor (BDNF) based on a baseline level of BDNF of the subject prior to the administering. The monitoring can be performed after three weeks of the administering of the composition of the present disclosure.

[0032] In some embodiments, the methods of the present disclosure further include monitoring a side effect during and / or after administration of the composition of the present disclosure. For example, the side effect can include one or more of(i) urinary retention,(ii) angioedema,(iii) decreased gastric mobility or gastric retention,(iv) narrow angle glaucoma,(v) a heart rate increase,(vi) a change in blood pressure,(vii) change in diastolic blood pressure of more than 1.5 mm Hg, and / or(viii) liver enzyme elevation as measured by serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of at least three times an upper limit normal (ULN) of the subject.

[0033] In some embodiments, the heart rate increase is more than 9.8 beats per minuteAttorney Docket No. 055920-814001WOmeasured as a 24-hour average heart rate.

[0034] In some instances, when the occurrence of the side effect is observed, the methods of the present disclosure further include managing the side effect. For example, the managing of the side effect can include modifying or adjusting the daily dose. For example, the managing of the side effect can include decreasing the daily dose. In some instances, the managing includes terminating the treatment.

[0035] In some embodiments, the composition is administered to the subject twice daily. The composition can be administered to the subject by a suitable method of administration. For example, the composition can be administered orally.

[0036] The pharmaceutical composition can be administered as a unit formulation. For example, the composition can have a unit dosage strength equivalent to about 50 mg to about 125 mg of xanomeline free base and equivalent to about 20 mg to about 30 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength equivalent to about 50 mg, about 75 mg, about 100 mg, or about 125 mg of xanomeline free base. In some embodiments, the composition had a unit dosage strength equivalent to about 50 mg of xanomeline free base. In some embodiments, the composition had a unit dosage strength equivalent to about 75 mg of xanomeline free base. In some embodiments, the composition had a unit dosage strength equivalent to about 100 mg of xanomeline free base. In some embodiments, the composition has a unit dosage strength equivalent to about 125 mg of xanomeline free base. In some embodiments, the composition has a unit dosage strength of about 20 mg or about 30 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength of about 20 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength of about 30 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength equivalent to about 50 mg xanomeline free base and about 20 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength equivalent to about 75 mg xanomeline free base and about 20 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength equivalent to about 100 mg xanomeline free base and about 20 mg of trospium chloride. In some embodiments, the composition has a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg of trospium chloride.

[0037] The pharmaceutical composition can be suitably formulated for administration. For example, the pharmaceutical composition can include a plurality of xanomeline beads and a plurality of trospium beads, the xanomeline beads including the xanomeline tartrate and the trospium beads including the trospium chloride. Suitable pharmaceutical compositionsAttorney Docket No. 055920-814001WOincluding xanomeline beads and trospium beads are described for example in WO 2020069301, the relevant contents of which are incorporated herein by reference for the subject matter and purpose referenced herein.

[0038] In some embodiments, the xanomeline beads has a size of about 0.425 mm to about 1.18 mm. For example, the xanomeline beads can have a size of about 0.6 mm to about 0.85 mm. In some embodiments, the trospium beads has a size of about 0.425 mm to about 1.18 mm. For example, the trospium beads can have a size of about 0.6 mm to about 0.85 mm.

[0039] In some embodiments, the plurality of xanomeline beads can have a dissolution rate of more than about 95% within about the first 45 minutes following entry of the composition into an aqueous solution. For example, the dissolution rate of the plurality of xanomeline beads is more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution. In some embodiments, the plurality of trospium beads can have a dissolution rate of more than about 95% within about the first 45 minutes following entry of the composition into an aqueous solution. For example, the dissolution rate of the plurality of trospium beads is more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.

[0040] The plurality of xanomeline beads and the plurality of trospium beads can further include other excipients. In some embodiments, the xanomeline beads further include microcrystalline cellulose and / or talc. In some instances, the xanomeline beads include about 15 wt% to about 65 wt% microcrystalline cellulose. For example, the xanomeline beads can include about 33.5 wt% microcrystalline cellulose. In some embodiments, the xanomeline beads include about 0 wt% to about 2 wt% talc. For example, the xanomeline beads can include about 0.5 wt% talc. In some embodiments, the xanomeline beads include about 30 wt% toa bout 80 wt% xanomeline tartrate. For example, the xanomeline beads can include about 66 wt% xanomeline tartrate.

[0041] In some embodiments, the xanomeline beads include about 30 wt% to about 80 wt% xanomeline tartrate, about 15 wt % to about 65 wt% microcrystalline cellulose, and about 0 wt% to about 2 wt% talc. In some embodiments, the xanomeline beads include about 66 wt% xanomeline tartrate, about 33.5 wt% microcrystalline cellulose, and about 0.5 wt% talc.

[0042] In some embodiments, the trospium beads include about 8 wt% to about 35 wt % trospium chloride. For example, the trospium beads can include about 17.7 wt% trospium chloride. In some embodiments, the trospium beads further include microcrystalline cellulose, lactose monohydrate and / or talc. In some embodiments, the trospium beads include about 25 wt% to about 80 wt% microcrystalline cellulose. For example, the trospium beads can includeAttorney Docket No. 055920-814001WOabout 46.8 wt% microcrystalline cellulose. In some embodiments, the trospium beads include about 15 wt% to about 70 wt% lactose monohydrate. For example, the trospium beads can include about 35 wt% lactose monohydrate. In some embodiments, the trospium include about 0 wt% to about 2 wt% talc. For example, the trospium beads include about 0.5 wt% talc.

[0043] In some embodiments, the trospium beads include about 8 wt% to about 35 wt % trospium chloride, about 25 wt% to about 80 wt% microcrystalline cellulose, about 15 wt% to about 70 wt% lactose monohydrate, and about 0 wt% to about 2 wt% talc. In some embodiments, the trospium beads include about 17.7 wt% trospium chloride, about 46.8 wt% microcrystalline cellulose, about 35 wt% lactose monohydrate, and about 0.5 wt% talc.

[0044] The pharmaceutical composition can be included in a suitable dosage form. For example, in some instances, the pharmaceutical composition is included in a capsule. The capsule can include the plurality of xanomeline beads and the plurality of trospium beads.

[0045] The pharmaceutical composition can further include other excipients such as preservatives and antioxidants. In some embodiments, the pharmaceutical composition further includes an antioxidant. For example, the antioxidant can be selected from ascorbic acid, butylated hydroxytoluene (BHT), and combination thereof. In some embodiments, the pharmaceutical composition further includes ascorbic acid. For example, the pharmaceutical composition can include about 0.2 wt% to about 1 wt% ascorbic acid. For example, the pharmaceutical composition can include about 0.5 wt% of ascorbic acid. In some embodiments, the pharmaceutical composition further includes BHT. In some embodiments, the pharmaceutical composition further includes about 0.01 wt% to about 0.1 wt% BHT. For example, the pharmaceutical composition can include about 0.05 wt% BHT.

[0046] Also provided herein are any of the pharmaceutical compositions disclosed herein for use in alleviating or treating a manic episode in a subject in need of the treatment (e.g., a human patient having a bipolar I disorder) following the treatment conditions also provided herein, as well as use of the pharmaceutical composition for the manufacture of a medicament for use in treating the target disease.

[0047] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, and also from the appended claims.BRIEF DESCRIPTION OF DRAWINGS

[0048] The following drawings form part of the present specification and are included toAttorney Docket No. 055920-814001WOfurther demonstrate certain aspects of the present disclosure, which can be better understood by reference to the drawing in combination with the detailed description of specific embodiments presented herein.

[0049] FIG. 1 is a schematic representation of the study design of Example 1. KarXT dose is expressed as xanomeline free base / trospium chloride (mg / mg).aWashout of prior antidepressants and / or antipsychotics.bFlexible dosing study up to day 14.CBID, twice daily.

[0050] FIG. 2 is a schematic representation of the study design of Example 2. KarXT dose is expressed as xanomeline free base / trospium chloride (mg / mg).bFlexible dosing study -patient’s dose can be up or down titrated if needed. Patients who do not tolerate 100 / 20 mg BID can decrease to 75 / 20 mg BID. BID, twice daily.DETAILED DESCRIPTION

[0051] Bipolar-I disorder is a lifelong episodic mood disorder characterized by both manic and depressive episodes, intermixed with symptom-free periods. Mania can include symptoms of excessive activity as well as psychotic symptoms (delusions, hallucinations, thought disorder). Depressive symptoms can co-occur with mania (i.e. mania with mixed features), which is more common than pure mania. Mania can be more common early in the disorder, with more frequent (and severe compared to major depressive disorder) depressive episodes over time. The lifetime prevalence of BP-I is estimated at 1% to 1.5%, and the mean age at onset of first manic episode is in the early 20s.

[0052] Muscarinic receptors are expressed in the cortex and hippocampus, regions that underly some of the cognitive and neurob ehavi oral symptoms of these disorders. Of the 5 subtypes of muscarinic receptors (ie, M1-M5), xanomeline exerts its therapeutic effect by preferentially binding and activating type 1 and 4 muscarinic receptors in the central nervous system (CNS). However, xanomeline also activates M2 and M3 receptors, particularly in the peripheral nervous system, which is likely responsible for adverse events (AEs) observed in clinical studies of xanomeline alone.

[0053] Trospium is a muscarinic antagonist that binds to and antagonizes all 5 muscarinic receptor subtypes with near-equal affinity as determined by half-maximal inhibitory concentration (IC50) values in radioligand displacement studies. It is a well-known generic drug approved by the FDA and by European authorities to treat overactive bladder and is generally recognized as safe when used as directed. The AEs associated with trospium are primarily attributable to its actions as a muscarinic antagonist in peripheral tissues (e.g. dry mouth, dry eyes, constipation, upset stomach, and gastrointestinal [GI] disturbance).Attorney Docket No. 055920-814001WODefinitions

[0054] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0055] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to ± 20 %, preferably up to ± 10 %, more preferably up to ± 5 %, and more preferably still up to ± 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.

[0056] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini -osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors.

[0057] As used herein, an “adverse event” is any untoward medical occurrence associated with treatment with a pharmaceutical composition described herein. A “mild adverse event” is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities. A “moderate adverse event” is sufficiently discomforting to interfere with everyday activities; intervention may be needed. A “severe adverse event” prevents everyday activities; treatment or other intervention is usually needed. A “serious adverse event” results in death; is life-threatening (immediate risk of death from the event as it occurred); requires or prolongs inpatient hospitalization; results in persistent or significant disability / incapacity; or results in a congenital anomaly / disability, cancer, or drug overdose. An adverse event is incapacitating or disabling if it results in a substantial or permanent disruption of the subject’s ability to carry out normal life functions.

[0058] As used herein, a patient is said to “tolerate” a dose of a compound if administering that dose to that patient does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is aAttorney Docket No. 055920-814001WOsubjective measure and that what may be tolerable to one patient may not be tolerable to a different patient. For example, one patient may not be able to tolerate a headache. In contrast, a second patient may find headaches tolerable but is not able to tolerate vomiting. For a third patient, either headache alone or vomiting alone is tolerable. Still, the patient cannot tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[0059] The term “alleviating” as used herein refers to the reducing or ameliorating at least one symptom of a disease, disorder or condition. For example, alleviating a manic episode, or alleviating mania can refer to reducing or ameliorating at least one symptom of the manic episode or mania.

[0060] A “subject” or “patient” is meant to describe a human or vertebrate animal including a mammal. In some embodiments, a subject or patient is a human.

[0061] The term “pharmaceutically acceptable excipient” is art-recognized. It refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable excipient include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0062] The term “pharmaceutically acceptable salt” or “salt” is art-recognized. It refers to a salt prepared from relatively nontoxic acids or bases, including inorganic acids and bases and organic acids and bases, including, for example, those contained in compositions of the present disclosure. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic,Attorney Docket No. 055920-814001WOmucic, nitric, pamoic, pantothenic, phosphoric, saccharinate, succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, and sulfuric acids and the like.

[0063] “ Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0064] The term “therapeutically effective amount,” as used herein, is the amount of compound disclosed herein present in a formulation described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a formulation is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound disclosed herein, the specific activity of the formulation, the delivery device employed, the physical characteristics of the formulation, its intended use, as well as subject considerations such as severity of the disease state, subject cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.

[0065] The term “therapeutic agent” is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance acting locally or systemically in a subject. Examples of therapeutic agents, also referred to as “drugs,” are described in well-known literature references such as the Merck Index (14th edition), the Physicians ’ Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition). These therapeutic agents include without limitation medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.Attorney Docket No. 055920-814001WOI. Pharmaceutical Compositions Comprising Xanomeline and Trospium

[0066] Provided herein is a pharmaceutical composition comprising xanomeline or a salt thereof and a trospium salt (e.g., trospium chloride, trospium bromide, trospium iodide, or trospium saccharinate). The pharmaceutical composition disclosed herein can be used in alleviating or treating a manic episode in a subject as disclosed herein. In some embodiments, the pharmaceutical composition may comprise xanomeline tartrate and trospium chloride. In some embodiments, the pharmaceutical composition is for oral administration (oral pharmaceutical composition).

[0067] In some embodiments, the pharmaceutical composition disclosed herein may comprise a plurality of xanomeline beads comprising xanomeline or a salt thereof (e.g., xanomeline tartrate and a plurality of trospium beads comprising a salt of trospium (e.g., trospium chloride). In some embodiments, each of the xanomeline beads further comprises a first coating. In some embodiments, each of the trospium beads further comprises a second coating. The first coating can be different or the same as the second coating. In some embodiments, the first coating has the same composition as the second coating.

[0068] In certain embodiments, the plurality of xanomeline beads has a core comprising xanomeline or a salt thereof (e.g., xanomeline tartrate). In some embodiments, the xanomeline beads further comprise a first coating. In certain embodiments, the plurality of trospium beads has a core comprising a trospium salt (e.g., trospium chloride). In some embodiments, the trospium beads further comprise a second coating.

[0069] Also provided is a pharmaceutical composition, comprising xanomeline and / or a salt thereof and 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l-methylpyridin-l-ium (Impurity A).

[0070] Also provided herein is the pharmaceutical composition as described herein, further comprising 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l-methylpyridin-l-ium (Impurity A). Also provided is an oral pharmaceutical composition, comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, a plurality of trospium beads comprising a salt of trospium; and 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l-methylpyridin-l-ium. Also provided is an oral pharmaceutical composition, comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l-methylpyridin-l-ium; and a plurality of trospium beads comprising a salt of trospium.

[0071] In some embodiments, the pharmaceutical composition comprises less than 0.5 wt% of Impurity A. In certain embodiments, the pharmaceutical composition comprises less than 0.30Attorney Docket No. 055920-814001WOwt.% of Impurity A, such as less than 0.25 wt.%, less than 0.20 wt.%, less than 0.15 wt.%, less than 0.14 wt.% or less than 0.1 wt.%. Also provided is a pharmaceutical composition, comprising xanomeline and / or a salt thereof and less than 0.15 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-l-methylpyridin-l-ium (Impurity A).

[0072] In certain embodiments, the pharmaceutical composition comprises less than 0.5 wt.%, less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.15 wt%, or less than 0.1 wt% of Impurity A after the pharmaceutical composition is stored for at least 3 months at 40 °C and 75% relative humidity.

[0073] In certain embodiments, the total impurities in the pharmaceutical compositions provided herein are no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2.5% by weight, no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, no greater than about 0.5% by weight, or no greater than about 0.1% by weight.Bead / Core Excipients

[0074] The bead or core can comprise one or more excipients. In one embodiment, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants. The xanomeline or a pharmaceutically acceptable salt thereof and the salt of trospium may be in separate matrices within the same medicament.

[0075] The amount of xanomeline free base in the core can be at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%. For example, the amount of xanomeline tartrate can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the core, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It is understood that all ranges including these values as endpoints are contemplated, for example, at least between about 15 wt.% and about 90 wt.%, between about 20 wt.% and about 85 wt.%, between about 30 wt.% and about 85 wt.%, or between about 50 wt.% and about 90 wt.%. In certain embodiments, the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate, such as 66 wt.% xanomeline tartrate.

[0076] The amount of trospium salt in the core can be at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%. For example, the amount of trospium chloride can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the core, inAttorney Docket No. 055920-814001WOa range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It is understood that all ranges including these values as endpoints are contemplated, for example, at least between about 15 wt.% and about 90 wt.%, between about 20 wt.% and about 85 wt.%, between about 30 wt.% and about 85 wt.%, or between about 50 wt.% and about 90 wt.%. In certain embodiments, the trospium is trospium chloride. In certain embodiments, the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride, such as 17.7 wt.% trospium chloride.

[0077] In a further embodiment, the matrix comprises a polymer, for example, to modify the release profile of the active in the matrix. In a further embodiment, the polymer comprises a water-soluble polymer. In a further embodiment, the water-soluble polymer is selected from Eudragit™ RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water-insoluble polymer. In a further embodiment, the water-insoluble polymer is selected from Eudragit™ RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof.

