Method of treating a neurological or psychiatric disease or disorder

Abstract

Provided are methods of treating a neurological or psychiatric disease or disorder, methods of treating behavioral problems associated with a neurological or psychiatric disease or disorder, and methods of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder in a subject in need thereof.

Description

Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTMETHODS OF TREATMENTBACKGROUND

[0001] Muscarinic acetylcholine receptors are G-protein coupled receptors (GPCRs) widely expressed both in the central nervous system (CNS) and the periphery. Depending on the muscarinic receptor subtype (M1-M5) and location, they mediate a variety of physiological functions. Individual subtypes differ in signaling profiles. Subtypes Ml, M3, and M5 preferentially activate the Gq / 11 class of G-proteins, while M2 and M4 preferentially activate inhibitory Gi / o G-proteins. The flexible G-protein interface of muscarinic receptors allows them to interact with several types of G-proteins with varying efficacy, potency, and kinetics. Moreover, muscarinic receptors can also couple to G-proteins from other classes.

[0002] Disruption of muscarinic signaling often contributes to pathologies in the CNS and periphery making muscarinic agonists potential tools for the treatment of a variety of pathologies. Importantly, selective modulation of individual subtypes of muscarinic receptors is necessary to avoid undesired side effects. Many muscarinic agonists targeting diseases of the CNS have failed in clinical trials mainly due to gastrointestinal and cardiovascular adverse effects attributed to the activation of peripheral M2 and M3 receptors.

[0003] Compounds that exhibit selectivity for the M4 receptor relative to the M2 and M3 receptor subtypes have been reported in WO 2015 / 118342 and WO 2024 / 028458.

[0004] Despite the advances that have been made in this field, there remains a need for new therapeutic products useful for the treatment of neurological and psychiatric diseases and disorders and other related diseases or conditions described herein. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0005] Provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structureor a pharmaceutically acceptable salt thereof.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0006] Also provided is a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof.

[0007] Also provided is a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof.

[0008] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGURE 1 shows an exemplary manufacture process flow diagram for 10 mg cis- Compound A citrate monohydrate capsules.

[0010] FIGURE 2 shows an exemplary manufacture process flow diagram for 20 and 30 mg cv.s-Compound A citrate monohydrate capsules.

[0011] FIGURE 3 shows an exemplary manufacture process flow diagram for 10 mg and 20 mg cv.s-Compound A citrate monohydrate capsules.

[0012] FIGURE 4 shows a summary of plasma pharmacokinetics after a single dose of 1.5 to 80 mg cv.s-Compound A.

[0013] FIGURE 5 shows a summary of plasma pharmacokinetics after a single dose or repeated doses of cv.s-Compound A.

[0014] FIGURE 6 shows the mean (±SEM) Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set).Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0015] FIGURE 7 shows Least Squares (LS) Mean (±SEM) change from baseline of Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set).

[0016] FIGURE 8 shows the mean (±SEM) Clinical Global Impression of Severity (CGLS) score by study visit (efficacy analysis set).DETAILED DESCRIPTION

[0017] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0018] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0019] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0020] As used herein, “Compound A” may be referred to as ethyl 2-[4-(l -methyl- 1H- pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6-carboxylate, or ethyl 2-[4-(l-methyl- U / -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6-carboxylate and has the following chemical structure:(Compound A).Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0021] As used herein, “Compound A citrate monohydrate” may be referred to as: ethyl 2-[4-(l -methyl- 17 / -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl 2-[4-( l -methyl- IT / -pyrazol-5-yl)piperidin- l -yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl 2-[4-(l -methyl- 1 H-pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl 2-[4-( l -methyl- IT / -pyrazol-5-yl)piperidin- l -yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate.

[0022] In some embodiments, the stereochemistry of “Compound A” is cis, i.e., cis- Compound A has the following chemical structure:Compound A) with a CAS number of 1803346-98-6. cv.s-Compound A may also be referred to as NBI- 1117568.

[0023] In some embodiments “c / .s-Compound A citrate monohydrate” may be referred to as: ethyl cA-2-[4-(l-methyl-17 / -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-17 / -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-17 / -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl cA-2-[4-(l-methyl-17 / -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; and has a CAS number of 2920742-36-3.

[0024] Compound A and its pharmaceutically acceptable salts, including Compound A citrate monohydrate, may be prepared according to WO 2015 / 118342 and WO 2024 / 028458. The disclosures of both publications are incorporated herein by reference in their entirety.

[0025] Compound A and its pharmaceutically acceptable salts may form solvates, including hydrates. Solvates are formed by the incorporation into the solid-state structure (e.g., crystal structure) of the compounds and salts described herein of molecules of a non-toxicAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT pharmaceutically acceptable solvent. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds and salts with a solvent, or a mixture of solvents, containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. The solvates can be stoichiometric or nonstoichiometric solvates. In some embodiments, the solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate.

[0026] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2%, and ± 1% of the stated value.

[0027] As used herein, “up-titration” of a therapeutic agent refers to increasing the amount of the agent administered to a patient at one or more instances for a specified period(s) to achieve a therapeutic effect while reducing the risk of dose-limiting intolerability that would likely otherwise occur if the agent were to be administered at the final dose at the beginning of the treatment.

[0028] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0029] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering off, reducing, or increasing the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.

[0030] As used herein, "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0031] As used herein, “adjunctive therapy" refers to a treatment that is used in conjunction with a primary treatment and its purpose is to assist the primary treatment. Adjunctive therapies are co-administered therapies. For example, if obsessive- compulsive disorder is being treated, the primary therapy may be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy. Likewise, if schizophrenia is being treated, the primary therapy may be, e.g., an antipsychotic agent.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0032] As used herein, "co-administer" and "co-administration" and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be coformulated as part of the same composition, or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.

[0033] Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Its clinical features include cognitive dysfunction, memory abnormalities, progressive impairment in activities of daily living (ADL), and a host of behavioral and neuropsychiatric symptoms. While the diagnostic criteria for AD focus mostly on the related cognitive deficits, it is the behavioral and neuropsychiatric symptoms that are most troublesome for caregivers and lead to poor quality of life for patients. These symptoms include agitation, aggressive behaviors, and psychosis.

[0034] As used herein, “amelioration of the symptoms” of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0035] As used herein, “baseline” refers to the period of time just prior to initiation of therapy. The patient's condition just prior to initiation of therapy can be referred to as the patient's baseline condition.

[0036] As used herein, “bipolar I disorder” (bipolar mania) is a manic-depressive illness characterized by the occurrence of at least one manic episode and may present with or without mixed or psychotic features. Most patients also exhibit one or more depressive episodes and often have had one or more major depressive episodes. Bipolar I disorder may coexist with other disorders, such as post-traumatic stress disorder (PTSD), substance use disorders, and mood disorders. Bipolar disorder is estimated to affect 2.8% of the United States Population.

[0037] As used herein, the “Clinical Global Impression - Severity” or “CGI-S” is an investigator administered, 7-point scale to assess patient’s severity of illness. See, e.g., Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0038] As used herein the term "disorder" is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[0039] As used herein, a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0040] As used herein, a "dose" means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not a free base, the quantity is the molar equivalent to the corresponding amount of free base.

[0041] As used herein, "dosing regimen" means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient, such as from about 5 to about 70 mg once daily, e.g., about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg once daily. The additional doses of the active agent can be different from the dose taken at the first time.

[0042] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0043] As used herein, "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.

[0044] As used herein, "labeling" means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0045] As used herein, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0046] As used herein, “a medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.

[0047] As used herein, "Medication Guide" means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 C.F.R. §208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product. A medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 C.F.R. §201.57, but the language need not be identical to the sections of approved labeling to which it corresponds. A medication guide is typically available for a pharmaceutical product with special risk management information.

