CA2761068A1 - Novel dosage regimens and methods for treatment, prevention, and/or management of at least one cns disorder - Google Patents

Abstract

Dosage regimens for at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof are disclosed as are kits and methods for treatment and/or prevention of at least one CNS
disorder such as, for example, mixed depression and bipolar disorder, and management of at least one CNS disorder, such as improving quality of life and reversing impairment in learning and memory associated with schizophrenia, comprising administering to a patient a therapeutically or prophylactically effective amount of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof.

Description

, NOVEL DOSAGE REGIMENS AND METHODS FOR TREATMENT, PREVENTION, AND/OR MANAGEMENT OF AT LEAST ONE CNS l/ DISORDER

[0001] Dosage regimens for at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof are disclosed as are kits and methods for treatment and/or prevention of at least one CNS
disorder such as, for example, mixed depression and bipolar disorder, and management of at least one CNS disorder, such as improving quality of life and reversing impairment in learning and memory associated with schizophrenia, comprising administering to a patient a therapeutically or prophylactically effective amount of the at least one compound.

[0002] Lurasidone is a compound exhibiting a pharmacological activity as a psychotropic agent. Lurasidone has a chemical name (3aR,4S,7R,7aS)-2-{(1R,2R)-(1 ,2-benzisoth iazol-3 -y Opiperazin- 1 -ylmethy l]cyclohexy lmethy 1 1 hexahydro-4,7-methano-2H- isoindole- l ,3 -dione], and has the following formula:
qZ-ri 0 H

Hi H N H

L.N =
NI .....s

[0003] Lurasidone is reported to have a high affinity for dopamine D2, serotonin 5-HT1A, 5-HT2A, 5-HT7, and noradrenaline a2c receptors, moderate affinity for 5-HTiA
receptors, and minimal to no affinity for histamine H1 and muscarinic M1 receptors.
Data from several placebo-controlled trials has demonstrated that lurasidone is effective in ameliorating the positive and negative symptoms of schizophrenia. Data from clinical and pre-clinical studies have suggested that lurasidone also demonstrates antidepressant-or anxiolytic-like effects, as well as pro-cognitive effects with potentially-reduced liability for extrapyramidal, weight and metabolic parameters, and other CNS
depressant side effects.

[0004] It has been reported that patients with schizophrenia are at an increased risk of developing metabolic syndrome independent of environmental exposure.
(Hennekens, I

_ CH et al., American Heart Journal (2005). Antipsychotics may significantly increase the cardiometabolic risk schizophrenic patients incur, such as effects on weight and BMI, glucose and insulin levels, hypertension, and total cholesterol and triglycerides.
(Newcomer, JW, Journal of Clin. Psychiatry (2007). Such effects can compromise the effectiveness, such as, for example, the efficacy, safety, and/or tolerability, of antipsychotics. Thus, there is a public health need for novel antipsychotic therapies exhibiting a benign metabolic profile.

[0005] It is also known that antipsychotic therapies may lead to adverse effects such as, for example, cognitive impairment, extrapyramidal side effects, and sedation.
Accordingly, there is an ongoing need to improve the quality of life and well-being of patients treated for schizophrenia and other CNS disorders in addition to reversing impaired cognitive functioning of patients.

[0006] It is also known that response to antipsychotic therapy varies between patients. For example, it is known that there may be a delayed effect in the treatment of patients with a CNS disorder, such as schizophrenia, between the start of antipsychotic therapies and the improvement in psychiatric symptoms. (See e.g., Kinon et al., Neuropsychopharmacology, 35:581-590 (2010)). As a result of the delayed onset of therapy, a waiting period of 4 to 8 weeks may be recommended before switching patients to other antipsychotic therapies if they are not responding to the initial therapy.
(Kinon et al., Schizophrenia Research, 102:230-240 (2008)). However, it has also been shown that response to antipsychotic therapies can rapidly occur in the first 1 to 2 weeks. (Stauffer et al., Psychiatry Research, 187: 42-48 (2011)). Such variations in response can have significant implications in subsequent reduction of psychiatric symptoms.

[0007] Thus, there is a need in the art for determining the relationship between initial response to antipsychotic therapy, for example, treatment with lurasidone, and subsequent response to the therapy in the treatment of CNS disorders such as, for example, mixed depression and bipolar disorder, and also for adjusting dose(s) and dosage intervals in certain patients in view of that determination in order to improve the safety and/or efficacy of treatment.

[0008] Disclosed herein are methods of treating, preventing and/or managing at least one CNS disorder comprising administering to a patient a therapeutically or prophylactically effective amount of at least one compound chosen from lurasidone and

[0009] Also disclosed herein are dosing regimens for treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof.

[0010] FIG. 1 illustrates improvement in QWB-SA score in patients with schizophrenia after 6 weeks of treatment with lurasidone (80 mg and 160 mg) and placebo.

[0011] FIG. 2 illustrates the correlation between QWB-SA scores and other outcome measurements in patients with schizophrenia after 6 weeks of treatment with lurasidone (80 mg and 160 mg) and placebo.

[0012] FIG. 3 illustrates the change in weight, lipids and tolerability parameters after 1 year of treatment with lurasidone (40-120 mg).

[0013] FIG. 4 illustrates the mean change in weight and BMI at 6 weeks after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0014] FIG. 5 illustrates the proportion of patients with clinically significant weight gain or weight loss at 6 weeks after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0015] FIG. 6 illustrates the mean change in weight and BMI at 6 months and months after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0016] FIG. 7 illustrates the median change in total cholesterol and triglycerides at 6 weeks after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0017] FIG. 8 illustrates the median change in total cholesterol and triglycerides at 6 months and 12 months after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0018] FIG. 9 illustrates the median change in glucose and HbA lc at 6 months and 12 months after the initiation of treatment by lurasidone and other currently available antipsychotics.