[0078] Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate. In one embodiment, the filler is not water-soluble, although it may absorb water. In one embodiment, the filler is a spheronization aid. Spheronization aids can include one or more of crospovidone, carrageenan, chitosan, pectinic acid, glycerides, P-cyclodextrin (P-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0079] The amount of filler in the xanomeline core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose) can range from about 10 wt.% to about 70 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example, about 20 wt.%. In certain embodiments, the xanomeline beads comprise between about 15Attorney Docket No. 055920-814001WOwt.% and about 65 wt.% microcrystalline cellulose, such as between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, between about 35 wt.% and about 40 wt.%, between about 40 wt.% and about 45 wt.%, between about 45 wt.% and about 50 wt.%, between about 50 wt.% and about 55 wt.%, between about 55 wt.% and about 60 wt.%, or between about 60 wt.% and about 65 wt.%. In certain embodiments, the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.

[0080] The amount of filler in the trospium core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in a range of about 10 wt.% to about 80 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example about 20 wt.%. In certain embodiments, the trospium beads comprise between 25 wt.% and 80 wt.% microcrystalline cellulose, such as between about 25 wt.% and 30 wt.%, between about 30 wt.% and 35 wt.%, between about 35 wt.% and 40 wt.%, between about 40 wt.% and 45 wt.%, between about 45 wt.% and 50 wt.%, between about 50 wt.% and 55 wt.%, between about 55 wt.% and 60 wt.%, between about 60 wt.% and 65 wt.%, between about 65 wt.% and 70 wt.%, between about 70 wt.% and 75 wt.%, or between about 75 wt.% and 80 wt.%. In certain embodiments, the trospium beads comprise 46.8 wt.% microcrystalline cellulose.

[0081] In certain embodiments, the trospium beads comprise between 15 wt.% and 70 wt.% lactose monohydrate, such as between about 15 wt.% and 20 wt.%, between about 20 wt.% and 25 wt.%, between about 25 wt.% and 30 wt.%, between about 30 wt.% and 35 wt.%, between about 35 wt.% and 40 wt.%, between about 40 wt.% and 45 wt.%, between about 45 wt.% and 50 wt.%, between about 50 wt.% and 55 wt.%, between about 55 wt.% and 60 wt.%, between about 60 wt.% and 65 wt.%, or between about 65 wt.% and 70 wt.%. In certain embodiments, the trospium beads comprise 35 wt.% lactose monohydrate.

[0082] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propyl cellulose, hydroxypropyl cellulose, lower-substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, Methocel™ E), carboxymethyl cellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, microcrystalline cellulose, and lower-alkyl-substituted hydroxypropyl cellulose. In one embodiment, the binders are selected from wet binders. In one embodiment, the binder is selected from cellulose ethers, e.g., hypromellose.

[0083] The amount of binder in the xanomeline core is not particularly limited. InAttorney Docket No. 055920-814001WOembodiments, the amount of binder (e.g., hypromellose) can be between about 1 wt.% and about 10 wt.%, between about 2 wt.% and about 8 wt.%, or between about 4 wt.% and about 6 wt.%, for example, about 5 wt.%.

[0084] The amount of binder in the trospium core is not particularly limited. In embodiments, the amount of binder (e.g., hypromellose) can be between about 1 wt.% and about 10 wt.%, between about 2 wt.% and about 8 wt.%, or between about 4 wt.% and about 6 wt.%, for example, about 5 wt.%.

[0085] Surfactants include, but are not limited to, anionic surfactants, including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate, nonionic surfactants, including polyoxyethylene ethers and polysorbate 80, and cationic surfactants, including quaternary ammonium compounds. In one embodiment, the surfactant is selected from anionic surfactants, e.g., sodium lauryl sulfate.

[0086] The amount of surfactant, e.g., as a processing aid, is not particularly limited in the xanomeline core. In embodiments, the amount of surfactant (e.g., microcrystalline cellulose) can range between about 0.1 wt.% and about 1 wt.%, between about 0.2 wt.% and about 0.8 wt.%, or between about 0.4 wt.% and about 0.6 wt.%, for example, about 0.5 wt.%.

[0087] The amount of surfactant, e.g., as a processing aid, is not particularly limited in the trospium core. In embodiments, the amount of surfactant (e.g., sodium lauryl sulfate) can range between about 0.1 wt.% and about 1 wt.%, between about 0.2 wt.% and about 0.8 wt.%, or between about 0.4 wt.% and about 0.6 wt.%, for example, about 0.5 wt.%.

[0088] Disintegrants include, but are not limited to, starch, sodium cross-linked carboxymethyl cellulose, carmellose sodium, carmellose calcium, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate, low- substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0089] Glidants include but are not limited to polyethylene glycols of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetanol, stearol, and talc.

[0090] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc. In certain embodiments, the xanomeline beads comprise between 0 wt.% and 2 wt.% talc, such as 0.5 wt.% talc. In certain embodiments, the trospium beads comprise between 0 wt.% and 2 wt.% talc, such as 0.5 wt.% talc.

[0091] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodiumAttorney Docket No. 055920-814001WOsulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the formulation comprises less than 1 wt.% antioxidant, such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.% , 0.08 wt.% , 0.07 wt.% , 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, or 0.01 wt.%.

[0092] In certain embodiments, the oral pharmaceutical composition further comprises ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises between 0.2 wt.% and 1 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition further comprises butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises between 0.01 wt.% and 0.1 wt.% butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises about 0.05 wt.% butylated hydroxytoluene. In certain embodiments, the formulation comprises about 0.05 wt.% BHT or 0.5 wt.% ascorbic acid. In certain embodiments, the antioxidant is present in the xanomeline core or the xanomeline beads.

[0093] In certain embodiments, the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate, between 15 wt.% and 65 wt.% microcrystalline cellulose, and between 0 wt.% and 2 wt.% talc. In certain embodiments, the trospium beads comprise between 0.2 wt.% and 2 wt.% talc, such as 0.5 wt.% talc. In certain embodiments, the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride, between 25 wt.% and 80 wt.% microcrystalline cellulose, between 15 wt.% and 70 wt.% lactose monohydrate, and between 0.2 wt.% and 2 wt.% talc.

[0094] In certain embodiments, the xanomeline tartrate drug beads comprise 66 wt.% xanomeline tartrate, 33-34 wt.% microcrystalline cellulose, and 0.5 wt.% talc. In certain embodiments, the trospium chloride beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc. In this example, the xanomeline tartrate beads contain at least about 2.5 times as much xanomeline as the trospium chloride beads contain trospium chloride.Bead Coatings

[0095] In other embodiments, the beads may be coated with functional or non-functional coatings, such as aesthetic, handling, or stability. In certain embodiments, the beads might beAttorney Docket No. 055920-814001WOcoated with a pH-sensitive coating so that they do not dissolve in the low pH of the stomach. A nonfunctional coating might be used to maintain chemical separation between the beads or for cosmetic reasons.

[0096] In certain embodiments, the beads comprise a coating of talc, which, for example, aids flowability and mixing. Generally, the beads comprise a coating of between 0 wt.% and 2 wt.% talc, such as 0 wt.% to 0.5 wt.% talc, 0.4 wt.% to 0.6 wt.% talc, 0.5 wt.% to 1 wt.% talc, 1 wt.% to 1.5 wt.% talc, or 1.5 wt.% to 2 wt.% talc. In certain embodiments, the beads comprise a coating of 0.5 wt.% talc (in relation to the total weight of the bead). In certain embodiments, the first coating comprises talc. In certain embodiments, the second coating comprises talc. In a further embodiment, the controlled release formulation comprises a semi-permeable coating. The xanomeline and trospium chloride may be in different coatings in the same formulation. The xanomeline and trospium chloride can be in different coatings in different formulations or dosing vehicles in another embodiment. In a further embodiment, the semi-permeable coating comprises a polymer. In a further embodiment, the controlled release formulation comprises a matrix that suspends the xanomeline and trospium chloride.

[0097] In certain embodiments, the distribution of coating thicknesses can be stated in the weight gain of coating material based on the total weight of the coated beads. Thus, in one embodiment, the distribution of coating thicknesses is at least 2% based on the total weight of the coated beads. In another embodiment, the distribution of coating thicknesses is at least 3%. In another embodiment, the distribution of coating thicknesses is at least 4%. In another embodiment, the distribution of coating thicknesses is at least 5%. In another embodiment, the distribution of coating thicknesses is at least 6%. In another embodiment, the distribution of coating thicknesses is at least 7%. In another embodiment, the distribution of coating thicknesses is at least 8%. In another embodiment, the distribution of coating thicknesses is at least 9%. In another embodiment, the distribution of coating thicknesses is at least 10%. In another embodiment, the distribution of coating thicknesses is at least 11%. In another embodiment, the distribution of coating thicknesses is at least 12%. In another embodiment, the distribution of coating thicknesses is at least 13%. In another embodiment, the distribution of coating thicknesses is at least 14%.

[0098] For example, the difference in coating thickness from bead to bead can be in a range of + / - 1-7% based on the coated beads' total weight. The distribution of coating thicknesses can be between about 2% and about 14% based on the weight of the coated beads, such as between about 3% and about 13%, between about 4% and about 12%, between about 5% and about 11%, between about 6% to about 10%, between about 7% and 9%, between about 3% and 14%,Attorney Docket No. 055920-814001WObetween about 4% and 14%, between about 4% and 13%, or between 4% and about 12%.Bead size and shape

[0099] The plurality of beads has a distribution of particle sizes. The plurality of beads has bead shapes. The plurality of beads has a distribution of coating thicknesses when present.

[0100] Beads having a distribution of particle sizes were shown to exhibit advantageous pharmacokinetics. Without intending to be bound by any theory, it is contemplated that the pharmacokinetics are influenced by the plurality of beads having a distribution of core sizes.

[0101] In one embodiment, the particle sizes of the beads range between about 0.4 mm and about 1.2 mm, such as between about 0.4 mm and about 0.5 mm, between about 0.5 mm and about 0.6 mm, between about 0.6 mm and about 0.7 mm, between about 0.7 mm and about 0.8 mm, between about 0.8 mm and about 0.9 mm, between about 0.9 mm and about 1.0 mm, between about 1.0 mm and about 1.1 mm, or between about 1.1 mm and about 1.2 mm. In certain embodiments, the size of the xanomeline beads is between about 0.425 mm and about 1.18 mm. In certain embodiments, the size of the xanomeline beads is between about 0.6 mm and about 0.85 mm. In certain embodiments, the size of the trospium beads is between about 0.425 mm and about 1.18 mm. In certain embodiments, the size of the trospium beads is between about 0.6 mm and about 0.85 mm.

[0102] The beads or bead mixtures may be used, for example, in suspensions, filled into capsules, compressed into tablets, or filled into sachets. One or more types of modified release beads can be mixed and encapsulated or used as a sprinkle on the subject’s food. In certain embodiments, the oral solid dosage form may be any of these forms. In certain embodiments, the dosage form is a capsule.

[0103] As the particle size of the beads becomes too small, the variability in the content of the active increases. As the particle size becomes too large, the beads are too large for drug products labeled to be administered via sprinkling (e.g., on applesauce or other soft foods, such as jellies) and swallowed without chewing or administered via an enteral feeding tube. Also, as the particle size increases, the larger particles get coated more than the smaller particles, resulting in lower relative assay than smaller particles. Relatively more beads are needed to meet the label strength per capsule. Filling a capsule shell with enough large particles to meet the label strength per capsule becomes difficult or impossible (e.g., to fill a size 0 capsule to a 75-mg strength of xanomeline-free base).

[0104] In one embodiment, the beads are formulated into capsules, e.g., with an encapsulation machine. Various capsule sizes may accommodate the strength and fill weight of the targetAttorney Docket No. 055920-814001WOformulations. Capsule size ranges from 00 to 5 for fill weights ranging between about 15 mg and about 630 mg.

[0105] The beads can be sorted (e.g., via sieving) to the desired particle size. In certain embodiments, the particle size range is any particle size range or combination described above regarding the cores. In one embodiment, the particle size range is the same as the particle size range of the uncoated cores. For example, the beads can be sieved such that 5% or less of the bead cores by weight is retained on a #12 mesh (1.68 mm) screen, and 10% or less by weight pass through a #20 mesh (0.84 mm) screen.Unit Formulation

[0106] The plurality of xanomeline beads and the plurality of trospium beads can be formulated in a unit formulation or a unit dosage form. For example, the plurality of xanomeline beads and the plurality of trospium beads can be comprised in tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps, and other methods of administration known to one skilled in the art. In some embodiments, the pharmaceutical composition is comprised in a capsule, the capsule comprising the plurality of xanomeline beads and the plurality of trospium beads.

[0107] In some embodiments, the xanomeline beads are as described herein. In some embodiments, the trospium beads are as described herein.

[0108] The capsule can comprise a capsule shell. For example, the capsule shell can comprise hydroxypropyl methylcellulose. In certain embodiments, a capsule shell comprising hydroxypropyl methylcellulose (HPMC) containing separate populations of drug beads containing xanomeline tartrate or trospium chloride wherein the drug beads are of comparable size and release the actives rapidly and at substantially similar rates. Following the dissolution of the capsule shell in the stomach, the drug beads may dissolve in the stomach or pass through the pyloric valve into the duodenum intact or partially intact. Still, the two drugs' ratio, both in dissolved form and in undissolved form, can remain relatively constant in the gastrointestinal tract until the drugs are absorbed.

[0109] The formulation for each drug bead allows substantially similar performance from two actives at different dose ranges. The actives are released into the blood serum at substantially similar rates or achieve a substantially similar Tmax. In certain embodiments, a capsule comprises 50 mg xanomeline in the form of the tartrate salt and 10 mg trospium chloride. Fifty mg xanomeline as a free base corresponds to about 76 mg xanomeline tartrate. In other words, in some embodiments a capsule comprises about 76 mg xanomeline tartrate and about 10 mgAttorney Docket No. 055920-814001WOtrospium chloride.

[0110] A discrepancy in the number of drug beads in the capsule increases the probability that the drug beads' ratio would not remain substantially constant after the beads are released and disperse. Thus, in certain embodiments, the trospium beads are formulated with a lower drug load. Effective doses of trospium and xanomeline are contained in roughly equivalent numbers of beads. Despite the differences in drug loads in certain embodiments, the trospium and xanomeline beads release at roughly similar rates. For example, if the dissolution of the capsules is assessed using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of xanomeline dissolved is substantially equivalent to the percentage of dissolved trospium chloride, such as at 10 min, 20 min, or 30 min.[OHl] In certain embodiments, the oral pharmaceutical composition is a capsule comprising a plurality of xanomeline beads, each of said plurality of xanomeline beads having a core comprising between 50 wt.% and 90 wt.% xanomeline tartrate, between 15 wt.% and 65 wt.% microcrystalline cellulose, and between 0 wt.% and 1 wt.% ascorbic acid, wherein each of said plurality of xanomeline beads has a size between 0.6 mm and 0.85 mm; a plurality of trospium beads, each of said plurality of trospium beads having a core comprising between 8 wt.% and 35 wt.% trospium chloride, between 45 wt.% and 50 wt.% microcrystalline cellulose, and between 35 wt.% and 40 wt.% lactose monohydrate, wherein each of said plurality of trospium beads has a size between 0.6 mm and 0.85 mm; and the plurality of xanomeline beads and the plurality of trospium beads each having a dissolution rate of more than about 95% within about the first 20 minutes following entry of the capsule into an aqueous solution. In some embodiments, the plurality of xanomeline beads further comprise the first coating. In some embodiments, the first coating comprises between 0 wt.% and 2 wt.% talc. In some embodiments, the plurality of trospium beads further comprise the second coating. In some embodiments, the second coating comprises between 0 wt.% and 2 wt.% talc.

[0112] In certain embodiments, each of the xanomeline beads comprises 66 wt.% xanomeline tartrate, 33 wt.% microcrystalline cellulose, 0.5 wt.% ascorbic acid, and 0.5 wt.% talc.

[0113] In certain embodiments, the plurality of trospium beads have a core comprising between 4 wt.% and 7 wt.% trospium chloride, between 45 wt.% and 60 wt.% microcrystalline cellulose, and between 35 wt.% and 50 wt.% lactose monohydrate. In some embodiments, each of the trospium beads further comprise the second coating and the second coating comprises between 0 wt.% and 2 wt.% talc.

[0114] In certain embodiments, each of the trospium beads comprises 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.%Attorney Docket No. 055920-814001WOtalc.

[0115] In certain embodiments, each of the trospium beads comprises 4.4 wt.% trospium chloride, 54.5 wt.% microcrystalline cellulose, 40.6 wt.% lactose monohydrate, and 0.5 wt.% talc. In certain embodiments, each of the trospium beads comprises a core comprising 4.4 wt.% trospium chloride, 54.5 wt.% microcrystalline cellulose, and 40.6 wt.% lactose monohydrate. In some embodiments, each of the trospium beads further comprises the second coating and the second coating comprises 0.5 wt.% talc.