[0048] Parkinson’s Disease (PD) is a neurodegenerative disease of the central nervous system affecting primarily the motor system. Common motor symptoms include tremors, rigidity, slowness of movement, and difficulty walking. Symptoms are progressive and, as the disease worsens, non-motor symptoms become common. These include cognitive conditions such as depression, anxiety, apathy, and dementia. The cause of PD is unknown and may involve both heritable and environmental factors. Parkinson’s Disease psychosis (PDF) is another common non-motor symptom of PD and may include visual and non-visual hallucinations and delusions. Between 20% and 40% of PD patients report experiencing hallucinations or delusions, with these symptoms being more common in more advanced cases of the disease. Hallucinations have been reported as the strongest predictor for eventual institutionalization of PD patients.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0049] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0050] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. "Pharmacologically active" (or simply "active") as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0051] As used herein, in some embodiments, "pharmaceutically acceptable salt" refers to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Ver lag Helvetica Chimica Acta, Zurich, 2002 which is incorporated herein by reference in its entirety. The organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like. In some embodiments,Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT"pharmaceutically acceptable salt" refers to base addition salts with an inorganic or an organic base. Inorganic bases which may be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates. Organic bases from which may be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0052] As used herein, the “Positive and Negative Symptoms Scale” or “PANSS” is a reliable, well known, widely used, clinician administered, validated, 30-item scale designed to evaluate the severity of various symptoms of schizophrenia and is commonly employed in clinical studies involving antipsychotics. The subscales of the PANSS and the 5-factor model of the PANSS are employed to assess different symptom domains of schizophrenia. The PANSS Positive Symptom Factor Score (PSFS) is broadly used in clinical studies of schizophrenia and has demonstrated both good test-retest reliability and validity for positive symptom assessment in patients. See, e.g., Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004 Feb;161(2 Suppl):l-56 and Marder SR, Davis JM, and Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived from factor analysis: combined results of the North American trials. J Clin Psychiatry . 1997;58:538-46.

[0053] As used herein, "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0054] As used herein, a "product" or "pharmaceutical product" means a dosage form of an active agent plus published material, and optionally packaging.

[0055] As used herein, "product insert" means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.

[0056] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA orAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTEMEA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as, for example indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.

[0057] As used herein, "published material" means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet popup window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0058] As used herein, the term "schizophrenia or schizoaffective disorder " includes, but is not limited to, illnesses that describe abnormal social behavior and failure to understand what is real. Schizophrenia is described in terms of positive and negative (or deficit) symptoms. Positive symptoms are those that most individuals do not normally experience, but are present in people with schizophrenia. Negative symptoms are deficits of normal emotional responses or of other thought processes.Methods of Treatment

[0059] Provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof.

[0060] Also provided is a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A),Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT or a pharmaceutically acceptable salt thereof.

[0061] Also provided is a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder, comprising: administering to the subject a dosing regimen of a compound having the structureor a pharmaceutically acceptable salt thereof.

[0062] Also provided is a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0063] Also provided is a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0064] Also provided is a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0065] Also provided is use of a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0066] Also provided is use of a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimenAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0067] Also provided is use of a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTIndications

[0068] In some embodiments, the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, and psychosis.

[0069] In some embodiments, the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, Alzheimer’s disease psychosis, bipolar disorder, Parkinson’s disease (or synucleinopathies) psychosis, and obsessive compulsive disorder.

[0070] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

[0071] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.

[0072] In some embodiments, the subject has at least one sign or symptom of schizophrenia.

[0073] In some embodiments, the subject has at least one positive, negative, and / or cognitive sign or symptom of schizophrenia.

[0074] In some embodiments, the at least one sign or symptom is delusions, hallucinations, disorganized speech, disorganized behavior or attention, anhedonia, catatonic behavior, affective flattening, alogia, avolition, conceptual disorganization, or any combination thereof.

[0075] In some embodiments, the subject is also being administered at least one co- therapeutic agent for the treatment of schizophrenia, and the neurological or psychiatric disease or disorder is adjunctive treatment of schizophrenia (ATS).

[0076] In some embodiments, the subject has a stable background antipsychotic medication dose.

[0077] In some embodiments, the subject is residually symptomatic or has at least one residual sign or symptom after first- or second-line treatment of schizophrenia.

[0078] In some embodiments, the subject is residually symptomatic or has at least one residual sign or symptom after mono- or combination therapy for schizophrenia.

[0079] In some embodiments, the mono- or combination therapy is initial therapy.

[0080] In some embodiments, the at least one co-therapeutic agent is at least one antipsychotic agent.

[0081] In some embodiments, the antipsychotic agent is a typical antipsychotic agent.

[0082] In some embodiments, the typical antipsychotic agent is benperidol, chlorpromazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, loxapine, molindone,Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT pericyazine, perphenazine, pimozide, prochlorperazine, promazine, sulpiride, thiothixene, trifluoperazine, thioridazine, zuclopenthixol, or any combination thereof.

[0083] In some embodiments, the antipsychotic agent is an atypical antipsychotic agent.

[0084] In some embodiments, the atypical antipsychotic agent is clozapine, olanzapine, risperidone, sertindole, quetiapine, paliperidone, asenapine, ziprasidone, surmontil, iloperidone, aripiprazole, or any combination thereof.

[0085] In some embodiments, the neurological or psychiatric disease or disorder is psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0086] In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder.Methods of Dosing

[0087] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprisesAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0088] In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0089] In some embodiments, the subject is assessed for one or more adverse events during the QD dosing. The one or more adverse events may be selected from blood pressure, heart rate, and 12-lead ECGs. In some embodiments, the QD dosing may last at least 5 weeks in the absence of one or more adverse events.

[0090] In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0091] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

[0092] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

[0093] In some embodiments, the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.

[0094] In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 10 mg of Compound A free base.

[0095] In some embodiments, the final daily dose is from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is fromAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT about 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is from about 8 mg to about 25 mg of Compound A free base.

[0096] In some embodiments, the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is about 10 mg of Compound A free base. In some embodiments, the final daily dose is about 15 mg of Compound A free base. In some embodiments, the final daily dose is about 20 mg of Compound A free base. In some embodiments, the final daily dose is about 25 mg of Compound A free base. In some embodiments, the final daily dose is about 30 mg of Compound A free base.

[0097] In some embodiments, the initial daily dose is administered QD. In some embodiments, the initial daily dose is administered BID. In some embodiments, the final daily dose is administered QD. In some embodiments, the final daily dose is administered BID. In some embodiments, the initial daily dose and final daily dose are administered QD.

[0098] In some embodiments, the titration period is from about 2 to about 14 days. In some embodiments, the titration period is from about 2 to about 7 days. In some embodiments, the titration period is from about 3 to about 7 days. In some embodiments, the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days. In some embodiments, the titration period is about 2 days. In some embodiments, the titration period is about 3 days. In some embodiments, the titration period is about 4 days. In some embodiments, the titration period is about 5 days. In some embodiments, the titration period is about 6 days. In some embodiments, the titration period is about 7 days.

[0099] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0100] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, whereinAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0101] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0102] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0103] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titrationAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0104] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0105] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0106] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some otherAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0107] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0108] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0109] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered QD. In some other embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.