[0019] FIG. 10 illustrates the comparative receptor binding affinities of lurasidone and other currently available antipsychotics.

[0020] FIG. 11 illustrates the effects of lurasidone on receptor function (D2, 5-HT7, 5-HT' A).

[0021] FIG. 12 illustrates the effects of lurasidone on D2 receptor function in the frontal cortex and striatum.

[0022] In certain embodiments, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof may include lurasdione in free base form, one or more pharmaceutically acceptable salts of lurasidone, one or more pharmaceutically acceptable solvates of lurasidone, one or more pharmaceutically acceptable clathrates of lurasidone, and/or one or more pharmaceutically acceptable stereoisomers of lurasidone. In certain embodiments, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates, and stereoisomers thereof may also include pharmaceutically acceptable salts of any of the foregoing (e.g., pharmaceutically acceptable solvates of lurasidone), pharmaceutically acceptable solvates of any of the foregoing (e.g., pharmaceutically acceptable salts of lurasidone), pharmaceutically acceptable clathrates of any of the foregoing, and/or pharmaceutically acceptable stereoisomers of any of the foregoing.

[0023] In certain embodiments, the "at least one compound" refers to lurasidone which may be in the form, for example, of its free base, a pharmaceutically acceptable salt, a solvate, a clathrate, a stereoisomer and/or a mixture of any of the foregoing forms.
In certain embodiments, the at least one compound is chosen from lurasidone and a pharmaceutically acceptable salt thereof. In certain embodiments, the at least one compound is a pharmaceutically acceptable salt of lurasidone. In certain embodiments, the at least one compound is lurasidone hydrochloride.

[0024] As used herein, unless otherwise specified, the term a "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric, p-toluenesulfonic acid and the like. In one embodiment, suitable acids are chosen from hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid.

= 100251 As used herein, unless otherwise specified, the term "solvate"
means a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is called a hydrate.
[0026] As used herein, unless otherwise specified, the term "stereoisomer"
encompasses all enantiomerically and/or stereomerically pure and enantiomerically and/or stereomerically enriched compounds disclosed herein.
100271 As used herein, unless otherwise indicated, the term "stereomerically pure"
means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A
stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90%
by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound or greater than about 99% by weight of one stereoisomer of the compound and less than about 1%
by weight of the other stereoisomers of the compound.
100281 As used herein, unless otherwise indicated, the term "stereomerically enriched" means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
100291 As used herein, unless otherwise specified, the terms "treat,"
"treating" and "treatment" refer to an action in a patient suffering from at least one CNS
disorder disclosed herein which inhibits, arrests, and/or relieves (retards or slows) the severity of the CNS disorder and/or the symptoms associated therewith.

= CA 02761068 2011-12-07 [0030] As used herein, unless otherwise specified, the terms "prevent,"
"preventing"
and "prevention" refer to treatment with or administration of at least one compound disclosed herein prior to the onset of at least one symptom, for example, in patients at risk of at least one CNS disorder disclosed herein. The term "prevention"
includes the inhibition and/or preclusion of at least one symptom of a particular disorder.
Patients with familial history of a disease in particular are candidates for preventive regimens in some embodiments. In some embodiments, patients with a history of recurring symptoms are candidates for preventive regimens. In this regard, the term "prevention"
may be interchangeable with the term "prophylactic treatment."
[0031] As used herein, unless otherwise specified, the terms "manage,"
"managing"
and "management" refer to preventing or slowing the progression, spread and/or worsening of at least one disorder or of at least one symptom thereof. In some embodiments, the effect(s) of a prophylactic or therapeutic agent may not result in a cure of the at least one disorder.
[0032] As used herein, unless otherwise specified, the term "therapeutically effective amount" is an amount sufficient to provide at least one therapeutic benefit in the treatment or management of at least one CNS disorder disclosed herein or sufficient to delay or minimize at least one symptom associated with at least one CNS
disorder disclosed herein. A therapeutically effective amount of at least one compound means an amount of the at least one compound which, alone or in combination with at least one other therapeutic agent, can provide at least one therapeutic benefit in the treatment or management of at least one CNS disorder disclosed herein. The term "therapeutically effective amount" therefore can encompass an amount that improves overall therapy, an amount that reduces at least one symptom of at least one CNS disorder disclosed herein, an amount that reduces at least one cause of at least one CNS disorder disclosed herein, and/or an amount that enhances the therapeutic efficacy of at least one other therapeutic agent.
[0033] As used herein, unless otherwise specified, a "prophylactically effective amount" of at least one compound is an amount sufficient to inhibit/ reduce at least one symptom of at least one CNS disorder disclosed herein or an amount sufficient to prevent recurrence of at least one CNS disorder disclosed herein. A
prophylactically effective amount of at least one compound means an amount of at least one compound that, alone or in combination with at least one other agent, can provide at least one prophylactic benefit in the inhibition/ reduction of at least one symptom of at least one = CA 02761068 2011-12-07 CNS disorder disclosed herein and/or in the recurrence of at least one CNS
disorder disclosed herein. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis and/or an amount that enhances the prophylactic efficacy of at least one other prophylactic agent.
[0034] As used herein, unless otherwise specified, the term "about," when used in connection with a specific value, means that acceptable deviations from that value are also encompassed. In certain embodiments, the term "about" means that a value higher or lower than the given value by 1%, 3%, 5% 10%, 15%, 20%, 25%, 30%, 35% or 40%
is encompassed.
[0035] The term "predict" generally means to determine or tell in advance.
When used to "predict" the effectiveness of the treatment of at least one CNS
disorder disclosed herein, for example, the term "predict" can mean that the likelihood of the outcome of the treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.
[0036] The term "likelihood" generally refers to an increase in the probability of an event. The term "likelihood" when used in reference to the effectiveness of a patient response generally contemplates an increased probability that the symptoms of a CNS
disorder disclosed herein will be lessened or decreased.
[0037] As used herein, the terms that refer to at least one CNS disorders disclosed herein elsewhere are used herein in a manner consistent with their accepted meanings in the art. See, e.g., Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM IVTm).
[0038] As used herein, unless otherwise indicated, the term "modulator," when used in connection with certain biochemicals or receptors, means an agent that can increase or decrease the level of the biochemicals or the activity of the receptors.
[0039] As used herein, unless otherwise indicated, the term "increase," when referring to level or activity, means that the level or activity can be increased, for example, by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 1,000%, 5,000% or more of the comparative control level.
[0040] As used herein, unless otherwise indicated, the term "decrease," when referring to level or activity, means that the level or activity can be decreased, for example, by about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 1%
or less of the comparative control level.