[0116] In certain embodiments, the capsule comprises an oral pharmaceutical composition wherein each of said plurality of xanomeline beads having a core comprising between 66 wt.% xanomeline tartrate, between 33 wt.% microcrystalline cellulose, 0.5 wt.% ascorbic acid, and a coating comprising 0.5 wt.% talc; each of said a plurality of trospium beads having a core comprising between 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and a coating comprising 0.5 wt.% talc.

[0117] The pharmaceutical composition can be formulated in unit formulation to obtain a particular pharmacokinetic profile.

[0118] In one embodiment, the absorption (area under the curve, AUC) of the dosage form when dosed orally is advantageously increased, compared to other dosage forms of xanomeline or trospium chloride. Without intending to be bound by any theory, the increase in absorption is influenced by the dosage form exhibiting a pseudo-extended release profile. The pseudo-extended-release profile is influenced by one or more factors, including distribution of coating thicknesses when present, distribution of bead particle sizes, and the beads having irregular bead shapes. For example, in an embodiment wherein the beads have a distribution of coating thicknesses, for beads with a relatively thin coating, the coating completely dissolves at the trigger pH relatively quickly to release the xanomeline and / or trospium chloride compositions, whereas for beads having a relatively thick coating the coating takes somewhat longer to completely dissolve and release the xanomeline and / or trospium chloride compositions. In an embodiment where the beads have a distribution of particle sizes and / or irregular bead shapes, the gut transit time of the beads could be varied due to bead size and / or shape, such that the transit time until reaching the coating dissolution pH is varied, thus contributing to a pseudo-extended-release profile. In another embodiment, the dosage form exhibits substantially equivalent (e.g., bioequivalent) Cmax and / or AUC characteristics when administered orally inside a capsule shell or without a capsule shell.

[0119] In certain embodiments, the dosage form provides a progressive and predictable absorption curve. In one embodiment, the Tmax of the dosage form, when dosed orally, is moreAttorney Docket No. 055920-814001WOstable on a dose-to-dose basis because the beads are individually coated. A predictable, consistent Tmax is advantageous for accomplishing a more consistent, sustained therapeutic effect. For example, process-related variations in coating thickness or other influences on coating dissolution affect only a fraction of the xanomeline and trospium chloride in the dosage form. They tend to lead to pseudo-extended release behavior. In contrast, coated capsules comprising xanomeline and trospium chloride microspheres exhibit significant variability in absorption time from the capsule to capsule.

[0120] In certain embodiments, the oral pharmaceutical composition comprises xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, which when administered to the patient in need thereof, the composition is sufficient to provide an in-vivo plasma profile comprising a median Tmax for xanomeline of 2 hours and a median Tmax for trospium of 1 hour. In certain embodiments, the in-vivo plasma profile further comprises a mean dose-normalized Cmax of between 48.5 and 121.3 pg / mL / mg. In certain embodiments, the in-vivo plasma profile further comprises a mean dose-normalized Cmax of trospium of between 156 and 375 pg / mL / mg. In certain embodiments, the in-vivo plasma profile further comprises a mean dose-normalized AUCO-12 of xanomeline of between 263 and 577 hr pg / mL / mg. In certain embodiments, the in-vivo plasma profile further comprises a mean dose-normalized AUCO-12 of trospium of between 881 and 2024 hr pg / mL / mg. In certain embodiments, the in-vivo plasma profile further comprises a mean Cmax of trospium at 7850 ± 3360 pg / mL. In certain embodiments, the in-vivo plasma profile further comprises a mean AUCO-12 of 41900 ± 15500 hr pg / mL.

[0121] In another embodiment, the dosage form exhibits advantageous storage stability, e.g., measured by the amount of xanomeline present following storage and / or by the total amount of related substances. The storage stability can be assessed following storage at typical ambient conditions (e.g., 25 °C and 60% relative humidity) or accelerated stability conditions involving increased temperature and / or humidity.

[0122] The dosage form and methods are contemplated to include embodiments of any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures and Examples) unless stated otherwise. Reference to a bead and properties thereof apply equally to a collection of beads (e.g., a plurality of such beads). Likewise, referring to a core and properties thereof apply equally to a collection of cores (e.g., a plurality of such cores).

[0123] The enteric (gastro-resistant) coating material, e.g., polymer, can be one that will dissolve in intestinal juices at a pH level higher than that of the stomach, e.g., a pH of greaterAttorney Docket No. 055920-814001WOthan 4.5, such as within the small intestine, and therefore permit the release of the active substance in the regions of the small intestine and substantially not in the upper portion of the GI tract. In one embodiment, the enteric material begins to dissolve in an aqueous solution at pH between about 4.5 and about 5.5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5.5.

[0124] For example, pH-sensitive materials do not significantly dissolve until the dosage form has emptied from the stomach. The small intestine's pH gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the small intestine's distal portions (ileum). To provide predictable dissolution corresponding to the small intestine transit time of about 3 hours (e.g., 2-3 hours) and permit reproducible release therein, the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve at the pH range within the small intestine. Therefore, the amount (thickness) of enteric coating should be substantially dissolved during the about three-hour transit time within the small intestine (e.g., the proximal and mid-small intestine).

[0125] Suitable enteric (gastro-resistant) materials include, but are not limited to, cross-linked polyvinyl pyrrolidone; non-crosslinked polyvinylpyrrolidone; hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate; methyl cellulose succinate; methyl cellulose phthalate succinate; methyl cellulose phthalic acid half ester; ethyl cellulose succinate; carboxymethylamide; potassium methacrylate divinylbenzene copolymer; polyvinyl alcohols; polyoxyethylene glycols; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with a monomer selected from the following: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g. Eudragit™ -L and -S series, including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5, available from Evonik Industries; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethylacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; polyarginine;Attorney Docket No. 055920-814001WOpoly (ethylene); poly(propylene); polyethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane. A combination of enteric materials may also be used. In one embodiment, the enteric material rapidly dissolves at pH 5.5 and higher to provide fast dissolution in the upper bowel. For example, the enteric material can be selected from a copolymer of methacrylic acid and methyl methacrylate and a copolymer of methacrylic acid and ethyl acrylate. For example, an enteric polymer is poly(methacrylic acid co-ethyl acrylate)l:l (Eudragit™ L 30 D-55 and Eudragit™ L 100-55).

[0126] Other suitable examples of enteric coating coatings include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, and shellac and stearic acid; polyvinyl acetate and ethyl cellulose; and a neutral copolymer of polymethacrylic acid esters (Eudragit™ L 30D); copolymers of methacrylic acid and methacrylic acid methylester, or a neutral copolymer of polymethacrylic acid esters containing metallic stearates. Such coatings comprise mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, e.g., those with free carboxyl content.

[0127] One or more plasticizers can be added to enteric polymers to increase their pliability and reduce brittleness, as known in the art. Suitable plasticizers include, for example, butyl citrates, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycols (PEGs, such as PEG 6000), acetyl triethyl citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. While some enteric materials are flexible and do not require plasticizers, more brittle polymers (e.g., Eudragit™ L / S types, Eudragit™ RL / RS, and Eudragit™ FS 30 D) benefit from plasticizers, for example, ranging from between 5 wt.% and 30 wt.% based on the dry polymer mass, between about 8 wt.% and about 12 wt.% tri ethyl citrate with poly(methacrylic acid co-ethyl acrylate) 1:1.

[0128] In certain embodiments, the enteric coatings comprise one or more anti-tacking agents (anti adherents) to reduce the film's tackiness and prevent agglomeration, as it is known in the art. Suitable anti-tacking agents include, but are not limited to, talc, glyceryl monostearate, fumed silica (e.g., Aerosil™ 200), precipitated silica (e.g., Sipernat™ PQ), and magnesium stearate. Anti-tacking agents can be used in any suitable quantity, for example ranging between about 10 wt.% and 100 wt.% based on dry polymer mass, between about 10 wt.% and about 50 wt.%, between about 10 wt.% and about 30 wt. %, or between about 15 wt.% and about 30 wt.%. For example, in one embodiment, it ranges between 15 wt.% and about 30 wt.% based on dry polymer mass.

[0129] One or more surfactants can also be added to an enteric coating mixture to increase substrate wettability and / or stabilize suspensions, as it is known in the art. Surfactants includeAttorney Docket No. 055920-814001WOPolysorbate 80, sorbitan monooleate, sodium dodecyl sulfate, and other surfactants described herein.

[0130] Any suitable process can form the enteric coating. Coating processes include pan coating, fluid bed coating, and dry coating (e.g., heat dry coating and electrostatic dry coating). Pan coating and fluid bed coating using solvent are well-established processes. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, anti-tacking agents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed into solid dosage forms in a pan coater or a fluid bed dryer and dried by hot air. For example, in a Wurster fluid bed coating process, the coating fluid is sprayed from the fluid bed apparatus's bottom. Alternatively, the coating fluid is applied by top spraying. In certain embodiments, a tangential spray is applied.

[0131] The amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics. For example, in one embodiment, the amount of enteric coating meets USP <711> requirements (USP 36-NF 31) for delayed-release dosage forms, thereby not releasing 10.0 wt.% of the drug after 2 hours in 0.1 N HC1. In certain embodiments, the formulation releases at least 80% of the active in 20 minutes in pH 6.8 buffer solution, e.g., using a dissolution method of USP 36-NF 31 section <711>.

[0132] In one embodiment, the enteric coating is present in an amount in a range between about 10% and 40%, or between 25% and about 35% as measured by the weight gain compared to the uncoated particle cores, or ranging between about 25% and about 31% weight gain, between about 27% and about 31% weight gain, or between about 28.5% and about 31% weight gain, based on the weight of the uncoated particle cores.

[0133] The formulation can include a capsule shell in which the beads are disposed. Soft and hard capsule shells are known. The capsule shell is a hard-capsule shell in one embodiment, e.g., a gelatin capsule shell or a vegetable-based hard capsule shell. In certain embodiments, the capsule shell comprises one or more enteric coatings described herein. During accelerated storage, gelatin capsules may collapse. Thus, in certain embodiments, the formulation can include a hydroxypropyl methylcellulose capsule shell.

[0134] Thus, for example, one embodiment combining various of the features described above includes a pharmaceutical dosage form comprising a plurality of xanomeline beads, the beads comprising a core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose), and an enteric coating (optionally Eudragit™ L 30 D-55) surrounding the core, wherein the plurality of beads has a distribution of particle sizes ranging between about 0.7 mm and about 2.5 mm, wherein the enteric coating ranges betweenAttorney Docket No. 055920-814001WOabout 20% and about 40% based on the weight of the bead cores, and wherein the beads are disposed in a capsule shell.Exemplary Pharmaceutical Compositions

[0135] Depending on dosing requirements, capsules can be prepared with different amounts of xanomeline tartrate and trospium chloride beads. In various embodiments, capsules contain xanomeline tartrate and trospium chloride in an amount equivalent to 25 mg xanomeline free base and 10 mg trospium chloride, 50 mg xanomeline free base and 10 mg trospium chloride, 50 mg xanomeline free base and 20 mg trospium chloride, 75 mg xanomeline free base and 10 mg trospium chloride, 75 mg xanomeline free base and 20 mg trospium chloride, 125 mg xanomeline free base and 30 mg trospium chloride, or 125 mg xanomeline free base and 40 mg trospium chloride. In certain embodiments, the capsule contains 25 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsule contains 50 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsule contains 50 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsule contains 75 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsule contains 75 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsule contains 125 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsule contains 125 mg xanomeline as xanomeline tartrate and 40 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 40 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 40 mg trospium chloride.Method of Makins the Pharmaceutical Compositions

[0136] Provided is a method for preparing a pharmaceutical composition comprising admixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium, such as trospium chloride. In certain embodiments, the method further comprises formulating the admixed beads into capsules.Attorney Docket No. 055920-814001WO

[0137] Also disclosed herein are a method for preparing the dosage form, comprising coating a core comprising xanomeline or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form the enteric coating, and coating a core comprising trospium chloride or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form the enteric coating. Optionally, the core can be formed by a wet granulation method. Optionally, drug beads are sorted (e.g., via sieving) to a desired particle size range before enteric coating and optionally again following enteric coating.

[0138] The drug beads may be made by different processes, including, but not limited to, spheronizing an extruded wet mass and coating of inert core spheres in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and spheronization.

[0139] The beads are formulated to flow freely and to be compatible with modem encapsulation equipment. In some embodiments, the beads are blended to form a uniform mixture filled into capsules in a single stage. In other embodiments, the beads are filled separately into capsules using a two-stage capsule filler.

[0140] Any suitable process can form the cores comprising xanomeline or pharmaceutically acceptable salts thereof. In one embodiment, the core is formed by granulating a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range. In another embodiment, the core can be formed by extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient.

[0141] Any suitable process can form the cores comprising trospium chloride or pharmaceutically acceptable salts thereof. In one embodiment, the core is formed by granulating a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range. In another embodiment, the core can be formed by extrusion and spheronization of a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient.

[0142] Granulating processes can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction. The mixtures to be granulated can first be dry -blended. The dry -blended dry ingredients can be mixed with water before extrusion.

[0143] Extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride with an excipient provide desirable cores with a distribution of particle sizes as described herein and one or more other desirable properties. In certain embodiments, short processing times can lead to a more stable product. For example,Attorney Docket No. 055920-814001WOreducing spheronization reduces friction and related heat, reducing the time the product is exposed to air (either when moist and / or before packaging) diminishes oxidation. On the other hand, rapid processing by extrusion and spheronization can lead to a poor-quality product, such as having a large fraction of the bead cores falling outside a desired particle size range. The moisture absorbed by spheronization aids (which happens over time) influences the beads' spheronization characteristics.

[0144] Accordingly, in one embodiment, the moisture content of the granulation mixture, before drying, ranging between about 20 wt.% and about 40 wt.%, such as between 25 wt.% and about 35 wt.%, between about 28 wt.% and about 32 wt.%, at least about 28 wt.%, at least about 28.5, between about 20 wt.% and about 40 wt.%, between about 25 wt.% and about 35 wt.%, between about 27 wt.% and about 31 wt.%, or between about 28.5 wt.% and about 31 wt.%.

[0145] In certain embodiments, the wet mass can be held before extrusion, allowing the spheronization aid to swell with granulating fluid. The hold time can be at least 15 minutes, such as at least 30 minutes, at least 45 minutes, or at least 60 minutes. In certain embodiments, the hold time ranges between about 15 minutes and about 120 minutes, such as between 30 and 100 minutes or between 60 and 90 minutes.

[0146] As described above relating to cores, the method can include a step of sorting (e.g., by sieving) the cores before optional coating to retain particles in a predetermined size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, between about 0.8 mm and about 1.7 mm, or any range described herein.

[0147] As described above relating to beads, the method can include a step of sorting (e.g., by sieving) the beads after optional coating to retain particles in a size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, or between about 0.8 mm and about 1.7 mm, or any range described herein.

[0148] In an extrusion and spheronization process, the following optional features can be employed, individually or in one or more combinations thereof. Water can be a granulation agent. Microcrystalline cellulose can be in the cores as a spheronization aid. Hypromellose can be included in the cores as a binder. The extrusion screen size can be 1.0 mm. The friction plate of the spheronizer can be cross-hatched. The friction plate of the spheronizer can be cross-hatched with a square pitch of at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or ranging between about 3 mm and about 7 mm, or about 5 mm. The spheronization time can be less than about 5 minutes, or less than about 4 minutes,Attorney Docket No. 055920-814001WOor less than about 3 minutes, or less than about 2 minutes, or up to 1 minute. The spheronized particles can include non-spherical particles (i.e., irregular shapes), for example, a substantial fraction thereof, such as at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 70 wt.% thereof.

[0149] In certain embodiments, the pharmaceutical composition is stored with a desiccant, for example, pharmaceutical grades of silica gel, crystalline sodium, potassium or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, and the like.

[0150] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0151] In certain embodiments, the pharmaceutical composition is stored under a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof.

[0152] In certain embodiments, the pharmaceutical composition is stored under reduced pressure compared to the external ambient air.

[0153] In certain embodiments, the pharmaceutical composition is stored at a reduced temperature, e.g., at refrigerated temperatures (e.g., 2 °C to 8 °C). In certain embodiments, the pharmaceutical composition is stored in such a manner that has fewer impurities, such as Impurity A, than when stored at 25 °C.

[0154] In certain embodiments, the pharmaceutical composition is stored by a manufacturer, a distributor, a pharmacy, or a hospital at a temperature of between about 2 °C and about 8 °C before dispensing the oral pharmaceutical composition to the subject. In certain embodiments, after the oral pharmaceutical composition is dispensed to the subject, the pharmaceutical composition is stored at a temperature of between about 20 °C and about 25 °C.

[0155] Also provided is a method of stabilizing a pharmaceutical dosage form or composition described herein, comprising storing the dosage form at a temperature of about 2 °C to about 8 °C.

[0156] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises forming a wet mass comprising xanomeline tartrate and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding and spheronizing the wet mass comprising xanomeline tartrate and excipient to make cores, sorting the cores to a target particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.