[0110] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

[0111] In some embodiments, the first titration period is from about 2 to about 14 days. In some embodiments, the first titration period is from about 2 to about 7 days. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0112] In some embodiments, the second titration period is from about 1 to about 7 days. In some embodiments, the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0113] In some embodiments, the first and second titration period combined is about 14 days. In some further embodiments, the first titration period is about 2 days, and the second titration period is about 12 days. In some further embodiments, the first titration period is about 3 days, and the second titration period is about 11 days. In some further embodiments, the first titration period is about 4 days, and the second titration period is about 10 days. In some further embodiments, the first titration period is about 5 days, and the second titration period is about 9 days. In some further embodiments, the first titration period is about 6 days, and the second titration period is about 8 days. In some further embodiments, the first titration period is about 7 days, and the second titration period is about 7 days.

[0114] In some embodiments, the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 10% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 15% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 30% of the final daily dose. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.

[0115] In some embodiments, the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.

[0116] In some embodiments, the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the increased dailyAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 30% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 35% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 40% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 45% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 50% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 55% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 60% of the final daily dose. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0117] In some embodiments, the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 15 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0118] In some embodiments, the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 10, about 15, about 20, about 25, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 20 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 25Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0119] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0120] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0121] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0122] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0123] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0124] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0125] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0126] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 25 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0127] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0128] Also provided is use of a compound having the structure ofCompound A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0129] Also provided is a compound having the structure ofCompound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; and administering cA-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0130] In some embodiments, the first period is from about 1 to about 3 weeks. In some embodiments, the first period is about 1 week. In some embodiments, the first period is about 2 weeks. In some embodiments, the first period is about 3 weeks.

[0131] In some embodiments, the second period is from about 1 to about 6 weeks. In some embodiments, the second period is about 1 week. In some embodiments, the second period is about 2 weeks. In some embodiments, the second period is about 3 weeks. In some embodiments, the second period is about 4 weeks. In some embodiments, the second period is about 5 weeks. In some embodiments, the second period is about 6 weeks.

[0132] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 10 mg of cis- Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 15 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cA-Compound A free base. In some embodiments, cis- Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 25 mg of cA-Compound A free base. In someAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 30 mg of cA-Compound A free base.

[0133] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 5 mg of cis- Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 15 mg of cA-Compound A free base.

[0134] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cis- Compound A free base and in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base.

[0135] In some embodiments, the method, compound, or use comprises administering cis- Compound A, or a pharmaceutically acceptable salt thereof, in a third period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base. In some further embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered at the same daily dose as the dose in the first period. In some further embodiments, the same daily dose is a dose equivalent to about 20 mg of cA-Compound A free base.

[0136] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0137] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0138] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0139] In some embodiments, the baseline assessment of heart rate is the heart rate recorded at 30 minutes (±20 minutes) predose on Day 1.

[0140] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structureor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cv.s-Compound A free base.

[0141] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structureor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis- Compound A free base.

[0142] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structureor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0143] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structureAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0144] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cv.s-Compound A free base.

[0145] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureor a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis- Compound A free base.

[0146] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0147] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0148] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cv.s-Compound A free base.

[0149] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis- Compound A free base.

[0150] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTCompound A) or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0151] Also provided is a compound for use in a method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0152] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some further embodiments, the method treats positive symptoms. In some further embodiments, the method treats negative symptoms.

[0153] In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder.

[0154] In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis.

[0155] In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0156] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0157] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTCompounds

[0158] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is Compound A free base.

[0159] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of Compound A.

[0160] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of Compound A. In some embodiments, the citrate salt of Compound A is crystalline.

[0161] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is Compound A citrate monohydrate, wherein the molar ratio between Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the Compound A citrate monohydrate is crystalline.

[0162] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A free base.

[0163] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of cA-Compound A.

[0164] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cA-Compound A. In some embodiments, the citrate salt of cA-Compound A is crystalline.

[0165] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate, wherein the molar ratio between cA-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cA-Compound A citrate monohydrate is crystalline

[0166] In some embodiments, the crystalline form of the citrate salt of Compound A, Compound A citrate monohydrate, or cA-Compound A citrate monohydrate, is characterized by at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrateAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT monohydrate is characterized by four XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.

[0167] While it may be possible for the compounds and salts of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical formulations disclosed herein may be manufactured in any manner known in the art, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0168] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLESExample 1

[0169] This was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, inpatient study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of cv.s-Compound A compared with placebo in adult subjects with a primary diagnosis of schizophrenia, who were experiencing an acute exacerbation or relapse of symptoms (Positive and Negative Syndrome Scale [PANSS] total score >80). The study included a Screening Period (washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications), a 6-week randomized Double-Blind Treatment Period, and a 2-week post-treatment Safety Follow-Up Period.

[0170] Approximately 213 subjects, 18 to 55 years of age (inclusive), were enrolled for study participation. Subjects were initially randomized 1 : 1 : 1 to receive placebo, cis- Compound A 20 mg, or 40 mg capsules once a day (QD) in a 6-week Double-BlindAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTreatment Period. Doses of 60 mg QD or 20 mg twice a day (BID), and 30 mg BID were also evaluated based on the results of 2 planned interim analyses. If any dose group was added or dropped based on the results of the interim analyses, then the randomization ratio and total number of subjects per group were adjusted to maintain an approximate 1 :2 randomization ratio for placebo to active treatment throughout the study.

[0171] Any antipsychotic and / or prohibited medications were washed out prior to randomization. Subjects who routinely take long-acting injectable (LAI) antipsychotic medications did not receive a dose of medication for at least 1.5 injection cycles prior to screening. Eligible subjects were housed in an inpatient study center for up to 10 weeks to monitor the efficacy, safety, tolerability, and PK of cv.s-Compound A.

[0172] Adverse events (AEs) were assessed throughout the study, and changes in vital signs (blood pressure and heart rate) and electrocardiograms (ECGs) were monitored. Dose tolerability was assessed throughout the 6-week Double-Blind Treatment Period and a 2- week post-treatment Safety Follow-Up Period was conducted after the final dose of study treatment.

[0173] The end of study was the last scheduled visit assessment or procedure of the last subject in the study globally.Screening Period

[0174] Subjects were admitted into the inpatient facility at the time of screening. The Screening Period was a washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications, and subjects were randomized as soon as confirmed to meet all eligibility criteria. Subjects and informants provided written informed consent. Subjects met the criteria for a primary diagnosis of schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) (American Psychiatric Association, 2022) and confirmed by the Mini International Neuropsychiatric Interview (MINI) for Schizophrenia and Psychotic Disorder Studies, Version 7.0.2.

[0175] Subjects were required to washout any antipsychotic and / or prohibited medications for a duration of at least 5 half-lives of those medications in use prior to Day-1. Subjects who routinely took LAI antipsychotic medications must not have received a dose of medication for at least 1.5 injection cycles prior to screening. During screening and prior to randomization, subjects who took antipsychotics and / or other prohibited medicationsAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT discontinued these medication(s) in a manner that was consistent with labeling recommendations and conventional medical practices.Double-Blind Treatment Period

[0176] Subjects were initially randomized in a 1 : 1 : 1 ratio to receive placebo, cv.s-Compound A 20 mg QD, or 40 mg QD for 6 weeks. Subjects were randomized via an interactive web response system (IWRS). In addition, dose group(s) of 60 mg QD or 20 mg BID, and 30 mg BID were added based on the results of interim analyses.

[0177] This was a fixed-dose titration study. Each subject in the 40 or 60 mg QD dose groups showed signs that cv.s-Compound A was tolerated before titrating to a higher dose on Day 8. Those subjects meeting titration hold criteria remained on their current dose until tolerability was established (i.e., no longer meeting titration hold criteria). If tolerability to the assigned higher dose was not achieved by Day 14, the subject continued on the current dose for the remainder of the study.