[0041] The terms "determining", "measuring", "evaluating", "assessing" and "assaying" as used herein, unless otherwise indicated, generally refer to any form of measurement, and include determining if an element is present or not. These terms include both quantitative and/or qualitative determinations. Assessing may be relative or absolute.
[0042] The term "sample" as used herein, unless otherwise indicated, relates to a material or mixture of materials, typically, although not necessarily, in fluid form, containing one or more components of interest.
[0043] "Biological sample" as used herein, unless otherwise indicated, refers to a sample obtained from a biological subject, including sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ. Such samples can be, but are not limited to, organs, tissues, fractions, sera and cells isolated from a mammal (e.g., human). Exemplary biological samples include but are not limited to cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like.
Preferred biological samples include but are not limited to whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.
[0044] After metabolomic profiling of samples obtained from patients who had been treated with at least one compound, the at least one compound being chosen from, for example, lurasidone, a pharmaceutically acceptable salt, solvate, clathrate and stereoisomer thereof, minimal or no metabolic side effects or weight gain were observed. Embodiments disclosed herein are based, in part, on the unexpected discovery that the administration of the at least one may result in improved quality of life and/or may reverse impairment in learning and memory associated with schizophrenia.
[0045] Accordingly, in some embodiments, disclosed herein are methods of treating, preventing and/or managing at least one CNS disorder comprising administering to a patient a therapeutically or prophylactically effective amount of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof.
[0046] Examples of at least one CNS disorder include, but are not limited to, adjunctive therapy in bipolar disorder, adjunctive therapy in depression, adolescent bipolar disorder, adolescent depression, alcohol dependence, Alzheimer's disease, anorexia nervosa, attention deficit disorder, an anxiety disorder including generalized anxiety disorder and social anxiety disorder, bipolar disorder, bipolar maintenance, = borderline personality disorder, childhood schizophrenia, circadian rhythm sleep disorder, cognitive function impairment, cognitive impairment associated with schizophrenia, cognitive remediation therapy, conduct disorder, delirium, depression maintenance, first episode psychosis, Fragile-X Syndrome, mixed depression, monotherapy in bipolar disorder, monotherapy in depression, neuropathic pain, obsessive compulsive disorder, panic disorder, pathological gambling, post-traumatic stress disorder, Prodromal Risk Syndrome, psychosocial function impairment, psychotic depression, quality of life in schizophrenia, bipolar disorder and depression, schizophrenia, negative symptoms associated with schizophrenia, schizophrenia maintenance, schizoaffective disorder, sleep disorder, social functioning impairment, substance abuse, treatment resistant depression, and Tourette's Disorder. In an embodiment, the at least one CNS disorder is Alzheimer's disease, bipolar disorder, mixed depression, schizophrenia, or negative symptoms associated with schizophrenia.
100471 In an embodiment, the at least one CNS disorder is bipolar disorder. As used herein, bipolar disorder, unless otherwise indicated, is at least one bipolar disorder chosen from disorders such as bipolar I disorder, bipolar II disorder, and cyclothymie disorder.
[0048] In an embodiment, the at least one CNS disorder is mixed depression. In one embodiment, mixed depression is depression and at least one symptom chosen from manic symptoms and hypomanic symptoms. In another embodiment, mixed depression is a major depressive disorder with mixed features, such as a major depressive episode associated with a limited number of manic symptoms.
[0049] In an embodiment, the at least one CNS disorder is schizophrenia. In another embodiment, the at least one CNS disorder is negative symptoms associated with schizophrenia. Examples of negative symptoms associated with schizophrenia include, but are not limited to, extrapyramidal symptoms, tardive dyskinesia, sedation, and metabolic side effects such as, for example, weight gain, hyperglycemia, hyperlipidemia, hypotension, cardiac disease, and diabetes.
[0050] In an embodiment, the at least one CNS disorder is chosen from learning and memory impairment and cognitive impairment associated with schizophrenia.
Examples of learning and memory impairment include, but are not limited to, decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, e.g., executive function and/or speed of processing.

[0051] Thus, disclosed herein are methods of treating, preventing and/or managing at least one CNS disorder comprising administering to a patient who received a prior therapy a therapeutically or prophylactically effective amount of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof. Examples of CNS disorders are disclosed above.
[0052) Also disclosed herein are methods of improving cognitive impairment, for example, in patients with at least one CNS disorder and/or in patients undergoing treatment for at least one CNS disorder. In an embodiment, improvement in cognitive impairment includes at least one improvement chosen from verbal learning improvements, visuospatial learning improvemenets, memory attention improvements, imorovements in speed of processing, and improvements in motor skills.
[0053] Also disclosed herein are methods of preventing development of cognitive impairment in patients who are at risk of developing at least one CNS
disorder, such as schizophrenia and/or psychosis.
[0054] Also disclosed herein are methods of reducing side effects associated with at least one CNS disorder and/or treatment of at least one CNS disorder, such as, for example, reducing daytime sleepiness and/or metabolic side effects.
[0055] In at least one embodiment, methods for reducing metabolic side effects include, but are not limited to reducing weight gain and/or maintaining benign levels of cholesterol, low-density and high-density lipoproteins, triglycerides, insulin, glycosylated hemoglobin, and/or glucose. In at least one embodiment, methods of lowering levels of cholesterol and/or triglycerides are disclosed.
[0056] Also disclosed herein are methods of treating, preventing and/or managing at least one CNS disorder without an increase of daytime sleepiness, and in at least one embodiment, the at least one CNS disorder is schizophrenia. In other embodiments, the at least one CNS disorder is bipolar depression or mixed depression. Yet, in other embodiments, the methods of treating, preventing and/or managing at least one CNS
disorder occur without a substantial increase of daytime sleepiness.
[0057] The term "substantial increase of daytime sleepiness," as used herein, unless otherwise indicated, relates to a score of greater than zero, such as greater than 0.5, on the Epsworth Sleepiness Scale (measuring the chance of dozing while sitting and reading, watching television, sitting inactive in a public place, as a passenger in a car without a break, afternoon resting, while talking with someone, sitting quietly after lunch without alcohol, and in a car, stopped for a few minutes in traffic).