[0157] In certain embodiments, a method for preparing a pharmaceutical dosage formAttorney Docket No. 055920-814001WOcomprising trospium beads comprises forming a wet mass comprising trospium chloride and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding, spheronizing, and drying the wet mass comprising trospium chloride and excipient to make cores, sorting the cores to a target particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.II. Methods of Alleviating a Bipolar Disorder in Patients

[0158] The present disclosure provides, in some aspects, methods of alleviating a manic episode in a subject in need thereof, for example, a manic episode associated with a bipolar disorder such as bipolar disorder I. Also provided herein is a method for treating a bipolar disorder such as bipolar disorder I in a human patient. In some embodiments, the method provided herein may alleviate a manic episode associated with the bipolar disorder. In other embodiments, the method provided herein may alleviate a depressive episode associated with the bipolar disorder. The methods can include administering to the subject a pharmaceutical composition comprising xanomeline tartrate and trospium chloride as described herein. The pharmaceutical composition can be administered to the subject at a daily dose equivalent to about 100 mg to about 300 mg xanomeline free base and about 40 mg to about 75 mg trospium chloride.

[0159] Bipolar-I disorder is a lifelong episodic mood disorder characterized by both manic and depressive episodes, intermixed with symptom-free periods. Mania or manic episodes can include symptoms of excessive activity as well as psychotic symptoms (delusions, hallucinations, thought disorder). Depressive symptoms can co-occur with mania (i.e. mania with mixed features), which can be more common than pure mania. Mania can be more common early in the disorder, with more frequent (and severe compared to major depressive disorder) depressive episodes over time.

[0160] In some embodiments, the manic episode is related to bipolar disorder. For example, the manic episode can be related to bipolar-I disorder. Bipolar-I disorder can be established based on the Diagnostic and Statistical Manual of Mental Disorders (5thEdition, Text Revision) (DMS 5-TR) criteria.A. Administration and Dosages

[0161] In some embodiments, the pharmaceutical composition administered is a pharmaceutical composition as described in the present disclosure. In some embodiments, theAttorney Docket No. 055920-814001WOpharmaceutical composition is administered to the subject at a daily dose equivalent to about 100 mg to about 250 mg xanomeline free base and about 40 mg to about 60 mg trospium chloride. For example, the pharmaceutical composition can be administered to the subject at a daily dose equivalent to about 200 mg or about 250 mg xanomeline free base, and about 40 mg or 60 mg trospium chloride. In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 150 mg xanomeline free base, and about 40 mg trospium chloride. In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 200 mg xanomeline free base, and about 40 mg trospium chloride. In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 250 mg xanomeline free base, and about 60 mg trospium chloride. In some embodiments, the pharmaceutical composition is administered to the subject at a daily dose equivalent to about 300 mg xanomeline free base, and of about 75 mg trospium chloride.

[0162] In some embodiments, the daily dose is administered via a titration scheme. In some embodiments, the methods of the present disclosure include:(i) administering to the subject the composition at a first total daily dose of about 100 mg of xanomeline about 40 mg of trospium chloride for a first period;(ii) administering to the subject, after the first period, the composition at a second daily dose of about 200 mg xanomeline and about 40 mg of trospium chloride for a second period, and(iii) administering to the subject, after the second period, the composition at the daily dose of about 250 mg xanomeline and about 60 mg of trospium chloride for a third period.

[0163] Depending on for example how the subject tolerates the daily dose administered, the daily dose can be modified, for example by reducing or increasing the daily dose, or it can be maintained. The reducing of the daily dose can be assessed for example based on whether the subject tolerates the daily dose in the second period. In some embodiments, the methods of the present disclosure further include reducing the daily dose to an amount equivalent to about 150 mg xanomeline free base and about 40 mg of trospium chloride to the subject who is not tolerating the daily dose in the second period.

[0164] In some embodiments, the methods of the present disclosure further comprise (iii) administering to the subject, after the second period, the composition at a third daily dose equivalent to about 250 mg xanomeline free base and equivalent to about 60 mg of trospium chloride for a third period. The reducing of the daily dose can be assessed for example based on whether the subject tolerates the daily dose in the third period. For example, if the subjectAttorney Docket No. 055920-814001WOdoes not tolerate the daily dose in the third period, the daily dose can be reduced to an amount equivalent to about 200 mg of xanomeline free base and 40 mg of trospium chloride.

[0165] In some embodiments, the methods of the present disclosure further comprise terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride.

[0166] If the subject tolerates the daily dose in the third period, the daily dose can be maintained. In some embodiments, the method of the present disclosure further includes maintaining the daily dose equivalent to about 250 mg of xanomeline free base and about 60 mg of trospium chloride to the subject, who is tolerating the daily dose in the third period.

[0167] In some embodiments, the first period is about 2 days to about 9 days, optionally about 2 days or 7 days. In some embodiments, the first period is about 2 days. In some embodiments, the first period is about 7 days. In some embodiments, the second period is about 3 days to about 9 days, optionally about 5 days to 7 days. In some embodiments, the second period is about 7 days.

[0168] The third period can be at least two weeks. In some embodiments, the third daily dose is administered for about 2 weeks. In some embodiments, the third daily dose is administered for at least about 2 weeks. In some embodiments, the third period is about 2 weeks to about 49 weeks.

[0169] In some embodiments, the methods of the present disclosure include(a) administering to the subject the composition as described herein to the subject two times a day orally for about two days, wherein the composition comprises a unit dosage strength equivalent to about 50 mg xanomeline free base and about 20 mg trospium chloride; and(b) administering to the subject, after step (a), the composition two times a day orally for about five days; wherein the composition comprises a unit dosage strength of about 100 mg xanomeline and a unit dose strength of about 20 mg trospium chloride.

[0170] In some embodiments, when the subject is not tolerating the doses administered in step (b), the method further includes reducing the doses by administering to the subject the composition a unit dosage strength equivalent to about 75 mg xanomeline free base and equivalent to about 20 mg trospium chloride two times per day orally. In some embodiments, when the subject is tolerating the doses administered in step (b), the method further comprises (c) administering to the subject the composition comprising a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg trospium chloride two times per dayAttorney Docket No. 055920-814001WOorally.

[0171] In some embodiments, when the subject is not tolerating the doses administered in step (c), the method further includes reducing the doses by administering to the subject the composition comprising a unit dosage strength equivalent to about 100 mg xanomeline free base and about 20 mg trospium chloride two times per day orally. If the composition comprising the unit dosage strength equivalent to about 100 mg xanomeline free base and about 20 mg trospium chloride is still not tolerated by the subject, the method can further include reducing the doses by administering to the subject the composition comprising a unit dosage equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride two times per day orally.

[0172] If the composition comprising the unit dosage strength equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride is still not tolerated by the subject, the treatment can be terminated. In some embodiments, the method further comprises terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg xanomeline and equivalent to about 40 mg trospium chloride.

[0173] In some embodiments, the composition of the present disclosure has:(a) a unit dosage strength equivalent to about 50 mg xanomeline free base and about 20 mg trospium chloride;(b) a unit dosage strength equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride;(c) a unit dosage strength equivalent to about 100 mg xanomeline free base and about 20 mg trospium chloride; or(d) a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg of trospium chloride.

[0174] In some embodiments, the composition is administered to the subject twice daily. The composition can be administered to the subject by a suitable method of administration. For example, the composition can be administered orally.

[0175] The methods of the present disclosure can be carried out via a titration scheme. For example, the methods of the present can include administering to the subject the composition at a first total daily dose equivalent to about 100 mg of xanomeline free base about 40 mg of trospium chloride for a first period. During the first period, the composition administered can have a unit dose strength equivalent to about 50 mg xanomeline free base and about 20 mg trospium chloride, and the composition can be administered twice daily. The first period can be about 2 days to about 9 days. For example, the first period can be 2 days, 5, days, 7 days, orAttorney Docket No. 055920-814001WO9 days.

[0176] During or after the first period, the subject can be assessed for tolerability, for example by monitoring the occurrence of one or more side effects (e.g. adverse events) as described herein. The assessment can be carried out for example on Day 3 of the treatment. The side effects can be reported by the subject and / or documented through laboratory testing. The side effects can be assessed for their severity and whether they are causally related to the treatment. If the side effects are causally related to the treatment and severe such that the subject cannot tolerate them, the daily dose can be reduced or the administration may be terminated. If the side effects are not causally related to the treatment and / or the side effects are mild or moderate such that the subject can tolerate them, the daily dose may be increased, for example to the second daily dose.

[0177] If the subject tolerates the first total daily dose, the first daily dose can be increased to the second daily dose. For example, the methods of the present disclosure can further include administering to the subject, after the first period, the composition at a second daily dose equivalent to about 200 mg xanomeline free base and about 40 mg of trospium chloride for a second period. The composition administered during the second period can have a unit dose strength equivalent to about 100 mg xanomeline free base and about 20 mg trospium chloride, and the composition can be administered twice daily. The second period can be about 3 days to about 9 days. For example, the second period can be about 5 days or 7 days. During and after the second period, the subject can be assessed for tolerability of the second daily dose, for example on Day 8 of the treatment. Tolerability assessment can be carried out similarly to the tolerability assessment for the first daily dose. If the side effects are causally related to the treatment and severe such that the subject cannot tolerate them, the daily dose can be reduced or the administration may be terminated. For example, if the subject does not tolerate the second daily dose, the daily dose can be reduced to a lower dose, such as to the first daily dose or to a dose equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride, or the treatment can be terminated. If the side effects are not causally related to the treatment and / or the side effects are mild or moderate such that the subject can tolerate them, the daily dose may be increased, for example to the third daily dose.

[0178] If the subject tolerates the second total daily dose, the second daily dose can be increased to the third daily dose. For example, the methods of the present disclosure can further include administering to the subject, after the second period, the composition at the daily dose equivalent to about 250 mg xanomeline free base and about 60 mg of trospium chloride for a third period. During the third period, the composition administered can have a unit dosageAttorney Docket No. 055920-814001WOstrength equivalent to about 125 mg xanom eline free base and about 30 mg trospium chloride, and the composition can be administered twice daily. The third period can be about 2 weeks. During and after the third period, the subject can be assessed for tolerability of the third daily dose. Tolerability assessment can be carried out similarly to the tolerability assessment for the first daily dose and the second daily dose. If the side effects are causally related to the treatment and severe such that the subject cannot tolerate them, the daily dose can be reduced. For example, the daily dose can be reduced to the second daily dose. For example, when the subject is not tolerating the doses administered in step (c), for example the third daily dose, the methods of the present disclosure can further include administering to the subject the composition two times a day orally; wherein the composition can have a unit dosage strength equivalent to about 100 mg xanom eline free base and a unit dose strength of about 20 mg trospium chloride.

[0179] If the subject tolerates the third daily dose, the third daily dose can be maintained or increased to a fourth daily dose. In some embodiments, if the subject tolerates the third daily dose, the third daily dose is maintained. In some embodiments, the subject tolerates the third daily dose, the methods of the present disclosure further include administering to the subject, after the third period, the composition at the daily dose equivalent to about 300 mg xanomeline free base and about 75 mg of trospium chloride for a fourth period.

[0180] In another embodiment, the pharmaceutical composition of the present disclosure is administered in combination (e.g. sequential or concomitant) with one or more therapies, including psychotherapy and drugs. Therapeutic agents include, but are not limited, to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to one skilled in the art. A therapeutic agent may fall under the category of more than one drug. For instance, benzodiazepines can be considered anxiolytics, sedatives, and tranquilizers.B. Patient Population

[0181] The subjects can be assessed for suitability for the methods of the present disclosure.

[0182] In some embodiments, the subject is a human patient. In some embodiments, the subject is at least 18 years old. For example, the subject can be between 18 to 65 years old.

[0183] Prior to the administration, the subject can have one or more of the following characteristics. For example, the subject can have a Young Mania Rating Scale (YMRS) of at least 14. In some embodiments, the YMRS is at least 20 prior to the administration. YMRS can be assessed using scoring system known in the field, for example as described herein. The YMRS is described in Young RC, Biggs JT, Ziegler YE, et al. A rating scale for mania:Attorney Docket No. 055920-814001WOreliability, validity and sensitivity. Br J Psychiatry 1978;133:429-435, the relevant contents of which are incorporated herein by reference for the subject matter and purpose referenced herein. For example, the subject can have a Clinical Global Impress! ons-Bipolar (CGI-BP) score of at least 3. In some embodiments, the subject can have a CGI-BP score of at least 4. CGI-BP can be assessed using scoring system known in the field, for example as described herein. CGI-BP is described in Spearing MK, Post RM, Leverich GS, et al. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res 1997;73(3): 159-71, the relevant contents of which are incorporated herein by reference for the subject matter and purpose referenced herein. In some embodiments, the subject has a YMRS of at least 14 and a CGI-BP of at least 3. In some embodiments, the subject has a YMRS of at least 20 and a CGI-BP of at least 4.

[0184] In some embodiments, the subject is diagnosed with bipolar-I disorder. In some embodiments, the subject has bipolar-I disorder that is not with rapid cycling. Diagnosis of bipolar disorder or bipolar-I disorder can be carried out by known methods in the field. For example, the primary diagnosis of Bipolar-I disorder can be established by a comprehensive psychiatric evaluation based on the DSM-5-TR criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI, v7.0.2). DSM-5-TR criteria for bipolar-I disorder are described in American Psychiatric Association, Diagnostic and statistical manual of mental disorders. 5th ed., text revision. Arlington: American Psychiatric Association; 2022, the relevant contents of which are incorporated herein by reference for the subject matter and purpose referenced herein. In some instances, the subject further has experienced an acute episode or relapse of mania with mixed features, for example as assessed by DSM-5-TR criteria described herein. In some instances, the subject further has a need for hospitalization for the acute episode or acute exacerbation, or relapse of mania. For example, the subject can have been hospitalized voluntarily before or during Screening with a mania diagnosis not more than 21 days before Screening. Hospital admission can be a result of the current manic episode. In some embodiments, the subject has a body mass index of about 18 kg / m2to about 40 kg / m2inclusively.

[0185] For example, to prevent or minimize one or more side effects, a suitable subject can be free of one or more of the following characteristics. However, the following characteristics may not on their own exclude the subject from treatment. In some embodiments, the subject is free of a diagnosis of mental disorders other than bipolar-I disorder. For example, mental disorders other than bipolar-I disorder can include bipolar-II disorder, major depressive disorder, and / or primary psychotic disorder. The diagnosis for the mental disorders can beAttorney Docket No. 055920-814001WOmade based on DSM 5-TR standards as described herein. In some embodiments, the subject is free of a diagnosis of moderate or severe substance use disorder within 12 months before the administering. For example, the moderate or severe substance use disorder does not include tobacco use disorder. For example, the subject is free of a moderate or severe substance use disorder that is concurrent with the administering, as measured by urine toxicology screen or alcohol test. In some embodiments, the subject is free from risk of suicidal behaviour as determined by clinical assessment with 6 months to 12 months of the administering. Risk of suicidal behaviour can be determined by methods known in the field, for example by a clinical assessment and / or Columbia-Suicide Severity Rating Scale (C-SSRS) as confirmed by (1) answering “Yes” on items 4 or 5 (C-SSRS ideation) with 6 months of screening, or between screening and baseline, or (2) answering “Yes” to any of the five items (C-SSRS behaviour) within 12 months of screening or between screening and baseline. In some embodiments, the subject is free of a history of or is free from a high risk of irritable bowel syndrome or severe constipation requiring treatment. In some embodiments, the subject is free of a history or free from high risk of urinary retention, gastric retention or untreated narrow-angle treatment.C. Efficacy Assessment

[0186] In some instances, the methods further include assessing treatment efficacy. The treatment efficacy can include monitoring one or more of the following parameters.

[0187] In some embodiments, the methods include monitoring a decrease of CGI-BP score from a baseline CGI-BP score of the subject prior to the administering. For example, the decrease in CGI-BP score can be 1 or at least 1. In some embodiments, the decrease in CGI-BP score can be 4 or at least 4. CGI-BP can be measured as described herein.

[0188] In some embodiments, the methods include monitoring a decrease of YMRS score from a baseline YMRS score of the subject prior to the administering. For example, the decrease in YMRS score can be about 50% or at least 50%. YMRS can be measured as described herein.

[0189] In some embodiments, the methods of the present disclosure include monitoring a change in Brief Assessment of Cognition (B AC) from a baseline assessment of B AC of the subject prior to the administering. BAC can be evaluated by methods known in the field, for example based on performance of Symbol Coding, Digit Sequencing, Verbal Fluency, and Verbal Memory subtests, and will be administered via paper.

[0190] In some embodiments, the methods of the present disclosure include monitoring a decrease in Montgomery-Asberg Depression Rating Scale (MADRS) total score from a baseline assessment of MADRS total score of the subject prior to the administering. ForAttorney Docket No. 055920-814001WOexample, the MADRS total score can decrease by about 20% to about 50%. MADRS can be assessed using methods known in the field. MADRS is described in Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382-389, the relevant contents of which are incorporated herein by reference for the subject matter and purpose referenced herein.