[0178] Subjects were dosed as follows:• 20 mg QD dose group: Subjects received 20 mg QD for 6 weeks.• 40 mg QD dose group:■ Days 1 to 7: Subjects received 20 mg QD.■ Days 8 to 42: Subjects received 40 mg QD. Subjects had to have demonstrated tolerability before titrating to this higher dose.• 60 mg QD dose group:■ Days 1 to 7: Subjects received 40 mg QD.■ Days 8 to 42: Subjects received 60 mg QD. Subjects had to have demonstrated tolerability before titrating to this higher dose.• 20 mg BID dose group: Subjects received 20 mg BID for 6 weeks.• 30 mg BID dose group: Subjects received 30 mg BID for 6 weeks.Titration Hold Criteria

[0179] Subjects were held at the current dose (titration dose) if any titration hold criteria were met at any point on the previous dosing day or on the current dosing day prior to the evening dose:• Subj ect’ s dose was reduced• Supine or standing heart rate >110 bpm continuously for >2 hours and <5 hoursAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT• Supine or standing systolic blood pressure (SBP) <95 mmHg (<90 mmHg if baseline SBP was <110 mmHg); the baseline assessment was the supine or standing value (whichever SBP measurement was lower) recorded 30 minutes (±10 minutes) predose on Day 1• Supine or standing SBP of >175 mmHg or diastolic blood pressure (DBP) of >110 mmHg continuously for >12 hours• Average QT interval corrected according to Fridericia's formula (QTcF) of 3 ECGs, recorded approximately 1 minute apart, >450 msec (male subjects) or >470 msec (female subjects)• Inability to stand due to reported AEs (e.g., dizziness, lightheadedness)• Unable to tolerate a higher dose of study treatment in the opinion of the investigator and after discussion with the study Medical Monitor (or designee) at any time during the fixed-dose titration period (Day 1 to Day 14)

[0180] Titration hold criteria were assessed based on the average value of triplicate vital signs or ECG readings. Subjects with elevated supine or standing heart rate (>110 bpm) had subsequent measurements obtained at least every hour (±10 minutes) until heart rate is <110 bpm. Similarly, if a subject met any other vital sign-related titration hold criterion, this vital sign measurement was repeated at least hourly (±10 minutes) until it was outside of the hold criterion thresholds. Hourly follow-up measurements were performed, at a minimum, in the same position (eg, supine or standing) as the assessment that initially met titration hold criteria. If hourly follow-up measurements coincided with planned protocol-specified timed vital signs measurements, measurements were collected in both the protocol-specified position(s) and the position in which the abnormal vital sign was previously measured. Interventions were used for elevated heart rate or low blood pressure if a subject was symptomatic and / or in distress, but interventions were not used based on the value of measurements alone. Tolerability was assessed based on cardiovascular parameters, investigator judgement, and / or consultation with the study Medical Monitor (or designee). Treatment was discontinued if there were signs that study treatment is not well tolerated.Dose Reductions During the Double-Blind Treatment Period

[0181] A dose decrease was made once during the first 2 weeks of study treatment in all dose groups if a subject experienced a supine or standing heart rate >110 bpm continuously for >5 hours postdose. Other tolerability concerns, in the opinion of the investigator and afterAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT discussion with the study Medical Monitor (or designee), were warranted a dose decrease. Thus, subjects receiving 20 mg QD, 40 mg QD, 60 mg QD, 20 mg BID, or 30 mg BID decreased their daily dose to 10 mg QD, 20 mg QD, 40 mg QD, 10 mg BID, or 20 mg BID, respectively. Subjects who tolerated the lower dose were subsequently titrated back up to the higher dose by Day 14.Study Treatment Discontinuation Criteria

[0182] Subjects were discontinued from study treatment if they experienced any of the following specific effects postdose at any time during the Double-Blind Period:• Supine or standing heart rate >110 bpm for >5 hours on 2 separate dosing days at the same or subsequent lower dose. If the subject was beyond Day 14, no dose reduction was allowed after the first experience of heart rate >110 bpm for >5 hours. The subject was rechallenged with the same dose and discontinued from study treatment if they experienced a second episode• Supine SBP was >200 mmHg and / or the DBP was >120 mmHg at any timepoint postdose after 15 minutes supine rest• Supine or standing SBP <95 mmHg (<90 mmHg if baseline SBP was <110 mmHg) postdose occurring on 3 different dosing days at the same or subsequent lower dose; the baseline assessment was the supine or standing value (whichever SBP measurement was lower) recorded 30 minutes (±10 minutes) predose on Day 1• Average QTcF of 3 ECGs, recorded approximately 1 minute apart, >500 msec or >60 msec over baseline• Inability to stand due to reported AEs (e.g., dizziness, lightheadedness) postdose, occurring on 3 different dosing days at the same or subsequent lower dose• Treatment-emergent cardiovascular-related symptoms (e.g., dyspnea, fatigue, chest pain, syncope) that impaired a subject’s ability to complete normal daily activities on any single dosing day• Unable to tolerate study treatment in the opinion of the investigator and after discussion with the study Medical Monitor (or designee)

[0183] Study treatment discontinuation criteria were assessed based on the average value of triplicate vital signs or ECG readings.Interim AnalysesAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0184] Two interim analyses were completed during this study. The first interim analysis assessed the safety and tolerability of cA-Compound A and was performed after 36 subjects (approximately 12 subjects in each dose group) had the opportunity to complete Week 4 assessments. The second interim analysis assessed the safety and tolerability (and PK, if available and requested) of cA-Compound A after approximately 60% of the planned subjects had the opportunity to complete Week 4 assessments. Depending on the results of each interim analysis, dose group(s) were added or dropped.

[0185] Interim Analysis 1 was used to assess the safety and tolerability of the 20 and 40 mg QD doses and to determine whether to add an additional dose group of 60 mg QD or to drop the 40 mg QD dose group and add a dose group at 20 mg BID. Either change to dose groups was decided following a review of unblinded safety data by a Data Review Committee (DRC).

[0186] The DRC considered the following criteria when determining to add or discontinue dose group(s):• DRC determination of a pattern of safety that precludes dose escalation• SAE that occurred in at least 1 subject who received cA-Compound A citrate monohydrate and which the DRC believed constitutes undue risk to subjects• Severe nonseri ous AEs in 2 or more subjects in the same cA-Compound A dose group, at an incidence rate greater than that observed in the placebo dose group, that the DRC believed constituted undue risk to subjects. The severe nonseri ous AEs did not have to be in the same Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC)• Discontinuation of study drug criteria were met for 3 or more subjects within the same cA-Compound A dose group• Three or more subjects did not reach their assigned dose due to meeting titration hold or dose reduction criteria during the first 2 weeks of dosing within the same cis- Compound A dose group

[0187] The DRC determined whether dose group(s) were added and / or dropped as follows:• If the 40 mg QD dose demonstrated adequate safety and tolerability, then a 60 mg QD dose group was added. New subjects were randomized in a 2: 1 : 1 :2 ratio to receive placebo, 20 mg, 40 mg, or 60 mg QD, respectively.• If the 40 mg QD dose group did NOT demonstrate adequate safety and tolerability, then the 40 mg dose group was dropped and a 20 mg BID dose group was added. NewAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT subjects were randomized in a 2: 1 :3 ratio to receive placebo, 20 mg QD, or 20 mg BID, respectively.

[0188] Interim Analysis 2 was conducted when approximately 60% of the planned subjects had the opportunity to complete the Week 4 assessments. This analysis was used to assess the safety and tolerability (and PK, if available and requested) from the dosing groups present after Interim Analysis 1, and to determine whether to add an additional dose group and / or to drop an existing dose group. Either change to dose groups was decided following a review of unblinded safety data by the DRC.