[0058] Further disclosed herein are methods of treating, preventing and/or managing at least one CNS disorder with decrease of daytime sleepiness, and in at least one embodiment, the at least one CNS disorder is schizophrenia. In other embodiments, the at least one CNS disorder is bipolar depression or mixed depression.
[0059] Also disclosed herein are methods of improving at least one symptom selected from positive symptoms, negative symptoms and cognitive impairment in patients with at least one CNS disorder without substantial increase of daytime sleepiness. In at least one embodiment, the at least one CNS disorder is schizophrenia, bipolar disorder, or mixed depression.
[0060] Further disclosed herein are methods of reducing risk of relapse of at least one CNS disorder. In at least one embodiment, the at least one CNS disorder is schizophrenia, bipolar disorder, or mixed depression.
[0061] Also disclosed herein are methods of preventing relapse of at least one CNS
disorder, and in at least one embodiment, the at least one CNS disorder is schizophrenia.
[0062] In some embodiments, a pharmaceutically acceptable salt, solvate, clathrate or stereoisomer of lurasidone is used.
[0063] In an embodiment, a pharmaceutically acceptable salt of lurasidone is used.
In an embodiment, a hydrochloride salt of lurasidone is used.
[0064] In an embodiment, a pharmaceutically acceptable solvate of lurasidone or salt thereof is used. In an embodiment, the solvate is a hydrate.
[0065] In connection with all of the embodiments described herein, any suitable route of administration can be employed for providing a therapeutically and/or prophylactically effective dose.
[0066] The amount to be administered to a patient to treat, prevent, and/or manage the at least one CNS disorder described herein will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well-known in the art.
[0067] In general, a suitable daily dose of the at least one compound disclosed herein will be that amount of the at least one compound that is the lowest dose effective to produce a therapeutic and/or prophylactic effect. Such an effective dose will generally depend upon the factors described above. The dosage may be formulated as a single or multiple unit dosage formulation. In an embodiment, the at least one compound is given in single or divided doses per day.
[0068] In an embodiment, the at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof may be used in an amount of about 0.1 mg to about 500 mg per day. In some embodiments, the dose may be adjusted in a conventional fashion (e.g., the same amount administered each day of the treatment, prevention or management period), in cycles (e.g., one week on, one week off), and/or in an amount that increases or decreases over the course of treatment, prevention, and/or management.
[0069] In some embodiments, the dose can be from about 1 mg to about 300 mg per day, from about 0.1 mg to about 160 mg per day, from about 1 mg to about 200 mg per day, from about 10 mg to about 120 mg per day, from about 20 mg to about 160 mg per day, from about 40 mg to about 120 mg per day, from about 10 mg to about 80 mg per day, from about 20 mg to about 80 mg per day, or from about 80 mg to about 160 mg per day. These doses can be administered in single or divided administrations.
[0070] In some embodiments, the dose can be about 10 mg per day, 20 mg per day, 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 110 mg per day, 120 mg per day, 130 mg per day, 140 mg per day, 150 mg per day, 160 mg per day, 170 mg per day, 180 mg per day, 190 mg per day, 200 mg per day, 240 mg per day, 280 mg per day, or 300 mg per day.

These doses can be administered in single or divided administrations.
[0071] In an embodiment, the dose is about 20 mg per day. In an embodiment, the dose is about 40 mg per day. In an embodiment, the dose is about 80 mg per day. In an embodiment, the dose is about 120 mg per day. In an embodiment, the dose is about 160 mg per day. In an embodiment, the dose is about 220 mg per day.
[0072] In some embodiments, the at least one compound may be used as monotherapy. In other embodiments, the at least one compound may be used in combination with at least one additional active agent to treat, prevent, and/or manage disorders disclosed herein. In these embodiments, the at least one compound can be administered simultaneously or sequentially with the at least one additional active agent.
[0073] In at least one embodiment, the at least one additional active agent is chosen from Selective Serotonin Reuptake Inhibitors, for example, citalopram.