[0191] In some embodiments, the methods of the present disclosure include monitoring a change in a level of inflammatory biomarkers based on a baseline level of the inflammatory biomarkers of the subject prior to the administering. For example, the inflammatory biomarkers can include TNF-a, IL-2, IL-6, IL- 10, IL- 17, CRP, or combinations thereof. In some embodiments, the methods of the present disclosure include monitoring a change in a level of brain-derived neurotropic factor (BDNF) based on a baseline level of BDNF of the subject prior to the administering. The monitoring can be performed after three weeks of the administering of the composition of the present disclosure.1). Safety Assessment and Adverse Events

[0192] In some embodiments, the methods of the present disclosure further include monitoring a side effect during and / or after the administration of the composition of the present disclosure. For example, the side effect can include one or more of(i) urinary retention,(ii) angioedema,(iii) decreased gastric mobility or gastric retention,(iv) narrow angle glaucoma,(v) a heart rate increase,(vi) a change in blood pressure,(vii) change in diastolic blood pressure of more than 1.5 mm Hg, and / or(viii) liver enzyme elevation as measured by serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of at least three times an upper limit normal (ULN) of the subject.

[0193] Urinary retention can be an anticholinergic adverse reaction for example associated with trospium chloride treatment. Angioedema, for example of the face, lips, tongue, and / or larynx can also be experienced with use of trospium chloride. Antimuscarinic agents may cause decrease in gastrointestinal motility. Trospium chloride can be associated with narrow-angle glaucoma.

[0194] Change in blood pressure can be measured for example after administration of theAttorney Docket No. 055920-814001WOcomposition of the present disclosure as a 24-hour ambulatory average diastolic BP (ABPM). In some instances, the change in blood pressure can be an increase in ABPN of about 1.9 mmHg.

[0195] KarXT may cause increase in hearth rate. In some embodiments, the heart rate increase is more than 9.8 beats per minute measured as a 24-hour average heart rate.

[0196] Liver enzyme elevation can be measured through level of alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST).

[0197] Further safety assessments can include Mini International Neuropsychiatric Interview (MINI), physical examination, vital signs, electrocardiograms (ECGs), clinical laboratory assessment of biosamples from the subject, Simpson-Angus Scale (Hawley C, Fineberg N, Roberts A et al. The use of the Simpson Angus Scale for the assessment of movement disorder: A training guide. Int J Psychiatry Clin Pract 2003;7(4):349-2257.), Barnes Akathisia Rating Scale (BARS, Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154(5):672- 676.), Abnormal Involuntary Movement Scale (Guy W. ECDEU Assessment Manual for Psychopharmacology: Revised (DHEW publication number ADM 76-338). Rockville, MD, US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976: 534-7.), C-SSRS, International Prosetate Symptom Score (IPSS, Barry MJ, Fowler FJ Jr, O'Leary MP et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148(5): 1549— 57), or combinations thereof.

[0198] Clinical laboratory assessment of biosamples of the subject can be conducted on biosamples such as blood sample, serum sample, urine sample and the like. Biosamples can be assessed for parameters and markers listed in Table A below.Table A - Clinical Laboratory Assessment of BiosamplesHematology Serum Chemistry UrinalysisHematocrit ALT AppearanceHemoglobin ALP ProteinMean corpuscular AST Glucosehemoglobin Albumin KetoneMean corpuscular Uric acid bodieshemoglobinBlood urea nitrogen or urea Leukocyteconcentration esteraseCarbon dioxideMean corpuscular volume SpecificC-reactive proteinPlatelet count gravityCreatinineRBC count BilirubinCreatine kinaseWBC count with differential UrobilinogenAttorney Docket No. 055920-814001WOHematology Serum Chemistry UrinalysisElectrolytes (sodium, Occult bloodpotassium, Nitritechloride, calcium, phosphorus)Gamma-glutamyl transferaseGlucose (fasting)LDHThyroid Stimulating HormoneTotal bilirubinDirect bilirubinTotal cholesterolLDL HDLTriglyceridesTotal proteinHbAlcSerum Prostate-specificantigen(screening only)IOCBP / INOCBP Serology Drugs of Abuse Test (Urine) Pregnancy: A serum HCV antibody A National Institute on Drug pregnancy test will be Hepatitis B surface antigen, Abuse -5 urine drug screen performed on all individuals of (cannabinoids or marijuana, childbearing potential at Hepatitis B core antibody phencyclidine, amphetamines, screening and a urine HIV-1 and HIV -2 antibody opiates, and cocaine). Urine pregnancy test (urine HCG) (HIV alcohol test will be performed at will be performed at other RNA as appropriate) Screening, and breathalyzer at Day scheduled visits at the site. If a 1 (Baseline) and each return urine pregnancy test is outpatient visit. If a participant equivocal or positive, a serum leaves the study site, he / she should sample should be sent to have a urine drug screen and test central laboratory for for alcohol (urine alcohol test or confirmation of the result breathalyzer) upon returning to the Post-Menopause: FSH study site.(screening only) for postmenopausal women <55 yearsof age.

[0199] In some instances, when the occurrence of the side effect is observed, the methods of the present disclosure further include managing the side effect. For example, the managing of the side effect can include modifying or adjusting the daily dose. For example, the managing of the side effect can include decreasing the daily dose. In some instances, the managing includes terminating the treatment.Attorney Docket No. 055920-814001WOE. Pharmacokinetics Assessment

[0200] Pre-dose and post-dose biosamples can be collected from the subject for PK analysis. For example. Plasma concentration of xanomeline and trospium can be measured using established bioanalytical methods.F. Biomarkers Assessment

[0201] Biosamples of subjects can also be used to assess levels of biomarkers. DNA sample can be used to assess presence or absence of any relationship between efficacy and genotype of the subject. For example, DNA samples can be used to assess presence or absence of single nucleotide polymorphism variants of genes related to cholinergic mechanisms.

[0202] Further biomarkers can include inflammatory biomarkers, neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Other biomarkers are described herein. For example, inflammatory biomarkers can include TNF-a, IL-2, IL-6, IL- 10, IL- 17, CRP, or combinations thereof.

[0203] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference for the purposes or subject matter referenced herein.EXAMPLES

[0204] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit, and scope of the present disclosure. All such modifications are intended to be within the scope of the disclosure.

[0205] The following examples are provided for illustration and are not intended to limit the scope of the disclosure.Example 1: Phase 3 Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder

[0206] A Phase 3, randomized, double-blinded, placebo-controlled study is conducted toAttorney Docket No. 055920-814001WOevaluate the efficacy and safety of xanomeline administered in combination with trospium for the treatment of manic episodes in subjects with bipolar disorder.Study Objectives and Rationale for Endpoints

[0207] A primary objective is to determine the efficacy of KarXT compared with placebo in reducing the severity of acute mania or mania with mixed features in participants with BP-1. Primary endpoints are measured by change in baseline in Young Mania Rating Scale (YMRS) score 3 weeks after initiation of the treatment. The YMRS is a validated clinical scale, which assesses mania severity and sensitivity to drug treatment effects in clinical trials. The YMRS is based on participants’ subjective report of their clinical condition and as administered by a trained physician is a useful metric for continuous evaluations of manic symptoms in interventional studies.

[0208] A secondary objective of this study is to evaluate improvement in overall disease by KarXT compared with placebo in the treatment of participants with acute mania or mania with mixed features associated with BP-1. Secondary endpoint is measured by change in the baseline in Clinical Global Impression-Bipolar (CGI-BP) at week 3. The CGI-BP assesses symptoms and function as they relate specifically to mania or mixed features. It is a clinician's rating of the participant's illness based on the overall clinical impression as assessed by an experienced rater.

[0209] Other secondary objectives are to evaluate the proportion of participants with a clinical response to KarXT compared with placebo in the treatment of acute mania or mania with mixed features associated with BP-I. For example, endpoints are determined by a > 50% decrease from baseline in YMRS score and / or a change in CGI-BP score from baseline > 1 at 3 weeks post-treatment. The higher the percentage of responders in a group lends confidence to differences in mean change from baseline on the same scales.

[0210] Safety objectives are to evaluate the safety and tolerability of KarXT, as determined by the absence or occurrence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and other TEAEs leading of study withdrawal, changes from the baseline in the Columbia-Suicide Severity Rating Scale (C-SSRS), the Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), Structured Interview Guide to the Montgomery-Asberg Depression Rating Scale (MADRS) Assessment (SIGMA), International Prostate Symptom Score (IPSS) for male participants, physical evaluations including but not limited to body temperature, respiratory rate, seated blood pressure, seated heart rate, body weight, or waist circumference, and results fromAttomey Docket No. 055920-814001WOlaboratory tests such as electrocardiograms, hematology, serum chemistry and urinalysis conducted during the treatment period. Any incidental findings of potential clinical relevance that are not directly associated with the objectives of the protocol are also documented and evaluated.

[0211] Briefly, the C-SSRS is designed to systematically assess and track suicidal behavior and ideation. This study utilizes 2 versions of the C-SSRS: at screening, the “lifetime” version with past 12 months is completed, and all subsequent visits utilize the “Since Last Visit” version. The BARS is a scale used to assess the severity of drug-induced akathisia, or restlessness, involuntary movement, and inability to sit still. The range of scores is 0 to 14, with higher scores indicating greater severity. The SAS is an instrument established to measure drug-related extrapy rami dal syndromes. The range of scores is from 0 to 40 with increased scores indicating increased severity. The AIMS is a scale used to measure involuntary movements such as tardive dyskinesia, that can at times develop as a side effect of long-term treatment with antipsychotic medications. Items are scored from 0 (none) to 4 (severe), with higher scores indicating more severe dyskinesia. The MADRS is a 10-item measure that assesses the severity of depression symptoms. The scale is an adaptation of the Hamilton Depression Rating Scale and has a greater sensitivity to changes over time. The scale can be completed using the Structured Interview of the MADRS (SIGMA). Lastly, the IPSS is based on answers to seven questions concerning urinary symptoms and one question concerning quality of life (QoL). The total score can range from 0 to 35 with a higher score being very symptomatic.

[0212] This study has multiple exploratory objectives. This study evaluates the Pharmacokinetics (PK) of KarXT in participants with mania or mania with mixed features associated with BP-I through a modeling approach utilizing an existing KarXT population PK model. Plasma concentrations of xanomeline and trospium in study participants are quantified by validated bioanalytical methods in a bioanalytical laboratory.

[0213] Additional exploratory objectives include:• Evaluation of the effect of KarXT compared with placebo on cognition of participants with acute mania or mixed features associated with BP-I as determined by the change from baseline in Brief Assessment of Cognition (B AC), a tool for cognition assessment, at Week 3. Change from baseline at Week 3 is evaluated via scores on Symbol Coding, Digit Sequencing, Verbal Fluency, and Verbal Memory subtests.• Evaluate of the effect of KarXT on fluid biomarkers in participants with mania or mania with mixed features associated with BP-I as measured by change from baseline in pro-Attorney Docket No. 055920-814001WOinflammatory biomarkers and Brain-derived Neurotrophic Factor (BDNF) levels at Week 3. BDNF a state-marker in BP-I and is correlated with severity of mania. The altered neuroimmune markers in the serum of participants with BP-I, including cytokines and chemokines, indicate a heightened proinflammatory systemic response especially during acute mania.• Evaluate the association between genetic biomarkers and the efficacy and tolerability of KarXT in participants with mania or mania with mixed features associated with BP- I as determined by the presence or absence of single nucleotide polymorphism variants in genes related to cholinergic mechanism. Given that BP-1 is strongly determined by inheritance and single nucleotide polymorphisms are associated with BP-1, the whole blood pharmacogenetics sample is collected at Day 1 of treatment as an exploratory endpoint to determine whether genetic differences may help subtype participants and determine differential tolerability and clinical efficacy to KarXT treatment.• Evaluate the effect of KarXT on physiological measures collected digitally in participants with mania or mania with mixed features associated with BP-I, and the association between physiological biomarkers and the efficacy and tolerability of KarXT in participants with mania or mania with mixed features associated with BP-I. The exploratory digital biomarkers of interest include but are not limited to heart rate variability (HRV), sleep duration and onset latency, average daily activity, skin temperature, or peripheral oxygen saturation (SpO2). These digital biomarkers are probative for the detection of manic and other states, or rest-activity cycle disruption that occur in BP-I. Further, a multi-modal modelling of time-series sensory data facilitated by collection of the digital biomarkers can be an effective methodology for disease subgroup classification in mood disorders such as BP-I. Other suite of sensor signals such as skin temperature, SpO? pulse rate and electrodermal activity is used as quality control for the raw signals and for context that enables interpretation for other more directedly relevant signals.• Explore the trend of participants-reported symptoms, functioning and overall health status when treated with KarXT compared with placebo by measuring the changes from baseline as reported in following the Patient-Reported Outcomes (PROs) questionnaires: Brief Quality Of Life In Bipolar Disorder (Brief Qol.BD), EQ-5D-5L, and Patient Global Impression of Severity (PGIS). Analysis can enable the understanding of the impact of treatment directly from the participant’s perspective.Attorney Docket No. 055920-814001WOSummary of Non-clinical and KarXT Phase I Clinical Studies

[0214] In non-clinical safety studies, no evidence of mutagenicity or treatment effects on reproduction, fertility, or fetal parameters has been demonstrated in animals following the administration of xanomeline, a component of KarXT. The acute toxicity of xanomeline tartrate was evaluated in mice and rats. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose of 40 mg. Gross findings at necropsy were generally unremarkable.

[0215] The clinical experience with KarXT includes multiple completed Phase 1 studies in healthy volunteers, 1 completed Phase 2 study, and multiple Phase 3 studies in adult participants with a DSM-5-TR diagnosis of schizophrenia. Among Phase 1 studies, TEAEs were primarily cholinergic or orthostatic and a few were anticholinergic. TEAEs were mild or moderate in severity and there were no SAEs or deaths. Safety and tolerability profiles were acceptable. Doses of KarXT 150 / 20 mg BID and 150 / 40 mg BID were not well tolerated. In completed studies, significant reductions in psychotic symptoms were observed. No new safety findings associated with KarXT were observed with either xanomeline alone or with trospium chloride alone in KarXT trials.Study Design

[0216] This study is a doble-blinded, randomized, placebo-controlled, global Phase 3 KarXT monotherapy trial with flexible dosing. It is conducted as a two-armed study of KarXT in participants with acute mania or mania with mixed features in BP-I. Total study duration is up to 7 weeks, including a maximum 14-day screening period, a 3 -week treatment period, and a 14-day follow-up period as summarized in FIG. 1. The first dose of study drug is no more than 2 weeks following screening and the last dose of study drug is on Day 21. The study participants inclusion and exclusion criteria and detailed study design are described below.A. Inclusion and Exclusion Criteria for Study Participants

[0217] Approximately 274 participants are randomized into one or two arms (approximately 137 participants per arm).

[0218] Key inclusion criteria for participants include:• Participant must be 18 to 65 years of age, inclusive, at the time of signing the informed consent form.• Individuals have a primary diagnosis of Bipolar-I disorder established by a comprehensive psychiatric evaluation based on the DSM-5-TR (Diagnostic and Statistical Manual ofAttorney Docket No. 055920-814001WOMental Disorders (5th Edition, Text Revision)) criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI, v7.0.2).• Individual is experiencing an acute exacerbation or relapse of mania or mania with mixed features (< 3 weeks). Mania and mixed features last a minimum of one week and include at least 3 symptoms associated with mania. Patients who have mixed features meet criteria for mania and have at least 3 symptoms associated with major depression as outlined in the DSM-5 TR.• The individual requires hospitalization for the acute exacerbation or relapse of mania. • The individual is hospitalized voluntarily before screening or admitted to the inpatient unit at Visit 1 with a mania diagnosis not > 21 days before Screening. Hospital admission must be a result of the current manic episode.• Participant is able to wash out psychotropic medications in up to 14 days (> 1 day, maximum of 14 days) before first dose.• Young Mania Rating Scale (YMRS) score of > 14 at screening and baseline, optionally, a YMRS score of > 20,• Clinical Global Impressions-Bipolar (CGI-BP) > 3 at screening and baseline, optionally CGI-BP of > 4.• Body mass index > 18 and < 40 kg / m2• The individual is able to comprehend and satisfactorily comply with protocol requirements per investigator judgment.