[0189] The DRC determined whether dose group(s) will be added and / or dropped as follows:• If the 60 mg QD dose group was added during Interim Analysis 1 :■ If the 60 mg QD dose demonstrated adequate safety and tolerability, then a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 : 1 :5 ratio to receive placebo, 20 mg QD, 40 mg QD, 60 mg QD, or 30 mg BID.■ If the 60 mg QD dose did NOT demonstrate adequate safety and tolerability, then the 60 mg QD dose group was dropped and a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 :6 ratio to receive placebo, 20 mg QD, 40 mg QD, or 30 mg BID.• If the 20 mg BID dose group was added during Interim Analysis 1 :■ If the 20 mg BID dose demonstrated adequate safety and tolerability, then a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 :6 ratio to receive placebo, 20 mg QD, 20 mg BID, or 30 mg BID.■ If the 20 mg BID dose did NOT demonstrate adequate safety and tolerability, then the 20 mg BID dose group was dropped. New subjects were randomized in a 1 :2 ratio to receive placebo or 20 mg QD.Safety Follow-Up Period

[0190] After the last dose of study treatment, subjects who completed Day 42 assessments on study treatment entered the Safety Follow-Up Period and had a final follow-up assessment 14 days after the last dose. Subjects remained in the inpatient facility during this period. No antipsychotic medications were administered during this time.Study population:Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0191] Subjects 18 to 55 years of age (inclusive) with a primary diagnosis of schizophrenia >1 year as defined by the DSM-5-TR and confirmed by the MINI Version 7.0.2.

[0192] Key inclusion criteria included the following:• Currently experiencing an acute exacerbation or relapse of symptoms of schizophrenia, with onset <2 months prior to screening• Have a total PANSS score >80 at screening and Day -1• PANSS score of >4 on at least 2 of the following at screening and Day -1 :■ Item 1 (Pl; delusions)■ Item 2 (P2; conceptual disorganization)■ Item 3 (P3; hallucinatory behavior)■ Item 6 (P6; suspiciousness / persecution)• Minimal to no improvement in PANSS total score (<20% improvement) between screening and Day -1• Clinical Global Impression of Severity (CGI-S) score of >4 at screening and Day 1• Subjects taking oral antipsychotic medications or prohibited medications must not have received a dose of medication within 5 half-lives of those medications and / or must discontinue at least 5 half-lives prior to Day 1• Subjects taking a LAI antipsychotic must not have received a dose of medication for at least 1.5 injection cycles before screening (e.g., 3 or more weeks off for a 2-week cycle)

[0193] Key exclusion criteria included the following:• Orthostatic hypotension (defined as a SBP decrease of >20 mmHg and / or DBP decrease >10 mmHg, or a symptomatic decrease in BP), pulmonary hypertension, obstructive coronary artery disease, myocardial infarction, coronary artery revascularization, heart failure, left ventricular hypertrophy, moderate or severe cardiac valvopathy, ECG abnormalities or arrythmia risks including tachyarrhythmia, cardiac arrhythmia, or any additional risk factors for torsades des pointes (eg, heart failure, hypokalemia, personal or family history of long QT syndrome, atrial fibrillation, ventricular tachycardia)• Had a triplicate average QT interval corrected for heart rate using QTcF of >450 msec (male subjects) or >470 msec (female subjects) or the presence of any clinically significant cardiac abnormality during the Screening PeriodAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT• Uncontrolled hypertension despite diet, exercise, or antihypertensive therapy defined as average supine SBP >140 mmHg or DBP >90 mmHg during screening, which continues to be above this range with repeated testing and predose at Day 1 or a resting supine heart rate >100 bpm after at least 5 minutes of rest or a standing heart rate >100 bpm after at least 3 minutes of rest predose on Day 1• History of non-febrile seizures (including family history of seizures), embolic or hemorrhagic stroke• Uncontrolled hyperthyroid or hypothyroid disease based on thyroid hormone above or below normal limits (thyroid-stimulating hormone [TSH] and free thyroxine [T4])Duration of study treatment and study participation

[0194] Subjects were required to remain in the inpatient unit for the duration of the study. The duration of study participation for each subject was up to 10 weeks as follows: a Screening Period (washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications), a 6-week randomized Double-Blind Treatment Period, and a 2-week post-treatment Safety Follow-Up Period.Investigational product, dosage, and mode of administration:

[0195] The doses, i.e., 20 mg QD and 40 mg QD, and if added, 60 mg QD or 20 mg BID, and 30 mg BID, were selected based on cumulative PK, safety, tolerability, and target engagement data.

[0196] cv.s-Compound A was supplied as capsule dosage forms of 10, 20, and 30 mg and placebo for oral administration with or without food for a total of 6 weeks. The active and placebo capsules were identical in both appearance and weight. Subjects were instructed to take 2 capsules in the morning and 2 capsules in the evening.Reference therapy, dose, and mode of administration:

[0197] Placebo was supplied as capsules identical in appearance to the investigational product. Subjects randomized to placebo were instructed to take 2 capsules in the morning and 2 capsules in the evening.Endpoints

[0198] Primary endpoints included change from baseline in total PANSS score at Week 6.

[0199] Other endpoints included:Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT• Change from baseline in CGI-S score at Week 6• Subject medication satisfaction from baseline to Week 6 as measured by the Medication Satisfaction Questionnaire (MSQ)

[0200] Safety endpoints included the occurrence of AEs; observed and changes from baseline in clinical laboratory tests (hematology, chemistry, serum prolactin, and high- sensitivity cardiac troponin I), vital sign measurements (including orthostatic blood pressure and heart rate), weight, 12-lead ECG parameters; and scores from the Columbia-Suicide Severity Rating Scale (C-SSRS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Modified Simpson Angus Scale (mSAS), and Physician Withdrawal Checklist-20 (PWC-20).Pharmacokinetics :

[0201] Plasma concentrations, and derived PK parameters (e.g., maximum plasma concentration [Cmax] and area under the plasma concentration versus time curve [AUC]) of cv.s-Compound A and metabolite were analyzed.Statistical Methods:

[0202] The primary endpoints were analyzed by comparing cv.s-Compound A and placebo over all assessed timepoints using estimates from a mixed model for repeated measures (MMRM) with baseline value as a covariate; treatment and visit as fixed factors; and treatment-by-visit and baseline-by-visit interactions. Subject were included as a random effect. The primary comparisons were the contrasts between each of the active treatment groups and placebo at Week 6, using a significance level of 0.05 (1 -sided) to compare each active treatment group with placebo. The Dunnett’s adjustment was used to control for the multiplicity resulting from the multiple pairwise comparisons.Data Analysis:

[0203] The Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression of Severity (CGI-S) were analyzed for the treatment and placebo groups.

[0204] FIGURE 6 shows the mean (±SEM) Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set). The Positive and Negative Syndrome Scale (PANSS) instrument has three sections with 7 items designed to evaluate positive symptoms (symptoms of the disease which manifest as the presence of traits), 7 items designed to evaluate negative symptoms (symptoms that manifest as the absence ofAttomey Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT traits), and 16 items that address general psychopathology. Each item is scored on a 7-point scale (l=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, 7=extreme). The PANSS total score is derived from the summation of the 30 item scores. Mean observed PANSS total scores are presented at each study week for the placebo and cis- Compound A (NBI-1117568) treatment groups. Error bars represent the standard error of the mean. Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of study treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.