100741 Pharmaceutical compositions can be used in the preparation of dosage forms useful herein. Such pharmaceutical compositions and dosage forms disclosed herein comprise at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof. The pharmaceutical compositions and dosage forms can further comprise at least one excipient.
[0075] Pharmaceutical compositions and dosage forms useful herein can also comprise at least one additional active ingredient.
[0076] In an embodiment, pharmaceutical compositions and dosage forms may further comprise at least one excipient.
[0077] Also disclosed are pharmaceutical compositions and dosage forms that comprise at least one compound that can reduce the rate by which at least one active ingredient will decompose. Such compounds are referred to herein as "stabilizers."
Pharmaceutical compositions and dosage forms useful herein can also be prepared using methods disclosed in U.S. 2009/0143404 Al, U.S. 2006/0025422 Al, and/or using conventional methods.
[0078] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
[0079] In an embodiment, dosage forms comprise at least one second active ingredient. The specific amount of the at least one second active agent may depend on the specific active agent used, the diseases and/or disorders being treated and/or managed, and the amount(s) of the at least one compound disclosed herein, and any optional additional active agent(s) concurrently administered to the patient.
[0080] Disclosed herein are methods relating to the effective use of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to treat patients with at least one CNS
disorder. For example, patients with an initial response to therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and patients with no response to therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof may be identified following initial treatment with the at least one compound.
[0081] Thus, in an embodiment, disclosed herein are methods for treating a patient having at least one CNS disorder with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof by administering a dose of the at least one compound for a first dosage period;
identifying early responders of treatment with the at least one compound and non-responders to treatment with the at least one compound; maintaining treatment with the at least one compound for early responders; and increasing the dose of the at least one compound for non-responders; wherein the second dose improves the safety and/or efficacy of the treatment during the second dosage period.
[0082] In some embodiments, an "early responder" is a patient who responds to treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof within the first two weeks after initial treatment. In some embodiments, a "non-responder" is a patient who fails to respond to treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof within the first two weeks of initiating treatment. Response to initial treatment may be measured by, for example, an improvement, such as 20%, on the Positive and Negative Syndrome Scale (PANSS).
[0083] In an embodiment, the first dose is 80 mg per day of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the first dosage period is two weeks. In an embodiment, the second dose is 160 mg per day of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the second dosage period is four weeks.
[0084] In an embodiment, the first dose is 20 mg per day of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the first dosage period is seven days. In an embodiment, the second dose is a flexible dose of 20 mg, 40 mg, or 60 mg, of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the second dosage period begins on the eighth day.
[0085] In an embodiment, disclosed herein are methods for treating a patient having at least one CNS disorder with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof by administering a dose of the at least one compound for a first dosage period;
identifying early responders of treatment with the at least one compound and non-responders to treatment with the at least one compound; decreasing the dose of the at least one compound for early responders; and increasing the dose of the at least one compound for non-responders; wherein the subsequent dose improves the safety and/or efficacy of the treatment during the second dosage period.
[0086] In an embodiment, the first dose is 80 mg per day of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the first dosage period is two weeks. In an embodiment, the second dose is 20 mg per day of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof and the second dosage period is four weeks.
[0087] In an embodiment, disclosed herein is a method of treating a patient with at least one CNS disorder with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereo isomers thereof, comprising:
administering to a patient at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof for a first dosage period;
classifying the patient as an early responder or a non-responder based on a response indicator;
determining a dose and dosage period of the at least one compound based on the response indicator;
administering a second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over the second dosage period; wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with the at least one compound.
[0088] In another embodiment, disclosed herein is a method of treating a patient with at least one CNS disorder with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof, comprising:
administering to a patient at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof for a first dosage period;
determining a second dose and dosage period of the at least one compound based on a response indicator;

administering a second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over the second dosage period; wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with the at least one compound.
[0089] In one embodiment, the second dose is lower than the first dose. Yet in another embodiment, the second dose is higher than the first dose.
[0090] Examples of at least one CNS disorder are disclosed herein elsewhere.
In an embodiment, the at least one CNS disorder is bipolar disorder. In an embodiment, the at least one CNS disorder is schizophrenia, cognitive impairment associated with schizophrenia ("CIAS"), and/or another negative symptom associated with schizophrenia. In an embodiment, the at least one CNS disorder is mixed depression.
[0091] In an embodiment, the initial dose of the at least one compound is 20 mg. In another embodiment, the first dose of the at least one is 40 mg. In another embodiment, the first dose of the at least one compound is 50 mg. In another embodiment, the first dose of the at least one compound is 60 mg. In another embodiment, the first dose of the at least one compound is 80 mg. In yet another embodiment, the first dose of the at least one compound is 120 mg. In another embodiment, the first dose is a flexible dose ranging from 20 mg to 60 mg, such as from 30 mg to 50 mg, or a flexible dose of 40 mg to 80 mg, such as from 50 mg to 70 mg.
[0092] In an embodiment, the first dosage period is 2 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 15 days, 16 days, 20 days, 21 days, 25 days, or 28 days.
[0093] In an embodiment, the response indicator is the PANSS score measured after two weeks of the initial dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof The PANSS score is evaluated to determine the second dose and dosage period of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof [0094] In an embodiment, a PANSS score of _20% will determine whether the patient is an early responder or a non-responder to the initial treatment of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof In an embodiment, a score of >20% will determine whether the patient qualifies as an early responder or a non-responder.
[0095] In another embodiment, the response indicator is improvement in cognition measured after two weeks of the initial dose of the at least one compound.
Improvement = CA 02761068 2011-12-07 = in cognition is evaluated to determine the second dose and dosage period of treatment with the at least one compound.
[0096] In an embodiment, the second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof is 80 mg per day. In another embodiment, the second dose of the at least one compound is 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, mg. In an embodiment, the second dose of the at least one compound ranges from mg to 300 mg. In another embodiment, the second dose is a flexible dose ranging from 40 mg to 160 mg, or a flexible dose of 60 mg to 180 mg, or a flexible dose of 80 mg to 250 mg.
[0097] In an embodiment, the second dosage period is 2 to 6 weeks, for example weeks. In another embodiment, the second dosage period is longer than 6 weeks, such as 12 weeks. In yet another embodiment, the second dosage period is 24 weeks, months, 3 months, 4 months, 6 months, or until improvement is observed.
[0098] In one embodiment, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 40 mg per day, in a single or divided doses. In an embodiment, a second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 80 mg per day, in a single or divided doses. In an embodiment, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 120 mg per day, in a single or divided doses. In an embodiment, a second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 160 mg per day, in a single or divided doses.
[00991 In some embodiments, the methods disclosed herein can additionally be used to track or perform quality control on human research trials or to monitor the patient response to a drug regimen by providing a means to confirm that the patient is responding or not responding to specific treatments. These methods can be used in connection with, for example, the management of patient treatment, clinical trials, and cell-based research.
[00100] In an embodiment, the methods disclosed herein can be used to track patient response during individual treatment regimes, or during clinical trials. For example, a = CA 02761068 2011-12-07 response indicator, such as the PANSS score, can be assessed after initiating treatment with lurasidone during a clinical trial to determine whether patients are responding or not responding to the initial dose and/or dosage period.
[00101] Accordingly, assessing the response to an initial dose and/or dosage period of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof, such as a PANSS score, can provide useful information as to whether the patients would be responsive to the treatment by at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof, or whether the patients may respond to an increased dose and/or dosage period of treatment with the at least one compound.
Tracking patient response to therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof may improve the efficacy of treatment and subsequent reduction in psychiatric symptoms.
[001021 In an embodiment, disclosed herein are methods of treating an early responder of therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof in a patient having at least one CNS disorder, comprising:
administering at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a first dosage period;
assessing the response of the patient to the first dosage and dosage period;
and administering a lower dose of the at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a second dosage period;
wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with the at least one compound.
[001031 In an embodiment, disclosed herein are methods of treating an early responder of therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof in a patient having at least one CNS disorder, comprising:
administering at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a first dosage period;
assessing the response of the patient to the first dosage and dosage period;
and ' .