[0219] Key exclusion criteria include:• Any primary DSM-5-TR disorder other than BP-I within 12 months before screening (confirmed using MINI v7.0.2 at screening) including BP depression, BP with rapid cycling (> 4 mood episodes in one year), first manic episode, and major depressive disorder, with the exception of mild anxiety disorders.• Individual has a DSM-5-TR diagnosis of moderate to severe substance use disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current use as determined by urine toxicology screen or alcohol test.• Risk for suicidal behavior at screening as determined by the investigator’s clinical assessment and the C-SSRS with an answer “Yes” to item 4 or 5 within 6 months of screening, or suicide attempt within 12 months of screening.• History of gastrointestinal obstructive disorders or irritable bowel syndrome (with orAttorney Docket No. 055920-814001WOwithout constipation) or serious constipation requiring treatment within the last 6 months.• History or high risk of urinary retention, gastric retention or untreated narrow-angle glaucoma.Study Population Rationale

[0220] Female and male participants aged 18-65 years old with a diagnosis of BP-I experiencing an acute episode of mania or mania with mixed features, defined by the DSM-5-TR are enrolled. Mania and mixed features last a minimum of one week and include at least 3 symptoms associated with mania. Participants who have mixed features meet criteria for mania and have at least 3 symptoms associated with major depression as outlined in the DSM-5-TR. Review of eligibility is performed prior to randomization. Eligibility verification benefits participants as it minimizes exposure to study intervention in participants who may not meet eligibility criteria.

[0221] Manic episodes may occur spontaneously when individuals are under stress or in the context of non-adherence to medication. Non-adherence is common in BP-I due to multiple factors including drug intolerance, to which patients with BP-I are particularly sensitive to during maintenance treatment. Manic episodes can result in high-risk behavior, impair patient functioning, put tremendous strain on family and friends, and often result in costly and disruptive hospitalizations.

[0222] Effective treatments that are more tolerable and lack the risk of EPS, hyperprolactinemia, weight gain, and metabolic disorder have the potential to address the needs of patients and dramatically affect their lives as well as those of their families.

[0223] Eligible participants are randomized to either the active treatment or placebo. Randomization is stratified by mixed features (present vs. absent) and psychotic features (present vs. absent) to ensure that the two arms are balanced with respect to the percentage of participants having these characteristics.B. Screening Period

[0224] Screening period of this study lasts from 1 to 14 days, all or part of which may take all or in part on an inpatient unit. The screening period allows participants to enroll for treatment need, while allowing enough time for needed washout of any long-acting medications. A total of 457 participants are screened (with 40% screen failure) to randomize 274 participants 1 : 1 to receive KarXT or placebo across 60 sites globally. During Screening, each participant provides their medical and psychiatric history. The following rating scales are administered during theAttorney Docket No. 055920-814001WOscreening period: The Mini International Neuropsychiatric Interview (MINI; to confirm diagnosis), Young Mania Rating Scale (YMRS), CGI-BP, Columbia-Suicide Severity Rating Scale (C-SSRS), and The International Prostate Symptom Score (IPSS, males only). Other assessments are performed, including electrocardiogram (ECG), clinical laboratory assessments, vital signs, and physical examination. Any prohibited concomitant medications are tapered and discontinued completely at least one day prior to randomization.C. Randomized Treatment Period

[0225] After Screening, eligible participants are randomized (1:1) to the investigational medicinal product (IMP) and be housed in an inpatient unit. Eligibility on Day 1 for randomization requires: YMRS > 14 or > 20 at Baseline and change from screening to Baseline assessment < 20% and CGI-BP score > 3 or > 4 (mild or moderate) at Baseline. Participants who do not meet these criteria are not randomized. Randomization is stratified by mixed features (present vs absent), and psychotic features (present vs absent). Each participant is titrated to the maximum dose of IMP suitable for the participant based on tolerability, up to 250 / 60 mg total per day (125 / 30 BID).

[0226] The dosing regimen in this study mimics that used in the EMERGENT program and is consistent with the US label for schizophrenia. Dose selection of KarXT for treatment of BP- 1 is based on KarXT dosing regimen used in the schizophrenia program (EMERGENT) Phase 1, Phase 2, and Phase 3 studies, in which safety, efficacy, and PK data has been collected. Further, the dosing from the present study is also considers that the dosing of antipsychotics for acute mania is as high as that for acute psychosis in schizophrenia. Ashok et al., Molecular psychiatry, 22(5), 666-679 (2017). The dosing regimen is flexible, allowing overall safety to be considered by the investigator with respect to dose escalation and the need for dose reduction.

[0227] Briefly, in the double-blind treatment period, all participants start a titration with a KarXT dose of 50 / 20 mg (xanomeline 50 mg / trospium chloride 20 mg, or matching placebo) BID for the first 2 days (Days 1 and 2), followed by KarXT 100 / 20 mg BID (or matching placebo) for the remainder of the first week (Days 3 to 7). The drugs are administered in a capsule format (Table X), under supervision by study site personnel to ensure compliance. Participants are evaluated for dose adjustments on Days 3 and 8 and as clinically indicated for issues of tolerability. On Day 8, dosing is titrated up to KarXT 125 / 30 mg (or matching placebo) BID. If the participant does not tolerate the escalated dose, the dose may be reduced to 100 / 20 mg (or matching placebo) BID (FIG. 1). Participants who cannot tolerate either ofAttorney Docket No. 055920-814001WOthese doses will be discontinued due to tolerability. The treatment period include 3 weeks of inpatient care. There is no study drug taper.

[0228] The study interventions administered in this study are outlined in Tables 1 and 2 below. The study interventions should be administered at the same time daily, in the morning and evening.Table 1: Study Intervention(s) AdministeredType / Unit DoseIMP / Non- Intervention Strength(s)IMP / AxMP Packaging and Name / Xanomeline SourcingBlinded or Labeling Dose (mg) / trospiumOpen labelFormulation chloride (mg)Blister pack Drug / 50 mg / 20 mg or (wallet). Each xanomeline / 100 mg / 20 mg or Provided container will be trospium chloride IMP- Blinded125 mg / 30 mg or centrally labeled as required / CapsulePlacebo per country requirements.Table 2: Study ArmsIntervention Description / Arm Title / Route of Administration Arm Use Dosage LevelsXanomeline (mg) / trospium chloride (mg)50 mg / 20 mg orKarXT 100 mg / 20 mg or Oral125 mg / 30 mgPlacebo OralD. Adverse Events

[0229] An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition occurring in a clinical investigation participant after signing of informed consent, whether or not considered related to the study intervention, and therefore can be any unfavorable and unintended sign (such as an abnormal laboratory test result), symptom, or disease temporally associated with the study intervention. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death or is life threatening. Adverse events of special interest (AESI) hepatic enzyme elevation, biliary disorders, urinary tract infection, and urinary retention.

[0230] The investigator or a qualified designee are responsible for detecting, documenting andAttorney Docket No. 055920-814001WOreporting Adverse Events (AEs) reported by the participant or by a caregiver promptly and not exceeding 24h of awareness of the event. All AEs and SAEs are collected from the time of signing the informed consent form, including those thought to be associated with protocol-specified procedures and until 28 days following discontinuation of dosing or the last scheduled visit. Investigators are not obligated to actively seek information on AEs or SAEs in former study participants, however, the investigator must report any SAE, including a death, that occurs any time after a participant is discharged from the study and that is reasonably believed to be related to a study intervention or protocol-specified procedure.E. End of Study

[0231] A participant fulfills the requirements for study completion when the participant has completed all study periods or has completed the treatment period and rolled over into an Open-Label Extension (OLE) study, in which for all participants to receive KarXT. Specifically, study completion occurs at the End of Study visit (Day 22 / End of Treatment / Early Termination visit) for participants who are eligible and choose to roll over into open label extension, or on Day 35 (Safety Follow-Up) for participants who do not roll over into the extension study.

[0232] Upon completion of the double-blind treatment period, a one-time safety follow-up is completed 14 days for participants who do not rollover into the long-term safety study. Unscheduled assessments may occur throughout the study periods at the discretion of the clinical investigator as clinically indicated.F. Efficacy Assessment

[0233] To evaluate the efficacy of KarXT compared with placebo in the treatment of participants with acute mania or mania with mixed features associated with BP-I, a number of clinical scores are used, including one or more YMRS, CGI-BP, BAC, and MADRS.

[0234] For YMRS and CGLBP, the main estimand is the mean change from baseline in one or more of the clinical scores at Week 3 between KarXT and placebo. The difference between KarXT and placebo at Week 3 is estimated using a mixed model for repeated measures (MMRM), which uses the change from baseline in YMRS and / or CGI-BP scores at each postbaseline visit as the response variable and include treatment group, visit and treatment group-by-visit interaction, stratification factors psychosis and mixed features as categorical variables and baseline score as a continuous covariate. An unstructured covariance matrix is assumed to model the within-participant errors.

[0235] Additional efficacy endpoints include Brief Assessment of Cognition (BAC) andAttorney Docket No. 055920-814001WOMontgomery- Asberg Depression Rating Scale (MADRS).

[0236] The overall incidence of AE, SAEs, AEs leading to discontinuation, severe AEs, AEs leading to death, and AESIs is presented by treatment group. Pharmacokinetic data is used for summary statistics and statistical analyses of PK parameters. Participant matrix concentrationtime data is listed and summarized. Other exploratory endpoints and safety assessment analyses are summarized using descriptive statistics by treatment group.YMRS Assessment

[0237] The YMRS is a rating scale completed by a clinician based on the participant’s subjective report of their mania symptoms over the past 48 hours. It is comprised of 11 items, and additional information can be obtained based on clinical observations made during the course of the clinical interview. All items are given a severity rating, with 4 items graded from 0 to 8 (irritability, speech, thought content, and disruptive / aggressive behavior), and the remaining 7 items are graded from 0 to 4 points. These 7 items are weighted twice that of the other 4 in order to compensate for potentially poor cooperation from more severe participants. The highest score obtainable on the YMRS is 60 and the higher the number the greater the number of symptoms and / or the greater their severity. The YMRS is a validated assessment for symptoms of mania, is widely accepted for use by health authorities, and is typically completed within 15-30 minutes.

[0238] A primary endpoint of the present study includes a change in the YMRS relative to a baseline YMRS before beginning treatment. A secondary optional endpoint includes a change in the YMRS of at least 50% (> 50%).CGI-BP Assessment

[0239] The CGI-BP is a specialized adaptation of the standard Clinical Global Impression scale, designed to assess the severity, improvement, and efficacy of treatment in individuals with bipolar disorder. It provides a quick, standardized way for clinicians to evaluate and track a patient's clinical status over time. Only section I, illness severity, will be used, which includes three components: mania, depression, and overall bipolar illness. Section I component 3 (overall bipolar illness) will be the key secondary endpoint. The ratings are on a 7-point scale (1 = normal, not ill; 2 = minimally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = very severely ill). The CGI-BP is brief and efficient, taking between 1-5 minutes to complete, depending on the complexity of symptoms being assessed.

[0240] An endpoint of the present study includes a change in the CGI-BP relative to a baselineAttorney Docket No. 055920-814001WOCGI-BP before beginning treatment. For example, the endpoint includes a change in the CGI-BP of at least 4.Brief Assessment of Cognition (BAC)

[0241] The Brief Assessment of Cognition (BAC) is a preferred tool for cognition assessment. It is a cognitive assessment battery that measures performance across several cognitive domains including working memory, processing speed, and verbal memory. It was developed as a quick and effective tool to evaluate cognitive change and requires less than 30 minutes of testing time. In this study, scores will be evaluated based on performance of Symbol Coding, Digit Sequencing, Verbal Fluency, and Verbal Memory subtests, and will be administered via paper.

[0242] Note: Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep medication.Montgomery-Asberg Depression Rating Scale (MADRS)

[0243] The MADRS is a 10-item measure that assesses the severity of depression symptoms. Each item is rated on a 7-point scale; higher scores indicate more severe symptoms. The scale is an adaptation of the Hamilton Depression Rating Scale and has a greater sensitivity to change over time. The scale can be completed in 20 to 30 minutes using the structured interview of the MADRS (SIGMA).G. Pharmacokinetic Assessment

[0244] Blood samples are collected for bioanalysis of xanomeline and trospium concentrations in plasma on Days 1, 3, 4, 8, 11, 13, 14, and 22 of the study.

[0245] Other analyses are conducted by combining PK data from this study with PK data from other studies in the clinical development program and reported separately. PK sample collection is performed after clinical assessment when feasible. Actual sample collection time and the dose administration of the medicinal product is accurately recorded.

[0246] The following time windows serve as a guideline for PK sample collections:• All pre-dose samples are taken within 60 minutes prior to dosing. If it is known that a dose will be delayed, then the pre-dose sample should be collected just prior to the delayed dose. However, if a pre-dose sample is collected but the dose is delayed, an additional pre-dose sample should not be collected.• All post-dose samples for xanomeline and trospium should be taken within 2 to 8 hours post-dosing. The actual sampling timepoint and dosing time shall be accuratelyAttorney Docket No. 055920-814001WOrecorded.

[0247] If samples cannot be taken within the specified time window, every effort should be made to take a sample as soon as possible. Deviations from the sampling windows must be noted in the source documents. All samples should be collected using the time point labels, even if they are outside the suggested time window. Actual sampling times must be recorded. Any missed PK sample collections must be noted in the source documents.

[0248] Plasma concentration analyses for xanom eline and trospium are performed by validated bioanalytical method(s). Placebo PK samples will not be analyzed.

[0249] Bioanalytical samples designated for assessment (eg, PK, biomarker) from the same collection time point are used interchangeably for analyses, if required (including, but not limited to, insufficient volume for complement assessment to follow-up on suspected related AEs, etc).H. Biomarker AssessmentsBiomarkers: Germline Genetics

[0250] Blood samples for DNA isolation are collected from all participants. Alternatively, the DNA collection is presented to participants as an optional collection.

[0251] The DNA samples are stored in a secure storage space with adequate measures to protect confidentiality. The samples may be retained for up to 20 years beyond the end of the study to understand genetic mechanisms of response and / or the disease / condition under study and related conditions.

[0252] The blood or DNA samples are used to determine among other things the presence or absence of single nucleotide polymorphism variants in genes related to cholinergic mechanisms, and any association between genetic biomarkers and the efficacy and tolerability of KarXT in participants with mania or mania with mixed features associated with BP-1.Other Biomarkers

[0253] The following samples for biomarker research are collected from all participants in this study on Day 1 and Day 22 of the study: Plasma biomarkers of inflammation and neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Biomarker samples are stored in a storage facility.

[0254] Any change from baseline in inflammatory biomarkers or BDNF level at for example Week 3 is evaluated for an effect of KarXT on biomarkers.Attorney Docket No. 055920-814001WODigital Biomarkers

[0255] A digital component of the study is performed using a compatible personal phone (Android or iOS) and a wrist-wearable device that features multiple sensors and analytics capacity to quantify a participant’s physiological parameters. The parameters collected using the wrist-wearable device include, but are not limited to, pulse rate (PR), pulse rate variability (PRV), peripheral skin temperature, electrodermal activity (EDA), and activity associated with movement during sleep.

[0256] Baseline values are collected on Day 1 visit. The device is worn continuously on the dominant arm, including during sleep for the 3 -week treatment period and during the 2-week follow-up if applicable, except during the approximately 90-minute charging period each day.

[0257] Any change in one or more of the digital biomarkers is evaluated for effect of KarXT on autonomic measures as well as sleep at for example Week 3.I. Patient Reported Outcomes

[0258] Patient-reported outcomes (PROs) questionnaires are studied. Such data provide an understanding of the impact of treatment directly from the participant’s perspective and offer insights into participant experience that may not be captured through physician reporting. Improving health-related quality of life (HRQoL) is an outcome of importance for individuals with bipolar disorder and therefore is considered when evaluating the efficacy of a new treatment. Additionally, generic HRQoL measures provide data needed for calculating utility values to inform health economic models.

[0259] The PROs to be administered include the Brief Quality of Life in Bipolar Disorder (Brief QoL.BD) Questionnaire, the EQ-5D-5L, and the Patient Global Impression of Severity (PGI-S) items. The questionnaires are provided to each participant to complete at baseline and subsequent study visits. Any change in Brief Qol. BD, EQ-5D-5L, or PGI-S is evaluated for any effect of KarXT at for example Week 3.Brief QoL.BD

[0260] The Brief Qol.BD is used as a condition-specific measure of health-related quality of life encompassing concepts that are most relevant to patients with bipolar disorder. It includes 12 items measuring domains of physical health, sleep, well-being, concentration, leisure, social relationships, spirituality, finances, household management, self-esteem, independence, and identity. Items are rated on a 5-level: 1 (“strongly disagree”), 2 (“disagree”), 3 (“neutral”), 4 (“agree”), 5 (“strongly agree”). Scores range from 12-60, and higher scores are evidence of aAttorney Docket No. 055920-814001WOhigher quality of life. The recall is the past 7 days.EQ-5D-5L

[0261] The EQ-5D-5L is a generic, self-reported preference-based measure of health outcome that is applicable to a wide range of health conditions and treatments. The EQ-5D-5L consists of a descriptive system scale and a visual analog scale (VAS). The descriptive system includes 5 items measuring functioning and well-being across 5 dimensions: mobility, self-care, pain / discomfort, usual activities, and anxiety / depression. Each of these dimensions comprise 5 levels of severity: 1 = “no problems,” 2 = “slight problems,” 3 = “moderate problems,” 4 = “severe problems,” and 5 = “unable to do / extreme problems.” A unique EQ-5D-5L health state (ie, health state preference) is defined by combining one level or response option from each of the 5 dimensions. Responses to the 5 items are then converted to a weighted health state index (utility score) by either cross-walking to country-specific EQ-5D-3L value sets or based on values derived from country specific general population samples directly for the EQ-5D-5L (ie, country specific value sets). The EQ- VAS records the respondent’s self-rated current health status on a vertical, 0 to 100 scale, where 100 = “best imaginable health state” and 0 = “worst imaginable health state.” This information can be used as a quantitative measure of health outcome as judged by the individual respondents.Patient Global Impression of Severity (PGI-S) Items

[0262] The PGI-S is a single patient-reported item that asks participants to rate the overall severity of their symptoms over the past 7 days. It reads as “Please choose the response that best describes the overall severity of your ‘X’ symptoms over the past 7 days.” Responses will be captured on a 5-point categorical rating scale (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe). A PGI-S is asked separately for “mania” symptoms and “depression” symptoms.Example 2: Phase 3 Study to Evaluate the Long-Term Safety and Efficacy of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder

[0263] De novo patients and patients from the Phase 3 study in Example 1 can enroll the Phase 3, open-label study, which is conducted to evaluate the long-term safety and efficacy of xanomeline administered in combination with trospium for the treatment of manic episodes in subjects with bipolar disorder.Attorney Docket No. 055920-814001WOStudy Objectives and Rationale for Endpoints

[0264] A primary objective is to determine the long-term safety and tolerability of KarXT in the treatment of patients with mania or mania with mixed features in participants with BP-1. Primary endpoints are measured by occurrence of treatment emergent adverse event (TEAE).