[0205] FIGURE 7 shows Least Squares (LS) Mean (±SEM) change from baseline of Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set). The Positive and Negative Syndrome Scale (PANSS) instrument has three sections with 7 items designed to evaluate positive symptoms (symptoms of the disease which manifest as the presence of traits), 7 items designed to evaluate negative symptoms (symptoms that manifest as the absence of traits), and 16 items that address general psychopathology. Each item is scored on a 7-point scale (l=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, 7=extreme). The PANSS total score is derived from the summation of the 30 item scores. Least-squares (LS) mean PANSS total scores are presented at each study week for the placebo and cv.s-Compound A (NBI-1117568) treatment groups. Error bars represent the standard error of the mean. The LS means are from a mixed-effect model for repeated measures, which includes treatment group, visit, and stage of randomization as fixed effects; treatment group-by-visit interaction; baseline PANSS total score as a covariate; and subject as a random effect. The stage of randomization included in the model as a fixed effect has 3 levels: Stage 1 corresponding to subjects randomized up to interim analysis 1, Stage 2 corresponding to subjects randomized between interim analyses 1 and 2, and Stage 3 corresponding to subjects randomized between interim analysis 2 and the final analysis. The cutoff dates for interim analyses 1 and 2 are 31Mar2023 and 20Dec2023, respectively.Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.

[0206] FIGURE 8 shows the mean (±SEM) Clinical Global Impression of Severity (CGLS) score by study visit (efficacy analysis set). The Clinical Global Impression of Severity (CGI-Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTS) was used to assess the overall global severity of schizophrenia on a 7-point scale (l=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients). Mean observed CGI-S scores are presented at each study week for the placebo and cA-Compound A (NBI- 1117568) treatment groups. Error bars represent the standard error of the mean. Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of study treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.Example 2

[0207] Plasma PK after a single dose of cA-Compound A as an oral solution were evaluated in men 18 to 55 years of age (Part la) and men and women >65 years of age (Part 1c).

[0208] After a single dose of 0.5 mg cA-Compound A, plasma concentrations were below the limit of quantification (BLQ) at all timepoints. After single doses of cA-Compound A 4.5 to 80 mg, plasma concentrations increased rapidly, with median time to maximum plasma concentration (tmax) of 0.5 to 2.0 hours across the 4.5 to 80 mg dose range, with no notable lag time in the detection of cA-Compound A in plasma. cA-Compound A elimination from plasma was biphasic in many subjects, with an inflection point between 12 to 24 hours postdose.

[0209] A summary of PK data for the remaining doses in Part 1 is provided in Figure 4. Mean AUC and Cmax values increased with increasing dose. Using 40 mg as a reference dose and accepting a 0.5- to 2-fold variability as normal at any given dose, AUC0-24 increased dose-proportionally between 10 and 60 mg, while Cmax increased dose-proportionally between 20 and 80 mg. Plasma PK parameters were generally similar between subjects 18 to 55 years of age (Part la) and those >65 years of age (Part 1c).

[0210] In Part lb, plasma PK were also evaluated in a pilot food-effect assessment in which male subjects 18 to 55 years of age received a single dose of 20 mg cA-Compound A after a high calorie meal or in the fasted state. Mean postdose area under the plasma concentrationtime curve from 0 hours to infinity (AUCo-inf) was approximately 1.3-fold higher in subjects in the fed state than in those in the fasted state and, conversely, the mean Cmax was approximately 1.2-fold higher (31.2 ng / mL) in the fasted state compared with the fed state.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT

[0211] In Part 2, cv.s-Compoiind A plasma concentrations increased rapidly after repeated doses (5 mg BID or 8 to 20 mg QD) for 7 days. Median tmax was 0.5 to 1.5 hours across the dose range.

[0212] A summary of PK data for Part 2 is provided in Figure 5. At comparable dose levels, the PK parameters obtained on Day 1 of repeated dosing in Part 2 were similar to those obtained after single doses in Part 1 (Figure 4). After repeated dosing, the plasma PK parameters were generally comparable between subjects 18 to 55 years of age (Part 2a) and those >65 years of age (Part 2b).

[0213] Across Parts 2a and 2b, the area under the plasma concentration-time curve over the dosing interval (AUCT) and Cmax values for cA-Compound A were dose-proportional over the 5 to 20 mg dose range after repeated dosing to steady state. CL / F appeared to be independent of dose with little variation in values for cA-Compound A orally administered at 5 mg BID, 10 mg QD, or 20 mg QD or 5 mg QD, ranging from 19.0 to 36.1 L / h. cA-Compound A elimination from plasma following repeat dosing was biphasic in many subjects, similar to that observed following single doses.

[0214] There was little accumulation of plasma cA-Compound A from the first to the last dose after repeated QD dosing; mean accumulation ratios of AUCh and Cmax were 1.07 to 1.57 in subjects 18 to 55 years of age (Part 2a) and 1.36 to 1.46 in subjects >65 years of age (Part 2b). Mean accumulation ratios after 5 mg BID dosing were slightly higher (2.31 to 2.34), consistent with the shorter dosing interval of 12 hours within that group.

[0215] Mean trough plasma concentrations indicated that steady state was achieved after 2 to 3 days of repeated dosing (i.e., by about Day 3 or 4).

[0216] Renal clearance was generally similar across the dose range and populations investigated. After repeated dosing in Part 2, CLR,24 was generally similar among subjects 18 to 55 years of age (Part 2a; 4.97 L / h to 7.10 L / h over 5 mg BID to 20 mg QD) and subjects >65 years of age (Part 2b; 5.43 L / h to 8.26 L / h over 8 to 15 mg QD).Example 3

[0217] The cA-Compound A citrate monohydrate capsule dosage forms, utilized in Example 1, of 10 mg, 20 mg, and 30 mg, included, respectively, the following ingredients in Tables 1, 1A, 2, 2A, 3, and 3A.Atorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 1Atorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 1AAtorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 2Atorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 2AAtorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 3Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTTable 3A

[0218] An exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg is provided in Figure 1. A separate exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 20 mg and 30 mg, is provided in Figure 2. The differences are the initial coating of bin blender with microcrystalline cellulose, order of addition, and stepwise blending to further improve homogenous distribution of cv.s-Compound A citrate monohydrate drug substance in the blend for 20 mg and 30 mg strengths.

[0219] The manufacture of cv.s-Compound A citrate monohydrate capsules, 10 mg, 20 mg, and 30 mg used a standard dry granulation manufacturing process followed by capsule filling. For 10 mg capsule manufacture, cv.s-Compound A citrate monohydrate drug substance was mixed with the excipients to prepare a homogenous blend in three stages: the first two stages to produce a homogenous blend followed by a third, shorter lubrication blended with magnesium stearate. For 20 mg and 30 mg capsule manufacture, approximately half of theAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT screened microcrystalline cellulose was charged to the bin blender and tumbled to coat the interior product contact surface. Screened components cv.s-Compound A citrate monohydrate, remaining microcrystalline cellulose, and dibasic calcium phosphate were charged to the bin blender and mixed, then de-lumped by passing through a screening mill, and mixed again. Screened components hypromellose and croscarmellose sodium were charged to the bin blender and mixed. Lastly, screened magnesium stearate was charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction.

[0220] The blend was then processed through a roller compactor to produce compacted ribbons. These ribbons were then sized through a screening mill to yield granules suitable for filling directly into a Size 3 Swedish orange hard gelatin capsule shells using either a manual PROFILL® capsule filling system (as was performed for the 10 mg product) or a fully automated encapsulation machine (as was performed for the 20 and 30 mg products). The filled capsules were then passed through deduster / metal detector and weight sorter.

[0221] Another exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg and 20 mg, described in Tables 1A and 2A, is provided in Figure 3. The process flow diagram in Figure 3 differs from that in Figure 2 in that the magnesium stearate lubricant is added in two stages. In the first stage, about half of the magnesium stearate is screened and charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction. In the second stage, the remaining magnesium stearate is screened and mixed with the sized granules that are produced by the roller compactor with inline milling.The lubricated granules have improved properties for rapid capsule filling in a dosator-based encapsulation. Additionally, pre-blending was optimized by removing redundant blending step post delumping.