=

administering the same dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof as the initial dose to the patient over a second dosage period;
wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof 1001041 In an embodiment, disclosed herein are methods of treating a non-responder of therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof in a patient having at least one CNS disorder, comprising:
administering at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a first dosage period;
assessing the response of the patient to the first dosage and dosage period;
and administering a higher dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a second dosage period;
wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof.
[00105] In another embodiment, disclosed herein are methods of treating a non-responder of therapy with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof in a patient having at least one CNS disorder, comprising:administering at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a first dosage period;
assessing the response of the patient to the first dosage and dosage period;
and administering a higher dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a second dosage period;
assessing the response of the patient to the second dosage and dosage period;
and administering a third dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof to the patient over a third dosage period, wherein the third dose and third dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof.
[00106] In an embodiment, the third dose is an amount ranging from 120 mg to mg. In an embodiment, the third dosage period is 3 weeks, 1 year, or until improvement is observed.
[00107] Examples of at least one CNS disorder are disclosed herein elsewhere.
In an embodiment, the at least one CNS disorder is bipolar disorder. In another embodiment, the at least one CNS disorder is schizophrenia, cognitive impairment associated with schizophrenia, and/or another negative symptom associated with schizophrenia.
In another embodiment, the at least one CNS disorder is mixed depression.
[00108] In an embodiment, the initial dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof is 40 mg, 80 mg, 120 mg, or 160 mg. In another embodiment, the first dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof is 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg. In another embodiment, the first dose is a flexible dose ranging from 20 mg to 60 mg, such as from 30 mg to 50 mg, or a flexible dose of 40 mg to 80 mg, such as from 50 mg to 70 mg.
[00109] In an embodiment, the first dosage period is 2 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 15 days, 16 days, 20 days, 21 days, 25 days, or 28 days.
[00110] In an embodiment, the response indicator is the PANSS score measured after two weeks of the initial dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof. The PANSS score is evaluated to determine the second dose and dosage period of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof.
[00111] In an embodiment, a PANSS score of ?-20% will determine whether the patient is an early responder or a non-responder to an initial treatment of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, = clathrates and stereoisomers thereof In some embodiments, a score of >20% will determine whether the patient qualifies as an early responder or a non-responder.
[00112] In another embodiment, the response indicator is improvement in cognition measured after two weeks of the initial dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof. Improvement in cognition is evaluated to determine the second dose and dosage period of treatment with at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof [00113] In an embodiment, the second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof is 80 mg per day. In another embodiment, the second dose of the at least one compound is 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, mg. In yet another embodiment, the second dose of the at least one compound ranges from 100 mg to 300 mg. In another embodiment, the second dose is a flexible dose ranging from 40 mg to 160 mg, or a flexible dose ranging from 60 mg to 180 mg, or a flexible dose ranging from 80 mg to 250 mg.
[00114] In an embodiment, the second dosage period is 2 to 6 weeks, for example 4 weeks. In another embodiment, the second dosage period is longer than 6 weeks, such as 12 weeks. In yet another embodiment, the second dosage period is 24 weeks, months, 3 months, 4 months, 6 months, or until improvement is observed.
[00115] In one embodiment, the third dose is an amount ranging from 120 mg to mg. In another embodiment, the third dosage period is 3 weeks, 1 year, or until improvement is observed.
[00116] In an embodiment, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 40 mg per day, in a single or divided doses. In an embodiment, a second dose of at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 80 mg per day, in a single or divided doses. In an embodiment, at least one compound chosen from lurasidone and pharmaceutically acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 120 mg per day, in a single or divided doses. In an embodiment, a second dose of at least one compound chosen from lurasidone and pharmaceutically = CA 02761068 2011-12-07 acceptable salts, solvates, clathrates and stereoisomers thereof can be administered at an amount of about 160 mg per day, in a single or divided doses.
[00117] A kit for treatment and/or prevention of at least one CNS disorder comprising at least two compartments, and further comprising in a first compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a first dosage amount, and in a second compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a second dosage amount, wherein the first dosage amount is administered to a patient in need thereof for a first dosage period, the patient is classified as an early responder or a non-responder based on a response indicator, and the second dosage amount is administered to the patient for a second dosage period based on the response indicator, and wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.
[00118] Also provided herein are kits for treatment and/or prevention of at least one CNS disorder comprising at least two compartments, and further comprising in a first compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a first dosage amount, and in a second compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a second dosage amount, wherein the first dosage amount is administered to a patient in need thereof for a first dosage period, and a second dosage amount is administered to the patient for a second dosage period based on a response indicator, and wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.
[00119] Certain embodiments disclosed herein can be illustrated by the following examples, which are not intended to limit the full extent of the disclosure herein in any way.
5. EXAMPLES
5.1 Quality of Well-Being (001201 Quality of Well-Being (QWB) was measured according to the procedures well-established in the art. The QWB was a self administered questionnaire (QWB-SA), where the combined score ranged from 0 to 1.0 (death to optimal functioning).
A patient diagnosed with schizophrenia answered five sections assessing the presence/absence of 19 chronic symptoms or problems, physical symptoms, and mental health symptoms and behaviors as well as an assessment of a person's mobility, physical activity and social activity including completion of role expectations.
[00121] QWB-SA assessments were conducted at Baseline and after a 6-week double-blind treatment period in patients treated with 80 mg or 160 mg of lurasidone per day. In addition, the relationship between other indicators of therapy outcome, for example, cognitive composite scores, PANSS scores, Negative Symptom Assessment Scale scores (NSA), and Montogomer-Asberg Depression Rating Scale scores (MADRS), was evaluated in relation to quality of life, as assessed by the QWB-SA. An endpoint ANCOVA analysis showed significant improvement in the QWB-SA score compared to placebo for both 80 mg and 160 mg lurasidone groups, as shown in Figure 1. The correlation between quality of life and other outcome measures are shown in Figure 2.
[001221 Significant improvements in health-related quality of life were found in patients who had received 80 mg and 160 mg of lurasidone over a 6-week, placebo controlled study. In addition, partial correlations were found between improvement of QWB-SA and PANSS scores, QWB-SA and MADRS scores, QWB-SA and NSA
scores, and QWB-SA and cognitive composite scores.