[0265] Secondary objective includes determining long-term safety and tolerability of KarXT in the treatment of patients with mania or mania with mixed features in participants with BP-1. Secondary endpoints are measured by occurrence of AESI, S AE, TEAE leading to treatment discontinuation during treatment period. Other secondary endpoints include change from baseline in Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and International Prostate Symptom Score (IPSS) (males > 45 years of age only) during the treatment period.

[0266] Exploratory endpoints include evaluating the long-term efficacy of KarXT in the treatment of participants with mania or mania with mixed features associated with BP-I, and the health status of the participants. Exploratory endpoints include changes from baseline in YMRS, CGI-BP as it relates specifically to mania or mania with mixed features, MADRS Total score, BAC scores (4 of 7 sub-tests), the brief QoL.BD, EQ-5D-5L, and / or PGI-S during the treatment period.

[0267] Other exploratory objectives include to evaluate the PK KarXT in participants with mania or mania with mixed features associated with BP-I. This exploratory endpoint is assessed by estimating through a modeling approach utilizing existing KarXT population PK model.Study Design

[0268] This study is a 52-week, open-label extension (OLE) treatment period for rollover participants from the Phase 3 parent monotherapy studies described in Example 1, and de novo participants with mania or mania with mixed features in BP-I. Participants who were randomized to either KarXT or placebo in Example 1 and completed the respective treatment periods, as well as de novo participants, are eligible for enrollment in the present study. The OLE ends with a two-week safety follow-up period. The maximum study duration for rollover participants is 54 weeks (52-week treatment period and 2-week safety follow-up period), and 56 weeks for de novo participants (2-week Screening period, 52-week treatment period, and 2-week safety follow-up period).

[0269] All participants undergo titration of open-label KarXT to maintain the blind from the parent study. De novo participants receive monotherapy KarXT and follow the titration scheme of Example 1.Attorney Docket No. 055920-814001WO

[0270] The present study design includes flexible dosing (FIG. 2). Female and male participants aged 18-65 years old (at the time of consent in the Example 1 study for rollover participants or the present study for de novo participants) with a diagnosis of BP-I, defined by the Diagnostic and Statistical Manual 5 (DSM-5-TR) are enrolled. The study includes up to a 2-week Screening period (for de novo participants), a 52-week open-label outpatient Treatment Period, and a single Safety Follow-up (SFU) visit 2 weeks following end of treatment and / or early termination (EOTZET). First dose of study drug for participants rolling over from Example 1 will be the EOT visit of the parent study / Day 1 of the present study. First dose of study drug for de novo participants will be the morning of Day 1. The maximum duration of participation, for de novo participants, is 56 weeks (including Screening), and 54 weeks for rollover participants. The open-label treatment period includes a two-week titration from 50 / 20 mg twice daily (BID) for 7 days, 100 / 20 mg BID from Days 8-14, and depending on tolerability discretion on Day 15, to 125 / 30 mg BID KarXT. Participants who remain on the 100 / 20 mg BID dose also have the option to decrease to 75 / 20 mg BID starting on Day 15. Participants who do not tolerate the 125 / 30 mg BID dose may have their dose decreased as per the monotherapy study. Participants may have their dose adjusted up or down per tolerability.A. Inclusion and Exclusion Criteria for Study Participants

[0271] Approximately 300 participants are enrolled.

[0272] Key inclusion criteria for participants include:• Participant must be 18 to 65 years of age, inclusive, at the time of signing the informed consent form.• Individuals have a primary diagnosis of Bipolar-I disorder established by a comprehensive psychiatric evaluation based on the DSM-5-TR (Diagnostic and Statistical Manual of Mental Disorders (5th Edition, Text Revision)) criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI, v7.0.2).• Young Mania Rating Scale (YMRS) score of > 14 at Screening and at baseline.• CGI-BP score of > 3 at Screening and at baseline.• Body mass index > 18 and < 40 kg / m2• Participant is able to wash out psychotropic medications in up to 14 days (> 1 day, maximum of 14 days) before first dose.• The individual is able to comprehend and satisfactorily comply with protocol requirements per investigator judgment.Attorney Docket No. 055920-814001WO

[0273] Key exclusion criteria for patients rolling over from Example 1 include:• Discontinuation from any KarXT parent studies.• If, in the opinion of the investigator (and / or Sponsor), participant is unsuitable for enrollment in the study or the participant has any finding that, in the view of the investigator (and / or Sponsor), may compromise the safety of the participant or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements.• Risk for suicidal behavior at baseline as determined by the Investigator’s clinical assessment, and / or C-SSRS as confirmed by the following:a. Answer “Yes” on items 4 or 5 (C-SSRS - ideation) since last visit b. Answer “Yes” to any of the 5 items (C-SSRS behavior) since last visit c. Suicide attempt during the parent study.• Risk of violent or destructive behavior• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, medical history, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population.• Anticipated use of lorazepam greater than 3 mg daily for more than 3 times a week during this study.• Blood pressure of > 160 / 100 mmHg (average of triplicate seated measures) at Screening • Heart rate of > 110 bpm (average of triplicate seated measures) at Screening.

[0274] Key exclusion criteria for de novo patients include:• Discontinuation from any KarXT parent studies.• Primary diagnosis of BP-I where present mania is first manic episode.• Primary diagnosis of BP-I with rapid cycling (ie, > 4 distinct mood episodes in one year).• Any primary DSM-5-TR disorder other than BP-I with mania or mania with mixed features within 12 months before Screening (ie, primary focus of treatment, confirmed using MINI version 7.0.2 at Screening) including BP-I with depression, (previous 3 months only), BP-II disorder, major depressive disorder, and primary psychotic disorder, with the exception of mild anxiety disorders.• Current manic episode requiring hospitalization.• A DSM-5-TR diagnosis of moderate to severe substance use disorder (except tobacco use disorder) within 12 months before Screening (confirmed using MINI version 7.0.2 at Screening), or current use as determined by urine toxicology screen or alcohol test.a. Participants who test positive for cannabis at Screening may be permitted to enroll in consultation with the Medical Monitor if the participant’s pattern ofAttorney Docket No. 055920-814001WOuse is not indica-tive of a substance use disorder.• Risk for suicidal behavior at Screening as determined by the Investigator’s clinical assessment, and / or C-SSRS as confirmed by the following:a. Answer “Yes” on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within 6 months of Screening or between Screening and baseline or, b. Answer “Yes” to any of the 5 items (C-SSRS behavior) with an episode occurring within 12 months of Screening or between Screening and baseline.• Currently receiving oral psychoactive drugs that cannot be safely discontinued in the 14 days of Screening prior to first dose, or whose half-life is greater than 14 days. For participants receiving monthly long-acting injectables (LAIs), the last injection cannot be less than five weeks before the first dose. Participants on LAIs with a two-month frequency cannot have had their last injection less than 10 weeks before the first dose of study treatment. Participants on LAIs with longer frequency periods will be excluded.• Lifetime history of any clozapine use.• Had a separate psychiatric hospitalization(s), unrelated to the current manic episode, within 90 days before Screening.• YMRS total score < 14 at baseline or > 20% reduction in YMRS from Screening to baseline.• If participant is unsuitable for enrollment in the study, or the participant has any finding that may compromise the safety of the participant or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements.• History or present illness suggestive of uncontrolled hyperthyroidism.• History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months.• History or high risk of urinary retention, gastric retention, or untreated narrow-angle glaucoma.• History or presence of clinically significant cardiovascular (eg, untreated or unstable hypertension, clinically significant tachycardia), pulmonary, renal, hematologic, gastrointestinal (eg, obstructive disorders [including conditions that may decrease GI motility, such as ulcerative colitis, intestinal atony, and myasthenia gravis], endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that would jeopardize the safety of the participant or the validity of the study results.• Participants with cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and / or active hepatic viral infections based on the liver function test results. Note: Participants withAttorney Docket No. 055920-814001WOany grade of hepatic impairment (Child-Pugh A or higher) are excluded.• Active biliary disease (eg, symptomatic gallstones). Participants with other biliary histories are eligible and should be discussed with the Medical Monitor.• Participants are excluded from the study if any of the following criteria apply:a. History of bladder stonesb. History of recurrent urinary tract infectionsc. Serum prostate-specific antigen > 10 ng / mL at Screeningd. For male participants > 45 years of age, IPSS score of 5 (ie, “almost always”) on items 1, 3, 5, or 6.e. For male participants > 45 years of age, an IPSS score > 9 for the sum of items 1, 3, 5, and 6.• History of ischemic stroke within 12 months prior to Screening or any evidence of hemorrhagic stroke.• History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, unstable thyroid function, or unexplained syncope, delirium, cognitive disorders (eg, mild cognitive impairment and dementias).• History or presence of any of the following:a. New York Heart Association Class II or greater heart failureb. Grade 2 or greater angina pectoris (as measured by Canadian Cardiovascular Society [CCS] Grading)c. Sustained ventricular tachycardiad. Ventricular fibrillatione. Torsade de pointesf. Implantable cardiac defibrillator• Myocardial infarction within 6 months prior to Screening.• Risk of violent or destructive behavior.• Donation of blood to a blood bank or in a clinical study (except a Screening visit) within 4 weeks prior to the first dose of study drug (within 2 weeks for plasma only) and until at least 90 days after the end of the study.• Blood transfusion within 4 weeks prior to the first dose of study drug.• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, medical history, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population.• Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, hepatitis B coreAttorney Docket No. 055920-814001WOantibody, or human immunodeficiency virus HIV-1 and HIV-2 antibody.• Elevations in hepatic transaminases at Screening > 2* ULN for ALT and AST and / or bilirubin > 1.5 x ULN, unless in the context of Gilbert’s syndrome.• Serum creatinine or blood urea nitrogen > ULN, at Screening, or eGFR at Screening < 60 mL / min.• Blood pressure of > 160 / 100 mmHg (average of triplicate seated measures) at Screening.• Heart rate of > 110 bpm (average of triplicate seated measures) at Screening.• History of any significant drug allergy (such as anaphylaxis).• History of allergy / hypersensitivity to any component (including excipients) of the study intervention or related compounds.Study Population Rationale

[0275] Female and male participants aged 18-65 years old with a diagnosis of BP-I mania or mania with mixed features, defined by the DSM-5-TR are enrolled. Mania and mixed features last a minimum of one week and include at least 3 symptoms associated with mania. Participants who have mixed features meet criteria for mania and have at least 3 symptoms associated with major depression as outlined in the DSM-5 TR. Eligibility review is performed prior to enrollment for de novo participants. Eligibility verification benefits participants as it minimizes exposure to study intervention in participants who may not meet eligibility criteria. Manic episodes may occur spontaneously when individuals are under stress or in the context of non-adherence to medication. Non-adherence is common in BP-I due to multiple factors including drug intolerance, to which patients with BP-I are particularly sensitive to during maintenance treatment. Manic episodes can result in high-risk behavior, impair patient functioning, put tremendous strain on family and friends, and often result in costly and disruptive hospitalizations.

[0276] Manic episodes may occur spontaneously when individuals are under stress or in the context of non-adherence to medication. Non-adherence is common in BP-I due to multiple factors, including drug intolerance, to which patients with BP-I are particularly sensitive, during maintenance treatment. Manic episodes can result in high-risk behavior, impair patient functioning, put tremendous strain on family and friends, and often result in costly and disruptive hospitalizations.

[0277] Effective treatments that are more tolerable and lack the risk of EPS, hyperprolactinemia, weight gain, and metabolic disorder have the potential to address the needs of patients and dramatically affect their lives as well as those of their families.Attorney Docket No. 055920-814001WOB. Screening Period

[0278] Specific sites that are not enrolling participants into the parent study may be allowed to enroll de novo participants into the open label study. Eligibility is reviewed for each potential de novo participant at the end of the Screening Period and prior to the Day 1 visit. Eligibility review includes review of ECG’s, labs, psychiatric history, medical history, concomitant medications and scales to ensure that participants meet protocol entry criteria. Once consented, these participants who have not participated in Example 1, enters the Screening Period (1 to 14 days) for assessment of study eligibility. This Screening Period is identical to the Screening period from the monotherapy trials. During Screening, each participant provides medical and psychiatric history. The Mini International Neuropsychiatric Interview (MINI; to confirm diagnosis), YMRS, CGI-BP, Columbia-Suicide Severity Rating Scale (C-SSRS), BAC, and The International Prostate Symptom Score (IPSS, males > 45 years of age only) assessments are performed, as well as electrocardiogram (ECG), clinical laboratory assessments, vital signs, and physical examination. Any prohibited concomitant medications are tapered and discontinued prior to the first dose.C. Open-Label Treatment Period

[0279] After Screening / completion of Example 1 study, eligible participants receive openlabel KarXT and treatment in an outpatient clinic. Participants rolling over from Example 1 may have up to 3 days as inpatients if needed.

[0280] Each participant is titrated to the maximum dose of IMP suitable for the participant based on tolerability, up to 125 / 30 mg BID. Titration for rollover and de novo participants takes two weeks. Participants may remain on 100 / 20 mg BID, or may increase dose to 125 / 30 mg BID on Day 15. Participants who do not tolerate the 125 / 30 mg BID dose may have their dose decreased to 100 / 20 mg BID. Participants who do not tolerate the 100 / 20 mg BID dose may have their dose decreased to 75 / 20 mg BID.

[0281] Participants may have their dose adjusted up or down in a step-wise fashion per tolerability and efficacy from 75 / 20 mg to 125 / 30 mg BID. If a participant’s dose is decreased due to poor tolerability / AE’s, approval is required for subsequent dose escalation. Participants who are unable to tolerate 75 / 20 mg BID have to discontinue participation.

[0282] The study interventions administered in this study are outlined in Tables 3 and 4 below. The study interventions should be administered at the same time daily, in the morning and evening.Attorney Docket No. 055920-814001WOTable 3: Study Intervention(s) AdministeredType / Unit DoseIMP / Non- Intervention Strength(s)IMP / AxMP Packaging and Name / Xanomeline SourcingBlinded or Labeling Dose (mg) / trospiumOpen labelFormulation chloride (mg)50 mg / 20 mg or Blister pack Drug / xanomeline / 75 mg / 20 mg or (wallet). Each trospium chloride IMP- open Provided container will be 100 mg / 20 mg or / Capsule label centrally labeled as required 125 mg / 30 mg or per country Placebo requirements.Table 4: Study ArmsIntervention Description / Arm Title / Dosage Levels Route of Administration Arm UseXanomeline (mg) / trospium chloride (mg)50 mg / 20 mg orKarXT 100 mg / 20 mg or Oral125 mg / 30 mgPlacebo OralD. Adverse Events

[0283] An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition occurring in a clinical investigation participant after signing of informed consent, whether or not considered related to the study intervention, and therefore can be any unfavorable and unintended sign (such as an abnormal laboratory test result), symptom, or disease temporally associated with the study intervention. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death or is life threatening. Adverse events of special interest (AESI) hepatic enzyme elevation, biliary disorders, urinary tract infection, and urinary retention.

[0284] The investigator or a qualified designee are responsible for detecting, documenting and reporting Adverse Events (AEs) reported by the participant or by a caregiver promptly and not exceeding 24h of awareness of the event. All AEs and SAEs are collected from the time of signing the informed consent form, including those thought to be associated with protocol- specified procedures and until 28 days following discontinuation of dosing or the last scheduled visit. Investigators are not obligated to actively seek information on AEs or SAEs in former study participants, however, the investigator must report any SAE, including a death, thatAttorney Docket No. 055920-814001WOoccurs any time after a participant is discharged from the study and that is reasonably believed to be related to a study intervention or protocol-specified procedure.