[0222] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0223] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not beAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCTWhat is claimed is:

1. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

2. A method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

3. A method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT4. A compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

5. Use of a compound having the structure of(Compound A), or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

6. The method, the compound, or the use of any one of the preceding claims, wherein the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, Alzheimer’s disease psychosis, bipolar disorder, Parkinson’s disease (or synucleinopathies) psychosis, and obsessive compulsive disorder.

7. The method, the compound, or the use of claim 6, wherein the neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

8. The method, the compound, or the use of claim 7, wherein the subject has at least one sign or symptom of schizophrenia.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT9. The method, the compound, or the use of claim 8, wherein the subject has at least one positive, negative, and / or cognitive sign or symptom of schizophrenia.

10. The method, the compound, or the use of claim 8 or 9, wherein the at least one sign or symptom is delusions, hallucinations, disorganized speech, disorganized behavior or attention, anhedonia, catatonic behavior, affective flattening, alogia, avolition, conceptual disorganization, or any combination thereof.

11. The method, the compound, or the use of claim 7, wherein the subject is also being administered at least one co-therapeutic agent for the treatment of schizophrenia and the neurological or psychiatric disease or disorder is adjunctive treatment of schizophrenia (ATS).

12. The method, the compound, or the use of claim 11, wherein the subject has a stable background antipsychotic medication dose.

13. The method, the compound, or the use of claim 11, wherein the subject is residually symptomatic or has at least one residual sign or symptom after first- or second-line treatment of schizophrenia.

14. The method, the compound, or the use of claim 11, wherein the subject is residually symptomatic or has at least one residual sign or symptom after mono- or combination therapy for schizophrenia.

15. The method, the compound, or the use of claim 11, wherein the mono- or combination therapy is initial therapy.

16. The method, the compound, or the use claim 11, wherein the at least one co- therapeutic agent is least one antipsychotic agent.

17. The method, the compound, or the use claim 16, wherein the antipsychotic agent is a typical antipsychotic agent.

18. The method, the compound, or the use of claim 17, wherein the typical antipsychotic agent is benperidol, chlorpromazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, loxapine, molindone, pericyazine, perphenazine, pimozide, prochlorperazine, promazine, sulpiride, thiothixene, trifluoperazine, thioridazine, zuclopenthixol, or any combination thereof.

19. The method, the compound, or the use of claim 16, wherein the antipsychotic agent is an atypical antipsychotic agent.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT20. The method, the compound, or the use of claim 19, wherein the atypical antipsychotic agent is clozapine, olanzapine, risperidone, sertindole, quetiapine, paliperidone, asenapine, ziprasidone, surmontil, iloperidone, aripiprazole, or any combination thereof.

21. The method, the compound, or the use of any one of the preceding claims, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

22. The method, the compound, or the use of claim 21, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

23. The method, the compound, or the use of claim 22, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

24. The method, the compound, or the use of claim 23, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

25. The method, the compound, or the use of claim 21, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

26. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

27. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.

28. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.

29. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT30. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

31. The method, the compound, or the use of any one of the preceding claims, wherein the dosing regimen does not include any titration period.

32. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

33. The method, the compound, or the use of claim 32, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

34. The method, the compound, or the use of claim 33, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

35. The method, the compound, or the use of claim 34, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

36. The method, the compound, or the use of claim 35, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

37. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

38. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.

39. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT40. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.

41. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

42. The method, the compound, or the use of any one of claims 32 to 41, wherein the dosing regimen does not include any titration period.

43. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

44. The method, the compound, or the use of claim 43, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

45. The method, the compound, or the use of claim 44, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

46. The method, the compound, or the use of claim 45, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

47. The method, the compound, or the use of claim 43, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

48. The method, the compound, or the use of claim 47, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

49. The method, the compound, or the use of claim 47, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT50. The method, the compound, or the use of claim 47, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.

51. The method, the compound, or the use of claim 47, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.

52. The method, the compound, or the use of claim 47, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

53. The method, the compound, or the use of any one of claims 43 to 52, wherein the dosing regimen does not include any titration period.

54. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

55. The method, the compound, or the use of claim 54, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

56. The method, the compound, or the use of claim 55, wherein the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose.

57. The method, the compound, or the use of claim 56, wherein the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose.

58. The method, the compound, or the use of claim 57, wherein the initial daily dose in the titration period is equivalent to about 25% of the final daily dose.

59. The method, the compound, or the use of claim 57, wherein the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.

60. The method, the compound, or the use of claim 55, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT61. The method, the compound, or the use of claim 60, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base.

62. The method, the compound, or the use of claim 61, wherein the initial daily dose in the titration period is about 2.5 mg of Compound A free base.

63. The method, the compound, or the use of claim 61, wherein the initial daily dose in the titration period is about 5 mg of Compound A free base.

64. The method, the compound, or the use of claim 61, wherein the initial daily dose in the titration period is about 7.5 mg of Compound A free base.

65. The method, the compound, or the use of claim 61, wherein the initial daily dose in the titration period is about 10 mg of Compound A free base.

66. The method, the compound, or the use of any one of claims 54 to 65, wherein the final daily dose is from about 5 mg to about 70 mg of Compound A free base.

67. The method, the compound, or the use of claim 66, wherein the final daily dose is from about 5 mg to about 40 mg of Compound A free base.

68. The method, the compound, or the use of claim 67, wherein the final daily dose is from about 7 mg to about 30 mg of Compound A free base.

69. The method, the compound, or the use of claim 68, wherein the final daily dose is from about 8 mg to about 25 mg of Compound A free base.

70. The method, the compound, or the use of claim 66, wherein the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

71. The method, the compound, or the use of claim 70, wherein the final daily dose is about 10 mg of Compound A free base.

72. The method, the compound, or the use of claim 70, wherein the final daily dose is about 15 mg of Compound A free base.

73. The method, the compound, or the use of claim 70, wherein the final daily dose is about 20 mg of Compound A free base.

74. The method, the compound, or the use of claim 70, wherein the final daily dose is about 25 mg of Compound A free base.

75. The method, the compound, or the use of claim 70, wherein the final daily dose is about 30 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT76. The method, the compound, or the use of any one of claims 54 to 75, wherein the initial daily dose is administered QD.

77. The method, the compound, or the use of any one of claims 54 to 75, wherein the initial daily dose is administered BID.

78. The method, the compound, or the use of any one of claims 54 to 77, wherein the final daily dose is administered QD.

79. The method, the compound, or the use of any one of claims 54 to 77, wherein the final daily dose is administered BID.

80. The method, the compound, or the use of any one of claims 54 to 75, wherein the initial daily dose and final daily dose are administered QD.

81. The method, the compound, or the use of any one of claims 54 to 80, wherein the titration period is from about 2 to about 14 days.

82. The method, the compound, or the use of claim 81, wherein the titration period is from about 2 to about 7 days.

83. The method, the compound, or the use of claim 82, wherein the titration period is from about 3 to about 7 days.

84. The method, the compound, or the use of claim 81, wherein the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

85. The method, the compound, or the use of claim 84, wherein the titration period is about 2 days.

86. The method, the compound, or the use of claim 84, wherein the titration period is about 3 days.

87. The method, the compound, or the use of claim 84, wherein the titration period is about 4 days.

88. The method, the compound, or the use of claim 84, wherein the titration period is about 5 days.

89. The method, the compound, or the use of claim 84, wherein the titration period is about 6 days.

90. The method, the compound, or the use of claim 84, wherein the titration period is about 7 days.

91. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises aAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

92. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

93. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

94. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

95. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

96. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is aboutAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

97. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

98. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

99. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

100. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

101. The method, the compound, or the use of any one of claims 91 to 100, wherein the titration period is about 3 days.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT102. The method, the compound, or the use of any one of claims 91 to 100, wherein the titration period is about 4 days.