5.2 Metabolic Effects [00123] Metabolic effects were analyzed in patients undergoing lurasidone therapy for the treatment of schizophrenia over a period of I year. Lurasidone was administered to patients at an initial dose of 40 mg per day, and adjusted up to a maximum of 120 mg/day over a 16-week period, followed by a fixed dose regimen from week-16 to week-52. Changes in weight, total cholesterol, triglycerides, fasting glucose, and prolactin were measured and compared to baseline levels.
[00124] As shown below in Figure 3, there were no adverse changes in mean weight, lipids, and prolactin from baseline levels after the 1-year study in patients with schizophrenia.

=

= [00125]
In addition to no adverse weight gain or increase in lipid or prolactin levels, lurasidone therapy was associated with a gradual and sustained improvement in total PANSS and Brief Psychiatric Rating Scale (BPRS) scores in patients with schizophrenia over a 1-year period.
[00126] In another study, potential adverse effects of lurasidone therapy (dose range, 20-120 mg) in patients with schizophrenia was evaluated in a short-term (6-week) study and long-term (6-month and 12-month) study, and compared to patients treated with olanzapine (15 mg), haloperidol (10 mg), risperidone (4 mg), quetiapine XR
(600 mg), and placebo. Table 1 below summarizes the baseline metabolic parameters of the patients in the short-term study.
[00127] Table 1. Baseline Characteristics of Short-term Safety Sample .,, Mean, -""7'n - = 1.01`tt - ; = s -Weight, kg 77.05 87.75 76.01 61.98 72.14 77.95 MI, kg/re 26.50 2861 26.01 23 01

25 47 208 Obese (8M1>30 kg/m1) 25.20% 37.50%
25.41% M5%
19.33% 26.41%
Glucose. mg/d1.
96.8 97.4 94.1 92.6 93.2 97.3 HbAlc, %
5.57% 5.64%
5.58% 5.38%
5.54% 5.57%
Total cholesterol, mg/dL
1913 1991.
193.6 180.2 182.4 1914.
Triglycerldes 147.7 182.8 133.4 117.0 137.2 151.2 Sample sizes may vary for individual tem.

[00128] The mean change in weight and BMI
was assessed at the LOCF endpoint for the short-term study. As shown in Figures 4-5, treatment with lurasidone was associated with minimal increases in weight and BMI as compared with other treatments. Figure 6 summarizes the mean change in weight and BMI in observed cases after 6 months and 12 months of treatment [00129] The median change in total cholesterol and triglycerides, and glucose and HbA 1 c, was also assessed for both the short-term and long-term studies. As shown in Figures 4-9, treatment with lurasidone was not associated with disturbances in lipids or glycemic control in both the short-term and long-term studies.

5.3 Comparison of Receptor Binding of Lurasidone and other Antipsychotics [00130] Receptor binding of lurasidone was compared to currently available first and second generation antipsychotics. In vitro binding studies were carried out according to the procedures well-established in the art. Membranes from male Wistar rat brain tissues or cells expressing cloned human receptors were prepared under assay conditions summarized in Ishibashi, T. et al. (Journal of Pharmacology and Experimental Therapeutics (2010)). Functional assays were carried out to analyze the binding affinity and effect on receptor function for dopamine D1-D4 receptor subtypes, serotonin 5-HTIA, 5-HT2A, 5-HT2c, 5-HT6, 5-HT7, norepinephrine cti, a2A, a2C, histamine H1 receptors, and muscarinic M1 receptors.
[001311 The binding profiles of lurasidone and other currently available antipsychotics are summarized in Table 2. Figure 10 illustrates the binding affinities of each antipsychotic tested, and Figures 11 and 12 demonstrate the effects of lurasidone on receptor function. The high selectivity of lurasidone for the D2 receptor, serotonin 5-HT2A, 5-HTIA (partial agonist) and 5-HT7 receptors, moderate affinity for a2C
adrenoreceptor, and low or negligible binding affinity for serotonin 5-HT2c receptor, ai adrenoreceptor, muscarinic M1 and histamine H1 receptors indicate that lurasidone is consistent with low liability for inducing sedation, EPS, cognitive impairment, hypotension and metabolic side effects.
1001321 Table 2. In vitro Receptor Binding Profiles: Comparative Data Ki values that < 10 fold different from D2 are highlighted Table 1. in Vitro Receptor Binding Profiles: Comparative Data Ki values that are <10-fold different from D2 are ' - . =