[0285] Potential symptoms that may qualify for an adverse effect include:• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results from other safety assessments (eg, electrocardiograms, radiological scans, vital sign measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator. Note that abnormal laboratory test results or other safety assessment findings should only be reported as AEs if the final diagnosis is not available. Once the final diagnosis is known, the reported term should be updated to be the diagnosis.• Exacerbation of a chronic or intermittent pre-existing condition, including either an increase in frequency and / or intensity of the condition.• New conditions detected or diagnosed after study intervention administration, even though the condition may have been present before the start of the study.• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication. Overdose, as a verbatim term should not be reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae and should specify “intentional overdose” as the verbatim term.• Any untoward medical occurrence resulting in death or is life-threatening.Potential Drug Induced Liver Injury

[0286] Wherever possible, timely confirmation of initial liver-related laboratory test result abnormalities can occur prior to the reporting of a potential drug-induced liver injury event. All occurrences of potential drug-induced liver injury meeting the defined criteria can be reported.

[0287] Potential drug-induced liver injury can be defined as:• ALT or AST elevation > 3* ULN; and• Total bilirubin > 2* ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase); and• No other immediately apparent possible causes of aminotransferase elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.Attorney Docket No. 055920-814001WOLiver Enzyme Elevation

[0288] Liver enzyme elevations can be defined as serum ALT or AST > 3 x ULN and at least 2x the baseline level. Such an occurrence can be followed by repeat testing within 48 to 72 hours of all 4 of the standard serum measures (ALT, AST, alkaline phosphatase, and total bilirubin) to confirm the abnormalities and to determine if they are increasing or decreasing. An inquiry can be made about symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash).

[0289] Management for liver enzyme elevations should include the following:• Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of retesting can decrease to once per week or less if abnormalities stabilize and the IMP has been discontinued, and the participant is asymptomatic.• Obtain additional tests to evaluate liver function, as appropriate (eg, international normalized ratio, direct bilirubin)• Obtain abdominal ultrasound when liver enzymes rise substantially (ie, ALT or AST > 5 x ULN and / or ALP > 2 x ULN)

[0290] Treatment can be held or discontinued if one of the following criteria are met, unless there is an obvious non-drug induced liver injury explanation:• ALT or AST > 8 x ULN• ALT or AST > 5 x ULN for more than 2 weeks• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or international normalized ratio > 1.5)• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (> 5%)Urinary Symptoms, Urinary Retention, Urinary Tract Infection or Renal Impairment

[0291] The following urinary symptoms are considered adverse events of special interest (AESI): urinary retention, frequent urination, difficulty voiding, difficulty urinating, reduced urinary flow, pain with urination, and urinary incontinence.

[0292] An AESI of urinary retention is defined as inability to void, and will include symptoms of bladder outlet obstruction, including urinary hesitation and urinary straining.

[0293] These urinary AEs can prompt consideration of reducing the dose of KarXT, discontinuing KarXT, and / or referring patients for urologic evaluation as clinically indicated.

[0294] Occurrence of a urinary tract infection should be recorded as an AESI, and culture results can be captured.Attorney Docket No. 055920-814001WO

[0295] Renal impairment can be caused by urinary retention or urinary tract infections. Renal impairment should be recorded as an AESI and can also prompt consideration of reducing the dose of KarXT, discontinuing KarXT, and / or referring patients for urology / nephrology evaluation as clinically indicated.E. End of Study

[0296] The start of the study is defined as the first participant’s first visit.

[0297] The primary completion date is defined as the date on which the last data point is collected for the study’s last primary endpoint (outcome). For this study, the last primary outcome for the primary endpoints is defined as end of Week 54 / Safety Follow Up Period. Participants are considered to have completed the study if they have completed all periods of the study, including end of week 54 / safety follow up period.F. Efficacy Assessment

[0298] To evaluate the efficacy of KarXT compared with placebo in the treatment of participants with acute mania or mania with mixed features associated with BP-I, a number of clinical scores are used, including one or more YMRS, CGI-BP, BAC, and MADRS.

[0299] Each of YMRS, CGI-BP, BAC, and MADRS is assessed as described in Example 1.

[0300] The overall incidence of AE, SAEs, AEs leading to discontinuation, severe AEs, AEs leading to death, and AESIs is presented by treatment group. Pharmacokinetic data is used for summary statistics and statistical analyses of PK parameters. Participant matrix concentrationtime data is listed and summarized. Other exploratory endpoints and safety assessment analyses are summarized using descriptive statistics by treatment group.G. Pharmacokinetic Assessment

[0301] Blood samples are collected on Days 1, 8, 15, 22, 112, 196, 280, 364 (all days ±2 days) for bioanalysis of xanomeline and trospium concentrations in plasma. All available PK concentrations of xanomeline and trospium are reported.

[0302] Other analyses are conducted by combining PK data from this study with PK data from other studies in the clinical development program and reported separately. PK sample collection is performed after clinical assessment when feasible. Actual sample collection time and the dose administration of the medicinal product is accurately recorded.

[0303] The following time windows serve as a guideline for PK sample collections:• All pre-dose samples are taken within 60 minutes prior to dosing. If it is known that aAttorney Docket No. 055920-814001WOdose will be delayed, then the pre-dose sample should be collected just prior to the delayed dose. However, if a pre-dose sample is collected but the dose is delayed, an additional pre-dose sample should not be collected.• All post-dose samples for xanomeline and trospium should be taken within 1 to 8 hours post-dosing. The actual sampling timepoint and dosing time shall be accurately recorded.

[0304] If samples cannot be taken within the specified time window, every effort should be made to take a sample as soon as possible. Deviations from the sampling windows must be noted in the source documents. All samples should be collected using the time point labels, even if they are outside the suggested time window. Actual sampling times must be recorded. Any missed PK sample collections must be noted in the source documents.

[0305] Plasma concentration analyses for xanomeline and trospium are performed by validated bioanalytical method(s). Placebo PK samples will not be analyzed.

[0306] Bioanalytical samples designated for assessment (eg, PK, biomarker) from the same collection time point are used interchangeably for analyses, if required (including, but not limited to, insufficient volume for complement assessment to follow-up on suspected related AEs, etc).H. Biomarker AssessmentsI. Patient Reported Outcomes

[0307] Patient-reported outcomes (PROs) questionnaires are studied. Such data provide an understanding of the impact of treatment directly from the participant’s perspective and offer insights into participant experience that may not be captured through physician reporting. Patient reported outcomes are collected and assessed as described in Example 1.

[0308] The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.OTHER EMBODIMENTS

[0309] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each featureAttorney Docket No. 055920-814001WOdisclosed is only an example of a generic series of equivalent or similar features.

[0310] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.EQUIVALENTS

[0311] While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0312] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0313] All references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may encompass the entirety of the document.

[0314] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0315] The phrase “and / or,” as used herein in the specification and in the claims, should beAttorney Docket No. 055920-814001WOunderstood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0316] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0317] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including moreAttorney Docket No. 055920-814001WOthan one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0318] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

Claims

Attorney Docket No. 055920-814001WOWHAT IS CLAIMED IS:

1. A method of alleviating a manic episode in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising xanomeline tartrate and trospium chloride, wherein the composition is administered to the subject at a daily dose equivalent to about 100 mg to about 300 mg xanomeline free base and equivalent to about 40 mg to about 75 mg trospium chloride.

2. The method of claim 1, wherein the manic episode is related to a bipolar disorder, which optionally is bipolar I disorder.

3. The method of claim 1 or 2, wherein the composition is administered to the subject twice daily orally.

4. The method of any one of claims 1 to 3, wherein the composition is administered to the subject at a daily dosage equivalent to about 200 mg xanomeline free base and equivalent to about 40 mg of trospium chloride; or at a daily dosage of about 250 mg xanomeline and about 60 mg of trospium chloride.

5. The method of any one of claims 1 to 4, wherein the method comprises:(i) administering to the subject the composition at a first total daily dose equivalent to about 100 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride for a first period; and(ii) administering to the subject, after the first period, the composition at a second daily dose equivalent to about 200 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride for a second period.

6. The method of claim 5, wherein the method further comprises reducing the daily dose, after the second period, to an amount equivalent to about 150 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride in the subject, who is not tolerating the daily dose in the second period.

7. The method of claim 5, wherein the method further comprises(iii) administering to the subject, after the second period, the composition at a third daily dose equivalent to about 250 mg of xanomeline free base and equivalent to about 60 mg of trospium chloride for a third period, and optionally maintaining the third daily dose after the third period when the subject is tolerating the third daily dose.Attorney Docket No. 055920-814001WO8. The method of claim 6, wherein the method further comprises reducing the daily dose, after the third period, (a) to an amount equivalent to about 200 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride in the subject, or (b) to an amount equivalent to about 150 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride, when the subject is not tolerating the daily dose in the third period.

9. The method of any one of claims 6 to 8, wherein the method further comprises terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg of xanomeline free base and equivalent to about 40 mg of trospium chloride.

10. The method of any one of claims 5 to 9, wherein the first period is about 2 days to about 9 days and / or wherein the second period is about 3 days to about 9 days.

11. The method of any one of claims 5 to 10, wherein the third period is at least 2 weeks, optionally wherein the third total daily dose is administered for 2 weeks.

12. The method of any one of claims 1 to 11, wherein the composition has a unit dosage strength equivalent to about 50 mg to about 125 mg of xanomeline free base and equivalent to about 20 mg to about 30 mg of trospium chloride.

13. The method of claim 12, wherein the composition has:(a) a unit dosage strength equivalent to about 50 mg xanomeline free base and about 20 mg trospium chloride;(b) a unit dosage strength equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride;(c) a unit dosage strength equivalent to about 100 mg xanomeline free base and about 20 mg trospium chloride; or(d) a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg of trospium chloride.

14. The method of any one of claims 1 to 13, wherein the composition comprises a plurality of xanomeline beads, and a plurality of trospium beads, the xanomeline beads comprising the xanomeline tartrate and the trospium beads comprising the trospium chloride.

15. The method of claim 14, wherein the xanomeline beads and / or the trospium beads have a size of about 0.425 mm to about 1.18 mm; optionally about 0.6 mm to about 0.85 mm.Attorney Docket No. 055920-814001WO16. The method of claim 14 or claim 15, wherein, the plurality of xanomeline beads and / or the plurality of trospium beads have a dissolution rate of more than about 95% within about the first 45 minutes following entry of the composition into an aqueous solution; optionally wherein the dissolution rate is more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.

17. The method of any one of claims 14 to 16, wherein the xanomeline beads comprise (a) about 30 wt.% to about 80 wt.% xanomeline tartrate, optionally about 66 wt.% xanomeline tartrate;(b) about 15 wt.% to about 65 wt.% microcrystalline cellulose, optionally about 33.5 wt.% microcrystalline cellulose; and(c) about 0 wt.% to about 2 wt.% talc; optionally about 0.5 wt.% talc.

18. The method of any one of claims 11 to 14, wherein the trospium beads comprise (a) about 8 wt.% to about 35 wt.% trospium chloride; optionally about 17.7 wt.% trospium chloride;(b) about 25 wt.% to about 80 wt.% microcrystalline cellulose; optionally about 46.8 wt.% microcrystalline cellulose;(c) about 15 wt.% to about 70 wt.% lactose monohydrate; optionally about 35 wt.% lactose monohydrate; and(d) about 0 wt.% to about 2 wt.% talc; optionally about 0.5 wt.% talc.

19. The method of any one of claims 14 to 18, wherein the composition is comprised in a capsule, the capsule containing the plurality of xanomeline beads and the plurality of trospium beads.

20. The method of any one of claims 1 to 19, wherein the composition further comprises ascorbic acid, butylated hydroxytoluene, or a combination thereof.

21. The method of claim 20, wherein the composition comprises about 0.2 wt.% to about 1 wt.% ascorbic acid, optionally about 0.5 wt.% ascorbic acid; and / orthe composition comprises about 0.01 wt.% to about 0.1 wt.% butylated hydroxytoluene; optionally about 0.05 wt.% butylated hydroxytoluene.

22. The method of claim 1, comprising:(a) administering to the subject the composition set forth in any one of claims 14 to 21 to the subject two times a day orally for about two days, wherein the compositionAttorney Docket No. 055920-814001WOcomprises a unit dosage strength equivalent to about 50 mg xanomeline free base and a unit dose strength equivalent to about 20 mg trospium chloride; and(b) administering to the subject, after step (a), the composition two times a day orally for about five days; wherein the composition comprises a unit dosage strength equivalent to about 100 mg xanomeline free base and a unit dose strength equivalent to about 20 mg trospium chloride.

23. The method of claim 22, wherein when the subject is not tolerating the doses administered in step (b), the method further comprises reducing the doses by administering to the subject the composition comprising a unit dosage strength equivalent to about 75 mg xanomeline free base and about 20 mg trospium chloride two times per day orally.

24. The method of claim 22, wherein when the subject is tolerating the doses administered in step (b), the method further comprises (c) administering to the subject the composition comprising a unit dosage strength equivalent to about 125 mg xanomeline free base and about 30 mg trospium chloride two times per day orally.

25. The method of claim 24, wherein when the subject is not tolerating the doses administered in step (c), the method further comprises reducing the doses by administering to the subject (a) the composition comprising a unit dosage strength equivalent to about 100 mg xanomeline and about 20 mg trospium chloride two times per day orally, or (b) the composition comprising a unit dosage strength equivalent to about 75 mg xanomeline and about 20 mg trospium chloride two times per day orally.

26. The method of any one of claims 23 to 25, wherein the method further comprises terminating the treatment when the subject is not tolerating the daily dose equivalent to about 150 mg xanomeline and equivalent to about 40 mg trospium chloride.

27. The method of any one of claims 1 to 26, wherein the subject is a human patient at least 18 years old, optionally between 18 and 65 years old.

28. The method of any one of claims 1 to 27, wherein prior to the administration of the composition, the subject has or is:(i) a Young Mania Rating Scale (YMRS) score of at least 14, optionally at least 20;(ii) a Clinic Global Impressions-Bipolar (CGI-BP) score of at least 3, optionally at least 4; and / orAttorney Docket No. 055920-814001WO(iii) diagnosed with bipolar I disorder; which optionally is not with rapid cycling,optionally the subject further has or is(a) experienced an acute episode or relapse of mania with mixed features,(b) a need for hospitalization for the acute exacerbation or relapse of mania.

29. The method of any one of claims 1 to 28, wherein the subject is free of one or more of the following:(i) diagnosis of mental disorders other than bipolar I; optionally diagnosis of depression, bipolar-II disorder, major depressive disorder, primary psychotic disorder;(ii) diagnosis of moderate or severe substance use disorder within 12 months before the administering, optionally the moderate or severe substance use disorder does not include tobacco use disorder;(iii) substance use disorder concurrent with the administering, as measured by urine toxicology screen or alcohol test;(iv) at risk of suicidal behaviour as determined by clinical assessment within 6 months to 12 months of the administering;(v) have a history of or is at high risk of irritable bowel syndrome or severe constipation requiring treatment; and(vi) have a history or is at high risk of urinary retention, gastric retention or untreated narrow-angle glaucoma.

30. The method of any one of claims 1 to 29, further comprising assessing treatment efficacy, which optionally comprises monitoring(a) decrease of CGI-BP score, optionally by at least 1 or at least 4,(b) decrease of YMRS score, optionally by at least 50%,(c) change in Brief Assessment of Cognition (BAC) from a baseline assessment of BAC prior to the administering,(d) decrease in Montgomery-Asberg Depression Rating Scale (MADRS) total score from a baseline assessment of MADRS prior to the administering, optionally by about 20% to about 50%,(e) change in a level of inflammatory biomarkers based on a baseline level of the inflammatory biomarkers prior to the administering, optionally the inflammatoryAttorney Docket No. 055920-814001WObiomarkers are selected from TNF-a, IL-2, IL-6, IL- 10, IL- 17, CRP, and combinations thereof,(f) change in a level of brain-derived neurotropic factor (BDNF) based on a baseline level of BDNF prior to the administering,optionally after 3 weeks of the administering of the composition.

31. The method of any one of claims 1 to 30, further comprising monitoring a side effect during and / or after administration of the composition, optionally wherein the side effect comprises(i) urinary retention,(ii) angioedema,(iii) decreased gastric mobility or gastric retention,(iv) narrow angle glaucoma,(v) a heart rate increase, optionally a hearth rate increase of more than 9.8 beats per minute measured as a 24-hour average heart rate,(vi) a change in blood pressure,(vii) change in diastolic blood pressure of more than 1.5 mm Hg, and / or(viii) liver enzyme elevation as measured by serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of at least three times an upper limit normal (ULN) of the subject.

32. The method of claim 31, wherein the method further comprises managing the side effect when occurrence of the side effect is observed.

33. The method of claim 32, wherein managing the side effect comprises decreasing the dose of the composition or terminating the treatment.

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