103. The method, the compound, or the use of any one of claims 91 to 100, wherein the titration period is about 5 days.

104. The method, the compound, or the use of any one of claims 91 to 100, wherein the titration period is about 6 days.

105. The method, the compound, or the use of any one of claims 91 to 100, wherein the titration period is about 7 days.

106. The method, the compound, or the use of any one of claims 91 to 105, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

107. The method, the compound, or the use of any one of claims 91 to 105, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.

108. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

109. The method, the compound, or the use of claim 108, wherein the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose.

110. The method, the compound, or the use of claim 109, wherein the initial daily dose is an amount equivalent to about 10% of the final daily dose.

111. The method, the compound, or the use of claim 109, wherein the initial daily dose is an amount equivalent to about 15% of the final daily dose.

112. The method, the compound, or the use of claim 109, wherein the initial daily dose is an amount equivalent to about 20% of the final daily dose.

113. The method, the compound, or the use of claim 109, wherein the initial daily dose is an amount equivalent to about 25% of the final daily dose.

114. The method, the compound, or the use of claim 109, wherein the initial daily dose is an amount equivalent to about 30% of the final daily dose.

115. The method, the compound, or the use of any one of claims 108 to 114, wherein the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT116. The method, the compound, or the use of claim 115, wherein the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base.

117. The method, the compound, or the use of claim 115, wherein the initial daily dose is an amount equivalent to about 5 mg of Compound A free base.

118. The method, the compound, or the use of claim 115, wherein the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base.

119. The method, the compound, or the use of claim 115, wherein the initial daily dose is an amount equivalent to about 10 mg of Compound A free base.

120. The method, the compound, or the use of any one of claims 108 to 119, wherein the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose.

121. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 20% of the final daily dose.

122. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 25% of the final daily dose.

123. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 30% of the final daily dose.

124. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 35% of the final daily dose.

125. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 40% of the final daily dose.

126. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 45% of the final daily dose.

127. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 50% of the final daily dose.

128. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 55% of the final daily dose.

129. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to about 60% of the final daily dose.

130. The method, the compound, or the use of claim 120, wherein the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base.

131. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 5 mg of Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT132. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base.

133. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 10 mg of Compound A free base.

134. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base.

135. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 15 mg of Compound A free base.

136. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base.

137. The method, the compound, or the use of claim 130, wherein the increased daily dose is an amount equivalent to about 20 mg of Compound A free base.

138. The method, the compound, or the use of any one of claims 108 to 137, wherein the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base.

139. The method, the compound, or the use of claim 138, wherein the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base.

140. The method, the compound, or the use of claim 138, wherein the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base.

141. The method, the compound, or the use of claim 138, wherein the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base.

142. The method, the compound, or the use of claim 138, wherein the final daily dose is equivalent to about 10, about 15, about 20, about 25, or about 30 mg of Compound A free base.

143. The method, the compound, or the use of any one of claims 108 to 142, wherein the doses are administered BID.

144. The method, the compound, or the use of any one of claims 108 to 142, wherein the doses are administered QD.

145. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mgAttorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 15 mg of Compound A free base.

146. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

147. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 25 mg of Compound A free base.

148. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

149. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

150. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

151. The method, the compound, or the use of any one of claims 1 to 20, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

152. The method, the compound, or the use of any one of claims 145 to 151, wherein the doses are administered BID.

153. The method, the compound, or the use of any one of claims 145 to 151, wherein the doses are administered QD.

154. The method, the compound, or the use of any one of claims 145 to 153, wherein the first titration period is from about 2 to about 14 days.

155. The method, the compound, or the use of claim 154, wherein the first titration period is from about 2 to about 7 days.

156. The method, the compound, or the use of claim 154, wherein the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

157. The method, the compound, or the use of any one of claims 145 to 156, wherein the second titration period is from about 1 to about 7 days.

158. The method, the compound, or the use of claim 154, wherein the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT159. The method, the compound, or the use of any one of claims 145 to 158, wherein the first and second titration period combined is about 14 days.

160. The method, the compound, or the use of claim 159, wherein the first titration period is about 2 days, and the second titration period is about 12 days.

161. The method, the compound, or the use of claim 159, wherein the first titration period is about 3 days, and the second titration period is about 11 days.

162. The method, the compound, or the use of claim 159, wherein the first titration period is about 4 days, and the second titration period is about 10 days.

163. The method, the compound, or the use of claim 159, wherein the first titration period is about 5 days, and the second titration period is about 9 days.

164. The method, the compound, or the use of claim 159, wherein the first titration period is about 6 days, and the second titration period is about 8 days.

165. The method, the compound, or the use of claim 159, wherein the first titration period is about 7 days, and the second titration period is about 7 days.

166. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is Compound A free base.

167. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of Compound A.

168. The method, the compound, or the use of claim 167, wherein Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of Compound A.

169. The method, the compound, or the use of claim 168, wherein the citrate salt of Compound A is crystalline.

170. The method, the compound, or the use of claim 168, wherein the citrate salt of Compound A is Compound A citrate monohydrate, and wherein the molar ratio between Compound A, citric acid, and water is about 1 : 1 : 1.

171. The method, the compound, or the use of claim 170, wherein Compound A citrate monohydrate is crystalline.

172. The method, the compound, or the use of any one of claims 1 to 165, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A free base.

173. The method, the compound, or the use of any one of claims 1 to 165, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of cv.s-Compound A.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT174. The method, the compound, or the use of claim 173, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cv.s-Compound A.

175. The method, the compound, or the use of claim 174, wherein the citrate salt of cis- Compound A is crystalline.

176. The method, the compound, or the use of claim 174, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate, and wherein the molar ratio between cv.s-Compound A, citric acid, and water is about 1 : 1 : 1.

177. The method, the compound, or the use of claim 176, wherein cA-Compound A citrate monohydrate is crystalline.

178. The method, the compound, or the use of any one of claims 174 to 177, wherein the citrate salt of cv.s-Compound A or cv.s-Compound A citrate monohydrate has at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.

179. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

180. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered via an immediate release formulation.

181. The method, the compound, or the use of any one of proceeding claims, wherein the subject is a human.

182. The method, the compound, or the use of any one of proceeding claims, wherein the neurological or psychiatric disease or disorder is schizophrenia.

183. The method, the compound, or the use of any one of proceeding claims, wherein the neurological or psychiatric disease or disorder is bipolar I disorder.

184. The method, the compound, or the use of any one of claims 1 to 5, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the neurological or psychiatric disease or disorder is schizophrenia; and the daily dose is equivalent to about 10 mg of cA-Compound A free base.

185. The method, the compound, or the use of any one of claims 1 to 5, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the neurological or psychiatric disease or disorder is bipolar I disorder; and the daily dose is equivalent to about 10 mg of cA-Compound A free base.Attorney Docket No. 46696-0210WO1 / NBI 331. WO 1. PCT186. The method, the compound, or the use of any one of claims 1 to 5, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the neurological or psychiatric disease or disorder is schizophrenia; and the daily dose is equivalent to about 20 mg of cA-Compound A free base.

187. The method, the compound, or the use of any one of claims 1 to 5, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the neurological or psychiatric disease or disorder is bipolar I disorder; and the daily dose is equivalent to about 20 mg of cA-Compound A free base.

188. The method, the compound, or the use of any one of claims 184 to 187, wherein cis- Compound A citrate monohydrate is administered once daily (QD).

189. The method, the compound, or the use of any one of claims 184 to 188, wherein the subject is a human.

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