Binding , Affinities turasidone Flaloperidol Risperidone Aripiprazok Clozapine Olanzapine (Ki; nM) 6() 1'37 189 58 02 0.994 2 0 4.9 0.95 431 72 DI 15.7 12 1?.2 4.5 646 6 3 D4 29.7 000 22.3. 1 Serotonin: 1202 427 5.6' s,! 105 -71 53 8.5 c 4 ;`'& s.716'.=
N'ex =

S-HTõ 415 3085=õ _ = 75 10.7 6.4 , , 5-HT. 3666 2241 574 17 6.0 elm 5-HT, 0.495 378 6.6 10 IS 105 Norepinephrine: 47.9, 12 - 5:0 25 1.6 109 m 40.7 1113 151 74 142 314 ;
ctic 10.8 550 , 4 38 Histamine H, >1000` 3002 = 29 7.C1 ' 4.9 Acetylcholine Mi >1000 >10000 >10000 6776 4 Cloned cells expressing human receptors unless otherwise noted tat. bporcine, 'guinea pig Ki for a. is reported for all antipsychotics except lurasidone [001331 From the foregoing, it will be appreciated that, although specific embodiments have been described herein for the purpose of illustration, various modifications may be made without deviating from the spirit and scope of what is disclosed herein.

26

Claims (30)

WHAT IS CLAIMED IS:

1. A method of treating at least one CNS disorder chosen from bipolar disorder and mixed depression comprising administering to a patient in need thereof at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the at least one compound is lurasidone hydrochloride.

3. A method of improving cognitive impairment in a patient having at least one CNS disorder comprising administering to a patient in need thereof at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein the cognitive impairment is chosen from impaired verbal and visuospatial learning, impaired memory attention, impaired speed of processing, and impaired motor skills.

5. The method of claim 3, wherein the at least one compound is lurasidone hydrochloride.

6. A method of reducing side effects associated with at least one CNS
disorder and/or treatment of at least one CNS disorders comprising administering to a patient in need thereof at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the side effects are metabolic side effects chosen from weight gain and/or maintaining benign levels of cholesterol, low-density and high-density lipoproteins, triglycerides, insulin, glycosylated hemoglobin, and/or glucose.

8. The method of claim 6, wherein the side effects are daytime sleepiness.

9. The method of clam 1, wherein the at least one compound is administered at a dose chosen from about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 210 mg, about 220 mg, about 240 mg, about 250 mg, and about 280 mg, per day.

10. The method of clam 3, wherein the at least one compound is administered at a dose chosen from about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 210 mg, about 220 mg, about 240 mg, about 250 mg, and about 280 mg, per day.

11. A method of treating a patient having at least one CNS disorder comprising:
administering to the patient at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof for a first dosage period;
classifying the patient as an early responder or a non-responder based on a response indicator;
determining a second dose and dosage period of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof based on the response indicator;
administering the second dose of the at least one compound to the patient over the second dosage period; wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the at least one CNS disorder is chosen from bipolar disorder, schizophrenia, cognitive impairment associated with schizophrenia, another negative symptom associated with schizophrenia, and mixed depression.

13. The method of claim 12, wherein the negative symptom associated with schizophrenia is cognitive impairment associated with schizophrenia.

14. The method of claim 11, wherein the initial dose of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof is administered at a dose chosen from about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 210 mg, about 220 mg, about 240 mg, about 250 mg, and about 280 mg, per day.

15. The method of claim 14, wherein the initial dose of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof is 80 mg.

16. The method of claim 11, wherein the first dosage period is 1 to 4 weeks.

17. The method of claim 16, wherein the first dosage period is 2 weeks.

18. The method of claim 11, wherein the response indicator is a PANSS

score.

19. The method of claim 18, wherein the PANSS score is measured after the initial dosage period of administration of the at least one compound.

20.

whether the patient is an early responder or a non-responder to the initial treatment with The method of claim 19, wherein a PANSS score of >= 20% will determine at least one compound.

21. The method of claim 11, wherein the response indicator is improvement in cognition.

22. The method of claim 11, wherein the second dose of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof is administered at a dose chosen from about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 210 mg, about 220 mg, about 240 mg, about 250 mg, and about 280 mg, per day.

23. The method of claim 11, wherein the second dosage period is greater than 6 weeks.

24. The method of claim 22, wherein the second dosage period is 12 weeks.

25. The method of claim 11, wherein the second dosage period is 2 to 6 weeks.

26. The method of claim 11, wherein the patient is classified as an early responder and is administered a second, lower dose of the at least one compound than the initial dose over a second dosage period.

27. The method of claim 11, wherein the patient is classified as an early responder and is administered a second dose of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof equivalent to the initial dose over a second dosage period.

28. The method of claim 11, wherein the patient is classified as a non-responder and is administered a second, higher dose of at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof than the initial dose over a second dosage period.

29. A method of treating at least one CNS disorder comprising administering to a patient in need thereof at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof without an increase of daytime sleepiness.

30. A kit for treatment and/or prevention of at least one CNS disorder comprising at least two compartments, and further comprising in a first compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a first dosage amount, and in a second compartment, at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof in a second dosage amount, wherein the first dosage amount is administered to a patient in need thereof for a first dosage period, the patient is classified as an early responder or a non-responder based on a response indicator, and the second dosage amount is administered to the patient for a second dosage period based on the response indicator, and wherein the second dose and second dosage period improve the safety and/or efficacy of treatment with at least one compound chosen from lurasidone and a pharmaceutically acceptable salt thereof.